Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:12]([O:21][CH3:22])[CH:11]=2)=[O:8])=[CH:5][C:4]=1[N+:25]([O-])=O.[CH3:28][S:29](Cl)(=[O:31])=[O:30].Cl.ClCCl>CO.[Pd].N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:12]([O:21][CH3:22])[CH:11]=2)=[O:8])=[CH:5][C:4]=1[NH:25][S:29]([CH3:28])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(NC(=O)c2ccc(OC)c([N+](=O)[O-])c2)ccc1NS(C)(=O)=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccc(NS(C)(=O)=O)c(OC)c2)cc1NS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
A suspension of 4-methoxy-3-nitro-N-(4-methanesulfonylamino-3-methoxyphenyl)benzamide (100 mg) in methanol (20 ml) was stirred under hydrogen with palladium on carbon (10%, 50 mg) for 18 hours. The solvents were removed in vacuo to give a brown gum. The residue was dissolved in pyridine (0.5 ml) and cooled to 0° C. when methanesulfonyl chloride (0.1 ml) was added, the mixture was kept at 0° C. for a further 30 minutes then brought to R.T. for 1 h. Dilute hydrochloric acid (10 ml, 1M) and dichloromethane were added, the organic layer separated, dried and evaporated in vacuo to give the product as a brown gum. Purification by column chromatography over silica gel eluting with dichloromethane containing ethyl acetate (0-100%) gave 3-methanesulfonylamino-4-methoxy-N-(3-methanesulfonylamino-4-methoxyphenyl)benzamide (65 mg, 56%) as a white solid.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([OH:20])[C@H:11]([NH:14][C:15](=[O:19])[CH:16]([Cl:18])[Cl:17])[CH2:12][F:13])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH2:21]([NH2:24])[C:22]#[CH:23]>C(O)(C)(C)C.O>[NH2:24][CH2:21][C:22]1[N:3]=[N:2][N:1]([C:4]2[CH:9]=[CH:8][C:7]([C@@H:10]([OH:20])[C@H:11]([NH:14][C:15](=[O:19])[CH:16]([Cl:17])[Cl:18])[CH2:12][F:13])=[CH:6][CH:5]=2)[CH:23]=1
Reactant: [N-]=[N+]=Nc1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Reactant: C#CCN
Solvent: CC(C)(C)O
Solvent: O
Product: NCc1cn(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.3 %

Procedure:
To the solution of ((N-[(1S,2R)-2-(4-Azido-phenyl)-1-fluoromethyl-2-hydroxy-ethyl]-2,2-dichloro-acetamide (150 mg, 0.465 mmol) in tert-butylalcohol:water (1:1, 3 mL) is added Na-ascorbate (12 mg, 0.060 mmol), CuSO4.5H2O (3 mg, 0.012 mmol), propargyl amine (26 mg, 0.472 mmol) resulting reaction mixture stirred at room temperature for 16 hours. Solvent is evaporated in vacuo to get the crude material purified by column chromatography eluting in 25-40% methanol in dichloromethane and washed with diethyl ether and dried under vacuum to afford the title compound (25 mg). 1H-NMR (400 MHz, DMSO-d6) δ: 3.84 (s, 2H), 4.23-4.29 (m, 1H), 4.30-4.34 (m, 0.5H), 4.42-4.46 (m, 0.5H), 4.58-4.61 (m, 0.5H), 4.69-4.73 (m, 0.5H), 4.93 (bs, 1H), 6.07 (d, 1H, J=4.28 Hz), 6.49 (s, 1H), 7.54 (d, 2H, J=8.48 Hz), 7.81 (d, 2H, J=8.52 Hz), 8.57 (s, 1H), 8.61 (d, 1H, J=5.6 Hz). LC-MS (m/z): [M+H]=376.2.
Reaction SMILES: Cl.[SH:2][C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)C(C)C)(C)C.Cl[Si](C)(C)C.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24]>CC#N.CCOC(C)=O>[N+:33]([C:30]1[CH:29]=[CH:28][C:27]([CH2:26][O:25][C:23]([N:5]2[CH2:6][CH2:7][C@H:3]([SH:2])[CH2:4]2)=[O:24])=[CH:32][CH:31]=1)([O-:35])=[O:34]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: S[C@H]1CCNC1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](S)C1
Reaction time: 1 h
Yield: 72 %

