Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[S:6].BrBr>ClC(Cl)(Cl)Cl>[C:14]1([CH:2]2[N:7]3[C:5]([S:6][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=43)=[N:4][CH2:3]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OC(CNC(=S)Nc1ccccc1)c1ccccc1
Agent: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: c1ccc(C2CN=C3Sc4ccccc4N32)cc1
Yield: 22 %

Procedure:
A mixture of 50 parts of N-(2-hydroxy-2-phenylethyl)-N'-phenylthiourea, 30 parts of bromine and 800 parts of tetrachloromethane is stirred and refluxed for 2 hours. The reaction mixture is evaporated. From the residue, the free base is liberated in the conventional manner with ammonium hydroxide and extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is suspended in boiling 4-methyl-2-pentanone. The product is filtered off and stirred in a diluted sodium hydroxide solution. The product is extracted with 4-methyl-2-pentanone. The extract is washed with water, dried, filtered and evaporated. The residue is crystallized from acetonitrile. The product is filtered off and dried, yielding 10 parts (22%) of 2,3-dihydro-3-phenylimidazo[2,1-b]benzothiazole; mp. 131.7° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Cl[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[CH2:17][N:16]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([O:47][CH3:48])[CH:40]=1)([S:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)[C:29]#[N:30])[CH2:15]2.[I-].[Na+]>CN(C)C=O.C1(C)C=CC=CC=1.O>[CH3:48][O:47][C:41]1[CH:40]=[C:39]([C:28]([S:31][C:32]2[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=2)([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][N:16]2[CH2:15][C:14]3[C:18](=[CH:19][C:20]([O:21][CH3:22])=[C:12]([O:11][CH2:10][CH2:9][N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[CH:13]=3)[CH2:17]2)[C:29]#[N:30])[CH:44]=[CH:43][C:42]=1[O:45][CH3:46]
Reactant: c1c[nH]cn1
Reactant: COc1ccc(C(C#N)(CCCCCN2Cc3cc(OC)c(OCCCl)cc3C2)Sc2ccc(C)cc2)cc1OC
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(C(C#N)(CCCCCN2Cc3cc(OC)c(OCCn4ccnc4)cc3C2)Sc2ccc(C)cc2)cc1OC
Temperature: 75 °C
Reaction time: 0.67 h

Procedure:
To a solution of 0.11 g of imidazole in 6 mL of N,N-dimethylformamide, under argon, is added 0.036 g of 60% of sodium hydride in oil . After stirring for 40 minutes, a solution of 0.3 g of 5-(2-chloroethoxy)-α-(3,4-dimethoxyphenyl)-1,3-dihydro-6-methoxy-α-[(4-methylphenyl)thio]-2H-isoindole-2-heptanenitrile in 8 mL of toluene is added followed by 0.3 g of sodium iodide. The resulting solution is heated at 75° C. for 21 hours. The solution is cooled and and poured into water. The solution is extracted with ethyl acetate and the organic layer washed with brine and dried over sodium sulfate. The solvent is removed at reduce pressure and the residual oil purified via column chromatography using a gradient elution from 4% methyl alcohol in methylene chloride to 9% methyl alcohol in methylene chloride. This affords 0.196 g of the desired product as a beige oil.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:25][C:26]1([CH3:46])[CH2:35][CH2:34][C:33]([CH3:37])([CH3:36])[C:32]2[CH:31]=[C:30]([CH:38]([CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:39]=O)[CH:29]=[CH:28][C:27]1=2>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:39][CH:38]([C:30]1[CH:29]=[CH:28][C:27]2[C:26]([CH3:46])([CH3:25])[CH2:35][CH2:34][C:33]([CH3:37])([CH3:36])[C:32]=2[CH:31]=1)[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCC(C=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCC(C=C(Br)Br)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 92.5 %

