Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([OH:12])[C:4]([CH3:13])=[N:3]1.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O>[CH2:16]([O:12][C:5]1[C:4]([CH3:13])=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1c(O)c(C)nn1C
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OCc2ccccc2)c(C)nn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
To a 5 ml solution of ethyl 1,3-dimethyl-4-hydroxypyrazole-5-carboxylate (2 g, 11.6 mmol) in anhydrous dimethylformamide (hereinafter, referred to as DMF) was added sodium hydride (60% dispersion in oil) (0.47 g, 11.8 mmol) under ice-cooling. Benzyl bromide (2 g, 11.7 mmol) was then added dropwise thereto, and the resulting mixture was stirred at room temperature for one hour and poured into water. The mixture was extracted with ethyl acetate. The extract was washed with water, and saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed over silica gel (eluent; ethyl acetate/n-hexane=1:4) to give ethyl 4-benzyloxy-1,3-dimethylpyrazol-5-carboxylate (2.5 g, 9.1 mmol, 78%).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:12][CH:11]([C:13]2[C:18]([CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:17][CH:16]=[CH:15][N:14]=2)[CH2:10]1)=O)(C)(C)C>CO>[ClH:1].[NH:9]1[CH2:12][CH:11]([C:13]2[C:18]([CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:17][CH:16]=[CH:15][N:14]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC(c2nccnc2C2CCOCC2)C1
Agent: Cl
Solvent: CO
Product: c1cnc(C2CNC2)c(C2CCOCC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 4 N HCl in MeOH (10 mL) was added 3-[3-(Tetrahydro-pyran-4-yl)-pyrazin-2-yl]-azetidine-1-carboxylic acid tert-butyl ester (116) (897 mg, 2.81 mmol) at 0° C. and the resulting mixture was stirred at RT for 1 h. The mixture was concentrated under reduced pressure to give 2-azetidin-3-yl-3-(tetrahydro-pyran-4-yl)-pyrazine hydrochloride (117) (716 mg, yield 100%) which was used for the next step without further purification. ESI-MS (M+1): 220 calc. for C12H17N3O 219.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[NH:8][CH:9]=[CH:10][CH:11]=2)=[N:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O.O>O1CCCC1>[Br:12][C:9]1[NH:8][C:7]([C:5]2[S:6][C:2]([CH3:1])=[CH:3][N:4]=2)=[CH:11][CH:10]=1
Reactant: Cc1cnc(-c2ccc[nH]2)s1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(-c2ccc(Br)[nH]2)s1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
5-Methyl-2-(1H-pyrrol-2-yl)-1,3-thiazole (100 mg, 0.61 mmol) synthesized in Example (3c) was dissolved in tetrahydrofuran (7 mL), and cooled to 0° C. N-Bromosuccinimide (108 mg, 0.61 mmol) was added, and stirring was carried out at room temperature for 18 hours under nitrogen atmosphere. Water (10 mL) was added, and the solution was separated with diethyl ether (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was used as it is in the next reaction.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4][NH:3]1.Br[CH2:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:33][O:32][C:30]([C:29]1[CH:28]=[C:27]([CH:36]=[CH:35][CH:34]=1)[CH2:26][N:3]1[C:2](=[O:1])[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[N:5]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:4]1)=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)c1
Temperature: 65 °C
Yield: 57.8 %