Procedure:
A suspension of mercaptoamine hydrochloride 7 (589 mg, 4.22 mmol) in anhydrous MeCN (3.2 ml) was stirred under a N2 atmosphere with ice-bath cooling. The mixture was treated with N,N-diisopropylethylamine (1.69 ml, 9.71 mmol), stirred 5 min, and treated with chlorotrimethyl silane (0.70 ml, 5.52 mmol). After stirring 10 more minutes in the cold, the mixture was treated with a solution of p-nitrobenzyl chloroformate (910 mg, 4.22 mmol) in MeCN (1.0 ml) followed by more N,N-diisopropylethylamine (0.74 ml, 4.25 mmol). The resulting mixture was stirred in the cold for 15 minutes and at room temperature for 1 hour. The reaction mixture was diluted with EtOAc, washed with H2O, 1N HCl, 5% aqueous NaHCO3 and brine, dried with MgSO4, filtered, and evaporated (i.v.) to a yellow gum. The crude product was chromatographed on EM silica gel 60 (60 g) using 25:1 CH2Cl2 --EtOAc as eluting solvent to afford derivative 25 (858 mg, 72%) as a pale yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[C:11]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:16]=[CH:15][C:14]([CH2:17][C@@H:18]([NH:27]C(OC(C)(C)C)=O)[CH2:19][C@:20]([CH2:25][OH:26])([CH3:24])[C:21]([OH:23])=[O:22])=[CH:13][CH:12]=1.CCN(CC)CC>CC(C)=O>[N:5]1([C:3](=[O:4])[CH2:2][O:23][C:21](=[O:22])[C@@:20]([CH2:25][OH:26])([CH3:24])[CH2:19][C@H:18]([NH2:27])[CH2:17][C:14]2[CH:15]=[CH:16][C:11]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:12][CH:13]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: O=C(CCl)N1CCOCC1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@](C)(CO)C(=O)O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)OCC(=O)N1CCOCC1

Procedure:
4-(2-chloroacetyl)morpholine (63 mg, 387 μmol) was added to a mixture of (2S,4R)-5-biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (100 mg, 242 μmol) and Et3N (35 μL, 254 μmol) in acetone (10 mL). The mixture was refluxed for 24 hours and the reaction monitored for completion. When the reaction was complete, the product was purified ((Interchim reverse phase chromatography column) the solvent was removed under vacuum to yield (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid 2-morpholin-4-yl-2-oxo-ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:15]([O:22][C:23](=[O:29])[C@@H:24]1[CH2:28][CH2:27][CH2:26][NH:25]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>O1CCCC1.C(OCC)(=O)C>[CH2:15]([O:22][C:23](=[O:29])[C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:11](=[O:13])[C@H:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
N-t-butyloxycarbonyl-L-alanine (3.8 g, 20 m mole), L-proline benzyl ester hydrochloride (5 g, 20.6 m mole) and 1-hydroxy benzotriazole, which is hereinafter referred to as HOBt (2.7 g, 20 m mole) were suspended in tetrahydrofuran, which is hereinafter referred to as THF (50 ml). N,N'-dimethylaminopropylethylcarbodiimide, which is hereinafter referred to as WSC (3.8 ml) in THF (10 ml) solution was added dropwisely to the above suspended solution while cooling at -15° C. and stirring. The reaction was carried for 3 hours at a temperature of less than 0° C. and thereafter at room temperature overnight. The thus obtained solution was distilled under reduced pressure leaving a residue. The residue was dissolved in ethyl acetate and washed with 1N hydrochloric acid, water, 5% aqueous sodium bicarbonate and water in order, and dried over anhydrous sodium sulfate. The thus obtained solution was distilled under reduced pressure leaving a residue. The residue was recrystallized in ether-n-hexan to give N-t-butyloxycarbonyl-L-alanyl-L-proline benzyl ester (6.7 g, yield: 89%) having melting point of 71° to 72° C. This product gave one spot by thin layer chromatography (developing solvent; chloroform:methanol:acetic acid=95:5:3, colour forming method; spraying with 0.1% ninhydrin and heating).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([CH:16]([CH3:18])[CH3:17])[C:3]=1[C:19]#[N:20].[OH:21]S(O)(=O)=O.[OH-].[Na+]>>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([CH:16]([CH3:18])[CH3:17])[C:3]=1[C:19]([NH2:20])=[O:21]
Reactant: O=S(=O)(O)O
Reactant: CC(C)c1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1C#N
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1C(N)=O
Yield: 92 %

