Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].S(=O)(=O)(O)O.O.[CH2:21](O)[CH3:22]>C(Cl)Cl>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:21][CH3:22])=[O:7])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: Cc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccc(C)c(C(F)(F)F)c1

Procedure:
To a slight suspension of 4-methyl-3-(trifluoromethyl)benzoic acid (2.18 g, 10.7 mmol, ABCR) in ethanol (30 ml) was added concentrated sulphuric acid specific gravity 1.84 (0.5 ml, 9.38 mmol). The resulting solution was heated to reflux overnight under nitrogen. The solution was diluted with DCM (100 ml) and then water (100 ml). The phases were separated and the organic extract washed with saturated aqueous sodium hydrogen carbonate (50 ml), dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound as a mobile pale yellow oil (2.27 g); LCMS: (System 4) MH+=233, tRET=3.29 min.
Reaction SMILES: C(OCC1SCC(=O)O1)(=O)CCC.[C:14]([O:19][CH2:20][CH:21]1[CH2:25][O:24]C(C)(C)[O:22]1)(=[O:18])[CH2:15][CH2:16][CH3:17]>CO>[C:14]([O:19][CH2:20][CH:21]([OH:22])[CH2:25][OH:24])(=[O:18])[CH2:15][CH2:16][CH3:17]
Reactant: CCCC(=O)OCC1COC(C)(C)O1
Agent: CCCC(=O)OCC1OC(=O)CS1
Solvent: CO
Product: CCCC(=O)OCC(O)CO

Procedure:
FIG. 2 illustrates four additional embodiments (methods A-D) for preparing the 1,3-oxathiolane ring. As a nonlimiting illustrative example of method A in FIG. 2, (5-oxo-1,3-oxathiolan-2-yl)methyl butanoate can be prepared by a four-step process which does not require purification of the intermediate products. In a first step, (2,2-dimethyl-1,3-dioxolan-4-yl)methyl butanoate is prepared from solketal and n-butyryl chloride in t-butyl methyl ether, DMAP and triethylamine. The (2,2-dimethyl-1,3-dioxolan-4-yl)methyl butanoate is then placed in solution with Dowex 50W X8-100 H+ resin in methanol, to yield 2,3-dihydroxypropyl butanoate. The resulting diol is then reacted with a solution of sodium periodate in distilled water to produce 2-oxoethyl butanoate. Using 2-oxoethyl butanoate, the (5-oxo-1,3-oxathiolan-2-yl)methyl butanoate can be prepared by reaction with mercaptoacetic acid as p-TsOH.H2O in acetonitrile. The (5-oxo-1,3-oxathiolan-2-yl)methyl butanoate can be converted into its 5-acetyloxy derivative by reacting with lithium tri-t-butoxy aluminum hydride in THF.
Reaction SMILES: O1CCOCC1.[NH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][N:9]=1.[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.C(OCC)C>O>[C:17]1(=[O:22])[N:7]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)[C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12
Reactant: Nc1n[nH]c2ccccc12
Reactant: O=C1OC(=O)c2ccccc21
Solvent: C1COCCO1
Solvent: O
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1c1n[nH]c2ccccc12
Yield: 87 %

Procedure:
To 50 ml of dioxane were added 5.0 g of 3-aminoindazole thus obtained and 6.68 g of phthalic anhydride, and the mixture was stirred for 5 hours at 120° C. After the mixture was condensed under reduced pressure, the condensed residue was added with 30 ml of diethyl ether and stirred under cooling with ice and water for 30 minutes to separate crystals. Then the crystals were obtained by filtration and dried under reduced pressure to give 8.6 g of 3-phthalimidoindazole having the following analytical values in a yield of 87%.
Reaction SMILES: [CH:1]1([OH:8])[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[C:9]([Si:13](Cl)([CH3:15])[CH3:14])([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C.O>CN(C)C=O.CN(C)C1C=CN=CC=1.CCOCC>[Si:13]([O:7][CH:4]1[CH2:5][CH2:6][CH:1]([OH:8])[CH2:2][CH2:3]1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CCC(O)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CCC(O)CC1
Reaction time: 1 h
Yield: 35.9 %

