Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:23]2([C:27]([O:29]CC)=[O:28])[CH2:26][CH2:25][CH2:24]2)[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:23]2([C:27]([OH:29])=[O:28])[CH2:26][CH2:25][CH2:24]2)[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C(C)C)cc3)c2)CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1ccc(-c2cc(C3(C(=O)O)CCC3)cc(Cl)c2OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.9 %

Procedure:
A mixture of ethyl 1-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylate (400 mg, 0.88 mmol) and lithium hydroxide monohydrate (215 mg, 5.1 mmol) in MeOH/THF/Water solvent mixture (10 ml/10 ml/10/ml) was stirred for 3 h at room temperature. After completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water, dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Flash Column Chromatography to give 1-(5-chloro-4′-isopropyl-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylic acid (289 mg) as white solid. 1HNMR (CDCl3): 7.44 (d, 2H), 7.38 (s, 1H), 7.31 (d, 2H) 7.21 (s, 1H), 3.86 (q, 2H); 2.99 (m, 1H), 2.86 (m, 2H), 2.52 (m, 2H), 2.13 (m, 1H), 1.92 (m, 1H); 1.28 (d, 6H).
Reaction SMILES: [I-].[CH3:2][S+](C)C.[H-].[Na+].[CH3:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1>CS(C)=O.O>[C:9]1([CH3:8])[CH:16]=[CH:15][C:12]([CH:13]2[CH2:2][O:14]2)=[CH:11][CH:10]=1
Reactant: C[S+](C)C
Reactant: Cc1ccc(C=O)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(C2CO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
The title compound was prepared by following general procedure 3. To a solution of trimethylsulfonium iodide (10.28 g, 50.37 mmol, 1.2 equiv.) in DMSO (70 mL) was added sodium hydride 60% dispersion in oil (2.82 g, 70.5 mmol, 1.7 equiv.) portionwise over 5 min. and stirred for 1 h at RT. A solution of 4-methylbenzaldehyde (5.0 g, 42.0 mmol, 1 equiv.) in DMSO (25 mL) was added to the reaction mixture dropwise over 20 min. It was stirred at RT for 4 h. The reaction mixture was checked by TLC and the reaction mixture was poured in water (150 mL) and extracted with ethyl acetate. The combined organic extract was washed with water and brine and dried over anhydrous sodium sulfate and evaporated to dryness to afford 2-p-tolyloxirane (5.2 g).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11](=[O:20])[C:10]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C(C)=CC=CC=1.C(O)CC(C)C.Cl.Cl[C:43]1[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=1>C(N(CC)CC)C>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11](=[O:20])[C:10]([N:21]2[CH2:22][CH2:23][N:24]([C:43]3[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=3)[CH2:25][CH2:26]2)=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(=O)c(N3CCNCC3)cn(Cc3ccccc3)c2c1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Solvent: CC(C)CCO
Product: COc1ccc2c(=O)c(N3CCN(c4ccncc4)CC3)cn(Cc3ccccc3)c2c1
Reaction time: 30 h
Yield: 58.1 %

Procedure:
A mixture of the product of step (v) (1.1 g), xylene (110 ml), isoamyl alcohol (11 ml), 4-chloropyridine hydrochloride (1.1 g) and triethylamine (11 ml) was heated to reflux and stirred for 30 hours. During this period extra aliquots of 4-chloropyridine hydrochloride (6×1.1 g) and triethylamine (3×11 ml) were added at intervals. The reaction mixture was evaporated to dryness and the residue was purified by flash chromatography on silica by elution with methanol/dichloromethane/concentrated ammonia (20:200:1) to give 1-benzyl-3-(4-(4-pyridyl)piperazin-1-yl)-7-methoxy-4-quinolone (780 mg) as an orange-red solid: NMR (d6DMSO) δ 3.2 (4H, m), 3.75 (3H, s), 3.80 (4H, m), 5.55 (2H, s), 6.90 (2H, m), 7.30 (7H, m), 7.88 (1H, s), 8.13 (1H, d), 8.24 (2H, d); m/Z 427 (M+H)+.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.[N:35]1([CH2:40][CH2:41][CH2:42][NH2:43])[CH:39]=[CH:38][N:37]=[CH:36]1>O1CCCC1.O>[N:35]1([CH2:40][CH2:41][CH2:42][NH:43][CH:5]=[O:7])[CH:39]=[CH:38][N:37]=[CH:36]1
Reactant: NCCCn1ccnc1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: O=CO
Solvent: O
Solvent: C1CCOC1
Product: O=CNCCCn1ccnc1
Reaction time: 2 h

