Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([CH2:16][CH2:17][CH2:18]Cl)[C:12](OC)=[O:13]>C(O)C>[NH2:2][N:3]1[CH2:18][CH2:17][CH2:16][CH:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[Br:4])[C:12]1=[O:13]
Reactant: COC(=O)C(CCCCl)c1ccccc1Br
Reactant: NN
Solvent: CCO
Solvent: O
Product: NN1CCCC(c2ccccc2Br)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of methyl 2-bromophenylacetate (2.0 g) in DMF (5 mL) was added to a suspension of sodium hydride (containing mineral oil at 40%, 384 mg) in DMF (20 mL) under ice-cooling. The reaction solution was stirred for 10 minutes, further stirred at room temperature for 30 minutes and then ice-cooled again. A solution of 1-chloro-3-iodopropane (1.96 g) in DMF (5 mL) was added to the reaction mixture, and the reaction solution was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The resulting organic layer washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain a crude product of methyl 2-(2-bromophenyl)-5-chloropentanoate. Hydrazine monohydrate (4 mL) was added to a solution of the resulting crude methyl 2-(2-bromophenyl)-5-chloropentanoate (2.895 g) in ethanol (20 mL), and the reaction solution was stirred at room temperature for three hours. Hydrazine monohydrate (8 mL) was further added to the reaction solution, and the reaction solution was stirred at room temperature for two days. The reaction solution was concentrated under reduced pressure. Saturated sodium bicarbonate water and ethyl acetate and were added to the residue, and the organic layer was separated. The resulting organic layer washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 1.504 g of the crude purified title compound. The property value of the compound is as follows.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[C:6]=1[CH2:25][CH3:26].COC(=O)CC1C2C(=NC=CC=2)NC=1CC.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.FC(F)(F)C1C=CC(CBr)=CC=1>CN(C=O)C.O>[CH2:25]([C:6]1[N:7]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=2)[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:13]2[C:5]=1[CH2:4][C:3]([OH:27])=[O:2])[CH3:26]
Reactant: CCc1c(CC(=O)OC)c2cccnc2n1Cc1ccc(C(F)(F)F)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: CCc1[nH]c2ncccc2c1CC(=O)OC
Agent: FC(F)(F)c1ccc(CBr)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(CC(=O)O)c2cccnc2n1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
[2-Ethyl-1-(4-trifluoromethyl-benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester: To an ice-cooled stirring solution of (2-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (80 mg, 0.37 mmol) in DMF (1 ml) is added BEMP (171 μl, 0.59 mmol). The solution is stirred at room temperature for 40 minutes and then re-cooled. 4-(Trifluoromethyl)benzyl bromide (91 μl, 0.59 mmol) is added and stirring continues while the reaction mixture gradually warmed up to room temperature overnight. The resulting mixture is poured into water (30 ml) and extracted with 1:1 EtOAc/ether. The organic layer is washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue is loaded on a pre-packed Isolute™ silica column and eluted with DCM to yield the titled compound as a pale yellow oil. (MH+377)
Reaction SMILES: [C:1]([C:5]([CH:7]=[O:8])=[O:6])([CH3:4])([CH3:3])[CH3:2].[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[O:15])=[CH:12][CH:11]=1>C1C=CC=CC=1>[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH:16][CH:7]([OH:8])[C:5](=[O:6])[C:1]([CH3:4])([CH3:3])[CH3:2])=[O:15])=[CH:12][CH:11]=1
Reactant: NC(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)C(=O)C=O
Solvent: c1ccccc1
Product: CC(C)(C)C(=O)C(O)NC(=O)c1ccc(Cl)cc1
Yield: 54 %

Procedure:
14 g (0.123 mol) of freshly distilled tert.-butylglyoxal were dissolved in 150 ml of absolute benzene. 19.1 g (0.123 mol) of p-chlorobenzamide were added and the mixture was heated for 15 hours under reflux. On cooling, the reaction product crystallised out. 16.1 g (54% of theory) of 1-(p-chlorobenzamido)-3,3-dimethyl-1-hydroxy-butan-2-one of melting point 130° C. were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:14][CH2:15][C:16](=O)[CH2:17][CH3:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:15]([C:16]1([CH2:17][CH3:18])[NH:6][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=2[O:1]1)[CH3:14]
Reactant: NC(=O)c1ccc([N+](=O)[O-])cc1O
Reactant: CCC(=O)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCC1(CC)NC(=O)c2ccc([N+](=O)[O-])cc2O1