Procedure:
To a solution of 1,4-cyclohexandiol (cis: trans=ca. 1:1, 25.0 g) and t-butylchlorodimethylsilane (32.4 g) in dimethylformamide (150 ml) was added slowly and dropwise a solution of triethylamine 21.8 g) and 4-(dimethylamino)pyridine (1.05 g) in dimethylformamide (50 ml) at 0° C. After stirring for one hour, to the reaction mixture were added water and ether. The ether layer was separated, washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by column chromatography (support; silica gel, 300 g, developing agent; ethyl acetate : hexane=1:5) to obtain the object compound (17.8 g) as a mixture of cis and trans isomers (ca. 1:1).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]([C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)=[O:11].[C:17]1([C:23](Cl)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[CH3:8][O:9][C:10]([C:12]1[N:13]=[CH:14][N:15]([C:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:16]=1)=[O:11]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 8 h
Yield: 95.8 %

Procedure:
Add triethylamine (1.88 mL, 13.48 mmol) to a mixture of methyl-4-imidazolecarboxylate (1.0 g, 7.93 mmol) and triphenylmethyl chloride (2.43 g, 8.72 mmol) in anhydrous acetonitrile (25 mL) over 10 min at room temperature and stir overnight. Quench with water and extract with ethyl acetate (3×). Combine the organic layers, wash with 1N hydrochloride solution, water, saturated aqueous sodium bicarbonate solution and brine sequentially, dry over sodium sulfate, and concentrate to provide the title compound 1-trityl-1H-imidazole-4-carboxylic acid methyl ester (2.8 g, 7.60 mmol).
Reaction SMILES: C(C1C=CC=CC=1)C(C)(C)C.C1(=O)OC(=O)C2=CC=CC=C12.[CH2:23]([C:28]1[CH:44]=[CH:43][C:31]([C:32]([C:34]2[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=2[C:36]([OH:38])=O)=[O:33])=[CH:30][CH:29]=1)[C:24]([CH3:27])([CH3:26])[CH3:25].OO>>[CH2:23]([C:28]1[CH:44]=[CH:43][C:31]2[C:32](=[O:33])[C:34]3[C:35](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:36](=[O:38])[C:30]=2[CH:29]=1)[C:24]([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C)Cc1ccc(C(=O)c2ccccc2C(=O)O)cc1
Agent: CC(C)(C)Cc1ccccc1
Agent: O=C1OC(=O)c2ccccc21
Agent: OO
Product: CC(C)(C)Cc1ccc2c(c1)C(=O)c1ccccc1C2=O

Procedure:
The novel compound 2-neopentylanthraquinone which is prepared by Friedel-Crafts acylation of neopentylbenzene with phthalic anhydride and subsequent cyclization of the resulting 2-(4-neopentylbenzoyl)-benzoic acid in the presence of a strong, anhydrous acid, is a catalyst for the preparation of hydrogen peroxide.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][C:20](=[S:22])[NH:19][C:18]2=[O:23])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].CC1NC(C)=C(C([O-])=O)CC=1C([O-])=O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([CH2:16][CH:17]2[S:21][C:20](=[S:22])[NH:19][C:18]2=[O:23])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1cc(C=C2SC(=S)NC2=O)cc(C(C)(C)C)c1O
Agent: CC1=C(C(=O)[O-])CC(C(=O)[O-])=C(C)N1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(CC2SC(=S)NC2=O)cc(C(C)(C)C)c1O
Yield: 56.9 %