Procedure:
1.62 g of carbon tetrabromide were dissolved in 25 ml of methylene chloride and treated, at −20° C., with a solution of 2.56 g of triphenylphosphine in 25 ml of methylene chloride. The mixture was stirred at 0° C. for 15 minutes. To the orange solution were added 733 mg of (RS)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-heptanal in 4 ml of methylene chloride, at 0° C. The reaction mixture was stirred at room temperature for 4 hours. The mixture was quenched with the addition of 50 ml of water followed by 6 ml of a saturated aqueous sodium bicarbonate solution. The phases were separated and the aqueous phase was further extracted with 2 portions of 25 ml of methylene chloride. The combined organic extracts were dried over MgSO4 and concentrated in vacuo, giving a yellow solid. The residue was triturated in pentane and the solid was removed by filtration. The filtrate was concentrated in vacuo, yielding a yellow oil which was purified by flash chromatography (SiO2, hexane), giving 1.03 g of (RS)-1,1-dibromo-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-oct-1-ene, as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[N:10][C:11]([NH2:17])=[C:12]([N+:14]([O-])=O)[CH:13]=1.Cl>CCO.[Fe]>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[N:10][C:11]([NH2:17])=[C:12]([NH2:14])[CH:13]=1
Reactant: Nc1nc(-c2cccnc2)c(-c2ccncc2Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: Nc1cc(-c2ccncc2Cl)c(-c2cccnc2)nc1N
Temperature: 70 °C
Yield: 44.8 %

Procedure:
3″-chloro-5′-nitro-3,2′:3′,4″-terpyridin-6′-amine (127 mg, 0.39 mmol) was dissolved in EtOH (4.0 mL) and conc. HCl (245 μL). Iron metal (109 mg, 1.09 mmol) was added to the suspension and the mixture was heated to 70° C. for 1 h. The suspension was then filtered through Celite® and the solvent removed in vacuo. NaHCO3 (20 mL of a 4% w/w aqueous solution) was added to the residue and the aqueous phase was extracted with AcOEt (3×20 mL). The organic layer was dried, filtered and concentrated to dryness to yield the title compound (52 mg, 45%), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:16][CH:17]=[C:18]([Cl:20])[CH3:19])([CH2:13][CH2:14][CH3:15])[C:8]2=[O:12])=[CH:4][C:3]=1[CH:21]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23].[H-].[Na+].Br[CH2:35][C:36]([O:38][CH3:39])=[O:37].C(O)(=O)C>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:39][O:38][C:36]([CH2:35][C:21]([C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([Cl:11])[C:2]=1[Cl:1])[C:8](=[O:12])[C:7]([CH2:16][CH:17]=[C:18]([Cl:20])[CH3:19])([CH2:13][CH2:14][CH3:15])[CH2:6]2)([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:37]
Reactant: CCCC1(CC=C(C)Cl)Cc2cc(C(C(=O)OCC)C(=O)OCC)c(Cl)c(Cl)c2C1=O
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCC1(CC=C(C)Cl)Cc2cc(C(CC(=O)OC)(C(=O)OCC)C(=O)OCC)c(Cl)c(Cl)c2C1=O
Temperature: 0 °C
Yield: 89 %

Procedure:
Diethyl 2-[6,7-dichloro-2-(3-chloro-2-butenyl)-2,3-dihydro-1-oxo-2-propyl-1H-inden-5-yl]malonate (10.7 g, 0.0218 mole) dissolved in toluene (45 ml) was added dropwise with stirring under N2 at 25° C. to a suspension of 56% sodium hydride/mineral (1.22 g, 0.0284 mole) in dimethylformamide (45 ml). Methyl bromoacetate (4.34 g, 0.0284 mole) was added in one portion 40 minutes after the previous addition and the mixture was heated at 65° for 41/2 hours. The mixture was then cooled, and after acetic acid (3 ml) was added, poured into ice water and extracted with diethyl ether. The organic extracts were washed with water, dried over MgSO4, concentrated under vacuum, and the residue was chromatographed on silica eluting with methlene chloride/hexane, 4/1 to obtain 10.9 g of the product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](O)=[O:19])[CH2:11][CH2:10]1.C(N(CC)CC)C.O=C1N(N(N2CCOC2=O)P(Cl)(Cl)=O)CCO1.[CH3:51][CH2:52][C:53]([NH2:58])([C:56]#[CH:57])[CH2:54][CH3:55]>C(Cl)Cl>[CH2:54]([C:53]([NH:58][C:18](=[O:19])[CH:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1)([CH2:56][CH3:57])[C:52]#[CH:51])[CH3:55]
Reactant: COc1ccccc1N1CCN(CCC(C(=O)O)c2ccccc2)CC1
Reactant: C#CC(N)(CC)CC
Agent: O=C1OCCN1N(N1CCOC1=O)P(=O)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CC(CC)(CC)NC(=O)C(CCN1CCN(c2ccccc2OC)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.8 %