Procedure:
12.3 ml of acetic anhydride was cooled below 0° C. and treated dropwise with 6.1 ml of 98% formic acid, keeping the reaction temperature below 0° C. by external cooling. The mixture was then slowly warmed, and kept at 50° C.-60° C. for two hours. 10 ml of tetrahydrofuran was added, and the solution of acetic formic anhydric cooled to -20° C. A solution of 6.2 g of 3-(1H-imidazol-l-yl)propanamine in 20 ml of tetrahydrofuran was then added dropwise, keeping the temperature below -10° C. The reaction mixture was allowed to come to room temperature, 10 ml of water was added, and the mixture taken to dryness in vacuo. Distillation of the viscous residue at 195° C.-200° C. gave 6.2 g of N-(3-(1H-imidazol-l-yl)propyl)formamide. This was reduced to N-methyl-3-(1H-imidazol-l-yl)propylamine by the use of borane dimethylsulfide in refluxing tetrahydrofuran.
Reaction SMILES: Br[CH2:2][CH2:3]Br.[OH:5][N:6]([CH:22]([CH3:24])[CH3:23])[C:7]([NH:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:18]([F:21])([F:20])[F:19])=[O:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH:22]([N:6]1[C:7](=[O:8])[N:9]([C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[C:18]([F:19])([F:20])[F:21])=[O:11])[CH2:3][CH2:2][O:5]1)([CH3:24])[CH3:23]
Reactant: CC(C)N(O)C(=O)NC(=O)c1cnccc1C(F)(F)F
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)N1OCCN(C(=O)c2cnccc2C(F)(F)F)C1=O
Reaction time: 3 h

Procedure:
1,2-Dibromoethane (0.06 ml) was added to a suspension of 1-hydroxyl-1-isopropyl-3-(4-trifluoromethyl-3-pyridylcarbonyl)urea (0.20 g) and potassium carbonate (0.20 g) in N,N-dimethylformamide at 20° C., and stirred for 3 hours. Ethyl acetate and water were added and the organic phase dried (magnesium sulfate), evaporated and the residue purified by column chromatography on silica gel, eluting with n-hexane/ethyl acetate (2:1), to give 2-isopropyl-4-(4-trifluoromethyl-3-pyridylcarbonyl)-perhydro-1,2,4-oxadiazin-3-one (0.25 g, Compound U-3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([NH:12][CH2:13][CH2:14][C:15]([OH:17])=O)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1.[NH2:48][C:49]([C:57]1[CH:64]=[CH:63][C:60]([C:61]#[N:62])=[C:59]([F:65])[CH:58]=1)([C:51]1[N:52]([CH3:56])[CH:53]=[N:54][CH:55]=1)[CH3:50]>CN(C=O)C>[C:61]([C:60]1[CH:63]=[CH:64][C:57]([C:49]([NH:48][C:15](=[O:17])[CH2:14][CH2:13][NH:12][S:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)(=[O:10])=[O:11])([C:51]2[N:52]([CH3:56])[CH:53]=[N:54][CH:55]=2)[CH3:50])=[CH:58][C:59]=1[F:65])#[N:62]
Reactant: Cn1cncc1C(C)(N)c1ccc(C#N)c(F)c1
Reactant: COc1cccc(S(=O)(=O)NCCC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(S(=O)(=O)NCCC(=O)NC(C)(c2ccc(C#N)c(F)c2)c2cncn2C)c1
Reaction time: 8 h