Procedure:
A suspension of the compound obtained in (1) described above (5 g), 3-pentanone (6.6 g) and p-toluenesulfonic acid monohydrate (1.6 g) in toluene (70 mL) was heated under reflux overnight. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate (100 mL) and the mixture was extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was recrystallized from ethyl acetate/dichloromethane (1:1) to give the titled compound (5 g) as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[H-].[Na+].[I-].[CH3:12][CH2:13][CH3:14].O>CN(C=O)C>[CH3:12][CH:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1)[CH3:14]
Reactant: Cc1ccc(O)cn1
Reactant: CCC
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(OC(C)C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
5-Hydroxy-2-methylpyridine (11.0 g, 100 mmol) was dissolved in N,N′-dimethylformamide (100 mL). The resultant mixture was added with sodium hydride (7.2 g, 150 mmol) and 1-methylethane iodide (12 mL, 121 mmol) under ice-cold conditions, and stirred at room temperature overnight. Subsequently, 1-methylethane iodide (4 mL) was added and the resultant mixture was stirred at 60° C. for 4 hours. The reaction solution was added with water and extracted with diethyl ether. The organic layer was washed with brine, dried using sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate), and 5-(1-methylethoxy)-2-methylpyridine (12.7 g, yield 84%) was obtained as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([CH2:22][C:23]1[CH:27]=[N:26][N:25]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:24]=1)[C:28]1[CH:29]=[CH:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Product: CCOC(=O)Cn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)cc2)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.12 g) and ethyl bromoacetate (0.31 mL), ethyl 2-(4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(4-isopropylphenyl)amino]methyl}pyrazol-1-yl)acetate (0.66 g) was obtained. This compound was dissolved in ethanol (20 mL), and 1 mol/L-aqueous sodium hydroxide solution (1.22 mL) was added. The mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1 mol/L-hydrochloric acid (1.22 mL), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. By the reaction and treatment of the obtained residue in the same manner as in Example 17 (0.58 g), 2-(4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(4-isopropylphenyl)amino]methyl}pyrazol-1-yl)acetic acid (0.23 g) was obtained. melting point: 180-182° C.
Reaction SMILES: C([C:3](CC)(P(=O)([O-])[O-])[C:4]1(OC)[CH:9]=[CH:8][CH:7]=[CH:6][CH2:5]1)C.C[C:19](C)([O-:21])C.[K+].[CH2:24]1[O:35][C:34]2[CH:33]=[C:32]3[C:28]([C:29](=O)[C:30](=[O:36])[NH:31]3)=[CH:27][C:26]=2[O:25]1>CN(C)C=O>[CH3:19][O:21][C:3](=[C:29]1[C:28]2[C:32](=[CH:33][C:34]3[O:35][CH2:24][O:25][C:26]=3[CH:27]=2)[NH:31][C:30]1=[O:36])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: CCC(CC)(C1(OC)C=CC=CC1)P(=O)([O-])[O-]
Reactant: O=C1Nc2cc3c(cc2C1=O)OCO3
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=C1C(=O)Nc2cc3c(cc21)OCO3)c1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
Under a nitrogen atmosphere 4.5 g of diethyl-1-methoxybenzylphosphonate (according to Burkhouse, D.; Zimmer, H.; Synthesis 1984, 330) are dissolved in 40 ml of absolute dimethylformamide and at −40° C. 4.0 g of potassium-tert-butoxide are added batchwise and stirred for 15 minutes at −10° C. 3.0 g of 5,6-methylenedioxyisatin (according to Lackey, K.; Sternbach, D. D.; Synthesis 1993, 993) are added to the clear solution and stirred for 1 hour at ambient temperature. After this time the mixture is poured into 20 ml of ice-cold saturated potassium hydrogen sulphate solution and extracted with ethyl acetate. The ethyl acetate phase is washed with water, dried over sodium sulphate and concentrated by evaporation. Finally the residue is separated through a silica gel column with toluene/ethyl acetate (5:1). The product obtained can be recrystallised from ether.
Reaction SMILES: [OH-].[K+].O.C([NH:7][C:8]1[S:9][CH:10]=[C:11](/[C:13](=[CH:19]/[CH3:20])/[C:14]([O:16]CC)=[O:15])[N:12]=1)(=O)C.FC(F)(F)C(O)=O>CC(C)=O>[NH2:7][C:8]1[S:9][CH:10]=[C:11](/[C:13](=[CH:19]/[CH3:20])/[C:14]([OH:16])=[O:15])[N:12]=1
Reactant: C/C=C(\C(=O)OCC)c1csc(NC(C)=O)n1
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC(C)=O
Product: C/C=C(\C(=O)O)c1csc(N)n1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
A solution of 16.5 parts by weight of potassium hydroxide in 111 parts by volume of water is heated up to 75° to 78° C. 14.9 parts by weight of ethyl Z-2-(2-acetamidothiazol-4-yl)-2-butenoate are added and the mixture is stirred at 75° to 78° C. for 2 hours. After cooling to 10° C., the mixture is brought to pH 7.0 with trifluoroacetic acid, the solution is filtered with suction over kieselguhr and the pH is then brought to 3.6 with further trifluoroacetic acid. The mixture is cooled to 0° C. and stirred at 0° C. for 30 minutes, and the crystals which have precipitated are isolated. After washing three times with 6 parts by volume of isopropanol each time, the crystals are dried. The product is then stirred with 62.4 parts by volume of acetone for 20 minutes, filtered off with suction, washed with 42 parts by volume of acetone and dried again. 6.3 parts by weight of pure product are obtained. Further product can be isolated from the mother liquor of the acetone extraction stirring.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=O)[O:8][C:6](=[O:7])[C:5]2=[CH:11][C:12]=1[F:13].C([NH2:16])=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][C:12]=1[F:13])[C:6](=[O:7])[NH:16][C:9]2=[O:8]
Reactant: O=C1OC(=O)c2cc(F)c(F)cc21
Reactant: NC=O
Product: O=C1NC(=O)c2cc(F)c(F)cc21

