Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=3)[C:10]([S:20][CH3:21])=[CH:9]2)=[N:6][CH:7]=1.Cl.[CH3:23][NH:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].CSC1C2C(=CC(C(N3C[C@@H]4C[C@H]3CN4C(OC(C)(C)C)=O)=O)=CC=2)N(C2N=CC(C3C=CC=CN=3)=CN=2)C=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:24]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH3:23])=[O:19])[CH:15]=3)[C:10]([S:20][CH3:21])=[CH:9]2)=[N:6][CH:7]=1
Reactant: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)O)ccc12
Reactant: CNCC(=O)OC
Agent: CSc1cn(-c2ncc(-c3ccccn3)cn2)c2cc(C(=O)N3C[C@@H]4C[C@H]3CN4C(=O)OC(C)(C)C)ccc12
Agent: Cl
Product: COC(=O)CN(C)C(=O)c1ccc2c(SC)cn(-c3ncc(Br)cn3)c2c1

Procedure:
Amide coupling of 1-(5-bromopyrimidin-2-yl)-3-(methylthio)-1H-indole-6-carboxylic acid (2.0 g, 5.49 mmol) with methyl 2-(methylamino)acetate hydrochloride (1.53 g, 10.9 mmol) analogously to the protocol 244c). White solid. Yield: 0.6 g (24% of theory)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](F)[C:9]=1[N+:15]([O-:17])=[O:16].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([Br:7])[C:9]=1[N+:15]([O-:17])=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1c(F)cccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=[N+]([O-])c1c(Br)cccc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Potassium carbonate (2.58 g, 18.73 mmol) was added to a solution of 1-bromo-3-fluoro-2-nitro-benzene (2.06 g, 9.36 mmol) and benzylamine (1.13 mL, 9.364 mmol) and the resulting suspension was stirred at room temperature for 18 hours. The reaction mixture was poured onto 500 mL of ice water and extracted four times with 100 mL ethyl acetate. The combined organic fractions were dried over sodium sulfate, and concentrated in vacuo to give an oil that was purified by recrystallization from 75 mL refluxing ethanol with 3 mL water. 1.83 g of benzyl-(3-bromo-2-nitro-phenyl)-amine was collected by filtration as fine red needles. MS: 308, 309 (M+H)+.
Reaction SMILES: Br[C:2]([CH3:8])([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[NH2:9][C:10]1[CH:11]=[C:12]([SH:16])[CH:13]=[CH:14][CH:15]=1.C(=O)(O)[O-].[Na+].O>CN(C=O)C>[NH2:9][C:10]1[CH:11]=[C:12]([S:16][C:2]([CH3:8])([CH3:7])[C:3]([O:5][CH3:6])=[O:4])[CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)C(C)(C)Br
Reactant: Nc1cccc(S)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)(C)Sc1cccc(N)c1
Reaction time: 8 h

Procedure:
At room temperature, 1.36 ml (10.5 mmol) of methyl 2-bromo-2-methylpropanoate were added slowly to a solution of 1.2 g (9.6 mmol) of 3-aminobenzenethiol and 1.046 g (12.5 mmol) of sodium bicarbonate in 6 ml of DMF, and the mixture was stirred overnight. After the reaction had ended, the reaction mixture was added to water. The reaction mixture was extracted three times with diethyl ether, and the combined organic phases were washed with saturated sodium chloride solution and dried over magnesium sulfate. After filtration, the solvent was removed to dryness under reduced pressure. This gave 1.45 g (6.4 mmol, 67% of theory) of a colorless solid.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[NH2:24][C:25]1[S:26][CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:29]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:24][C:25]4[S:26][CH:27]=[C:28]([C:30]5[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=5)[N:29]=4)=[O:2])([CH2:11][CH2:10]2)[CH2:9][CH2:8]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Nc1nc(-c2ccc(F)cc2)cs1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3nc(-c4ccc(F)cc4)cs3)(CC1)CC2
Yield: 65.5 %

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-amino-4-(4-fluorophenyl)thiazole (66.1 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-[4-(4-fluorophenyl)thiazol-2-yl]amino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (50.6 mg).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]([C@H:9]1[C:31](=[O:32])[N:11]2[CH:12]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])[C:13]([OH:17])([CH3:16])[CH2:14][S:15][C@H:10]12)=[N+:7]=[N-:8].CCN(CC)CC>C(Cl)Cl>[N:6]([C@H:9]1[C:31](=[O:32])[N:11]2[CH:12]([C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=3)=[O:19])[C:13]([O:17][S:2]([CH3:1])(=[O:4])=[O:3])([CH3:16])[CH2:14][S:15][C@H:10]12)=[N+:7]=[N-:8]
Reactant: CC1(O)CS[C@@H]2[C@@H](N=[N+]=[N-])C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(OS(C)(=O)=O)CS[C@@H]2[C@@H](N=[N+]=[N-])C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 97.3 %