Procedure:
A mixture of tert-butyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (2 g, 6.02 mmol, 1 equiv), methyl 3-(bromomethyl)benzoate (1.38 g, 6.02 mmol, 1 equiv) and potassium carbonate (1.25 g, 9.03 mmol, 1.5 equiv) in N,N-dimethylformamide was heated at 65° C. for 16 h. Upon cooling the mixture was partitioned between ethyl acetate and water. The organic layer was further washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified using the Biotage flash chromatography system (SNAP 50 g cartridge, Rf=0.5, gradient—10%-50% ethyl acetate in hexanes) to afford tert-butyl 3-(3-(methoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (1.67 g, 58%); MS for C27H33N3O5 m/z 479.24 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:31][C:32]1([CH3:39])[O:36][CH:35]([CH2:37]O)[CH2:34][O:33]1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:37][CH:35]2[CH2:34][O:33][C:32]([CH3:39])([CH3:31])[O:36]2)[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5]
Reactant: CC1(C)OCC(CO)O1
Reactant: O=Cc1c(Cl)cc(O)cc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)OCC(COc2cc(Cl)c(C=O)c(Cl)c2)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6.64 g (35.0 mmol) A1, 10.03 g (38.0 mmol) triphenylphosphine and 5.06 g (38.0 mmol) (rac)-2,2-dimethyl-[1,3]-dioxolane-4-methanol in 100 ml dry tetrahydrofurane a solution of 6.48 g (37.0 mmol) diethyl azodicarboxylate in 20 ml dry tetrahydrofurane was added and the mixture was stirred at room temperature overnight. After removal of the solvent and column chromatography on SiGel (hexane/ethyl acetate 4:1) 6.12 g (57%) A8 were obtained as a colorless oil that solidified on ice standing.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([CH2:13]I)[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:16]1[O:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[CH:20]=1>>[O:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[CH:20]=[C:16]1[CH2:13][C@H:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]([O:11][CH3:12])=[O:10]
Reactant: Brc1cc2ccccc2o1
Reactant: COC(=O)[C@@H](CI)C(=O)OC(C)(C)C
Product: COC(=O)[C@H](Cc1cc2ccccc2o1)C(=O)OC(C)(C)C

Procedure:
The title compound was synthesized in a manner analogous to that described Example 475, using (R)-methyl 2-(tert-butoxycarbonyl)-3-iodopropanoate and 2-bromobenzofuran. (MS m/z: 220.1 (100%, M−99).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH2:11][CH2:10][CH2:9][N:8]3[CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C.O>[C:6]1([C:4]([OH:5])=[O:3])[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH2:11][CH2:10][CH2:9][N:8]3[CH:7]=1
Reactant: CCOC(=O)c1cn2c3c(cccc13)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cn2c3c(cccc13)CCC2
Temperature: 22 °C
Yield: 82.4 %

Procedure:
To a solution of 5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid ethyl ester (31 g, 0.14 mol) in ethanol (200 mL) and water (70 mL) was added 5 N aqueous sodium hydroxide(60 mL, 0.3 mol) and the resulting mixture stirred at reflux for 3 hours. The reaction mixture was cooled to 20-24° C., diluted with water (2 L) and washed with dichloromethane(2×200 mL) and diethyl ether (1×200 mL). The aqueous layer was filtered through Celite and the filtrate was acidified with conc. HCl (25 mL) to precipitate the product. The solid was filtered, washed with water (200 mL), and dried in vacuo to give 23.2 g (85%) of the desired compound as a light yellow solid.
Reaction SMILES: [C:1](NC1C(Cl)=CC(C(O)=O)=C(OC)C=1)(=O)[CH3:2].C(N(CC)CC)C.[NH2:24][C:25]1[C:41]([Cl:42])=[CH:40][C:28]([C:29]([NH:31][N:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH3:39])[CH2:34][CH2:33]2)=[O:30])=[C:27]([O:43][CH3:44])[CH:26]=1>CCOC(C)=O>[NH2:24][C:25]1[C:41]([Cl:42])=[CH:40][C:28]([C:29]([NH:31][N:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:1][CH3:2])[CH2:34][CH2:33]2)=[O:30])=[C:27]([O:43][CH3:44])[CH:26]=1
Reactant: CCN1CCN(NC(=O)c2cc(Cl)c(N)cc2OC)CC1
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCN1CCN(NC(=O)c2cc(Cl)c(N)cc2OC)CC1
Yield: 124.7 %