Procedure:
At 130° C., 1.0 g (5.4 mmol) of 4,5-difluorophthalic anhydride was stirred in 6 ml of formamide for 2 h. After cooling, the reaction mixture was then added to ice-cold water. The precipitated yellow solid was filtered off with suction, washed thoroughly with cold water and dried under high vacuum. This gave 744 mg of a white solid (74.8% of theory).
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[CH2:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>>[CH2:1]=[CH:2][C:3](=[CH2:4])[CH3:5].[CH2:1]=[CH:2][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:1]=[CH:2][CH:3]=[CH2:4].[CH2:1]=[CH:2][C:3]1[CH:4]=[CH:11][CH:6]=[CH:7][CH:5]=1.[CH2:1]=[CH:2][CH:3]=[CH2:4].[CH2:1]=[CH:2][C:3](=[CH2:4])[CH3:5].[CH2:1]=[CH:2][C:3]1[CH:4]=[CH:11][CH:6]=[CH:7][CH:5]=1
Reactant: C1CCCCC1
Solvent: C=CC(=C)C
Product: C=CC=C
Product: C=Cc1ccccc1

Procedure:
Finally, thereto was added a cyclohexane solution containing 1.5 parts by mass of isoprene, and the resulting mixture was polymerized for 30 minutes at 70° C. to obtain a polymer.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:7]=1.[C:14]([Si:16]([CH3:19])([CH3:18])[CH3:17])#[CH:15].C(N(C(C)C)CC)(C)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[N:9]1([CH2:8][C:6]2[CH:5]=[N:4][CH:3]=[C:2]([C:15]#[C:14][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Brc1cncc(CN2CCCC2)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cncc(CN2CCCC2)c1
Temperature: 50 °C

Procedure:
A mixture of 3-bromo-5-(pyrrolidin-1-ylmethyl)pyridine (0.76 mmol), ethynyltrimethylsilane (0.91 mmol), Pd(PPh3)4 (0.038 mmol), CuI (0.076 mmol), and 0.26 mL (1.52 mmol) of diisopropylethylamine in 3.8 mL of DMF can be heated at 50° C. overnight under an atmosphere of N2. Upon cooling to ambient temperature, the reaction mixture is concentrated and the crude product is purified by silica gel flash chromatography (eluted with 50% EtOAc/hexanes).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:9][C:8]2=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:25][C:26](Br)(CCC)[CH2:27][CH2:28]C.C(=O)([O-])[O-].[K+].[K+].[CH3:40][C:41](=O)[CH2:42][CH3:43]>>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=[C:8]2[O:24][CH2:40][CH2:41][CH2:42][CH2:43][CH2:28][CH2:27][CH2:26][Br:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC(Br)(Br)CCC
Reactant: O=c1[nH]c(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: BrCCCCCCCOc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Yield: 21 %

