Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[C:7]1([NH:13][CH:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3B3OC(C)(C)C(C)(C)O3)[CH2:16][CH2:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[C:33]1[N:38]=[C:37]([CH2:39][NH:40][C:41]2[C:46]([CH:47]([CH3:49])[CH3:48])=[CH:45][CH:44]=[CH:43][C:42]=2[CH:50]([CH3:52])[CH3:51])[CH:36]=[CH:35][CH:34]=1.C1(C)C=CC=CC=1>O.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:47]([C:46]1[CH:45]=[CH:44][CH:43]=[C:42]([CH:50]([CH3:52])[CH3:51])[C:41]=1[NH:40][CH2:39][C:37]1[N:38]=[C:33]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:22]=2[CH:14]([NH:13][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:15][CH2:16]3)[CH:34]=[CH:35][CH:36]=1)([CH3:48])[CH3:49]
Reactant: CC1(C)OB(c2cccc3c2C(Nc2ccccc2)CC3)OC1(C)C
Reactant: CC(C)c1cccc(C(C)C)c1NCc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1NCc1cccc(-c2cccc3c2C(Nc2ccccc2)CC3)n1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A solution of 2.21 g (21.0 mmol) of Na2CO3 in a mixture of 80 ml of water and 25 ml of methanol was purged with argon for 30 min. The obtained solution was added to a mixture of 2.80 g (8.40 mmol) of N-phenyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-amine, 2.90 g (8.40 mmol) of N-[(6-bromopyridin-2-yl)methyl]-2,6-diisopropylaniline, 0.48 g (0.40 mmol) of Pd(PPh3)4, and 120 ml of toluene. This mixture was stirred for 12 h at 70° C., then cooled to room temperature. The organic layer was separated, the aqueous layer was extracted with 3×50 ml of ethyl acetate. The combined organic extract was washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography on silica gel 60 (40-63 um, eluent: hexane-ethyl acetate-triethylamine=100:5:1, vol.). Yield 2.00 g (50%) of a yellow oil. Anal. calc. For C33H37N3: C, 83.33; H, 7.84; N, 8.83. Found: C, 83.49; H, 7.66; N, 8.65. 1H NMR (CDCl3): δ 7.56-7.61 (m, 3H, 6-H in indane and 4.5-H in Py); 7.46-7.51 (m, 2H, 3,5-H in phenyl); 7.14-7.16 (m, 1H, 4-H in indane); 7.08-7.12 (m, 5H, 3-H in Py, 3,4,5-H in 2,6-diisopropylphenyl and 5-H in indane); 6.65 (m, 1H, 4-H in phenyl); 6.53 (m, 2H, 2,6-H in phenyl); 5.21-5.22 (m, 1H, 1-H in indane); 3.95-4.15 (m, 4H, CH2NH and NH-phenyl and NH-2,6-diisopropylphenyl); 3.31 (sept, J=6.8 Hz, 2H, CH in 2,6-diisopropylphenyl); 3.16-3.24 (m, 1H, 3- or 3′-H in indane); 2.91-2.97 (m, 1H, 3′- or 3-H in indane); 2.21-2.37 (m, 2H, 2,2′-H in indane); 1.19-2.21 (m, 12H, CH3 in 2,6-diisopropylaniline).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([N:8](COCCOC)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[N:19]([S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:11])=[O:10])[O:4][N:3]=1.Cl>CCO>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[N:19]([S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:28])=[O:29])[C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:10])=[O:11])[O:4][N:3]=1
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Agent: Cl
Solvent: CCO
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2cc3ccccc3n2S(=O)(=O)c2ccccc2)c1C
Temperature: 5 °C
Yield: 86.7 %