Procedure:
A mixture of 4-[4-(2-methoxyphenyl)piperazin-1-yl]-2-phenylbutanoic acid (1.772 g, 5 mmole), triethylamine (1.518 g, 15 mmole), and N,N-bis(2-oxo-3-oxazolidinyl)phosphoramidic chloride (1.527 g, 6 mmole) was stirred in methylene chloride (80 mL) under exclusion of moisture at ambient temperature for 30 minutes, after which 1,1-diethylpropargylamine (0.668 g, 6 mmole) was added at once at 0° C. The reaction mixture was stirred at room temperature overnight, washed with water (2×100 mL), dried over magnesium sulfate, filtered, and evaporated to dryness in vacuo. Chromatography on silica gel with methanol/chloroform as eluant, followed by trituration from diethyl ether with addition of ethanolic hydrochloric acid gave 0.6 g of the title compound as the trihydrochloride hemihydrate, m.p. 110°-12° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=O)[CH2:11][C@@H:10]([NH:16][C:17]([O:19][CH2:20][CH:21]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:9]1)=[O:7])([CH3:4])[CH3:3].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.CCN(CC)CC.[F:56][C:57]1[CH:58]=[C:59]([Mg]Br)[CH:60]=[CH:61][CH:62]=1.P([O-])([O-])([O-])=O.Cl>C(Cl)Cl.CCOC(C)=O>[CH:27]1[C:22]2[CH:21]([CH2:20][O:19][C:17]([NH:16][C@H:10]3[CH2:9][N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C@H:12]([C:13](=[O:15])[C:61]4[CH:60]=[CH:59][CH:58]=[C:57]([F:56])[CH:62]=4)[CH2:11]3)=[O:18])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:23]=2[CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)O
Reactant: Fc1cccc([Mg]Br)c1
Agent: Cl
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)c1cccc(F)c1
Temperature: -78 °C