Procedure:
A solution of CH3SO2Cl (34 μl, 0.44 mMol) in anhydrous CH2Cl2 (0.5 ml.) is added dropwise over 4 min. to an ice-cold, stirring solution of p-nitrobenzyl 7α-azido-3-hydroxy-3-methyl-cepham-4-carboxylate (135 mg., 0.34 mMol) and Et3N (71 μl, 0.51 mMol) in anhydrous CH2Cl2 (2 ml.). After stirring 15 more min. in the cold, the reaction mixture is diluted with cold CH2Cl2 (2 ml.), washed with ice-cold H2O (2 ml.), ice-cold 5% HCl (2 ml.), and ice-cold 5% NaHCO3 (2 ml.), dried over MgSO4, and filtered. Evaporation of the solvent in vacuo gives p-nitrobenzyl 7α-azido-3-methanesulfonyloxy-3-methyl-cepham-4-carboxylate (156 mg.) as a pale yellow oil: ir (CHCl3) 4.76, 5.62, 5.75, 6.57, 7.40, 8.47, and 11.1μ; nmr (CDCl3) δ2.10 (s, 3, CH3), 2.93 (s, 3, SO2CH3), 3.02 (d, l, J=14Hz, SCH), 3.87 (d, l, J=14Hz, SCH), 4.53 (d, l, J=1.2Hz, H7), 4.80 (s, l, H4), 4.97 (d, l, J=1.2Hz, H6), 5.35 (s, 2, CH2Ar), and 7.60, 8.28 (two d's 4, J=8.7Hz, ArH).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][N:38]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][N:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: N#Cc1ccc(Br)nc1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccc(C#N)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (200 mg, 0.42 mmol) in 1,4-dioxane (1.5 mL) was added 6-bromonicotinonitrile (123 mg, 0.67 mmol), Pd(PPh3)2Cl2 (30 mg, 0.042 mmol), and Cs2CO3 (1 mL, 2 M) were added. The vessel was sealed with a septum and placed into the microwave cavity. Microwave irradiation of 100 W was used, and the temperature being ramped from rt to 120° C. Once this temperature was reached, the reaction mixture was held at this temperature for 30 min. After the mixture was cooled to rt, the mixture was filtered. The filtrate was extracted with EtOAc (4×20 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated to give the crude product, which was purified by preparative TLC to give 6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinonitrile (120 mg, 62%). LC-MS Method 2 tR=1.33, m/z=398; 1H NMR (CDCl3): 1.13 (s, 3H), 1.19 (s, 3H), 1.58 (d, 3H), 2.22 (m, 2H), 2.27 (m, 2H), 2.40 (m, 1H), 2.89 (m, 1H), 3.49 (s, 1H), 5.73 (m, 1H), 7.11 (d, 2H), 7.28-7.38 (m, 5H), 7.80 (m, 3H), 8.00 (d, 1H), 8.93 (s, 1H).
Reaction SMILES: C([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=[O:8])(=O)C.C1(O)C=CC=CC=1.[Na].[O-]C1C=CC=CC=1.[Na+:29].C(=O)=O>>[C:7]([O-:9])(=[O:8])[C:6]1[C:5](=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:4].[Na+:29]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Agent: O=C=O
Agent: [Na+]
Agent: [Na]
Solvent: Oc1ccccc1
Product: O=C([O-])c1ccccc1O

Procedure:
Acetyl salicylic acid is commercially synthesized by Kolbe-Schmidt reaction which is a multi-step process. In this process, phenol is treated with a sodium base generating sodium phenoxide, which is then reacted with carbon dioxide under high temperature (125° C.) and pressure (100 atmosphere) to yield sodium salicylate, which on acidification yields salicylic acid. Salicylic acid is then acetylated with acetic anhydride to prepare acetyl salicylic acid. Existing process of the synthesis of acetyl salicylic acid is an acid catalyzed esterification reaction by the acetylation of the salicylic acid with acetic anhydride using conventional liquid acids, namely, conc. H2SO4 or conc. H3PO4 at the temperature of 80-90° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9][C:8]([C:11](=O)[CH2:12][C:13](=O)[CH:14]([F:16])[F:15])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[S:20]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1)(=[O:23])(=[O:22])[NH2:21]>>[Cl:1][C:2]1[C:10]2[S:9][C:8]([C:11]3[N:30]([C:27]4[CH:26]=[CH:25][C:24]([S:20]([NH2:21])(=[O:23])=[O:22])=[CH:29][CH:28]=4)[N:31]=[C:13]([CH:14]([F:16])[F:15])[CH:12]=3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CC(=O)C(F)F)c1nc2cccc(Cl)c2s1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)F)cc2-c2nc3cccc(Cl)c3s2)cc1