Procedure:
Reaction between 4-acetylamino-5-chloro-2-methoxy benzoic acid (3.2 g, 0.013 mole), triethylamine (1.3 g) and N-n-butyl-N'-amino piperazine (2.06 g) (prepared in similar manner to that described in Example 5) and hydrolysis as described in Example 1 gave 4-amino-5-chloro-2-methoxy-N-[4-n-butyl-1-piperazinyl]benzamide (2.80 g, 63%) as colourless microcrystals, m.p. 173.5°-174° C. (ex. EtOAc/light petrol 40°-60°).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([NH2:12])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C(O)C>[CH3:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([NH2:12])[CH:3]=[C:2]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:7]=1
Reactant: Cc1nc(Cl)cc(N)c1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: CCO
Product: Cc1nc(N2CCOCC2)cc(N)c1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 72 h

Procedure:
To a pressure vessel, a mixture of 6-chloro-2-methyl-3-nitro-pyridin-4-ylamine (0.75 g, 4.00 mmol) and morpholine (1.40 mL, 16.0 mmol) in absolute ethanol (16 mL) was stirred at 120° C. for 3 days. Absolute ethanol was evaporated in vacuo and the crude product was dissolved in a mixture of THF:EtOAc and this then subjected on top of a silica gel pad. Elution with EtOAc gave, after evaporation, the title compound as a yellow solid (0.89 g, 93%): IR (KBr, cm−1) 3460, 3330, 1627, 1597, 1553, 1233, 1113; 1H NMR (400 MHz, DMSO) δ 7.13 (s, 2H), 5.89 (s, 1H), 3.66–3.63 (m, 4H), 3.46–3.44 (m, 4H), 2.50 (s, 3H); LCMS (+ESI, M+H+) m/z 239; HPLC: 99% (220 nm).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[CH:26]=[CH:25][C:17]([C:18]([NH:20][CH:21]4[CH2:24][S:23][CH2:22]4)=[O:19])=[C:16]([N+:27]([O-])=O)[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1>C(O)(C)C.C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:31])([F:33])[F:32])[O:13][N:12]=[C:11]([C:14]3[CH:26]=[CH:25][C:17]([C:18]([NH:20][CH:21]4[CH2:22][S:23][CH2:24]4)=[O:19])=[C:16]([NH2:27])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(NC1CSC1)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: Nc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC1CSC1
Temperature: 70 °C
Yield: 43.7 %

Procedure:
A suspension of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4H-isoxazol-3-yl]-2-nitro-N-(thietan-3-yl)benzamide (40 mg, 0.07 mmol) and iron powder (26 mg) in isopropanol (10 ml) and acetic acid (1 ml) was heated at 70° C. for 3 hours. Isopropanol was evaporated and the residue was treated with water (10 ml) and extracted with dichloromethane (25 ml). The combined organic layers were dried over sodium sulfate, concentrated, and purified by column chromatography (hexane/ethyl acetate as eluent) to give 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4H-isoxazol-3-yl]-2-amino-N-(thietan-3-yl)benzamide (15 mg). 1H-NMR (400 MHz, CDCl3): 7.49 (2H, d), 7.42 (1H, m), 7.34 (1H, d), 6.92-6.94 (2H, m), 6.48 (1H, d) 5.18-5.20 (1H, m), 4.03 (1H, d), 3.64 (1H, d), 3.31-3.41 (4H, m), 0.82 (3H, m) ppm.
Reaction SMILES: [C:1](=[O:22])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.CCN(C(C)C)C(C)C.[C:32]1([CH:38]2[CH2:42][CH2:41][NH:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[C:32]1([CH:38]2[CH2:42][CH2:41][N:40]([C:1]([O:2][CH2:3][CH2:4][N:5]3[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH2:10]3)=[O:22])[CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CN1CCN(CCOC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: c1ccc(C2CCNC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(CCOC(=O)N2CCC(c3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.8 %

