Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[OH:11])=[CH:5][CH:4]=1)[CH3:2].[C:20](#[N:24])[CH2:21][C:22]#[N:23].C(NCC)C.O>CN(C=O)C.C(OCC)(=O)C>[NH2:24][C:20]1[O:11][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[C:21]=1[C:22]#[N:23]
Reactant: N#CCC#N
Reactant: CCc1ccc(C(=O)C(O)c2ccccc2F)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1ccc(-c2c(-c3ccccc3F)oc(N)c2C#N)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Put 50 g (0.19 mol) 1-(4-ethylphenyl)-2-(2-fluorophenyl)-2-hydroxyethanone and 17 g (0.25 mol) malononitrile in 93 ml DMF. After stirring for five minutes, add 17 ml (12 g, 0.12 mol) diethylamine, cooling with ice. Stir the reaction mixture for 1 h with ice cooling. Then leave to warm to room temperature and stir for 4 h at this temperature. After adding 500 ml water and stirring for 30 min, decant the aqueous phase. Add 500 ml water again and decant again, obtaining an oily residue, which is dissolved in ethyl acetate, dried over sodium sulphate and filtered. Concentrate the filtrate by vacuum evaporation. According to DC analysis (solvent: cyclohexane/ethyl acetate 4:1), the residue still contains 1-(4-ethylphenyl)-2-(2-fluorophenyl)-2-hydroxyethanone. Therefore, the residue is again reacted in 90 ml DMF with 5.5 g (0.08 mol) malononitrile and 10 ml (7 g, 0.10 mol) diethylamine in accordance with the above procedure. Add the reaction mixture to 500 ml ethyl acetate and wash three times with 300 ml water each time and once with 300 ml satd. sodium chloride solution. Dry the organic phase over sodium sulphate, and filter. Concentrate the filtrate by vacuum evaporation. Purify the residue by flash chromatography on silica gel (solvent: cyclohexane/ethyl acetate 3:1). 36 g (61% of theor.) of the title compound is obtained, and is reacted without further characterization.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]23[CH2:16][CH:15]2[C:14](=[O:17])[NH:13][C:12]3=[O:18])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH2:21](Br)[CH:22]=[CH2:23]>CN(C)C=O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]23[CH2:16][CH:15]2[C:14](=[O:17])[N:13]([CH2:23][CH:22]=[CH2:21])[C:12]3=[O:18])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: C=CCBr
Reactant: CC(=O)Nc1ccc(C23CC2C(=O)NC3=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1C(=O)C2CC2(c2ccc(NC(C)=O)cc2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.2 g of 1-(4-acetylaminophenyl)-3-azabicyclo[3.1.0]hexane-2,4dione are dissolved in 25 ml of dimethylformamide and to this solution are added 180 mg of sodium hydride under nitrogen. The mixture is stirred for 1 hour at room temperature. The clear, pale yellow solution is cooled in an ice-water bath and then a solution of 0.65 ml of allyl bromide in 5 ml of dimethylformamide is added dropwise. The reaction mixture is stirred overnight and then the solvent is stripped off. The residue is partitioned twice between ethyl acetate and water. The organic phases are dried over magnesium sulfate, filtered and concentrated, and the residue is crystallised from ethyl acetate/ether/petroleum ether. The title compound is obtained in the form of white crystals with a melting melting point of 113°-116° C. and with Rf=0.33 on thin-layer silica gel plates in the system methylene chloride/methanol (10:1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][NH:9][NH2:10]>COCCO>[CH3:8][N:9]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[NH2:10]
Reactant: Clc1ccccn1
Reactant: CNN
Solvent: COCCO
Product: CN(N)c1ccccn1

Procedure:
is obtained by boiling an admixture of 2-chloropyridine and methylhydrazine in 2-methoxyethanol under reflux.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:6][C@@H:5]([C@@H:7]([OH:21])[C@@H:8]2[O:12][C:11]([CH3:14])([CH3:13])[O:10][C@@H:9]2[C@@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[CH2:4][O:3]1.N1C(C)=CC=CC=1C.[Si:31](OS(C(F)(F)F)(=O)=O)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].CCOC(C)=O>C(Cl)Cl.CCCCCC>[Si:31]([O:21][C@H:7]([C@H:5]1[CH2:4][O:3][C:2]([CH3:22])([CH3:1])[O:6]1)[C@@H:8]1[O:12][C:11]([CH3:13])([CH3:14])[O:10][C@@H:9]1[C@@H:15]([OH:20])[C:16]([F:18])([F:17])[F:19])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC1(C)O[C@@H]([C@H](O)[C@H]2COC(C)(C)O2)[C@@H]([C@@H](O)C(F)(F)F)O1
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Solvent: CCCCCC
Product: CC1(C)O[C@@H]([C@H](O[Si](C)(C)C(C)(C)C)[C@H]2COC(C)(C)O2)[C@@H]([C@@H](O)C(F)(F)F)O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
In a 100 mL 2 neck round bottom flask, (R)-1-((4R,5S)-5-((R)—((R)-2,2-dimethyl-1,3-dioxolan-4-yl)(hydroxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2,2-trifluoroethanol (1 g, 3.03 mmol) and 2,6-lutidine (1 g, 9.09 mmol, commercially available from Sigma Aldrich, India) was taken up in dry DCM (50 mL) at 0° C. under a nitrogen atmosphere. TBSOTf (2.4 g, 9.09 mmol, commercially available from Sigma Aldrich, India) was added to the above reaction mixture at the same temperature under a nitrogen atmosphere. The reaction mixture was stirred for 30 min at 0° C. and then the temperature was slowly raised to rt and the mixture stirred at rt for 3 h. Upon completion of the reaction (TLC, 20% EtOAc in hexane Rf 0.5), the reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), and were then concentrated under reduced pressure. The residue obtained was purified by silica gel (60-120 mesh) column chromatography (gradient elution 10-15% EtOAc-hexanes) to give (R)-1-((4R,5R)-5-((R)-((tert-butyldimethylsilyl)oxy)((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2,2-trifluoroethanol as a pale yellow oil (0.7 g, 50%): 1H NMR (400 MHz, CDCl3) δ 4.52-4.45 (m, 2H), 4.29-4.25 (m, 1H), 4.22-4.19 (m, 1H), 4.04-3.93 (m, 2H), 3.78-3.74 (t, J=8.0 Hz, 1H), 2.70 (d, J=11.2 Hz, 1H), 1.55 (s, 3H), 1.40 (d, J=9.6 Hz, 3H), 0.86 (s, 9H), 0.11 (d, J=3.2 Hz, 6H), 5 H were obscured.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH:5]=[CH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[CH2:18]([O:20][C:21](=[O:26])[CH2:22][C:23](=[NH:25])[NH2:24])[CH3:19]>C(O)C>[CH2:18]([O:20][C:21]([C:22]1[CH:5]([C:4]2[CH:15]=[CH:16][CH:17]=[C:2]([Cl:1])[CH:3]=2)[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:24][C:23]=1[NH2:25])=[O:26])[CH3:19]
Reactant: O=C(C=Cc1cccc(Cl)c1)c1ccccc1
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(c2ccccc2)=CC1c1cccc(Cl)c1
Yield: 73 %

Procedure:
Upon heating a solution of 24.3 g of 3-chlorobenzylideneacetophenone and 13.0 g of amidinoacetic acid ethyl ester in 250 ml of ethanol for 4 hours, 2-amino-6-phenyl-4-(3-chlorophenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester of melting point 161°C is obtained. Yield: 73 percent of theory.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.[F:10][C:11]([F:22])([F:21])[C:12]([C:17]([F:20])([F:19])[F:18])([CH3:16])[C:13](F)=[O:14].C(N(CC)CC)C>C(#N)C>[F:10][C:11]([F:21])([F:22])[C:12]([C:17]([F:18])([F:20])[F:19])([CH3:16])[C:13]([O:9][CH2:8][CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:14]
Reactant: CC(C(=O)F)(C(F)(F)F)C(F)(F)F
Reactant: OCCN1CCOCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C(=O)OCCN1CCOCC1)(C(F)(F)F)C(F)(F)F
Temperature: 60 °C
Reaction time: 20 h
Yield: 69.9 %

Procedure:
A mixture of 26.2 g of 2-morpholinoethanol, 21.2 g of 2,2-bis(trifluoromethyl)propionic acid fluoride, 20.2 g of triethylamine, and 100 g of acetonitrile was stirred at 60° C. for 20 hours. This was followed by conventional aqueous work-up and purification by silica gel column chromatography. There was obtained 22.6 g of 2-morpholinoethyl 2,2-bis(trifluoromethyl)propionate (yield 70%).