Procedure:
N-Boc-trans-4-N-Fmoc-amino-L-proline (0.24 g, 0.19 mL, 0.001 mol) in CH2Cl2 (10 mL) was treated with diphenylphosphinic chloride (0.001 mol) at 0° C. in the presence of Et3N (0.10 g, 0.14 mL, 0.001 mol) for 2 h. EtOAc (10 mL) was then added to the mixture, which was then washed successively with H2O (5 mL), saturated NaHCO3 aqueous solution (5 mL), and brine (5 mL), and dried over Na2SO4. The organic layer was concentrated in vacuo, and the resulting residue was dissolved in THF (10 mL). The solution was then cooled to −78° C. 3-Fluorophenylmagnesium bromide solution (1.0 M in THF, 1 mL, 0.001 mol) was added, and the mixture was gradually warmed to room temperature before being poured into a mixture of 0.1 M phosphate buffer (pH=7.2, 5 mL) and 1 M HCl aqueous solution (5 mL) at 0° C. The aqueous layer was extracted with CH2Cl2 (10 mL×3). The combined organic layers were washed successively with saturated aqueous NaHCO3 (10 mL) and brine (10 mL) and dried over Na2SO4. The solvent was evaporated in vacuo, and the residue was purified by column chromatography (silica gel, hexanes:EtOAc=7:3) to afford a white solid (XIII-5, 0.27 g, 50%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[C:22]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)(=[O:24])[CH3:23]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([C:22](=[O:24])[CH3:23])[CH:30]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Reactant: CC(=O)c1cccc(B(O)O)c1
Product: COc1ccc(-c2nc3cc(-c4cccc(C(C)=O)c4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 3-acetylphenylboronic acid (139 mg, 0.85 mmol) the subtitle compound was obtained (89 mg, 26%). 1H NMR (DMSO) δ 8.75(d, 1H), 8.46(dd, 1H), 8.23(t, 1H), 7.98–7.96(m, 2H), 7.69–7.56(m, 3H), 7.27(d, 1H), 4.08(s, 3H), 2.68(s, 3H).
Reaction SMILES: [Na].Cl.[NH2:3][OH:4].C([NH:11][C:12]1[N:13]=[C:14]([OH:33])[C:15]2[CH2:21][CH:20]([CH2:22][CH2:23][C:24]3[S:28][C:27]([C:29](OC)=[O:30])=[CH:26][CH:25]=3)[CH2:19][NH:18][C:16]=2[N:17]=1)(=O)C(C)(C)C>CO>[NH2:11][C:12]1[N:13]=[C:14]([OH:33])[C:15]2[CH2:21][CH:20]([CH2:22][CH2:23][C:24]3[S:28][C:27]([C:29]([NH:3][OH:4])=[O:30])=[CH:26][CH:25]=3)[CH2:19][NH:18][C:16]=2[N:17]=1
Reactant: NO
Reactant: COC(=O)c1ccc(CCC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)s1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: Nc1nc(O)c2c(n1)NCC(CCc1ccc(C(=O)NO)s1)C2
Reaction time: 0.25 h
Yield: 77.5 %

Procedure:
To 10 mL of anhydrous methanol was added 0.33 g (14.4 mmol) of sodium metal and a solution of 0.050 g (0.72 mmol) of hydroxylamine hydrochloride in 7 mL of methanol was then added. The resulting reaction mixture was stirred for 15 minutes and 0.23 g (0.5 mmol) of methyl 5-[2-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]thien-2-ylcarboxylate was added under nitrogen. The reaction mixture was stirred for 30 minutes, 0.011 g (0.16 mmol) of hydroxylamine hydrochloride was added, and the reaction was stirred a total of 4.5 hours, and then filtered. The filtrate was then treated with diethyl ether and the solid collected and dried in vacuo to give 0.13 g (71%) of N-{5-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]thien-2-ylcarbonyl}hydroxylamine as a tan colored solid. Rf=0.09 (10% CH3OH/CHCl3); 1H NMR (300 MHz, DMSOd6 /TFAd4) δ1.55-1.70 (m, 4H), 1.83; 1.91 (m, 1H), 2.82-2.87 (m, 4H), 3.29-3.33 (m, 1H), 6.82 (d, J=3.6 Hz, 1H), 7.43 (d, J=1.4 Hz, 1H);
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[CH:10]([C:14]([O:16]CC)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:25]([Si:29]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)Cl)([CH3:28])([CH3:27])[CH3:26].C(N1CC(C)C(CO)C1)C1C=CC=CC=1.[H-].[Na+]>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[CH:10]([CH2:14][O:16][Si:29]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC1C
Agent: CC1CN(Cc2ccccc2)CC1CO
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC1CN(Cc2ccccc2)CC1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C

Procedure:
Ethyl 1-benzyl-4-methylpyrrolidine-3-carboxylate synthesized in accordance with the method of International Patent Publication WO 2000/15611 was reduced with lithium aluminum hydride in accordance with the method of International Patent Publication WO 2000/59502. Tert-butyldiphenylchlorosilane was added to a THF solution of the thus obtained (1-benzyl-4-methylpyrrolidin-3-yl)methanol, sodium hydride was added thereto under ice-cooling, and the mixture was stirred at room temperature for 2Hours. Thereafter, its work-up and purification were carried out in the standard method to obtain 1-benzyl-3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methylpyrrolidine. AP: 444.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[CH:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[N+:33]([CH2:36][CH3:37])([O-])=[O:34]>C(#N)C.CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[O:34][N:33]=[C:36]([CH3:37])[CH:17]=3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CC[N+](=O)[O-]
Reactant: C#Cc1cccc2oc(C(=O)OCC)c(C)c12
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CCOC(=O)c1oc2cccc(-c3cc(C)no3)c2c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 25 %