Procedure:
2-(4-Methylpiperazin-1-yl)ethyl 4-nitrophenyl carbonate (Intermediate 4; 2.10 g, 6.79 mmol) was dissolved in DMF (30 mL). DIPEA (2.37 mL, 13.59 mmol) and 3-phenylpyrrolidine (1.00 g, 6.79 mmol) were added and the reaction mixture was stirred at room temperature for 4 hours, and the reaction mixture was then concentrated in vacuo. The resulting residue was dissolved in EtOAc (300 mL) and washed with 1M aq Na2CO3 solution (6×200 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in DCM (100 mL) and methyl isocyanate resin (2.0 g) was added, the reaction mixture shaken for 14 h, filtered and then concentrated in vacuo. The residue was purified by reverse phase chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-30%). The resulting residue was dissolved in DCM (60 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo, to give 2-(4-methylpiperazin-1-yl)ethyl 3-phenylpyrrolidine-1-carboxylate (1.03 g, 48.0%) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([CH3:12])=[C:6]([O:13][CH3:14])[C:5]=1[O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([CH3:24])[C:17]=1[C:25]([OH:27])=[O:26].[CH3:29][O:30]C(Cl)Cl.Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([CH3:12])=[C:6]([O:13][CH3:14])[C:5]=1[O:15][C:16]1[C:21]([CH:29]=[O:30])=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([CH3:24])[C:17]=1[C:25]([OH:27])=[O:26]
Reactant: COC(Cl)Cl
Reactant: COC(=O)c1cc(OC)c(C)c(OC)c1Oc1cc(OC)cc(C)c1C(=O)O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1cc(OC)c(C)c(OC)c1Oc1c(C=O)c(OC)cc(C)c1C(=O)O
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
2-(3-methyl-2-carboxy-5-methoxy-phenoxy)-3,5-dimethoxy-4-methyl-benzoic acid methyl ester (1 mmol) and dichloromethyl methyl ether (2 mmol) were taken in anhydrous dichloromethane (2 ml). The mixture was stirred and cooled to −10° C. in an ice-salt bath. Titanium tetrachloride (2.5 mmol) in dichloromethane (0.5 ml) was then added dropwise over 0.5 h. Stirring was continued for a further 1.5 h at −10° C. and then for 1.5 h at room temperature. To the reaction mixture was then added cold, dilute hydrochloric acid, and the reaction mixture was extracted with dichloromethane. The organic layer was washed with water, brine and then dried (MgSO4). The solvent was evaporated by a rotary evaporator and the residue was purified by column chromatography to afford 2-(3-methyl-6-Formyl-2-carboxy-5-methoxy-phenoxy)-3,5-dimethoxy-4-methyl-benzoic acid methyl ester (63%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:19]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:18]=[CH:17][N:16]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:28]=1.ClCCl.[I-].C(OC([N:40]1[CH2:43][CH:42]([Zn+])[CH2:41]1)=O)(C)(C)C.Cl>CN(C)C(=O)C.[Cu]I>[NH:40]1[CH2:43][CH:42]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[S:12][C:13]([C:15]5[N:19]([C:20]6[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=6[F:27])[N:18]=[CH:17][N:16]=5)=[CH:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:28]=2)[CH2:41]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2ccc(Br)cc2OCC3)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CC([Zn+])C1
Agent: [Cu]I
Agent: Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2ccc(C4CNC4)cc2OCC3)c(F)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 8.1 %

Procedure:
5-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-1-(2,4-difluorophenyl)-1H-1,2,4-triazole (300 mg, 0.6 mmol) was dissolved in N,N-dimethyacetamide and purged with nitrogen. Added [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (30 mg, 0.04 mmol) and copper(I) iodide (10 mg, 0.08 mmol). Bubbled in nitrogen for 10 minutes. Added (1-(tert-butoxycarbonyl)azetidin-3-yl)zinc(II) iodide (230 mg, 0.65 mmol) in 2.3 mL DMA. Heated at 80° C. overnight. Complete reaction was confirmed by LCMS. Diluted reaction mixture with 1 M HCl and extracted the t-Boc protected intermediate, tert-butyl 3-(2-(1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)azetidine-1-carboxylate, with ethyl acetate. Dried over magnesium sulfate and concentrated in vacuo. Purified by flash chromatography (0 to 50% ethyl acetate in hexanes). Concentrated in vacuo and re-dissolved the residue in 10 mL 1,4-dioxane. Added 5 mL 4 N HCl in dioxane and let stir for 2 hours. Complete deprotection was confirmed by LCMS. Concentrated in vacuo purified by HPLC to give 419 (21.1 mg, 7% yield, M=1 437.1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].S(O)(O)(=O)=O.CO[C:18](=[NH:20])[NH2:19].[Na]>CO.O>[NH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:18]([NH2:20])=[NH:19]
Reactant: NCCCCCCC(=O)O
Reactant: COC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CO
Solvent: O
Product: N=C(N)NCCCCCCC(=O)O
Yield: 66.1 %