Reaction SMILES: Cl(O)(=O)(=O)=O.[OH2:6].O.O.O.[N+]([O-])([O-])=O.[Tl+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:31])=[CH:26][CH:25]=1>C(Cl)Cl.COCCOC>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([C:32]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:6])=[O:31])=[CH:28][CH:29]=1
Reactant: O=C(Cc1ccccc1)c1ccc(Br)cc1
Reactant: O
Agent: O=[N+]([O-])[O-]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [Tl+3]
Solvent: COCCOC
Solvent: ClCCl
Product: O=C(C(=O)c1ccc(Br)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
Perchloric acid (250 mL), water (250 mL), ethylene glycol dimethyl ether (glyme) (500 mL), thallium (III) nitrate trihydrate (222.0 g, 0.5 mol) and 4-bromodeoxybenzoin (68.75 g, 0.25 mol) are charged to a 2-liter round bottom 3-necked flask equipped with a reflux condenser and a mechanical stirrer. The reaction mixture is heated under nitrogen to reflux for 6 hours. After cooling to ambient temperature, methylene chloride (500 mL) is added. The resulting bilayer is decanted off the precipitated Tl(I) salts formed. The layers are separated and the organic layer is washed with water, saturated aqueous NaHCO3 and brine, followed by recrystallization of the resulting solid from 2-propanol gives the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.OS(O)(=O)=O.[OH-].[Na+].[CH3:23]O>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([O:13][CH3:23])=[O:12])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1ccc(-c2ccncc2)cc1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
To a solution of 4-[pyridin-4-yl]-benzoic acid (2.0 g, 10 mmol) (reference example 11a) in methanol (30 mL) is added conc. H2SO4 (4 mL). The resulting solution is warmed to 60° C. and stirred at this temperature for 2.5 hours. The reaction mixture is then allowed to cool to room temperature then poured into ice. The pH of the resulting solution is adjusted to 7 using a 10 M solution of NaOH. The product is then extracted into ethyl acetate. This solution is washed with brine, dried over MgSO4 and concentrated to give 2.1 g of the title compound as a white solid. 1H NMR (CDCl3) d 3.94 (s, 3H), 7.50 (d, J=5 Hz, 2H), 7.69 (d, J=8 Hz, 2H), 8.13 (d, J=5 Hz, 2H) 8.68 (d, J=5 Hz, 2H). MS (EI) m/z 213 (M)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C:15]2[CH:31]=[CH:30][C:18]([O:19]S(C(F)(F)C(OC)=O)(=O)=O)=[CH:17][CH:16]=2)[C:10]=3[C:32]([F:35])([F:34])[F:33])[CH2:3][CH2:2]1.CO.C[O-].[Na+].[Cl-].[NH4+]>CO>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C:15]2[CH:31]=[CH:30][C:18]([OH:19])=[CH:17][CH:16]=2)[C:10]=3[C:32]([F:34])([F:35])[F:33])[CH2:3][CH2:2]1
Reactant: COC(=O)C(F)(F)S(=O)(=O)Oc1ccc(-n2nc3cc(OCC4CC4)ccc3c2C(F)(F)F)cc1
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Oc1ccc(-n2nc3cc(OCC4CC4)ccc3c2C(F)(F)F)cc1
Reaction time: 3 h
Yield: 73.3 %

Procedure:
To a solution of methyl ({4-[6-(cyclopropylmethoxy)-3-(trifluoromethyl)-2H-indazol-2-yl]phenoxy}sulfonyl)(difluoro)acetate (365 mg) in methanol (4 mL) was added dropwise 27% sodium methoxide methanol solution (1 mL) at room temperature, and the mixture was stirred for 3 hr. The reaction mixture was neutralized with saturated aqueous ammonium chloride solution, and extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a colorless powder (179 mg).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=C[CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=2)[N:5]([CH3:18])[C:4](=[O:19])[C:3]=1[C:20](=[O:27])[CH2:21][CH2:22][C:23]([O:25]C)=[O:24].C1(B(O)O)C=CC=CC=1.OC1C2C(=NC=C(I)C=2)[N:41](C)C(=O)C=1C(=O)CCC(O)=O.C([Sn](CCCC)(CCCC)C1C=CC=CC=1)CCC.OC1C2C(=NC=C(I)C=2)N(C)C(=O)C=1C(=O)CCC(OC)=O>[Pd]>[OH:1][C:2]1[C:11]2[C:6](=[N:41][CH:8]=[C:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:10]=2)[N:5]([CH3:18])[C:4](=[O:19])[C:3]=1[C:20](=[O:27])[CH2:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: Cn1c(=O)c(C(=O)CCC(=O)O)c(O)c2cc(I)cnc21