Procedure:
To a solution of 3-(3-methoxy-benzenesulfonylamino)-propionic acid (0.261 g, 1.01 mmol) in DMF (4 mL) at room temperature was added 1-hydroxybenzotriazole hydrate (HOBT) (0.146 g, 0.96 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (0.202 g, 1.05 mmol), 4-methylmorpholine (0.102 g, 1.01 mmol), and (+)-4-[1-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-2-fluoro-benzonitrile (Step I) (0.246 g, 1.01 mmol). After stirring overnight, the reaction was concentrated in vacuo. The residue was partitioned between EtOAc and water, the organic layer separated, washed with brine, dried (Na2SO4), and concentrated in vacuo to provide the title compound after purification by chromatography on silica gel (5% to 7.5% methanol/0.1% ammonium hydroxide in CH2Cl2).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:32](Br)[C:33](=[CH2:35])[CH3:34]>CN(C)C=O.C(OCC)(=O)C.O>[CH3:25][C:23]1[CH:22]=[CH:21][C:5]2=[C:6]3[C:11](=[C:2]([NH2:1])[N:3]=[C:4]2[CH:24]=1)[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:34][C:33]([CH3:35])=[CH2:32])=[CH:18][CH:19]=1)=[CH:7]3
Reactant: C=C(C)CBr
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(C)COc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenol (from Example 170) (1.0 equiv.) in dimethylformamide (0.10 M) was added anhydrous potassium carbonate (1.5 equiv.) followed by methallyl bromide (1.2 equiv.). The resulting mixture was allowed to stir for 18 hours at 100° C. After cooling to ambient temperature, the mixture was diluted with ethyl acetate and water. The biphasic layers were separated and the aqueous layer was washed twice with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH® system (ISCO) using 0-60% ethyl acetate in hexanes to provide 8-methyl-2-(4-(2-methylallyloxy)phenethyl)benzo[f][1,7]naphthyridin-5-amine as a solid. 1H NMR (Acetone-d6): δ 8.75 (s, 1H), 8.68 (s, 1H), 8.27 (d, 1H), 7.41 (s, 1H), 7.12-7.19 (m, 3H), 6.87 (d, 2H), 6.60 (br, 2H), 5.06 (s, 1H), 4.93 (s, 1H), 4.43 (s, 2H), 3.20 (t, 2H), 3.05 (t, 2H), 2.45 (s, 3H), 1.79 (s, 3H). LRMS [M+H]=384.2
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N+:8]([C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]=1Cl)[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15])([O-:10])=[O:9]>>[N+:8]([C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]=1[N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15])([O-:10])=[O:9]
Reactant: CN1CCNCC1
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Product: CN1CCN(c2ccc(C(=O)c3ccccc3)cc2[N+](=O)[O-])CC1
Yield: 90 %

Procedure:
N-methyl-piperazine is reacted with 3-nitro-4-chloro-benzophenone as described in Example 7 or 8 to obtain 3-nitro-4-(N-methyl-piperazino)-benzophenone with a yield of 90 %. The product melts at 94° C.
Reaction SMILES: [C:1]1([C:6]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[NH:10][C:9]2=[O:18])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21]>C(#N)C>[Cl:19][S:20]([NH:23][C:24]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:8]([C:6](=[O:7])[C:1]2[S:5][CH:4]=[CH:3][CH:2]=2)[C:9]1=[O:18])=[O:25])(=[O:22])=[O:21]
Reactant: O=C1Nc2ccc(Cl)cc2C1C(=O)c1cccs1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CC#N
Product: O=C(c1cccs1)C1C(=O)N(C(=O)NS(=O)(=O)Cl)c2ccc(Cl)cc21

Procedure:
To a stirred slurry of 1.5 g. (5.4 mmole) of 3-(2-thenoyl)-5-chloro-2-oxindole in 15 ml. of dry acetonitrile was added 0.52 ml. (5.9 mmole) of chlorosulfonyl isocyanate, and the reaction mixture was stirred at room temperature for 2 hours. A small sample was removed, filtered and evaporated in vacuo to give a small sample of N-chlorosulfonyl-3-(2- thenoyl)-5-chloro-2-oxindole-1-carboxamide, mp 166°-169° C. To the remainder of the reaction mixture, 30 ml. of water was added slowly with stirring and stirring was continued for 1 hour. The reaction mixture was then poured into 50 ml. of 1N hydrochloric acid containing ice chips, and the resulting mixture was stirred for 20 minutes. The yellow solid was recovered by filtration, washed with water and diisopropyl ether and recrystallized from glacial acetic acid to give 200 mg. of a first crop of the title compound, mp 213°-215° C. The mother liquors from which the first crop had been recovered deposited a further yellow solid. The latter solid was recovered by filtration to give 470 mg. of a second crop of the title compound. The second crop was recrystallized from glacial acetic acid and combined with the first crop and recrystallized from glacial acetic acid. This gave 280 mg. of the title compound, mp 232°-234° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:14][C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cccc(-c2cccc(Cl)c2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cccc(-c2cccc(CBr)c2)c1
Yield: 93.4 %