Procedure:
50.0 g (0.344 mols) of 7-aminoheptanoic acid and 63.5 g (0.514 mol) of O-methylisourea sulfate were dissolved in 250 ml of 50% aqueous methanol (v/v). To the solution was added dropwise a solution of 34.3 g (0.858 mol) of sodium hdyroxide in 400 ml of water. Then, the mixture was heated overnight under reflux. The reaction mixture was concentrated to about a half volume under reduced pressure followed by cooling the concentrate to precipitate white crystals. The crystals were collected by filtration, and dried to give 42.6 g (yield: 66.1%) of 7-guanidinoheptanoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[CH:26][C:27]([F:36])=[C:28]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:29]=2)[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:25]=[CH:26][C:27]([F:36])=[C:28]([NH:30][C:31](=[O:35])[CH:32]([CH3:33])[CH3:34])[CH:29]=3)[CH2:20][CH2:19]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cc(C2CCN(CCCN)CC2)ccc1F
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Product: CC(C)C(=O)Nc1cc(C2CCN(CCCNC(=O)C(C)(C)c3ccc(Cl)cc3)CC2)ccc1F

Procedure:
Example 49 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 8.34–8.20 (m, 1H), 7.46–7.14 (m, 5H), 7.10–6.95 (m, 1H), 6.92–6.77 (br, 1H), 6.74–6.59 (br, 1H), 3.39–3.25 (m, 2H), 3.00–2.82 (m, 2H), 2.67–2.51 (m, 1H), 2.51–2.40 (m, 1H), 2.40–2.27 (m, 2H), 2.03–1.86 (m, 2H), 1.85–1.71 (m, 2H), 1.71–1.57 (m, 4H), 1.56 (s, 6H), 1.27 (d, 6H, J=6.8 Hz); ESMS m/e: 502.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH:8][S:18]([C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=2)(=[O:20])=[O:19])=[N:6][CH:7]=1
Reactant: COc1nc(Br)cnc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: COc1nc(Br)cnc1NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5-bromo-3-methoxy-2-pyrazinamine (0.1 g) and 4-chlorobenzenesulphonyl chloride (0.13 g).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[NH:21][C:19]3[C:20]4[C:11](=[N:12][NH:13][C:14](=[O:22])[C:15]=4[CH:16]=[CH:17][CH:18]=3)[CH:10]2[C:23]2[CH:33]=[CH:32][C:26]([C:27]([N:29]([CH3:31])[CH3:30])=[O:28])=[CH:25][CH:24]=2)=[CH:5][CH:4]=1)=O.C(O)(=O)C.[CH3:38][NH:39][CH3:40].[BH4-].[Na+]>C(Cl)Cl>[CH3:38][N:39]([CH2:1][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[NH:21][C:19]3[C:20]4[C:11](=[N:12][NH:13][C:14](=[O:22])[C:15]=4[CH:16]=[CH:17][CH:18]=3)[CH:10]2[C:23]2[CH:24]=[CH:25][C:26]([C:27]([N:29]([CH3:30])[CH3:31])=[O:28])=[CH:32][CH:33]=2)=[CH:7][CH:8]=1)[CH3:40]
Reactant: CNC
Reactant: CN(C)C(=O)c1ccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccc(C=O)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(C)Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(C(=O)N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a stirred solution of 4-(8-(4-formylphenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)-N,N-dimethylbenzamide (140 mg, 0.32 mmol) in dried DCM (20 mL) was added acetic acid followed by dimethylamine (57 mg, 1.3 mmol). After the addition, the mixture was stirred at room temperature overnight. Then the mixture was cooled to 0° C. Sodium borohydride (102 mg, 0.48 mmol) was added. After the addition, the mixture was stirred at this temperature for 12 hr. DCM was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product, which was purified by prep-HPLC to give the title compound as a white solid (15 mg, yield 10%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.19 (dd, 6H), 2.93 (s, 3H), 3.06 (s, 3H), 3.40 (dd, 2H), 4.34 (d, 1H), 4.16-7.19 (m, 5H), 7.23-7.26 (m, 4H), 7.54 (d, 1H), 7.61 (t, 1H). LC-MS (ESI) m/z: 468(M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][C:11]=3[N:12]=2)[CH:7]=1.[CH:29]1[C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]2[C:38]([O:40][C:41](=O)[C:31]=2[CH:30]=1)=[O:39]>>[N:23]1([C:5]2[CH:4]=[CH:3][C:2]([N:1]3[C:38](=[O:39])[C:32]4[C:31](=[CH:30][CH:29]=[C:34]([C:35]([OH:37])=[O:36])[CH:33]=4)[C:41]3=[O:40])=[CH:7][C:6]=2[C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:13][C:11]=3[N:12]=2)[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: Nc1ccc(N2CCOCC2)c(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: O=C(O)c1ccc2c(c1)C(=O)N(c1ccc(N3CCOCC3)c(-c3nc4cc(-c5ccccc5)ccc4o3)c1)C2=O