Procedure:
A mixture of the title product of Step (C) (210 mg; 0.35 mmol), 6N HCl (5 ml) and EtOH (5 ml) was refluxed for 1.5 hours. A solid began precipitating during the reaction. After slowly cooling to 5° C., the suspension was filtered and the solid was washed with water. Drying afforded 154 mg (87%) of the title product of this Example as a cream colored solid. mp 207-209° C. (dec.; darkened at 196° C.); Rf=0.50, EtOAc (UV detection).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:22])[C:12](=[O:20])[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][C:5]=1Br.[CH:32]([B-](F)(F)F)=[CH2:33].[K+].CCN(CC)CC.C(O)CC>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:22])[C:12](=[O:20])[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][C:5]=1[CH:32]=[CH2:33]
Reactant: C=C[B-](F)(F)F
Reactant: COC(=O)c1ccc(CC(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCCO
Solvent: CCN(CC)CC
Solvent: O
Product: C=Cc1cc(CC(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)ccc1C(=O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl-2-bromo-4-{3-oxo-3-(phenylamino)-2-[(phenylamino)carbonyl]propyl}benzoate (0.15 g, 0.312 mmol), Pd(dppf)Cl2(0.012 g, 0.02 mmol), potassium vinyltrifluoroborate (0.42 g, 0.312 mmol) were placed in a sealed tube and purge with argon 3×. Et3N (0.13 mL, 0.935 mmol) and n-PrOH (4.0 mL) were then added and the tube was placed in an oil bath at 100° C. for 3 h. The reaction was cool to room temperature and water was added. After extraction with ethyl acetate 3×, dried over Na2SO4, filter and concentrate. The residue was then purified by column chromatography to provide methyl-2-ethenyl-4-{3-oxo-3-(phenylamino)-2-[(phenylamino)carbonyl]propyl}benzoate. MS: Cal'd (MH+) 429, exp (MH+) 429.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:5].[H-].[Na+].[I-].[Na+].Cl[CH2:29][C:30]([NH2:32])=[O:31]>CN(C)C=O.O>[C:30]([CH2:29][O:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:5])(=[O:31])[NH2:32]
Reactant: O=C(NCc1ccccn1)c1cc(OCC(F)(F)F)ccc1O
Reactant: NC(=O)CCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)COc1ccc(OCC(F)(F)F)cc1C(=O)NCc1ccccn1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A solution of 6.5 g (0.02 mole) of 2-hydroxy-N-(2-pyridylmethyl)-5-(2,2,2-trifluoroethoxy)benzamide in 20 ml of dimethylformamide was added dropwise to a suspension of 0.021 mole of sodium hydride in 10 ml dimethylformamide. The resulting mixture was stirred at about 25° C. for 30 minutes, at 60° C. for 30 minutes, and then 0.3 g of sodium iodide was added followed by the addition of a solution of 1.7 g (0.018 mole) of 2-chloroacetamide in 15 ml dry dimethylformamide. The reaction mixture was stirred for about 16 hours at 60° C. and then poured into 500 ml cold water. The resulting precipitate was collected and dried, then dissolved in a minimum of 5% methanol in chloroform and washed through a column of basic alumina. The eluent was evaporated to give a white solid which was recrystallized from about 300 ml of 3:4 water:ethanol to give 4.9 g of white crystalline 2-carbamoylmethoxy-N-(2-pyridylmethyl)-5-(2,2,2-trifluoroethoxy)benzamide.
Reaction SMILES: CO[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][O:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[CH3:19][O:20]C1C=CC2C(=CC=CC=2)C=1CON>>[CH3:19][O:20][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][CH:3]=[CH:4][CH:5]=2)[C:10]=1[CH2:13][O:14][NH:15][C:16](=[O:18])[CH3:17]
Reactant: COc1ccc2cccc(CONC(C)=O)c2c1
Reactant: COc1ccc2ccccc2c1CON
Product: COc1ccc2ccccc2c1CONC(C)=O