Procedure:
The procedure of Example 9 was repeated using 1-(7-chlorobenzothiazol-2-yl)-4,4-difluorobutane-1,3-dione and 4-sulfamoylphenylhydrazine hydrochloride as the starting materials to obtain 4-[5-(7-chlorobenzothiazol-2-yl)-3-difluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide. NMR(DMSO-d6) δ: 7.24 (1H, t, J=54.1 Hz), 7.56-7.68 (5H, m), 7.80 (2H, d, J=8.6 Hz), 7.91-7.97 (3H, m); mp 238-239° C. (ethanol)
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]>[Cu]>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)=[C:12]([N+:20]([O-:22])=[O:21])[CH:13]=1)(=[O:19])[CH3:18]
Reactant: COc1ccc(I)cc1
Reactant: CC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Agent: [Cu]
Product: COc1ccc(-c2ccc(C(C)=O)cc2[N+](=O)[O-])cc1
Temperature: 80 °C

Procedure:
A stirred mixture of 4-iodoanisole (174.5 g.), 4'-bromo-3'-nitroacetophenone (162.5 g.) and copper powder (144 g.) was heated at 80°C. for 5 hours and the temperature was then gradually raised during 4 hours to 110°C. The stirred mixture was maintained at 110°C. for a further period of 3 days. The reaction mixture was cooled to room temperature and extracted with methylene dichloride. The extract was filtered and the filtrate evaporated under reduced pressure to remove methylene dichloride. The residue was distilled in vacuo to give the product, b.p. 200° - 210°C./0.6 mm., which solidified on cooling. This product was recrystallized from methanol to give 4-acetyl-4'-methoxy-2-nitrobiphenyl, m.p. 127° - 129°C. (novel intermediate A).
Reaction SMILES: C([Mg]Cl)C.I[C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1.[O:30]=[C:31]1[CH2:40][CH2:39][CH2:38][C:37]2[CH:36]=[C:35]([C:41]#[N:42])[CH:34]=[CH:33][C:32]1=2>ClCCl>[OH:30][C:31]1([C:6]2[N:7]=[CH:8][N:9]([C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:10]=2)[CH2:40][CH2:39][CH2:38][C:37]2[CH:36]=[C:35]([C:41]#[N:42])[CH:34]=[CH:33][C:32]1=2
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: N#Cc1ccc2c(c1)CCCC2=O
Agent: CC[Mg]Cl
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CCCC2(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 0.75 h

Procedure:
12 mmol of ethylmagnesium chloride (3M in diethyl ether) are added to a solution of 10 mmol of 4-iodo-1-trityl-1H-imidazole [96797-15-8] in 40 ml of dichloromethane. The mixture is stirred for 45 minutes, and a solution of 10 mmol of 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [90401-84-6] in 15 ml of dichloromethane is added. The reaction mixture is stirred at room temperature overnight and quenched with saturated ammonium chloride solution. The phases are separated, and the aqueous phase is extracted with dichloromethane (3×). The combined organic phases are washed with brine, dried with sodium sulphate and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60F).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH2:13]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:28]1[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=1)[OH:27])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:13]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:28]1[CH:29]=[C:30]([CH:31]=[CH:32][CH:33]=1)[O:34][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[OH:27])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: Oc1cccc(C(O)CCCCCOCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: OC(CCCCCOCc1ccccc1)c1cccc(OCc2ccc3ccccc3n2)c1
Yield: 24.3 %