Procedure:
3'-Chloro-3-methyl[1,1'-biphenyl] (7.0 g, 0.035 mole) and N-bromosuccinimide (6.4 g, 0.035 mole) in 100 ml of carbon tetrachloride were irradiated for 4 hours with white light to afford 3-bromomethyl-3'-chloro[1,1'-biphenyl] (9.2 g). The nmr spectrum was consistent with that expected for the named compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=O)=[CH:14][CH:15]=2)[N:10]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH:9]=1.[O-:27][N+:28]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[C:30]([C@H:38]([NH2:40])[CH3:39])[CH:29]=1.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([NH:40][C@@H:38]([C:30]3[CH:29]=[N+:28]([O-:27])[C:33]([C:34]([F:35])([F:36])[F:37])=[CH:32][CH:31]=3)[CH3:39])=[O:19])=[CH:14][CH:15]=2)[N:10]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[CH:9]=1
Reactant: Cc1ccc(-n2cc(-c3ccccc3Cl)c3ccc(C(=O)O)cc32)cc1
Reactant: C[C@@H](N)c1ccc(C(F)(F)F)[n+]([O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ccc(-n2cc(-c3ccccc3Cl)c3ccc(C(=O)N[C@H](C)c4ccc(C(F)(F)F)[n+]([O-])c4)cc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
To a solution of 3-(2-chlorophenyl)-1-(4-methylphenyl)-1H-indole-6-carboxylic acid (9.5 mg, 26.0 μmol) in N,N-dimethylformamide (0.5 mL) were added hydrochloride salt of (1R)-1-[1-oxido-6-(trifluoromethyl)pyridin-3-yl]ethanamine (7.3 mg, 30.0 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (12.5 mg, 65.0 μmol), 1-hydroxy-7-azabenzotriazole (2.2 mg, 16.0 μmol) and N-methylmorpholine (12.0 μL, 0.11 mmol). The mixture was stirred at ambient temperature for 30 min. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the bistrifluoroacetate salt of the title compound (9.7 mg): HRMS [M+1] found=550.1505; 1H NMR (500 MHz, CDCl3): δ 8.50 (s, 1H); 8.08 (s, 1H); 7.67 (t, J=7.7 Hz, 3H); 7.61-7.47 (m, 4H); 7.44-7.21 (m, 6H); 6.66 (d, J=6.6 Hz, 1H); 5.31-5.23 (m, 1H); 2.44 (s, 3H); 1.64 (dd, J=20.9, 7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10](=[O:18])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10](=[O:18])[CH2:9][CH:8]3[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: O=C1CC(c2cccc(Cl)c2)c2ccccc2N1
Product: O=C1CC(c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc2N1
Temperature: 0 °C
Yield: 2.4 %

Procedure:
Intermediate (1-a) (58.6 g), 4-chlorobenzoic acid (71.2 g) and polyphosphoric acid (580 g) were stirred at 140° C. for 48 hours. The mixture was poured into ice water and filtered off. The precipitate was washed with water, then with a diluted NH4OH solution and taken up in DCM. The organic layer was dried (MgSO4), filtered off and evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH99/1/0.1). The pure fractions were collected and evaporated, and recrystallized from CH2Cl2/CH3OH/DIPE, yielding 2.2 g of (±)-6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-3,4-dihydro-2(1H)-quinolinone (interm. 1-b, mp. 194.8° C.).
Reaction SMILES: O=[C:2](Cl)[O:3][C:4](Cl)(Cl)Cl.[NH2:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH2:12][S:13][CH3:14].C>O1CCOCC1>[N-:9]=[C:4]=[O:3].[CH3:2][O:16][C:15](=[O:17])[C@H:10]([CH2:11][CH2:12][S:13][CH3:14])[NH2:9]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CSCC[C@H](N)C(=O)O
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)CCSC
Product: [N-]=C=O