Procedure:
Part B: Thirty grams (91.0 mmol) of 5-amino-4-cyano-3-isopropyl-1-(2,4,6-trichlorophenyl)pyrazole was dissolved in 80 mL of con. H2SO4 and stirred 24 h at RT. The solution was added to cold aqueous NaOH, and the resulting precipitate was filtered, washed with water, and dried under vacuum to give 29.1 g (92%) of 5-amino-3-isopropyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide as a white solid. 1H NMR (CDCl3, 300 MHz) δ 7.49(s, 2H); 5.06-5.63(m, 4H); 3.06(septet, 1H, J=6.8 Hz); 1.39(d, 6H, J=6.9 Hz).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]([CH:20]([CH3:22])[CH3:21])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=2)[CH2:4][C@H:3]1[O:23][CH3:24].[Cl:25][C:26]1[N:27]=[C:28]([C:33](O)=[O:34])[NH:29][C:30]=1[CH2:31][CH3:32].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CC(N(C)C)=O>[Cl:25][C:26]1[N:27]=[C:28]([C:33]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[O:9][C:10]([CH:20]([CH3:21])[CH3:22])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=3)[CH2:4][C@H:3]2[O:23][CH3:24])=[O:34])[NH:29][C:30]=1[CH2:31][CH3:32]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](N)[C@H](OC)C2)oc1C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)oc1C(C)C
Yield: 80.6 %

Procedure:
The same operation as in Example (106d) was performed using butyl cis(±)-2-(4-amino-3-methoxypiperidin-1-yl)-5-isopropyl-1,3-oxazole-4-carboxylate obtained in Example (111c) (0.31 g, 0.91 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.11 g, 0.6 mmol), WSC hydrochloride (0.39 g, 2 mmol), HOBt (0.13 g, 1 mmol), DMA (3 mL) and dichloromethane (3 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 2/3, 3/2, 4/1) to obtain 0.24 g of the title compound as a colorless solid (77%).
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.Cl.[CH3:36][O:37][NH2:38]>CN(C=O)C>[Br:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([NH:38][O:37][CH3:36])=[O:15]
Reactant: CON
Reactant: O=C(O)c1cnn(-c2ccccc2)c1Br
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CONC(=O)c1cnn(-c2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 34.7 %

