Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:7]=[C:8]([C:13]2[NH:17][C:16]([C:18]([F:21])([F:20])[F:19])=[N:15][C:14]=2[C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:9]=[C:10]([CH3:12])[CH:11]=1.C(N(CC)CC)C>C(#N)C>[Cl:5][C:6]1[CH:7]=[C:8]([C:13]2[N:17]([C:1](=[O:3])[CH3:2])[C:16]([C:18]([F:21])([F:19])[F:20])=[N:15][C:14]=2[C:22]2[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=2)[CH:9]=[C:10]([CH3:12])[CH:11]=1
Reactant: Cc1cc(Cl)cc(-c2[nH]c(C(F)(F)F)nc2-c2ccc(S(C)(=O)=O)cc2)c1
Reactant: CC(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)n1c(C(F)(F)F)nc(-c2ccc(S(C)(=O)=O)cc2)c1-c1cc(C)cc(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 10.9 %

Procedure:
Acetyl chloride (50 mg, 0.6 mmol) was added to a cold (5° C.), stirred solution of Example 54 (150 mg, 0.3 mmol) and triethylamine (80 mg, 0.8 mmol) in acetonitrile (3 ml). The reaction was warmed to room temperature and stirred for 4 hours. The solvent was removed and the residue was purified by chromatography on silica gel using 20% ethyl acetate in toluene as the eluent to give 15 mg of the desired product as a crystalline solid: mp 257° C. Anal. Calc'd. for C20H16N2O3ClF3S (MW 456.87): C, 52.58; H, 3.53; N, 6.13; S, 7.02. Found: C, 52.21; H, 3.61; N, 5.95; S, 7.30.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH2:9].[C:11](OOC(C)(C)C)(C)(C)[CH3:12].Cl[C:22]1[CH:27]=[C:26](Cl)[C:25](Cl)=[CH:24][C:23]=1Cl>C(C1C=CC=CC=1)C>[C:22]1([CH:11]([NH:9][C:2]2[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=2[CH3:10])[CH3:12])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Clc1cc(Cl)c(Cl)cc1Cl
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: Cc1cc(C)c(N)c(C)c1
Solvent: CCc1ccccc1
Product: Cc1cc(C)c(NC(C)c2ccccc2)c(C)c1

Procedure:
To a solution of 104 μL, (100 mg; 0.741 mmol) of mesitylamine, 136 μL, (108 mg; 0.741 mmol) t-butyl peroxide, 20 mL (neat) ethylbenzene was added the appropriate amount of {[Cl2NNF6Cu]}2(C6H6) from a stock solution in benzene. The reaction mixture was allowed to react inside a sealed pressure vessel and allowed to react at the specified temperature and time. Yields were determined via 1H NMR using 1,2,4,5-tetrachlorobenzene as a standard. See FIGS. 22 and 23. 1H NMR (benzene-d6, RT): δ 7.105 (m, 7, Ar—H), 4.159 (m, 1, CBz—H), 2.907 (br, 1, N—H), 2.142 (s, 3, p-CH3), 2.040 (s, 6, o-CH3), 1.341 (d, 3, CH3); m/z=240 (CI mode); byproduct diazene MesN═NMes 1H NMR (benzene-d6): δ 6.742 (s, 4, Ar—H), 2.461 (s, 12, o-CH3), 2.116 (s, 6, p-CH3); m/z=267 (CI mode).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:22]([O:24]CC)=[O:23])[CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:27][CH2:28][C:29]([F:32])([F:31])[F:30].[Li+].[OH-]>CO.C1COCC1.O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:27][CH2:28][C:29]([F:30])([F:31])[F:32]
Reactant: CCOC(=O)C1(c2cc(OCC(F)(F)F)c(Cl)c(-c3ccc(C(F)(F)F)cc3)c2)CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C1(c2cc(OCC(F)(F)F)c(Cl)c(-c3ccc(C(F)(F)F)cc3)c2)CCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.6 %