Procedure:
Under a nitrogen atmosphere, 13.98 g of 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene-2-thioxo-4-thiazolidinone, 13.17 g of die 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate and 600 ml of toluene were stirred to effect solution. Forty grams of silica gel 60 (finer than 230 mesh), previously dried in vacuo at 50° C. for 7 hours, were added to the reaction. The reaction was heated at reflux for 18 hours and filtered hot. The filtrate was evaporated to dryness. The residue was dissolved in 500 ml of ethyl acetate, washed 5 times each with 400 ml of 1N hydrochloric acid, dried over sodium sulfate, filtered, and evaporated in vacuo to provide a yellow solid. Chromatography over silica gel eluting with 2.5% ethyl acetate in toluene provided 8.0 g of title product, m.p 178°-179° C.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[K+].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[O:25][CH3:26]>CS(C)=O.O>[Br:1][C:2]1[C:3](=[O:8])[N:4]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=2[O:25][CH3:26])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc([N+](=O)[O-])ccc1F
Reactant: O=c1[nH]cccc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1-n1cccc(Br)c1=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
70 g (403 mmol) of 3-bromopyridin-2(1H)-one are dissolved in 1 l of anhydrous dimethyl sulphoxide, and 54 g (484 mmol) of potassium tert-butoxide are added at room temperature. The suspension is stirred at this temperature for 1 h. 69 g (403 mmol) of 1-fluoro-2-methoxy-4-nitrobenzene are added, and the reaction solution is heated at 80° C. for 20 h. Carefully, the mixture is diluted with 5 l of water. The precipitated solid is filtered off, washed with water and dried under reduced pressure. This gives 103 g (72% of theory) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].S(Cl)(Cl)=O.[CH3:17]O>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:17])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CO
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(O)c(F)c1
Temperature: 85 °C

Procedure:
(3-Fluoro-4-hydroxy-phenyl)-acetic acid (25 g, 150 mmol) was dissolved in methanol (100 mL), and thionyl chloride (5 mL) was added dropwise to the solution. The solution was heated to 85° C. for 16 hours. The reaction mixture was allowed to cool and evaporated to dryness in vacuo. The residue was partitioned between ethyl acetate and saturated NaHCO3. The organic layer was dried over MgSO4, filtered, and the filtrate was evaporated to dryness under reduced pressure to yield the crude title compound as an off white solid (25.3 g). 1H NMR (500 MHz, CDCl3): δ 7.07 (d, J=7.07 Hz, 1H), 7.00-6.97 (m, 2H), 3.74 (s, 3H), 3.73 (s, 2H).
Reaction SMILES: [CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].Cl.[OH-].[K+]>>[CH3:1][N:2]([CH3:3])[C:4]([NH:6][C:7](=[NH:8])[NH2:9])=[NH:5]
Reactant: CN(C)C(=N)N=C(N)N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CN(C)C(=N)NC(=N)N
Reaction time: 2 h

Procedure:
Metformin hydrochloride (331.25 g, 2 moles) was weighed into a 4000 mL beaker containing a stir bar. 1N KOH (1980 mL, 1.998 moles) was added, the beaker was covered, and the mixture was stirred for 2 h. The solids were collected by vacuum filtration, and the filtrate was concentrated to a damp solid. Isopropanol (500 mL) was added and after brief swirling, the mixture was concentrated. The residual white solid was dried for 16 h in a vacuum oven (yield: 269.08 g).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1
Reactant: COC(=O)c1cc(-c2ccnn2C)c(Cl)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc(C(=O)O)sc1Cl
Yield: 96.6 %

Procedure:
A solution of methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (304 mg, 1.18 mmol) in 6N sodium hydroxide (2 ml, 12 mmol) and Tetrahydrofuran (10 ml) was stirred at 70° C. in a sealed tube for 1 h. The resulting solution was cooled and then partitioned between H2O-DCM. The aqueous phase was adjusted to pH ˜3 and then washed several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated affording the desired product (276 mg, 1.14 mmol, 96% yield) as a yellow oil: LC-MS (ES) m/e 244 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[N:5]([C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:16]=[C:15](Cl)[C:14]=1[N+:24]([O-:26])=[O:25])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[NH3:28]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:27])[N:5]([C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:16]=[C:15]([NH2:28])[C:14]=1[N+:24]([O-:26])=[O:25])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: N
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(C(F)(F)F)nc(Cl)c1[N+](=O)[O-]
Solvent: C1CCOC1
Product: CCOC(=O)N(Cc1ccccc1)c1cc(C(F)(F)F)nc(N)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Ethyl-[2-chloro-3-nitro-6-(trifluoromethyl)-pyridin-4-yl]-benzylcarbamate (63 gm 160 mmol) was dissolved in tetrahydrofuran (300 mL) and to this was added 0.880 ammonia solution (100 mL) to give two phases. This was transferred to a pressure vessel, sealed and heated to 80° C. with stirring for 2 hours. The tetrahydrofuran was evaporated and the residue was partitioned between saturated brine and diethyl ether. The organic extracts were dried over sodium sulphate, filtered and evaporated to give a thick yellow slurry (65 gm) of crude product.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]#[N:12].F[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].[OH-].[Li+]>CS(C)=O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:1][C:2]2[S:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[C:3]=2[C:11]#[N:12])=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=1
Reactant: N#Cc1c(N)sc2ccccc12
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#Cc1c(Nc2ccc(F)cc2[N+](=O)[O-])sc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.2 %