Procedure:
By carrying out the procedure in the same manner as for the synthesis of the compound of Example 1, but using the O-[(2-methoxynaphth-1-yl)methyl]hydroxylamine of preparation 6, the title compound is obtained.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH:34][C@H:35]([C:56]1[CH:61]=[CH:60][C:59]([O:62][CH3:63])=[CH:58][CH:57]=1)[C@H:36]([NH:40][C:41](=[O:55])[C@@H:42]([NH:45][C:46](=[O:54])[CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1)[CH2:43][OH:44])[C:37](O)=[O:38].[NH2:64][C@@H:65]([CH2:72][C:73]1[CH2:78][CH2:77][CH2:76][CH2:75][CH:74]=1)[C:66]([C@@:68]1([CH3:71])[CH2:70][O:69]1)=[O:67]>CN(C=O)C>[C:73]1([CH2:72][C@H:65]([NH:64][C:37](=[O:38])[C@@H:36]([NH:40][C:41](=[O:55])[C@@H:42]([NH:45][C:46](=[O:54])[CH2:47][N:48]2[CH2:49][CH2:50][O:51][CH2:52][CH2:53]2)[CH2:43][OH:44])[C@H:35]([OH:34])[C:56]2[CH:61]=[CH:60][C:59]([O:62][CH3:63])=[CH:58][CH:57]=2)[C:66]([C@@:68]2([CH3:71])[CH2:70][O:69]2)=[O:67])[CH2:78][CH2:77][CH2:76][CH2:75][CH:74]=1
Reactant: C[C@]1(C(=O)[C@@H](N)CC2=CCCCC2)CO1
Reactant: COc1ccc([C@@H](O)[C@H](NC(=O)[C@H](CO)NC(=O)CN2CCOCC2)C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc([C@@H](O)[C@H](NC(=O)[C@H](CO)NC(=O)CN2CCOCC2)C(=O)N[C@@H](CC2=CCCCC2)C(=O)[C@@]2(C)CO2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
Sequentially HATU (537 mg, 1.41 mmol) and DIEA (1.02 mL, 5.88 mmol) were added to a 0° C. solution of (2S,3R)-3-hydroxy-2-((S)-3-hydroxy-2-(2-morpholinoacetamido)propanamido)-3-(4-methoxyphenyl)propanoic acid (500 mg, 1.18 mmol) and (S)-2-amino-3-(cyclohex-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)propan-1-one (TFA salt, 364 mg, 1.18 mmol) in DMF (10 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 30 min. The mixture was concentrated and the residue was purified by flash column chromatography on silica gel (DCM/MeOH=50:1 to 30:1) twice to afford (2S,3R)-N-((S)-3-(cyclohex-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-3-hydroxy-2-((S)-3-hydroxy-2-(2-morpholinoacetamido)propanamido)-3-(4-methoxyphenyl)propanamide (500 mg, 57% yield) as a colorless solid. 1H NMR (300 MHz, DMSO-d6): δ 7.97 (d, J=7.5 Hz, 1H), 7.86 (d, J=9.0 Hz, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.26 (d, J=8.7 Hz, 2H), 6.80 (d, J=8.7 Hz, 2H), 5.61 (d, J=4.5 Hz, 1H), 5.40-5.38 (m, 1H), 5.23-5.21 (m, 1H), 5.04-5.02 (m, 1H), 4.62-4.51 (m, 1H), 4.45-4.35 (m, 2H), 3.71 (s, 3H), 3.68-3.41 (m, 6H), 3.33 (s, 1H), 3.21 (d, J=5.1 Hz, 1H), 2.97-2.80 (m, 3H), 2.39-2.21 (m, 4H), 2.11-1.71 (m, 4H), 1.56-1.40 (m, 4H), 1.26 (s, 3H), 1.28-1.22 (m, 1H). MS(EI) for C31H44N4O9, found 617.4 (MH)+.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C@H:8]2[CH2:9][C@H:5]([CH2:6][CH2:7]2)[C@@H:4]1[C:10]([O:12][CH3:13])=[O:11].C([O-])(=O)C.[Na+].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:2][C@@H:3]2[C@H:8]3[CH2:9][C@H:5]([CH2:6][CH2:7]3)[C@@H:4]2[C:10]([O:12][CH3:13])=[O:11])=[CH:22][CH:21]=1
Reactant: COC(=O)[C@H]1[C@H]2CC[C@H](C2)[C@H]1N
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1[C@H]2CC[C@H](C2)[C@H]1NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
Methyl (1S,2S,3R,4R)-3-aminobicyclo[2.2.1]heptane-2-carboxylate hydrochloride (1 g, 4.86 mmol) was dissolved in methanol (23 mL). Sodium acetate (0.755 g, 9.2 mmol) was added followed by 4 Å powdered molecular sieves (1 g) and 4-fluoro-benzaldehyde (0.571 g, 4.6 mmol). Sodium cyanoborohydride (0.578 g, 9.2 mmol) was added and the mixture was stirred at 25° C. for 16 h. The mixture was poured into a mixture of saturated aqueous sodium bicarbonate solution (200 mL) and ethyl acetate (300 mL). After shaking, both layers were passed through a plug of Celite. The organic layer was further washed with saturated aqueous sodium bicarbonate solution (100 mL), saturated aqueous brine solution (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product, methyl (1S,2S,3R,4R)-3-[(4-fluorobenzyl)amino]bicyclo[2.2.1]heptane-2-carboxylate (1.11 g, 4.0 mmol, 87%), as a clear oil. LC-MS (ESI) calcd for C16H20FNO2 277.15, found 278.2 [M+H+].
Reaction SMILES: C1(O[C:8](=[O:24])[NH:9][C:10]2[S:14][N:13]=[C:12]([S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:11]=2[C:21](=[O:23])[NH2:22])C=CC=CC=1.[NH2:25][CH2:26][CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.[OH-].[Na+]>O1CCCC1>[CH2:16]([S:15][C:12]1[C:11]([C:21]([NH2:22])=[O:23])=[C:10]([NH:9][C:8]([NH:25][CH2:26][CH2:27][CH2:28][N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:24])[S:14][N:13]=1)[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCSc1nsc(NC(=O)Oc2ccccc2)c1C(N)=O
Reactant: NCCCN1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCSc1nsc(NC(=O)NCCCN2CCCC2)c1C(N)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.4 %