Procedure:
Ethyl 1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate (0.1 g) dissolved in MeOH/THF/H2O (10 mL/10 mL/5 mL) and 70 mg LiOH added. The reaction mixture was stirred at room temperature for 5 h and concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO4, filtered and evaporated under reduced pressure. Purification by column chromatography over silica gel (hexane/EtOAc 9:1) gave 1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylic acid (75 mg) of the product as a white solid. 1H-NMR (500 MHz, CDCl3): 7.74 (d, 2H), 7.53 (d, 2H), 6.99 (s, 1H), 6.97 (s, 1H), 4.43 (q, 2H), 2.88 (m, 2H), 2.54 (m, 2H), 2.15 (m, 1H), 1.93 (m, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1N=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[OH-].[K+].[CH3:14][N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.[CH3:22]O>>[CH3:1][O:2][C:3]1[CH:22]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:18]1[CH2:17][CH2:16][N:15]([CH3:14])[CH2:20][CH:19]=1
Reactant: CO
Reactant: CN1CCC(=O)CC1
Reactant: COc1ccc2[nH]ccc2n1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc2[nH]cc(C3=CCN(C)CC3)c2c1
Temperature: 25 °C
Yield: 79 %

Procedure:
To a mixture of 5-methoxy-4-aza-1H-indole(7.0 g, 47 mmol) and potassium hydroxide (9.2 g, 165 mmol) in 350 mL of methanol was added 1-methyl-4-piperidone (9.86 mL, 80 mmol) in one portion. The reaction was heated at reflux temperature overnight, and cooled to room temperature. The resulting precipitate was collected, and the filtrate was concentrated to a minimal volume. A second crop of crystals was collected, washed with cold methanol, and combined with the previous crop to afford 9.0 g (79%) of the title compound. MS(m/e): 243 (M+). EA calculated for C14H17N3O: C, 69.11; H, 7.04; N, 17.27. Found: C, 69.22; H, 7.13; N, 17.47.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9](=[N:18][OH:19])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17].[CH:20]([S:23](Cl)(=[O:25])=[O:24])([CH3:22])[CH3:21]>C(OCC)C>[CH:20]([S:23]([O:19][N:18]=[C:9]([Cl:8])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])(=[O:25])=[O:24])([CH3:22])[CH3:21]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: ON=C(Cl)c1c(Cl)cccc1Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)ON=C(Cl)c1c(Cl)cccc1Cl

Procedure:
A 3.6 (0.036 mol) sample of triethylamine was added slowly to a cooled mixture (ice bath) of 7.8 g (0.035 mol) alpha-chloro-2,6-dichlorobenzaldoxime (U.S. Pat. No. 3,234,255) and 5.5 g (0.035 mol) isopropylsulfonyl chloride in 125 ml diethyl ether. The reaction was slightly exothermic. The reaction mixture was filtered to remove a small amount of salts and the filtrate was evaporated under reduced pressure to give a yellow oil. The oil was chromatographed through a silica gel column with hexane/dichloromethane elution. O-isopropylsulfonyl-alpha-chloro-2,6-dichlorobenzaldoxime (white solid, m.p. 48°-50° C.) was eluted from the column with dichloromethane. Elemental analysis for C11H12Cl3NO3S showed: %S, calc. 9.3, found 8.1; %Cl, calc. 30.9, found 32.8.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[I-].[K+].BrC[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1>CC(C)=O.CO.C(O)(=O)C>[NH:19]1[CH:23]=[N:22][C:21]([CH2:1][C:13]2[CH:12]=[CH:11][CH:18]=[CH:17][C:14]=2[C:15]#[N:16])=[N:20]1
Reactant: c1nc[nH]n1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(CBr)cc1
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1ccccc1Cc1nc[nH]n1