Procedure:
2-Chloromethyl quinoline (3.6 g) was refluxed with 3-(6-benzyloxy-1-hydroxyhexyl)phenol (4.2 g), powdered potassium carbonate (8 g) and potassium iodide (0.2 g) in dry acetone (150 ml) overnight (16 hrs.). The suspension was filtered, the filtrate was concentrated in vacuo and then taken up in ethyl acetate. This solution was washed with 5% NaOH solution, water and brine and then dried. All solvent was removed to obtain the crude product which was purified by chromatography (silica gel; 30% ethyl acetate in hexanes). The pure compound was dissolved in ether, and was precipitated as the hydrochloride salt with a dry ethereal solution of HCl. The pure salt was filtered, washed with cold water, and dried in vacuo to yield a tan powder (1.5 g), mp 86°-89° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]([CH3:19])[CH3:18])[CH:15]=2)[C:10]([CH:20]=[CH:21][C:22](O)=[O:23])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:27]=[C:28]([CH:36]=[CH:37][CH:38]=1)[C:29]([NH:31][NH:32][CH:33]([CH3:35])[CH3:34])=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[F:25][C:26]1[CH:27]=[C:28]([CH:36]=[CH:37][CH:38]=1)[C:29]([NH:31][N:32]([C:22](=[O:23])/[CH:21]=[CH:20]/[C:10]1[C:11]2[C:16](=[CH:15][C:14]([CH:17]([CH3:18])[CH3:19])=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH:9]=1)[CH:33]([CH3:35])[CH3:34])=[O:30]
Reactant: CC(C)c1ccc2c(C=CC(=O)O)cn(C(=O)OC(C)(C)C)c2c1
Reactant: CC(C)NNC(=O)c1cccc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1ccc2c(/C=C/C(=O)N(NC(=O)c3cccc(F)c3)C(C)C)cn(C(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing 3-(1-(tert-butoxycarbonyl)-6-isopropyl-1H-indol-3-yl)acrylic acid (183.0 mg, 0.56 mmol), 3-fluoro-N′-isopropylbenzohydrazide (163.5 mg, 0.83 mmol) and HATU (316.9 mg, 0.83 mmol) dissolved in DMF (3.0 ml), N,N-diisopropylethylamine (DIPEA)(0.14 ml, 0.83 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (33% EtOAc) for refinement, and dried so that white (E)-tert-butyl 3-(3-(2-(3-fluorobenzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-5-methyl-1H-indole-1-carboxylate was obtained (138.0 mg, 48.6%).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:26][CH:27]([F:29])[F:28])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:10]([CH3:17])=[N:11]2.CO.[OH-].[Li+]>O>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:30])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:17])[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)=[C:8]2[O:26][CH:27]([F:29])[F:28]
Reactant: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(Cl)cc3)c(OC(F)F)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc2c(Cl)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(Cl)cc1

Procedure:
A solution of [8-chloro-3-(4-chlorobenzyl)-4-difluoromethoxy-2-methylquinolin-5-yloxy]acetic acid methyl ester (0.10 g), methanol (6.0 mL), water (0.6 mL) and saturated aqueous lithium hydroxide solution (0.3 mL) was stirred at room temperature for 17 hours. The methanol was removed under reduced pressure and the pH of the residue adjusted to 4 by the addition of glacial acetic acid. The resulting precipitate was collected by filtration and washed with water. Purification of the solid by preparative reverse-phase HPLC using a gradient over 37 minutes of acetonitrile in water (20% to 95% of organic modifier) gave title compound as a cream solid, 0.020 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[C:22]([CH3:23])=[CH:21][N:20]=[C:19]1[CH2:24][N:25]1C(=O)C2=CC=CC=C2C1=O.NN>C(O)C>[N+:15]([C:13]1[CH:12]=[CH:11][C:10]2[N:18]3[C:22]([CH3:23])=[CH:21][N:20]=[C:19]3[CH2:24][N:25]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]=2[CH:14]=1)([O-:17])=[O:16]
Reactant: Cc1cnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Agent: NN
Solvent: CCO
Product: Cc1cnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 25, 2'-chloro-5-nitro-2-[5-methyl-2-(phthalimidomethyl)imidazol-1-yl]benzophenone in ethanol is heated with hydrazine to give 8-nitro-6-(o-chlorophenyl)-1-methyl-4H-imidazo[1,2-a][1,4]benzodiazepine
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].O>CN(C)C=O>[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: COC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCCn1ccnc1
Reaction time: 18 h
Yield: 81.5 %