Procedure:
Combine 2-amino-benzo[b]thiophene-3-carbonitrile (3.75 g, 21.5 mmol), 1,4-Difluoro-2-nitro-benzene (2.33 mL, 21.5 mmol), and lithium hydroxide (1.03 g, 43.0 mmol) in anhydrous dimethylsulfoxide (50 mL), and heat at 55° C. for about 5 hours. Cool to ambient temperature, pour into a beaker filled with ice/deionized water (200 mL), and stir for 30 minutes. Isolate the precipitated material by suction filtration, wash the solid with dichloromethane, and dry it under reduced pressure to give the title compound (0.618 g). Add deionized water and ethyl acetate to the filtrate, and then separate the organic layer. Extract the aqueous layer with ethyl acetate many times, and then with dichloromethane many times. Then wash the organics with deionized water (3×). Combine the washes and back extract them with ethyl acetate. Wash the organics with a saturated solution of sodium chloride, and then dry (sodium sulfate), filter, and concentrate the organics under reduced pressure to a dark solid. After triturating with methanol, isolate the resulting solid by suction filtration, wash with methanol, and dry at ambient temperature under reduced pressure to give the title compound (4.422 g). Total solid: 5.04 g (74.8%): Mass spectrum (ES+, m/e): 314 (M+1); NMR (1H, 300 MHz, CDCl3), δ (ppm): 9.96 (s, 1H), 8.06-7.98 (m, 1H), 7.85-7.77 (m, 1H), 7.77-7.69 (m, 1H), 7.68-7.59 (m, 1H), 7.56-7.47 (m, 1H), 7.45-7.34 (m, 2H).
Reaction SMILES: [OH:1][CH:2]([P:13](=[O:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[C:5]([Cl:11])[C:4]=1[CH3:12].C/C(/[O-])=C/C(C)=O.C(OO)(C)(C)C>ClC1C=CC=CC=1.[O-][V]([O-])([O-])=O.[Na+].[Na+].[Na+]>[Cl:11][C:5]1[C:4]([CH3:12])=[C:3]([C:8]([CH3:9])=[CH:7][C:6]=1[CH3:10])[C:2]([P:13](=[O:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:1]
Reactant: Cc1cc(C)c(C(O)P(=O)(c2ccccc2)c2ccccc2)c(C)c1Cl
Agent: O=[V]([O-])([O-])[O-]
Agent: CC(=O)/C=C(/C)[O-]
Agent: CC(C)(C)OO
Solvent: Clc1ccccc1
Product: Cc1cc(C)c(C(=O)P(=O)(c2ccccc2)c2ccccc2)c(C)c1Cl
Reaction time: 20 h
Yield: 81 %