Procedure:
Potassium carbonate (70 g, 0.507 mole) and potassium iodide (8.4 g, 0.051 mole) were added to a solution of 4-bromomethylbenzonitrile (100 g, 0.510 mole) in acetone (500 ml). To this reaction mixture, a solution of 1,2,4-triazole (35 g, 0.507 mole) in methanol (500 ml) was slowly added under nitrogen at 25 to 35° C. over a period of 1 hour. The reaction mixture was stirred for a further two to four hours and, after completion of the reaction, the solid was filtered and the filtrate was concentrated by distillation at 40 to 45° C. under reduced pressure. Water (2000 ml) was added to the residue and the pH of reaction mixture was adjusted to between 6 and 7 with acetic acid (3 to 4 ml). The aqueous layer was extracted with dichloromethane (2000 ml) and the organic extract was washed with water (200 ml) and the organic solvent was removed by distillation at 40 to 45° C. under reduced pressure to afford 4-[(1-(1,2,4-triazolyl)methyl]-benzonitrile (III) as a crude residue.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:5]=[C:4]1[CH2:12][C:13]#[N:14])[CH3:2].[N:15]([O-:17])=O.[Na+].[OH-].[Na+].[NH2:21]O>CO.Cl.O>[CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:5]=[C:4]1[C:12]1[C:13]([NH2:21])=[N:14][O:17][N:15]=1)[CH3:2]
Reactant: CCn1c(CC#N)nc2cnccc21
Reactant: NO
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCn1c(-c2nonc2N)nc2cnccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
The product from Step 3 (200 mg, 1.1 mmol) in methanol (4 ml) and 2N hydrochloric acid (4 ml) was treated portionwise with sodium nitrite (150 mg, 2.2 mmol) and stirred at room temperature for 2 hours. The pH of the mixture was adjusted to 12 by addition of 50% sodium hydroxide solution and a 50% solution of hydroxylamine in water (3 ml) was added. The mixture was heated at 90° C. for 2.5 hours and the reaction allowed to cool to room temperature. The resulting precipitate was filtered and dried in vacuo to afford the title compound (110 mg, 43%); MS (ES+) m/e 231 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:4]=[CH:5][N:6]=1.C(Cl)(=O)CCCCCCC[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[C:35](Cl)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>>[O:40]=[C:35]([N:12]1[CH2:13][CH2:14][CH:9]([CH2:8][CH2:7][N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH2:1][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23])[CH2:10][CH2:11]1)[C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: Cc1nccn1CCC1CCNCC1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC(C)(C)C(=O)Cl
Product: CCCCCCCCCCCc1nccn1CCC1CCN(C(=O)C(C)(C)C)CC1

Procedure:
Following essentially the last step of the procedure for preparing the compound of Example 1, and using in place of 4-[2-(2-methyl-1H-imidazol-1-yl)ethyl]piperidine and stearoyl chloride, approximately equivalent amounts of the compound of Example (5A) and pivaloyl chloride, respectively, the title compound was obtained as an oil.
Reaction SMILES: O[CH:2]1[C:12]2[C:13]3[C:5](=[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3]1.S(Cl)(Cl)=O.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.O>C(Cl)Cl>[O:27]1[CH2:28][CH2:29][N:24]([CH:2]2[C:12]3[C:13]4[C:5](=[C:6]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[NH:7][C:8]=4[CH:9]=[CH:10][CH:11]=3)[CH2:4][CH2:3]2)[CH2:25][CH2:26]1
Reactant: C1COCCN1
Reactant: OC1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Solvent: O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: c1ccc(-c2[nH]c3cccc4c3c2CCC4N2CCOCC2)cc1
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A portion (0.47 g) of the compound obtained in Example 256 was suspended in anhydrous methylene chloride (15 ml) and to the suspension was added dropwise a solution of thionyl chloride (0.15 ml) in anhydrous methylene chloride (5 ml) under cooling with ice. After stirring for 30 minutes, a solution (10 ml) of morpholine (1.65 ml) in anhydrous methylene chloride was added dropwise and the mixture was stirred for 3 hours. Water was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was washed with diethyl ether and methanol to yield 0.38 g (63%) of the titled compound as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O.C(Cl)(=O)C([Cl:24])=O>CN(C)C=O.ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([Cl:24])=[O:20]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cccc(C)c1C=CCCCCCCCC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1C=CCCCCCCCC(=O)Cl