Procedure:
A solution of 2.6 g of 5-bromo-1-phenyl-1H-pyrazole-4-carboxylic acid and 2.4 g of carbonyldiimidazole in 60 ml DMF was stirred at room temperature for 30 minutes. Two grams of triethylamine and 1.7 g of methoxyamine hydrochloride were added to the solution. The mixture was stirred at room temperature for 24 hours and another equivalent of triethylamine and methoxyamine hydrochloride were added. The mixture was heated on the steam bath for two hours and poured into ice water. The precipitated solid was collected by filtration and recrystallized from ethanol to afford 1.0 g of 5-bromo-1-phenyl-N-methoxy-1H-pyrazole-4-carboxamide. Yield 34%. mp=194°-197° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].N1C=CC=CC=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([N+:32]([O-:34])=[O:33])=[C:27]([CH:31]=1)[C:28](Cl)=[O:29]>ClCCl>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([N+:32]([O-:34])=[O:33])=[C:27]([CH:31]=1)[C:28]([NH:15][C:12]1[N:11]=[CH:10][C:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)=[CH:14][N:13]=1)=[O:29]
Reactant: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Cc1ccc(-c2cnc(N)nc2)cc1C
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(-c2cnc(NC(=O)c3cc(Cl)ccc3[N+](=O)[O-])nc2)cc1C

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of 5-(3,4-dimethylphenyl)pyrimidin-2-amine (1.41 g, 7.07 mmol, 1.00 equiv) in dichloromethane (90 mL), and pyridine (1.73 g, 3.00 equiv). This was followed by dropwise addition of a solution of 5-chloro-2-nitrobenzoyl chloride (1.60 g, 7.27 mmol, 1.00 equiv) in dichloromethane (30 mL) with stirring. The resulting solution was stirred overnight at 25° C. in an oil bath. The resulting solution was diluted with 60 mL of dichloromethane. The resulting mixture was washed with 1×30 mL of hydrogen chloride (aq) and 3×200 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was dissolved in 100 mL of methanol, to this was added potassium carbonate (5.12 g). The mixture was stirred for 3 h at 30° C. The resulting mixture was concentrated under vacuum and dissolved in 100 mL of ethyl acetate. The resulting mixture was washed with 3×50 mL brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was washed with ethyl acetate:n-hexane (30 mL:30 mL). This resulted in 0.78 g (29%) of 5-chloro-N-(5-(3,4-dimethylphenyl)pyrimidin-2-yl)-2-nitrobenzamide as a off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](C([O-])=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[C:17]([OH:20])(=O)C.S(Cl)([Cl:23])=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:17]([Cl:23])=[O:20])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: O=C([O-])c1ccccc1-c1ccc(F)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
4′-Fluorobiphenyl carboxylate (10 mmol) was dissolved in thionyl chloride (30 mL) and refluxed for 3 hours. The mixture was poured into acetic acid (100 mL) and left to stand until bubbling ceased. Volatile components were removed under vacuum and the mixture left to crystallise overnight. The title compound was collected by filtration.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.[C:23]1(C)C=C[CH:26]=[CH:25][CH:24]=1.ClC(Cl)([O:33][C:34](=O)[O:35]C(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)CCC.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:34](=[O:33])[O:35][CH2:26][CH2:25][CH2:24][CH3:23])=[CH:18][CH:17]=1
Reactant: Cc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CCCCOC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Yield: 58 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-butanol (19 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (46 mg, yield 58%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=1.Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([OH:30])[CH:28]=2)[N:23]=[CH:22][N:21]=1>>[CH3:18][N:15]1[CH:16]=[CH:17][C:13]([NH:12][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][C:2]4[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=4)[CH:28]=3)[N:23]=[CH:22][N:21]=2)=[N:14]1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: Cn1ccc(N)n1
Product: Cn1ccc(Nc2ncnc3ccc(Oc4ncccc4C(F)(F)F)cc23)n1

Procedure:
The compound of Example 123 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 2-chloro-3-(trifluoromethyl)pyridine, 3-amino-1-methyl-1H-pyrazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: BrCCCCCCCCCC[O:12]C1C=CC(C(O)=O)=CC=1.C1(C=CC=C(O)C=1)O.[CH2:30]([O:42][C:43]1[CH:59]=[CH:58][C:46]([C:47]([O:49][C:50]2[CH:55]=[CH:54][C:53]([CH:56]=[O:57])=[CH:52][CH:51]=2)=[O:48])=[CH:45][CH:44]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].[O-]Cl=O.[Na+]>>[CH2:30]([O:42][C:43]1[CH:44]=[CH:45][C:46]([C:47]([O:49][C:50]2[CH:55]=[CH:54][C:53]([C:56]([OH:12])=[O:57])=[CH:52][CH:51]=2)=[O:48])=[CH:58][CH:59]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: O=C(O)c1ccc(OCCCCCCCCCCBr)cc1
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Agent: Oc1cccc(O)c1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Product: CCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)O)cc2)cc1