Procedure:
Add sodium hydride (0.212 g; 1.2 equiv; 5.29 mmoles) to a solution of 1H-imidazole (0.30 g; 1.0 equiv; 4.41 mmoles) and methyl 5-bromopentanoate (1.03 g; 1.2 equiv; 5.29 mmoles) in dimethylformamide (20 mL). Stir the mixture for 18 hours then add water (15 mL). Extract the mixture with dichloromethane and wash with brine (20 mL). Dry the organic phase over sodium sulfate, filter, and concentrate to give the crude product, which is purified by column chromatography (0 to 10% methanol in dichloromethane) to afford methyl 5-imidazol-1-ylpentanoate (0.655 g; 82%) as a yellow oil: MS (m/z): 183(M+1).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[C:9]3[C:5]([CH2:6][C:7](=O)[NH:8]3)=[CH:4][C:3]=2[O:2]1.[N+](C1C=C2OCOC2=CC=1CC(OC)=O)([O-])=O.[N+](C1OC2C(=C(CC(OC)=O)C=CC=2)O1)([O-])=O.C1OC2C(=C3C(=CC=2)NC(=O)C3)O1.C1OC2C(=CC=C3C=2NC(=O)C3)O1>>[CH2:1]1[O:12][C:11]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][C:3]=2[O:2]1
Reactant: O=C1Cc2cc3c(cc2N1)OCO3
Agent: COC(=O)Cc1cc2c(cc1[N+](=O)[O-])OCO2
Agent: COC(=O)Cc1cccc2c1OC([N+](=O)[O-])O2
Agent: O=C1Cc2c(ccc3c2OCO3)N1
Product: c1cc2cc3c(cc2[nH]1)OCO3

Procedure:
5,6-Methylenedioxyoxindole can be prepared via the reduction of methyl 2-nitro-4,5-methylenedioxyphenylacetate according to the procedure of McEvoy et al., J. Org. Chem., 38, 3350 (1973). By a similar procedure, starting with the appropriate methyl 2-nitromethylenedioxyphenylacetate, 4,5-methylenedioxyoxindole and 6,7-methylenedioxyoxindole are prepared.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:23])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH:32]1[CH2:34][CH2:33]1.O>CN(C)C=O>[CH:32]1([CH2:31][N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[CH:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]3=[O:23])[CH2:5][CH2:6]2)[CH2:34][CH2:33]1
Reactant: O=C1Nc2ccccc2C(c2ccccc2)N1C1CCNCC1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2ccccc2C(c2ccccc2)N1C1CCN(CC2CC2)CC1
Temperature: 50 °C
Reaction time: 5 h
Yield: 98.5 %

Procedure:
To a solution of 200 mg (0.65 mmol) of 3-(piperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone in 5 ml of N,N-dimethylformamide (DMF), 270 mg (1.95 mmol) of potassium carbonate and 176 mg (1.30 mmol) of bromomethylcyclopropane were added at room temperature subsequently and stirred at about 50° C. for 5 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to afford a residue, which was purified by silica gel column chromatography (chloroform—10% methanol/chloroform) to give 231 mg (0.64 mmol) of the title compound as colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[N:9]=1.S(=O)(=O)(O)O.[CH2:34](O)[CH3:35]>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:34][CH3:35])=[O:25])=[CH:27][CH:28]=2)[N:9]=1
Reactant: O=C(O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1

Procedure:
10 g of 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid (Example 5) and 0.5 ml of sulfuric acid are boiled under reflux for 20 h in 200 ml of ethanol. The crystals precipitating on cooling are crystallized from isopropanol/water. After drying, ethyl 4-[3,5-bis(2-hydroxy-phenyl)-[1,2,4]triazol-1-yl]benzoate is obtained as colorless crystals of m.p. 148-149° C.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:5](=[O:16])[O:6][C:7]2[C:12]([C:13]=1[CH3:14])=[CH:11][C:10]([OH:15])=[CH:9][CH:8]=2.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C=O)C.O>[OH:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[O:6][C:5](=[O:16])[C:4]([CH2:3][CH2:2][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[C:13]2[CH3:14]
Reactant: Cc1c(CCBr)c(=O)oc2ccc(O)cc12
Reactant: C1CCNC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CCN2CCCC2)c(=O)oc2ccc(O)cc12
Temperature: 25 °C
Yield: 250.9 %

Procedure:
A solution of Example 41A (0.20 g, 0.70 mmol) and pyrrolidine (0.50 mL, 6.0 mmol) in DMF (2 mL) was heated to 75° C. for 16 hours, cooled to ambient temperature, diluted with water (20 mL) and extracted with ethyl acetate (3×50 mL). The combined ethyl acetate was dried (MgSO4), filtered, concentrated under reduced pressure and chromatographed on silica with 10% methanol in dichloromethane to give the titled compound (0.48 g, 25%). MS (DCI) m/z 274 (M+H)+;