Procedure:
A mixture of 1,4,5-triphenylimidazol-2-one (15.3 g), dibromoheptane (50.6 g) and potassium carbonate (13.8 g) was heated at reflux temperature in dry butanone (750 ml) for 20 hours. The mixture was cooled, filtered and the filtrate evaporated to an oil which was chromatographed on silica gel (hexane/ethyl acetate) to give 1,4,5-triphenyl-2-(7-bromoheptyloxy)imidazole (5.0 g, 21%) as a white solid, m.p. 97°-9° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH:6]([NH2:8])[CH3:7])[CH3:2].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH:6]([NH:8][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:7])[CH3:2]
Reactant: CCOC(=O)CC(C)N
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)CC(C)NCc1ccccc1
Reaction time: 20 h
Yield: 27.7 %

Procedure:
To a solution of 3-amino-butyric acid ethyl ester (5.00 g, 34.3 mmol), benzaldehyde (4.1 mL, 40 mmol) and acetic acid (1.9 mL, 34 mmol) in 1,2-dichloroethane (120 mL) was added sodium triacetoxyborohydride (17 g, 80 mmol) at room temperature and the mixture was stirred for 20 hours. The reaction mixture was poured into sodium bicarbonate saturated aqueous solution and extracted with chloroform. The organic phase was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by flash column chromatography on silica gel (chloroform/methanol=10/1 as an eluant) to afford 3-benzylamino-butyric acid ethyl ester (2.1 g, 9.5 mmol, 28%) as colorless oil.
Reaction SMILES: N(C(C)C)C(C)C.C([Li])CCC.[C:13]1([C:19]2[N:23]3[C:24]4[C:29]([CH:30]=[CH:31][C:22]3=[N:21][N:20]=2)=[CH:28][C:27]([S:32][C:33]2[S:34][CH:35]=[CH:36][N:37]=2)=[CH:26][CH:25]=4)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:38]1([C:41]([CH:43]2[CH2:45][CH2:44]2)=[O:42])[CH2:40][CH2:39]1>C1COCC1>[CH:38]1([C:41]([CH:43]2[CH2:45][CH2:44]2)([C:35]2[S:34][C:33]([S:32][C:27]3[CH:28]=[C:29]4[C:24](=[CH:25][CH:26]=3)[N:23]3[C:19]([C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=5)=[N:20][N:21]=[C:22]3[CH:31]=[CH:30]4)=[N:37][CH:36]=2)[OH:42])[CH2:40][CH2:39]1
Reactant: O=C(C1CC1)C1CC1
Reactant: c1ccc(-c2nnc3ccc4cc(Sc5nccs5)ccc4n23)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OC(c1cnc(Sc2ccc3c(ccc4nnc(-c5ccccc5)n43)c2)s1)(C1CC1)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
iPr2NH (0.12 g, 0.84 mmol) was dissolved in THF (2 mL) and cooled to −78° C. n-Butyllithium (2.5M, 0.37 mL, 0.84 mmol) was added dropwise, followed by 10f (150 mg, 0.42 mmol) in THF (5 mL). Dicyclopropylmethanone (53 mg, 0.46 mmol) in THF (0.25 mL) was added, and the reaction was stirred overnight at room temperature. The reaction was quenched with 5% aqueous NH4Cl (10 mL). The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by preparative HPLC to give the desired product, 10g.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10](O)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN1CCOCC1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.O>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([CH2:10][OH:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To 5.7 g (0.023 mol) of Boc-PheOH dissolved in THF (30 mL) at −10° C. under N2 are added NMM (2.5 mL, 0.023 mol) and IBCF (3 mL, 0.023 mol). The reaction mixture is stirred for 15 minutes and filtered. The filtrate is slowly added to an ice-cold solution of NaBH4 (2.3 g, 0.061 mol) in H2O (10 mL) and then stirred for 1 hour at ice-bath temperature followed by stirring for 1 hour at room temperature. The reaction is cooled to 0° C., treated with saturated NaHCO3 solution, extracted with EtOAc, washed with 1M HCl, washed with water, dried over anhydrous MgSO4, and evaporated to dryness. The crude product is purified over a silica gel column eluted with 95:5 EtOAc/MeOH.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH3:12].CCOCC>ClCCl.CN(C=O)C>[ClH:3].[Cl:3][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH3:12]
Reactant: O=S(Cl)Cl
Reactant: Cc1nccn1CO
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1nccn1CCl
Product: Cl
Reaction time: 2 h
Yield: 71.2 %