Procedure:
Synthesized as described above for compound 7. Quantities: resorcinol (1.79 g, 16 mmol), 11 (5.52 g, 13 mmol), NaH2PO4·H2O (6.29 g, 40 mmol), NaClO2 (7.03 g, 77 mmol). Yield 5.55 g (quant.). 1H NMR: δH (CDCl3; 300 MHz): 0.89 (3 H, t, 3J=6.9 Hz, CH3), 1.17-1.71 (18 H, m, CH2), 1.83 (2 H, m, O—CH2—CH2), 4.05 (2 H, t, 3J=6.6 Hz, O—CH2), 6.99 (2 H, d, 3J=8.9 Hz, Ar—H), 7.35 (2 H, d, 3J=8.6 Hz, Ar—H), 8.14 (2 H, d, 3J=8.9 Hz, Ar—H), 8.17 (2 H, d, 3J=8.6 Hz, Ar—H). 13C NMR: δC (CDCl3; 300 MHz): 14.1, 22.7, 26.0, 29.1, 29.3, 29.5, 29.6, 29.6, 29.7, 31.9, 68.4, 114.4, 120.9, 122.0, 126.5, 131.9, 132.4, 155.5, 170.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:24])[CH:5]=[CH:6][CH:7]=1.Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:24])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(F)c1
Reaction time: 0.05 h
Yield: 63.2 %

Procedure:
40% Methanolic Triton B (0.086 mL, 0.19 mM) was added to a solution of the 9-[(3-fluorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (51.9 mg, 0.155 mM) in 3 mL DMF at room temperature. After 3 minutes, t-butyl bromoacetate (87.8 mg, 0.44 mM) Was added and the resultant mixture stirred at room temperature for 5 hours. The mixture was diluted with ethyl acetate, washed four times with H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 44.0 mg (63%) of the {9-[(3-fluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, tert-butyl ester as a white solid. 1H NMR (DMSO-d6) δ7.6 (d, 1H, J=8 Hz), 7.5-6.8 (m, 10H), 6.55 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.8 (s, 2H), and 1.45 (s, 9H). IR (CHCl3, cm−1) 3450, 3400, 1746, 1674, 1592, 1457, 1369, and 1151. MS (FD) m/e 448.
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[CH2:11][C:10](=[O:14])[N:9]([CH2:15][CH2:16][CH:17]3[CH2:19][CH2:18]3)[C:8]2=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)CC(Cl)=O.C1([N:34](CCC2CC2)[C:35](N)=[O:36])CCCCC1.CCCCCC.[C:49]([O:52]CC)(=[O:51])[CH3:50].CCCCCC>ClCCl>[CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:35]([NH:34][CH2:50][C:49]([OH:52])=[O:51])=[O:36])[C:10](=[O:14])[N:9]([CH2:15][CH2:16][CH:17]3[CH2:18][CH2:19]3)[C:8]2=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CC(=O)N(C2CCCCC2)C(=O)N1CCC1CC1
Reactant: NC(=O)N(CCC1CC1)C1CCCCC1
Reactant: CCOC(C)=O
Agent: O=C(Cl)CC(=O)Cl
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)n(CCC2CC2)c1=O
Reaction time: 8 h
Yield: 35 %