Procedure:
To a solution of 4-ethynyl-3-methyl-benzofuran-2-carboxylic acid ethyl ester (228 mg, 0.99 mmol, 1 eq.) in acetonitrile (5 mL) under argon, was added di-tert-butyl dicarbonate (327 mg, 1.5 mmol, 1.5 eq.), and 4-(dimethylamino)pyridine (12 mg, 0.1 mmol, 0.1 eq.). Nitroethane (79 uL, 1.1 mmol, and 1.1 eq.) in acetonitrile (5 mL) was added drop-wise to the reaction mixture, and the reaction was stirred at room temperature for 72 hours. After work-up and flash column chromatography, 3-methyl-4-(3-methyl-isoxazol-5-yl)-benzofuran-2-carboxylic acid ethyl ester was obtained in 25% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.4 (t, J=7.1 Hz, 3 H) 2.3 (s, 3 H) 2.4 (s, 3 H) 4.4 (q, J=7.1 Hz, 2 H) 6.8 (s, 1 H) 7.5 (dd, J=7.5, 0.9 Hz, 1 H) 7.6 (m, 1 H) 7.9 (dd, J=8.5, 0.9 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:24])[NH:18][NH:19][C:20]=2[CH:21]([CH3:23])[CH3:22])=[C:11]([CH3:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O:32][C@@H:33]1[C@@H:38]([O:39][C:40](=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42])[C@H:37]([O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[C@@H:36]([CH2:53][O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])[O:35][C@@H:34]1Br)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].C(OCCCOC1C=CC(CC2C(=O)NNC=2C(C)C)=CC=1)C1C=CC=CC=1.CC(OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O)=O>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17]([O:24][C@@H:34]3[O:35][C@H:36]([CH2:53][O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])[C@@H:37]([O:46][C:47](=[O:52])[C:48]([CH3:49])([CH3:50])[CH3:51])[C@H:38]([O:39][C:40](=[O:45])[C:41]([CH3:42])([CH3:43])[CH3:44])[C@H:33]3[O:32][C:26](=[O:31])[C:27]([CH3:30])([CH3:28])[CH3:29])=[N:18][NH:19][C:20]=2[CH:21]([CH3:22])[CH3:23])=[C:11]([CH3:25])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@H](Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: Cc1cc(OCc2ccccc2)ccc1Cc1c(C(C)C)[nH][nH]c1=O
Agent: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(C)c1[nH][nH]c(=O)c1Cc1ccc(OCCCOCc2ccccc2)cc1
Product: Cc1cc(OCc2ccccc2)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 17 using 4-[(4-benzyloxy-2-methylphenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (Kunz, H.; Harreus, A. Liebigs Ann. Chem. 1982, 41-48 Velarde, S.; Urbina, J.; Pena, M. R. J. Org. Chem. 1996, 61, 9541-9545) instead of 4-{[4-(3-benzyloxypropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-glucose, respectively.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]3[C:15]([C:18]([OH:20])=O)=[CH:16][N:17]=[C:11]3[CH:10]=2)[CH2:4][O:3]1.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.C(N(CC)CC)C.[CH2:41]([C:43]1[C:51]2[C:50]([NH2:52])=[CH:49][CH:48]=[CH:47][C:46]=2[N:45]([CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([CH3:60])[N:55]=2)[N:44]=1)[CH3:42].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[CH3:21][C:2]1([CH3:1])[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]3[C:15]([C:18]([NH:52][C:50]4[CH:49]=[CH:48][CH:47]=[C:46]5[C:51]=4[C:43]([CH2:41][CH3:42])=[N:44][N:45]5[CH2:53][C:54]4[CH:59]=[CH:58][CH:57]=[C:56]([CH3:60])[N:55]=4)=[O:20])=[CH:16][N:17]=[C:11]3[CH:10]=2)[CH2:4][O:3]1
Reactant: CC1(C)OCC(COc2ccn3c(C(=O)O)cnc3c2)O1
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(N)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(OCC5COC(C)(C)O5)ccn34)c12
Reaction time: 0.5 h
Yield: 16.3 %