Procedure:
To a mixture of (4-carbamoyl-3-pentylsulfanyl-isothiazol-5-yl)-carbamic acid phenyl ester (0.10 g, 0.27 mmol) and 1 mL of tetrahydrofuran was added N-3-aminopropylpyrollidine (0.175 g, 1.4 mmol). After stirring for 72 hours at ambient temperature, the mixture was poured into 1M NaOH, extracted twice with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated. Purification of the residue by radial chromatography (2 mm plate, 3% ethanol-CH2Cl2— 30% ethanol-CH2Cl2 containing 0.5% NH4OH), followed by concentration and trituration of the residue with ether-hexane afforded 0.076 g (78%) of 3-pentylsulfanyl-5-[3-(3-pyrrolidin-1-yl-propyl)-ureido]-isothiazole-4-carboxylic acid amide as a colorless solid 1H NMR (400 MHz, CDCl3) δ 7.57 (bs, 1H), 7.06 (bs, 2H), 3.35 (m, 2H), 3.26(m, 2H), 2.53 (t, 2H, J=6.8Hz), 2.47(m, 4H), 1.73 (m, 8H), 1.4-1.2 (m, 4H), 0.88 (t, 3H, J=7.2 Hz) ppm; MS (APCl, m/z): 400 [M+H]+.
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.[C:6]1([CH3:16])[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1.Cl>N1C=CC=CC=1>[CH3:16][C:6]1[CH:11]=[CH:10][C:9]([S:12]([O:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: OC1CCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.3 %

Procedure:
To a solution of cyclobutanol (1 g, 13.9 mmol) in pyridine (20 mL) was added p-toluenesulfonyl chloride (2.9 g, 15.3 mmol) and the solution stirred at room temperature for 4 hours. Aqueous HCl was then added, and the solution extracted with ethyl acetate (×3). The combined organic layers were washed successively with saturated aqueous copper(II) sulfate (×3) and brine, then dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified using flash column chromatography on silica gel (gradient of 0% to 5% ethyl acetate in petrol) to give cyclobutyl 4-methylbenzenesulfonate (2.05 g, 9.07 mmol, 65%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:15]C(=O)C>[OH-].[Na+].C(O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH2:15]
Reactant: CC(=O)Nc1ccc(-c2ccncc2)c(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(-c2ccncc2)c(Cl)c1Cl
Yield: 59 %