Reactant: COC(=O)CCC(=O)c1c(O)c2cc(-c3ccccc3)ccc2n(C)c1=O
Agent: [Pd]
Agent: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: COC(=O)CCC(=O)c1c(O)c2cc(I)cnc2n(C)c1=O
Product: Cn1c(=O)c(C(=O)CCC(=O)O)c(O)c2cc(-c3ccccc3)cnc21

Procedure:
Methyl 4-(4-hydroxy-1-methyl-2-oxo-6-phenyl-1,2-dihydroquinolin-3-yl)-4-oxobutanoate. The title compound is prepared by Palladium mediated Suzuki cross coupling reaction of phenyl boronic acid and methyl 4-(4-hydroxy-6-iodo-1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)-4-oxobutanoate (Method 4) according to the procedure set forth in Miyaura, N.; Suzuki, A. Chem. Rev., 95, 2457-83 (1995). Alternatively, the title compound is prepared by Palladium mediated Stille cross coupling reaction of tributyl(phenyl)stannane and methyl 4-(4-hydroxy-6-iodo-1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)-4-oxobutanoate according to the procedure set forth in Stille, J. K. Angew. Chem. Int. Ed. Engl., 25, 508-24 (1986).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH3:6][C:7]1([CH3:18])[CH2:13][CH2:12][CH2:11][NH:10][C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]1=2.C([O-])(O)=O.[Na+]>OS(O)(=O)=O>[CH3:6][C:7]1([CH3:18])[CH2:13][CH2:12][CH2:11][NH:10][C:9]2[CH:14]=[C:15]([N+:1]([O-:4])=[O:2])[CH:16]=[CH:17][C:8]1=2
Reactant: O=[N+]([O-])[O-]
Reactant: CC1(C)CCCNc2ccccc21
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC1(C)CCCNc2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86.8 %

Procedure:
At 0° C., KNO3 (0.76 g, 7.54 mmol) was added portionwise to a solution of 5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine (1.1 g, 6.28 mmol) in H2SO4 (15 mL). After stirring 15 min at this temperature, the mixture was poured into ice water, basified with sat. NaHCO3 to pH 8 and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give crude 5,5-dimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (1.2 g), which was used directly in the next step without further purification.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[N:10]1([C:15]2[CH:29]=[CH:28][C:18]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]3)=[O:20])=[CH:17][CH:16]=2)[CH:14]=[CH:13][N:12]=[CH:11]1>>[N:10]1([C:15]2[CH:16]=[CH:17][C:18]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([NH:27][C:1]([C:2]4[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=4)=[O:9])[CH2:23][CH2:22]3)=[O:20])=[CH:28][CH:29]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: O=C(O)c1cccnc1
Reactant: NC1CCN(C(=O)c2ccc(-n3ccnc3)cc2)CC1
Product: O=C(NC1CCN(C(=O)c2ccc(-n3ccnc3)cc2)CC1)c1cccnc1

Procedure:
In a manner similar to that described in Example 4, nicotinic acid and 1-[4-(1H-imidazol-1-yl)benzoyl]-4-piperidinamine are converted to the title compound.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([NH2:15])[CH:14]=1)[C:9]([OH:11])=[O:10].[CH3:16]O>>[NH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([NH2:15])[CH:14]=1)[C:9]([O:11][CH3:16])=[O:10]
Reactant: Nc1cc(N)cc(C(=O)O)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(N)cc(N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
Thionyl chloride (3.7 g) was added dropwise under ice cooling to a solution of 5.0 g (33 mmol) of 3,5-diaminobenzoic acid in 250 ml of methanol, followed by stirring at room temperature for 2 hours and then stirring under heating and reflux for additional 6 hours. After the solvent was distilled out under reduced pressure, the residue was neutralized with aqueous ammonia and then extracted with methylene chloride. The extract was dried over sodium sulfate and then dried up under reduced pressure, whereby 3.3 g of white powder were obtained (yield: 60%).