Procedure:
To a stirred mixture of 7-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (128 mg, 0.44 mmol) in tetrahydrofuran (6 mL), under nitrogen, was added 2,4,6-trichlorobenzoyl chloride (115 mg, 0.47 mmol) and triethylamine (51 mg, 0.51 mmol). The mixture was stirred for 30 minutes. To the reaction mixture was added 3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (90 mg, 0.34 mmol), followed by lithium bis(trimethylsilyl)amide (1.7 mL, 1.7 mmol; 1M solution in tetrahydrofuran). The mixture was concentrated under reduced pressure and purified by flash chromatography on silica, eluting with dichloromethane/methanol (10:1) to give 7-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (30 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1.[CH3:15][O:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH2:25][CH2:26][CH3:27])[C:19]=1[OH:28].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH3:15][O:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:2][CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=2)=[C:20]([CH2:25][CH2:26][CH3:27])[C:19]=1[OH:28]
Reactant: COc1ccc(CCCBr)cc1OC
Reactant: CCCc1c(O)ccc(C(=O)OC)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCCc2ccc(OC)c(OC)c2)ccc(C(=O)OC)c1O
Yield: 56.2 %

Procedure:
A mixture of 9.5 g (0.037 mol) of 1-(3-bromopropyl)-3,4-dimethoxybenzene [G. H. Douglas, C. R. Walk and H. Smith, J. Med. Chem., 9, 27 (1966)], 7.0 g (0.033 mol) of 2,4-dihydroxy-3-propylbenzoic acid methyl ester, 6.9 g (0.05 mol) of potassium carbonate and 8.3 g (0.05 mol) of potassium iodide in 250 mL of acetone was stirred at reflux for 24 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to an oil which was purified by high pressure liquid chromatography using 15% ethyl acetate-hexane to give 7.2 g (56% yield) of 4-[3-(3,4-dimethoxyphenyl)propoxy]-2-hydroxy-3-propylbenzoic acid methyl ester as an oil.
Reaction SMILES: CO[CH2:3][C:4]1OC(C)=CC(=O)C=1OCC1C=CC=CC=1.[OH:20][CH:21]([C:23]1[O:24][C:25]([CH3:38])=[CH:26][C:27](=[O:37])[C:28]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:22].ICC>>[CH2:3]([O:20][CH:21]([C:23]1[O:24][C:25]([CH3:38])=[CH:26][C:27](=[O:37])[C:28]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:22])[CH3:4]
Reactant: COCc1oc(C)cc(=O)c1OCc1ccccc1
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(C(C)O)o1
Solvent: CCI
Product: CCOC(C)c1oc(C)cc(=O)c1OCc1ccccc1
Yield: 94 %

Procedure:
In an analogous procedure in the preparation of 2-methoxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one using 2-(1-hydroxyethyl)-3-benzyloxy-6-methyl-pyran-4(1 H)-one (5.2 g, 20 mmol, 1 eq.) and 9.36 g iodoethane (60 mmol, 3 eq.) yielded the title compound as an orange oil (5.4 g, 94% Crude). Further purification by column chromatography on silica gel (eluant: EtOAc) furnished the pure product as a bright yellow oil.
Reaction SMILES: [O:1]=[C:2]([O-])[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].O=C([O-])[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[Na+]>>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C([O-])[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The chelating agent GLC, which is sometimes referred to as gluconate and/or as sodium gluconate, can be purchased from Jungbunzlauer AG, St. Alben—Vorstadt 90, CH-4002, Basel, Switzerland. It can be purchased as a powdered concentrate in 25 kg bags and 1000 kg bags. Sodium gluconate is the sodium salt of gluconic acid, which can be produced by fermentation of glucose. It can be white to tan in color, granular to fine in particle size, very soluble in water, non-corrosive, non-toxic, and/or readily biodegradable (98% after 2 days).