Procedure:
A stirred suspension of N-[2,3-dichloro-4-(pyridin-4-yl)phenyl]acetamide (D8, 1 g, 3.6 mmole) in a mixture of 2M NaOH solution and ethanol (30 ml) was heated under reflux for 36 hours. The mixture was concentrated in vacuo and the residue extracted with dichloromethane. The extract was dried (Na2SO4) and concentrated in vacuo to afford the title compound as an orange solid (59%).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[N:18]1([CH2:24][CH2:25][CH2:26][Cl:27])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[ClH:27].[N:18]1([CH:24]([C:14]2[C:13]([CH3:16])=[CH:12][CH:11]=[C:10]3[C:15]=2[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8][NH:9]3)[CH2:25][CH3:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1ccc2[nH]nc(-c3ccccc3)c2c1
Reactant: ClCCCN1CCCCC1
Agent: Cl
Product: CCC(c1c(C)ccc2[nH]nc(-c3ccccc3)c12)N1CCCCC1

Procedure:
By the procedure similar to that described in Example 1, 3-phenyl-5-methylindazole (4.17 g) and piperidinopropyl chloride hydrochloride were treated to obtain 5.0 g of 1-piperidinopropyl-3-phenyl-5-methylindazole hydrochloride (m.p. 222°-223° C).
Reaction SMILES: [C:1]([CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:21][OH:22]>C(O)C>[NH2:2]/[C:1](=[N:21]\[OH:22])/[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1
Reactant: CCOC(=O)c1cnn(CC#N)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cnn(C/C(N)=N/O)c1

Procedure:
The compound (1.6 g) obtained in Example 1a was suspended in ethanol (20 mL), and potassium carbonate (10.4 g) and hydroxylamine hydrochloride (5.2 g) were added. The reaction mixture was heated under reflux for 12 hr, and the insoluble material was removed by filtration. The solvent was evaporated under reduced pressure from the obtained filtrate to give the title compound as a bister solid.
Reaction SMILES: Br[C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:22][O:23][C:24]1[CH:29]=[C:28]([C:2]2[C:3]([CH:8]3[CH2:11][N:10]([C:12]4[CH:21]=[CH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[N:13]=4)[CH2:9]3)=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Brc1cccnc1C1CN(c2ccc3ccccc3n2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(-c2cccnc2C2CN(c3ccc4ccccc4n3)C2)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
To a solution of 2-[3-(3-bromo-pyridin-2-yl)-azetidin-1-yl]-quinoline (339 mg, 1 mmol), 3-methoxy-phenylboronic acid (167.2 mg, 1.1 mmol), K3PO4 (414 mg, 2.0 mmol) in dioxane (20 mL) and water (2 mL) was added Pd(dppf)Cl2 (36.6 mg, 0.05 mmol) then the reaction mixture was stirred at 90° C. under nitrogen atmosphere overnight. The reaction mixture was filtered through CELITE® and washed with EtOAc (50 mL). The filtrate was concentrated and the crude product was purified by ISCO silica gel column (10% to 80% EtOAc in petroleum ether) to give 2-{3-[3-(3-methoxy-phenyl)-pyridin-2-yl]-azetidin-1-yl}-quinoline (132 mg, 0.36 mmol, yield 36%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][N:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.[CH3:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[CH:29]1[CH2:33][CH2:32][CH2:31][NH:30]1>CN1C(=O)CCC1>[CH3:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]1[C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[C:2]1[N:15]=[CH:14][C:13]2[C:12]3[N:8]([CH:9]=[C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[N:11]=3)[CH2:7][CH2:6][O:5][C:4]=2[CH:3]=1
Reactant: Clc1cc2c(cn1)-c1nc(-c3ccccn3)cn1CCO2
Reactant: CN1CCCCC1C1CCCN1
Solvent: CN1CCCC1=O
Product: CN1CCCC[C@H]1[C@@H]1CCCN1c1cc2c(cn1)-c1nc(-c3ccccn3)cn1CCO2
Temperature: 150 °C
Reaction time: 24 h