Procedure:
A solution of 10-(2,6-dimethyl-phenyl)-dec-9-enoic acid (239 mg, 0.87 mmol), oxalyl chloride (0.11 mL, 1.3 mmol), and N,N-dimethylformamide (one drop) in dichloromethane (3 mL) was stirred at room temperature for 2 hours, then volatile material was removed by distillation to afford 10-(2,6-dimethyl-phenyl)-dec-9-enoyl chloride. This was redissolved in dichloromethane, then N,N-diisopropylethylamine (140 mg, 1.04 mmol) was added dropwise, followed by (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride. The reaction mixture was stirred at room temperature for 16 h, then washed with water. The organic layer was evaporated and the residue purified by preparative HPLC to afford (R)-4-dimethylamino-3-[10-(2,6-dimethyl-phenyl)-dec-9-enoylamino]-butyric acid benzyl ester.
Reaction SMILES: C([Mg]CCCC)CCC.C([Li])CCC.Br[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH3:25])[CH:20]=[C:19]2[CH2:26][CH2:27][CH2:28][O:29][CH3:30].CN1CCOCC1.[CH:38]([CH:40]([CH:56]([CH3:58])[CH3:57])[CH2:41][CH:42]1[CH2:46][O:45][C:44]([CH3:48])([CH3:47])[N:43]1[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[O:39]>O1CCCC1>[OH:39][CH:38]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH3:25])[CH:20]=[C:19]2[CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH:40]([CH:56]([CH3:58])[CH3:57])[CH2:41][CH:42]1[CH2:46][O:45][C:44]([CH3:48])([CH3:47])[N:43]1[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50]
Reactant: COCCCc1cn(C)c2ccc(Br)cc12
Reactant: CC(C)C(C=O)CC1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: CCCC[Mg]CCCC
Agent: [Li]CCCC
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COCCCc1cn(C)c2ccc(C(O)C(CC3COC(C)(C)N3C(=O)OC(C)(C)C)C(C)C)cc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 12.51 ml of dibutylmagnesium (1M in heptane) in 70 ml of tetrahydrofuran is cooled to 0° C. and admixed with 7.80 ml of n-butyllithium (1M in hexane). After 10 minutes, the mixture is admixed with a solution of 3.60 g of 5-bromo-3-(3-methoxypropyl)-1-methyl-1H-indole (residue 3) and 0.14 ml of N-methylmorpholine in 15 ml of tetrahydrofuran and stirred at 0° C. for 30 minutes. The reaction mixture is cooled to −78° C. and admixed with the solution of 3.02 g of tert-butyl 4-(2-formyl-3-methylbutyl)-2,2-dimethyloxazolidine -3-carboxylate in 15 ml of tetrahydrofuran over 2 minutes. The resulting mixture is stirred at −78° C. for another 45 minutes and subsequently successively quenched with 1M ammonium chloride solution, diluted with water and extracted with tert-butyl methyl ether (3×). The combined organic phases are washed successively with 0.5N HCl (cold)(2×), water and brine, dried over sodium sulphate and filtered, and the filtrate is concentrated by evaporation. The title compound (diastereomer mixture) is obtained as a white foam from the residue by means of flash chromatography (SiO2 60F). Rf=0.21 (1:2 EtOAc-heptane). Rt=24.2/25.4 (gradient II).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[OH:16][N:17]1[C:21](=[O:22])[CH2:20][CH2:19][C:18]1=[O:23].[CH2:24]([C:52]([OH:54])=[O:53])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([C:49](O)=[O:50])([C:46]([OH:48])=[O:47])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH:44]=[CH2:45]>C(Cl)Cl.C1COCC1>[O:23]=[C:18]1[CH2:19][CH2:20][C:21](=[O:22])[N:17]1[O:16][C:49]([C:34]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH:44]=[CH2:45])([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:52]([OH:54])=[O:53])[C:46]([OH:48])=[O:47])=[O:50]
Reactant: O=C1CCC(=O)N1O
Reactant: C=CCCCCCCCCCC(CCCCCCCCCCC(=O)O)(C(=O)O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CCCCCCCCCCC(CCCCCCCCCCC(=O)O)(C(=O)O)C(=O)ON1C(=O)CCC1=O
Reaction time: 8 h
Yield: 33.4 %