Procedure:
1-Cyclohexyl-3-(2-cyclopropylethyl)-2,4,6(1H,3H,5H)-pyrimidinetrione. Malonyl dichloride (250 uL, 2.57 mmoles) was added dropwise to a solution of N-cyclohexyl-N-(2-cyclopropylethyl)urea (500 mg, 2.38 mmoles) in dichloromethane under argon. The mixture was stirred overnight then heated under reflux for 2 hours. Flash chromatography (hexane to 20% ethyl acetate-hexane) gave the title compound (230 mg, 35%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.57-4.71 (m, 1 H), 3.94-4.04 (m, 2 H), 3.60-3.68 (m, 2 H), 2.20-2.36 (m, 2 H), 1.86 (d, J=13.39 Hz, 2 H), 1.60-1.73 (m, 3 H), 1.45-1.60 (m, 2 H), 1.29-1.44 (m, 2 H), 1.15-1.29 (m, 1 H), 0.62-0.77 (m, 1 H), 0.40-0.51 (m, 2 H), −0.00-0.12 (m, 2 H).
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[CH3:5][CH:6]([N:11]=[N:12][C:13](Br)([CH2:15][CH3:16])[CH3:14])[CH2:7][CH:8]([CH3:10])[CH3:9].O>CC(C)=O>[CH3:5][CH:6]([N:11]=[N:12][C:13]([N:3]=[C:2]=[O:1])([CH2:15][CH3:16])[CH3:14])[CH2:7][CH:8]([CH3:9])[CH3:10]
Reactant: CCC(C)(Br)N=NC(C)CC(C)C
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCC(C)(N=C=O)N=NC(C)CC(C)C
Temperature: 25 °C

Procedure:
To a stirred solution of 3.25 grams (0.04 moles) of potassium cyanate in 75 ml of 70% aqueous acetone in a 125 ml erlenmeyer flask was added 9.4 grams (0.0377 moles) of 2-(1,3-dimethylbutylazo)-2-bromobutane (from Example III) over 5 minutes while holding the reaction temperature at 15°-20° C. with a cold water bath. After the addition was complete the reaction was stirred an additional hour at room temperature, poured into 200 ml of water and the product extracted with 100 ml of pentane. The pentane solution was separated, washed with 50 ml portions of water and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure on a rotating evaporator. The product was a yellow liquid and weighed 6.4 grams (80.5% crude yield). The infrared spectrum was in agreement with the structure of 2-(1,3-dimethylbutylazo)-2-isocyanatobutane (strong broad isocyanate band at 2125-2225 cm-1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([C:12](=[O:16])[NH:13][C:14]=2[CH:15]=1)=[CH:10][C:9]([Cl:17])=[CH:8][CH:7]=3.[O-2].[Ba+2].[CH2:20](Br)[C:21]#[CH:22]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([C:12](=[O:16])[N:13]([CH2:22][C:21]#[CH:20])[C:14]=2[CH:15]=1)=[CH:10][C:9]([Cl:17])=[CH:8][CH:7]=3
Reactant: O=c1[nH]c2cc(Cl)ccc2c2ccc(Cl)cc12
Reactant: C#CCBr
Agent: [Ba+2]
Agent: [O-2]
Solvent: CN(C)C=O
Product: C#CCn1c(=O)c2cc(Cl)ccc2c2ccc(Cl)cc21

Procedure:
A mixture of 5 g (19 mmol) of 3,8-dichloro-6(5H)phenanthridinone, 3,2 g (21 mmol) of barium oxide and 1.9 ml (21 mmol) of propargyl bromide in 40 ml of dimethylformamide was heated on the steam bath for 1 hour. After cooling, the product was precipitated by addition of water, filtered off and washed with water. It was dissolved in methylene chloride and the solution was dried and evaporated. The residue was chromatographed over 150 g of silica gel using 10% (v/v) of hexane in methylene chloride. The fractions containing the product were combined and evaporated. The solid residue was recrystallized from ethanol to give colorless crystals of 3,8-dichloro-5-(2-propynyl)-6(5H)-phenanthridinone with m.p. 248°-250°.