Procedure:
Thionyl chloride (7.2 g) was added over 5 min to a stirred suspension of 1-(hydroxymethyl)-2-methyl-1H-imidazole (5.0 g) in a mixture of dichloromethane (50 ml) and DMF (0.5 ml) at 0°, and the mixture was stirred at 0° for 2h. It was then poured into dry ether (500 ml) and left for 1h. The cloudy supernatant was decanted from the insoluble colourless oil which separated. This oil was triturated with acetone (100 ml) with scratching to give a solid which was filtered off and dried to give the title compound (3.6 g), m.p. 122°-124°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[CH3:2].[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[OH:12])[CH:7]=[O:8])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOc1cc(C=O)ccc1O
Solvent: CC(=O)O
Product: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reaction time: 17 h

Procedure:
To a solution of 3-ethoxy-4-hydroxybenzaldehyde (5 g) in acetic acid (50 ml) was added nitric acid (1.4 ml) in 2 portions. The resulting suspension was stirred for 17 h. The solid was collected by filtration, washed with water and dried in vacuo.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1C(C2C=CC=CC=2)=CS[C:25]=1C(OC)=O.C(OCC)(OCC)OCC.C(C1C=CC(N)=CC=1)C>C(O)(=O)C>[CH2:24]([C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)=[CH:2][CH:3]=1)[CH3:25]
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Agent: CCc1ccc(N)cc1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: CCc1ccc(-n2cnc3c(-c4ccccc4)csc3c2=O)cc1
Yield: 60 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (50 mg, 0.21 mmol), triethyl orthoformate (0.42 ml), 4-ethylaniline (0.05 ml, 0.39 mmol), and acetic acid (0.05 ml) were used to give 59.5 mg (0.18 mmol, 60% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[N:4]([CH3:10])[N:3]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][C:44]=1[CH3:45])[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[N:32]=1>CN(C)C=O.CN(C)C(=O)C>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([NH:22][C:23]2[CH:24]=[C:25]([O:26][C:27]3[CH:28]=[CH:29][C:30]4[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]5[CH2:40][CH2:41]5)=[O:38])[N:35]=4)[N:32]=3)[CH:42]=[CH:43][C:44]=2[CH3:45])=[O:8])[N:4]([CH3:10])[N:3]=1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: Cn1nc(Cl)cc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1cc(Cl)nn1C
Yield: 76.2 %

Procedure:
In the same manner as in Example 259 and using 3-chloro-1-methyl-1H-pyrazole-5-carboxylic acid (60 mg, 0.37 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (130 μL, 1.5 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (100 mg, 0.31 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (110 mg, 74%) was obtained as a white solid.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]([O:16][CH:17]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29])(=[O:15])[CH3:14]>>[C:13]([O:16][CH:17]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:12][CH2:11][CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:29])(=[O:15])[CH3:14]
Reactant: O=C(OCCO)c1ccccc1
Reactant: CCCCCCC(C/C=C\CCCCCCCC(=O)Cl)OC(C)=O
Product: CCCCCCC(C/C=C\CCCCCCCC(=O)OCCOC(=O)c1ccccc1)OC(C)=O

Procedure:
2-Benzoyloxyethyl 12-acetoxyoleate was prepared by the procedure of Example 1 from 16 gms (0.1 mole) of ethylene glycol monobenzoate and 36 gms (0.1 mole) of 12-acetoxyoleoyl chloride. The structure of the final product was characterized on the basis of NMR and IR spectral analyses as described in Example 1.
Reaction SMILES: [O:1]=[Al-:2]=O.[Na+].[O-:5][Si:6]([O-:8])=[O:7].[Na+].[Na+].Cl>>[Si:6]([O-:1])([O-:8])([O-:5])[O-:7].[Al+3:2].[Si:6]([O-:1])([O-:8])([O-:5])[O-:7].[Si:6]([O-:1])([O-:8])([O-:5])[O-:7].[Al+3:2].[Al+3:2].[Al+3:2]
Reactant: O=[Al-]=O
Reactant: O=[Si]([O-])[O-]
Agent: Cl
Agent: [Na+]
Product: [Al+3]
Product: [O-][Si]([O-])([O-])[O-]

Procedure:
A second mixture, consisting of a solution of sodium aluminate and water glass, is neutralized by adding hydrochloric acid to form an aluminum silicate gel.