Procedure:
0.35 mol diphosgene is added dropwise over 1 hour to a mixture of 0.28 mol of the methyl ester of methionine and 0.4 g activated charcoal in 400 mL dioxane under N2. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is re-dissolved in 100 mL THF, and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the filtrate is fractionally distilled to give methionine methyl ester isocyanate.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]([CH3:53])([CH3:52])[CH2:15][O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[C:49]([CH3:51])[N:50]=[C:24]23)[CH2:19][CH2:18]1>O.C(OCC)(=O)C>[OH:13][C:14]([CH3:52])([CH3:53])[CH2:15][O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[C:49]([CH3:51])[N:50]=[C:24]23)[CH2:19][CH2:18]1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2nc(C)nn12
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.44 g), sodium hydrogen carbonate (0.72 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.23 g) was added, and the mixture was stirred at 90° C. for 21 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.084 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.078 mL) were added, and the mixture was stirred at room temperature for 18 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.10 g, 39%).
Reaction SMILES: S(=O)(=O)(O)O.[NH:6]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=O)[C:7]1=[O:8].[OH-:17].[Na+].[N:19]([O-])=O.[Na+]>O.Cl>[NH:6]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9]([C:7]([OH:8])=[O:17])=[N:19]1
Reactant: [OH-]
Reactant: O=N[O-]
Reactant: O=C1Nc2ccccc2C1=O
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1n[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 44.8 %

Procedure:
A solution of concentrated sulfuric acid (19.1 g, 0.19 mol) in water (200 ml) prepared in a 2 litre beaker was cooled to 0° C. Isatin (14.7 g, 0.1 mol) was added to a solution of sodium hydroxide (4.1 g, 0.105 mol) in water(65 ml) at 50° C. and the dark red solution cooled to 0° C. A solution of sodium nitrite (6.9 g, 0.1 mol) in water (235 ml) at 0° C. was added and the mixture added to the rapidly stirred solution of sulfuric acid during 5 minutes. The temperature was not allowed to rise above 4° C. (controlled by the addition of ice). The yellow brown foamy mixture was stirred for a further 15 minutes before being treated with a solution of stannous chloride hydrate (54 g, 0.24 mol) in concentrated hydrochloric acid (85 ml) at 0° C. The mixture was stirred for one hour and the crude product filtered. The material was recrystallized as follows: about half of the solid was placed in a 1 litre flask and ~500 ml of water was added. The solution was heated on a hot-plate until boiling and was then filtered hot to give a dark yellow-brown precipitate and an orange-yellow solution. The solution was left to cool overnight. The recrystallizing solution was filtered to give a yellow solid and a pale yellow filtrate. The solid was put in the oven to dry. The process was repeated with the other half of the crude product and the two mother liquors were pooled together as were the solid products. The dark yellow-brown substance filtered off during recrystallization was boiled with 150 ml of water, filtered and the resulting solution was left to recrystallize. It was then treated as above. The pooled mother liquors were concentrated to 1/3 volume and the solution allowed to crystallize. The solid thus obtained was added to the rest. On drying, 7.27 g solid yellow powder product was obtained, with an m.p. 263-264° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[OH:25][C:26]1[C:27]([C:32](O)=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>O.CC(N(C)C)=O>[OH:25][C:26]1[C:27]([C:32]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)c1ncccc1O
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3ncccc3O)cc2)c2ccc3ccccc3c2N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.2 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (63 mg, 0.2 mmol), 3-hydroxypyridine-2-carboxylic acid (33 mg, 0.24 mmol), dry dimethylacetamide (6 mL), triethylamine (0.07 mL, 0.5 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (95 mg, 0.25 mmol) were mixed, and the mixture was stirred at room temperature for 24 hours. This reaction mixture was added with water, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/chloroform=1/100), and then washed several times with ethyl acetate to give the title compound (37 mg, yield 42%) as white crystals.