Procedure:
DCC (187 mg, 0.908 mmol) in DCM (2 mL) was added to a solution of N-hydroxysuccinimide (99 mg, 0.862 mmol) and docos-21-ene-1,11,11-tricarboxylic acid (Intermediate 45: 400 mg, 0.908 mmol) in DCM (7 mL) and THF (0.7 mL). The reaction was stirred overnight before the solvent was evaporated. The residue was purified by HPLC (Sunfire C18 30×50 mm; 55-80% ACN/water+0.1% TFA) to yield the title compound (155 mg, 0.288 mmol, 32%): by LCMS Method E Rt=1.51 min, M+H 538.3; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.16-1.46 (m, 28H) 1.60-1.87 (m, 3H) 1.91-2.17 (m, 5H) 2.38 (t, J=7.03 Hz, 2H) 2.86 (br. s., 4H) 3.68 (dd, J=11.25, 7.34 Hz, 1H) 3.78 (dd, J=11.31, 5.20 Hz, 1H) 3.99-4.10 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[NH:14][C:15](=[O:26])[NH:16][C:17]1[S:18][CH:19]=[C:20]([CH2:22][C:23]([OH:25])=O)[N:21]=1)=[O:6].[CH3:31][S:32]([CH2:35][CH2:36][NH2:37])(=[O:34])=[O:33]>>[CH3:31][S:32]([CH2:35][CH2:36][NH:37][C:23](=[O:25])[CH2:22][C:20]1[N:21]=[C:17]([NH:16][C:15]([NH:14][C:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]=2[C:5](=[O:6])[C:4]2[CH:27]=[CH:28][CH:29]=[CH:30][C:3]=2[O:2][CH3:1])=[O:26])[S:18][CH:19]=1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)CCN
Reactant: COc1ccccc1C(=O)c1ccc(C)cc1NC(=O)Nc1nc(CC(=O)O)cs1
Product: COc1ccccc1C(=O)c1ccc(C)cc1NC(=O)Nc1nc(CC(=O)NCCS(C)(=O)=O)cs1
Yield: 68.2 %

Procedure:
N-(2-Methanesulfonyl-ethyl)-2-(2-{3-[2-(2-methoxy-benzoyl)-5-methyl-phenyl]-ureido}-thiazol-4-yl)-acetamide (181 mg, 68%) was prepared from (2-{3-[2-(2-methoxy-benzoyl)-5-methyl-phenyl]-ureido}-thiazol-4-yl)-acetic acid (213 mg, 0.5 mmol) and 2-methanesulfonyl-ethylamine (61 mg, 0.5 mmol) following the general procedure K.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:11]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([NH2:24])=[CH:13][CH:12]=1.C(N(CC)CC)C>C(O)CCC>[CH:11]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([NH:24][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1cccc2c1oc1ccccc12
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: O=[N+]([O-])c1cccnc1Nc1cccc2c1oc1ccccc12