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20]CC)=[O:19].[C:23](=O)([O-])[O-].[K+].[K+].CI.O>CC(C)=O>[CH3:23][O:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([OH:20])=[O:19]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c(C)nc2cc(-c3ccccc3)nn2c1O
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CC(C)=O
Product: COc1c(C(=O)O)c(C)nc2cc(-c3ccccc3)nn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.8 %

Procedure:
The ethyl 7-hydroxy-5-methyl-2-phenylpyrazolo[1.5-a]pyrimidine-6-carboxylate (297 mg) obtained above was suspended in acetone (5 ml), and potassium carbonate (138 mg) was added thereto and stirred for 30 minutes at room temperature. Methyl iodide (1.0 ml) was added to the mixture which was then refluxed for 2 hours. The reaction mixture was cooled to room temperature, and water was added to the reaction mixture which was extracted with chloroform, and the organic phase was washed with a saturated saline solution and dried over sodium sulfate anhydrous. The product was concentrated under reduced pressure, and the resulting crystals were dissolved in ethanol (5 ml). 5 N Sodium hydroxide solution (1 ml) was added thereto and stirred for 1 hour at 50° C. The reaction mixture was cooled to room temperature, and water was added to the mixture which was then washed with ethyl acetate. 2 N Hydrochloric acid was added to the aqueous phase until it became acidic, and precipitated crystals were collected by filtration and washed with water and n-hexane. The crystals were dried under reduced pressure to give the title compound (121 mg, Y.:45%) as white crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][N:20]=[C:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=3)[N:18]=2)=[CH:13][CH:12]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.O[N:51]1[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=2[N:53]=[N:52]1>ClCCl>[N:51]1([O:27][C:26](=[O:28])[C:25]2[CH:24]=[CH:23][C:22]([C:19]3[N:18]=[C:17]([C:14]4[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:12][CH:13]=4)[O:21][N:20]=3)=[CH:30][CH:29]=2)[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=2[N:53]=[N:52]1
Reactant: COCCCCCCCOc1ccc(-c2nc(-c3ccc(C(=O)O)cc3)no2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCCCCCOc1ccc(-c2nc(-c3ccc(C(=O)On4nnc5ccccc54)cc3)no2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a mixture of 4-[5-[4-(7-methoxy-n-heptyloxy)phenyl]-1,2,4-oxadiazol-3-yl]benzoic acid (2.0 g) and triethylamine (1.1 g) in dichloromethane (60 ml) was added 3-(3-dimethylaminopropyl)-1-ethylcarbodimide hydrochloride (1.4 g) and 1-hydroxybenzotriazole (0.8 g). The mixture was stirred at room temperature overnight. The reaction mixture was washed with water, brine and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure, and the residue was triturated with isopropyl ether. The precipitates were collected by filtration, washed with isopropyl ether and dried to give 4-[5-(4-(7-methoxy-n-heptyloxy)phenyl]-1,2,4-oxadiazol-3-yl]benzoic acid benzotriazol-1-yl ester (2.1 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C-:12]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13]1)=O)C.[CH-:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.[Fe+2:24]>CCOCC>[OH:9][CH2:10][C-:12]1[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13]1.[CH-:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.[Fe+2:24]
Reactant: CCOC(=O)[c-]1ccc(C=O)c1
Agent: [Fe+2]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: OCc1cc[c-](CO)c1
Reaction time: 4.5 h
Yield: 72.6 %

Procedure:
To a stirring suspension of 60 mg (15.7 mmol) of lithium aluminum hydride in 30 ml of ether was added dropwise to a solution of 150 mg (0.56 mmol) of 1-ethoxycarbonyl-3-formylferrocene in ether (30 ml). Stirring was continued for 4.5 hours at room temperature. The mixture was then quenched with saturated aqueous solution of NH4Cl, and 30 ml of ether was added to the resulting solution. After separation of the organic and aqueous layers, the latter was extracted twice with ether and the combined organic solutions were then washed with water and dried over Na2SO4. Evaporation of the solvent yielded 100 mg (77.5%) of yellow crystals. Selected NMR data 1H (acetone-d6, 22° C.): δ4.11 (s, 5H,C5H5), 4.13 (d, 2H, 4.5-H), 4.25 (t,1H, 2-H), 429 (s, 4H, CH2)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([O-])=[O:25])=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Li+].[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.C(N(CC)CC)C.[N:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[CH2:61][NH2:62]>CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:10][CH2:11][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([NH:62][CH2:61][C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][N:55]=4)=[O:25])=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:14]1
Reactant: NCc1ccccn1
Reactant: O=C([O-])c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccn1)c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Reaction time: 0.25 h
Yield: 49.3 %

Procedure:
Lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (0.060 g, 0.17 mmol) was dissolved in dry DMF (1.7 mL), and then TSTU (0.064 g, 0.21 mmol) was added followed by triethylamine (0.059 mL, 0.43 mmol). The reaction was stirred for 15 min then 2-picolylamine (0.019 mL, 0.19 mmol) was added. The reaction was stirred at room temperature under argon over night. The crude product was purified by preparative LC. The fractions were combined and the acetonitrile was evaporated. DCM was added and the layers separated. The aq phase was extracted with DCM (3×). The combined organic phases were dried (Na2SO4), filtered and evaporated to give 37 mg (49%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][NH:8][S:9]([NH:12][C:13](=O)OC(C)(C)C)(=[O:11])=[O:10])([O-:3])=[O:2].[C:23]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][NH:8][S:9]([NH:12][CH2:13][CH3:23])(=[O:11])=[O:10])([O-:3])=[O:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCc1cccc([N+](=O)[O-])c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CCO
Solvent: C1CCOC1
Product: CCNS(=O)(=O)NCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude tert-butyl N-(3-nitrobenzylsulfamoyl)carbamate, triphenylphosphine (2 g) and diisopropyl azodicarboxylate (DIAD, 1.6 g) were dissolved in THF (20 mL) and ethanol (0.47 ml). The solution was stirred at ambient temperature overnight. The reaction solution was evaporated to dryness. The residue was dissolved in methanol (10 mL) and treated with 4.0 M HCl in dioxane (10 mL). It was stirred at rt overnight and then evaporated. The residue was diluted with ethyl acetate (100 mL) and washed with NaHCO3 aq. (2×100 mL). The organic solution was evaporated and purified by flash column chromatography (EtOAc/hexane=1/2, 1/1) to give N-(3-nitrobenzyl)-N′-ethylsulfamide. 1H NMR (DMSO-d6): δ 1.02 (t, J=7.2 Hz, 3H), 2.82 (p, J=6.9 Hz, 2H), 4.14 (d, J=6.6 Hz, 2H), 6.93 (t, J=5.4 Hz, 1H), 7.54 (t, J=6.3 Hz, 1H), 7.61 (t, J=7.8 Hz, 1H), 7.77 (d, J=7.2 Hz, 1H), 8.10 (d, J=8.1 Hz, 1H), 8.20 (s, 1H); LCMS: purity: 1.2 g, 88.4%; MS (m/e): 260.16 (MH+).