Procedure:
A mixture of 12-chloro-4-(pyridin-2-yl)-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene (300 mg, 1.00 mmol), TEA (0.5 mL), and 1-methyl-2-(pyrrolidin-2-yl)piperidine (507 mg, 3.01 mmol) in NMP (0.5 mL) was stirred at 150° C. for 24 h under nitrogen atmosphere. After cooling down, the resultant mixture was purified directly by reverse phase Combiflash eluting with 0-50% gradient of CH3CN in 0.5% NH4HCO3 to give diastereomeric 111: 15 mg of diasteromer A and 12 mg diasteromer B (48% total yield). Diasteromer A: LCMS (ESI): RT=4.48 min, m/z: 431.3 [M+H+]. 1H-NMR (500 MHz, DMSO-d6): δ 9.14 (s, 1H), 8.50 (d, J=4.5 Hz, 1H), 7.96 (d, J=7.5 Hz, 1H), 7.83-7.79 (m, 2H), 7.22-7.19 (m, 1H), 6.05 (s, 1H), 4.52-4.45 (m, 4H), 4.11 (s, 1H), 3.45-3.34 (m, 2H), 2.78 (s, 1H), 2.17 (s, 3H), 2.11-2.01 (m, 2H), 1.95-1.85 (m, 4H), 1.70 (s, 1H), 1.50-1.35 (m, 3H), 1.30-1.19 (m, 2H). Diasteromer B: LCMS (ESI): RT=4.75 min, m/z: 431.3 [M+H+]. 1H-NMR (500 MHz, DMSO-d6): δ 9.15 (s, 1H), 8.50 (d, J=4.0 Hz, 1H), 7.96 (d, J=8.2 Hz, 1H), 7.83-7.78 (m, 2H), 7.22-7.19 (m, 1H), 5.98 (s, 1H), 4.52-4.45 (m, 5H), 3.42 (s, 2H), 2.77 (s, 1H), 2.29 (s, 3H), 2.16-2.13 (m, 2H), 2.00-1.88 (m, 4H), 1.64 (s, 1H), 1.50-1.25 (m, 3H), 1.20-0.90 (m, 2H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13](O)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:13]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][CH:34]=2)=[O:14])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc(Br)cc1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)c2ccc(Br)cc2)cc1

Procedure:
The procedure described in Example 180 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino)-3-phenylpropanoic acid (2 g) and ethyl 4-aminobenzoate were condensed in dichloromethane (100 ml) in the presence of N,N'-dicyclohexylcarbodiimide (1.29 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from a mixture of carbon tetrachloride and ethanol to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-phenylpropanamide (623 mg).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[CH2:18]([O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25](F)=[CH:24][CH:23]=1)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)=[CH:24][CH:23]=1)[CH3:19]
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: CCOC(=O)c1ccc(F)cc1
Product: CCOC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C)c2)cc1
Yield: 71.8 %

Procedure:
As described for Example 1, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (2.25 g, 10.0 mmol) was converted, using 4-fluorobenzoic acid ethyl ester (1.54 g, 10.0 mmol) instead of 4-fluoroacetophenone, to the title compound (2.68 g, 72%) which was obtained as brown oil. MS: m/e=374.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([O:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH:5]=1.Cl>CO.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([O:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OCC2CC2)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N)c(OCC2CC2)c1
Reaction time: 5 h
Yield: 95.7 %

Procedure:
3-Cyclopropylmethoxy-4-nitro-benzoic acid methyl ester (12.7 g) was dissolved in MeOH (100 ml) and EtOAc (100 ml); 10% Pd/C (1.0 g, suspended in 20 ml of water) was added, and the mixture is hydrogenated in a Parr apparatus (H2: 20 psi) for 5 hours. 37% HCl was added (10 ml), and hydrogenation was continued for additional 2 hours to obtain complete conversion. The catalyst was filtered over a celite pad, the mixture was diluted with EtOAc (200 ml) and washed with an aqueous saturated solution of NaHCO3 (2×100 ml). The organic layer was dried over Na2SO4 and the solvent was removed by evaporation to yield 10.7 g of the desired intermediate.