Procedure:
2-chloro-3-nitropyridine (4.39 g, 27.7 mmol), dibenzo[b,d]furan-4-amine (5.58 g, 30.5 mmol), triethylamine (4.3 mL, 30.9 mmol), and butanol (90 mL) were mixed in a 250 mL round bottom flask. The reaction mixture was refluxed overnight under nitrogen. The solvent was evaporated, leaving an orange solid which was dried under vacuum. The solid was taken up in ethyl acetate, water was added and the layers were separated. The organic layer with washed with brine, dried over magnesium sulfate, filtered, and evaporated to a residue. The residue was purified on by column chromatography eluting with 10% ethyl acetate/hexanes followed by ethyl acetate (4.6 g, 54%).
Reaction SMILES: [CH:1]1[C:6]([CH2:7][N:8]2[CH2:9][CH2:10][NH:11]/[C:12]/2=[N:13]\[N+:14]([O-:16])=[O:15])=[CH:5][N:4]=[C:3]([Cl:17])[CH:2]=1.Br[CH2:19][CH:20]=[CH:21][CH2:22]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:17][C:3]1[CH:2]=[CH:1][C:6]([CH2:7][N:8]2[CH2:9][CH2:10][N:11]([CH2:19][CH:20]=[CH:21][CH2:22][N:11]3[CH2:10][CH2:9][N:8]([CH2:7][C:6]4[CH:1]=[CH:2][C:3]([Cl:17])=[N:4][CH:5]=4)[C:12]3=[N:13][N+:14]([O-:16])=[O:15])[C:12]2=[N:13][N+:14]([O-:16])=[O:15])=[CH:5][N:4]=1
Reactant: O=[N+]([O-])/N=C1\NCCN1Cc1ccc(Cl)nc1
Reactant: BrCC=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])N=C1N(CC=CCN2CCN(Cc3ccc(Cl)nc3)C2=N[N+](=O)[O-])CCN1Cc1ccc(Cl)nc1

Procedure:
Imidacloprid (3.37 g, 12 mmol), 1,4-dibromo-2-butene (1.60 g, 6 mmol), and potassium carbonate (1.83 g, 12 mmol) were mixed in 30 ml of acetonitrile, and the mixture was refluxed for 19 hours. After distilling off the solvent under reduced pressure, the residue was extracted with chloroform, and the chloroform layer was dried over magnesium sulfate. After distilling off the solvent, the residue was then subjected to silica gel column chromatography with a mixed solvent of ethyl acetate and ethanol (15:1 (v/v)) as the eluate. The crude product was purified by recrystallizing from ethanol. The yield of crystalline product was 0.22 g (7%), and the melting point was 199 to 202° C. The results of elementary analysis and NMR analysis are shown below.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:20])=[O:19])=[CH:16][C:3]1=2.[OH-].[Na+].[BH4-].[Na+].O>C(O)(=O)C>[OH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:20])=[O:19])=[CH:16][C:3]1=2
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc2c(c1)C(O)c1ccccc1CO2
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of 5.0 g. of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid in 16 ml. of 5% sodium hydroxide is added dropwise to a cold solution of 1.36 g. of sodium borohydride in 40 ml. of water. The reaction mixture is stirred at 0° C. for 4 hours, poured onto ice, and acidified with glacial acetic acid. The precipitate is filtered and washed with water to provide colorless crystals, m.p. 132°-133.5° C. of 6,11-dihydro-11-hydroxydibenz[b,e]oxepin-2-acetic acid.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]=1[C:20]([NH2:22])=[O:21].Cl[C:24]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:25]=1[C:26](OC)=[O:27].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N+:34]([C:31]1[CH:30]=[C:25]2[C:24](=[CH:33][CH:32]=1)[N:6]1[N:5]=[C:4]([C:7]3[CH:8]=[CH:9][C:10]([O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:11][CH:12]=3)[C:3]([C:20]([NH2:22])=[O:21])=[C:2]1[NH:1][C:26]2=[O:27])([O-:36])=[O:35]
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1[nH]c(=O)c1cc([N+](=O)[O-])ccc12
Temperature: 80 °C
Yield: 25.7 %

Procedure:
A mixture of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (220 mg, 0.75 mmol), methyl 2-chloro-5-nitrobenzoate (160 mg, 0.75 mmol) and K2CO3 (155 mg, 1.13 mmol) in DMF (10 mL) was heated to 80° C. for 16 hr under N2. The reaction was poured into water (30 ml), and extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure to a residue, which was purified by a silica gel column eluting with 10% to 50% EA in PE to afford 85 mg (27.3%) of 7-nitro-5-oxo-2-(4-phenoxyphenyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide as a yellow solid. MS (ESI, m/e) [M+1]+ 442.1.