Procedure:
Prepared by the method of Example 1b), from 2-(5-amino-2-(4-morpholinyl)phenyl)-5-phenylbenzoxazole (175 mg, 0.47 mmol) and 1,2,4-benzenetricarboxylic anhydride (90 mg, 0.47 mmol) the title compound was obtained (136 mg, 53%). 1H NMR (DMSO) δ 8.43(dd, 1H), 8.32(s, 1H), 8.18(d, 1H), 8.09(m, 2H), 7.90(d, 1H), 7.75(m, 3H), 7.65(dd, 1H), 7.50(t, 2H), 7.38(m, 2H), 3.80(m, 4H), 3.05(m, 4H). MS 546 m/z (M+H)+.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[CH:13][CH:12]=2)[CH2:6]1)=[O:4].Cl>O1CCOCC1>[F:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([N:7]2[C:8](=[O:10])[CH2:9][C@H:5]([C:3]([OH:4])=[O:2])[CH2:6]2)=[CH:16][CH:15]=1
Reactant: COC(=O)[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 50 °C

Procedure:
A solution of 74.6 mmol of (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester in 650 ml of dioxane was treated with 175 ml of hydrochloric acid (37%). The mixture was heated at 50° C. for 18 h in a closed flask. The solution was evaporated under reduced pressure to yield the crude acid as a yellow solid. The crude acid was triturated at 0° C. in 50 ml of ethyl acetate. The solid was collected on a filter funnel and then dried under high vacuum to yield (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid as a yellowish solid; MS: m/e=330 (M+H)+.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[NH:5][C:6](=[O:14])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.O>C(O)(=O)C>[Br:1][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:14])[NH:5][C:4]=1[CH3:3]
Reactant: Cc1cc2ccccc2c(=O)[nH]1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Cc1[nH]c(=O)c2ccccc2c1Br
Reaction time: 3 h
Yield: 87.5 %

Procedure:
A solution of bromine 491 mL, 9.58 mmol) in acetic acid (10 mL) is added to a stirred solution of 3-methyl-2H-isoquinolin-1-one (1.45 g, 9.12 mmol) in acetic acid (1 mL). After 3 hr, water (60 mL) is added and the resulting solids are collected by filtration to afford 4-bromo-3-methyl-2H-isoquinolin-1-one (1.90 g, 88% yield) as a white solid. LC/MS: MS m/e=238/240 (M+H); RT 2.97 min.