Procedure:
To 15.4 g (0.04 mol) of α-hydroxy-(3-chloro-2,4,6-trimethylbenzyl)-diphenyl phosphine oxide and 0.4 S (1.5mmol) of vanadyl (IV) bis-acetylacetonate in 100 g of chlorobenzene there were added 8.2 g (0.06 mol) of 70w t% strength aqueous tert-butylhydroperoxide and isolated by crystallization following a period of 20 h. Yield: 81%, mp 125°-126° C.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:7])=[C:4]([OH:17])[CH:3]=1.[OH-].[Na+:19]>O>[OH:17][C:4]1[CH:3]=[CH:2][CH:16]=[CH:15][C:5]=1[C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([O-:14])=[O:13])=[O:7].[Na+:19]
Reactant: O=C(O)CCCNC(=O)c1ccc(Cl)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])CCCNC(=O)c1ccccc1O
Temperature: 25 °C
Yield: 111.3 %

Procedure:
A 22 L flask was equipped with an overhead stirrer. Deionized water (2000 mL) and 4-[(4-chloro-2-hydroxy-benzoyl)amino]butanoic acid (380.0 g, 1.47 mol) were added and stirring was started. A solution of sodium hydroxide (59.0 g, 1.48 mol) in water (500 mL) was added to the reactor. Water (1500 mL) was added to the reactor, and the resulting slurry was heated until a complete solution was obtained. The reaction mixture was cooled to ambient temperature, and then concentrated to dryness under reduced pressure. The resulting solids were scraped from the flask and vacuum dried at 50° C. to give 401.2 g of sodium 4-[(2-hydroxybenzoyl)amino]butanoate as an off-white solid. The yield was 96.9%.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:7])=[C:4]([OH:17])[CH:3]=1.[OH-].[Na+:19]>CC(C)=O>[OH:17][C:4]1[CH:3]=[CH:2][CH:16]=[CH:15][C:5]=1[C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([O-:14])=[O:13])=[O:7].[Na+:19]
Reactant: O=C(O)CCCNC(=O)c1ccc(Cl)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C([O-])CCCNC(=O)c1ccccc1O
Temperature: 50 °C
Yield: 110.8 %

Procedure:
A 22 L, five neck round bottom flask, was equipped with an overhead stirrer, reflux condenser, thermocouple temperature read out, and heating mantle. The following reaction was run under a dry nitrogen atmosphere. Reagent acetone (13000 mL) and 4-[(4-chloro-2-hydroxy-benzoyl)amino]butanoic acid (500.0 g, 1.94 mol) were charged to the reactor and stirring was started. The reaction slurry was heated to 50° C. until a hazy brown solution was obtained. The warm solution was pumped through a warm pressure filter dressed with Whatman #1 paper into a clean 22 L reactor. The clear yellow filtrate was heated to 50° C. while stirring. Sodium hydroxide solution (50% aqueous; 155 g, 1.94 mol) was charged to the reactor while maintaining vigorous agitation. After the base addition was complete, the reactor was heated to reflux (60° C.) for 2.5 hours and then allowed to cool slowly to ambient temperature. The product was isolated by vacuum filtration through a sintered glass funnel and dried in a vacuum oven at 50° C. for 24 hours to give 527.3 g of sodium 4-[(2-hydroxybenzoyl)amino]butanoate as an off-white solid. The yield was 97.2%.
Reaction SMILES: I[CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]1[CH2:10][C:11]([O:13][CH3:14])=[O:12].[Cl-].[Na+]>CN(C)C=O>[Cl:9][C:7]1[CH:6]=[C:5]2[CH:10]([C:11]([O:13][CH3:14])=[O:12])[CH2:2][CH2:3][N:4]2[CH:8]=1
Reactant: COC(=O)Cc1cc(Cl)cn1CCI
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1CCn2cc(Cl)cc21
Reaction time: 2 h

Procedure:
In an atmosphere of argon, 2.52 g. of 50% sodium hydride in mineral oil (0.053 mol.) is washed free of the carrier with dry hexane (2×20 ml.). Thereafter 150 ml. of anhydrous dimethylformamide is added and the mixture is cooled to 0°. To this mixture is added, with stirring, 16.4 g. of methyl 1-(2-iodoethyl)-4-chloropyrrol-2-acetate (0.05 mol.) dissolved in 50 ml. dimethylformamide. The reaction mixture is left at room temperature for 2 hours, when saturated aqueous sodium chloride solution is added and the product extracted into benzene (3×200 ml.). The organic extract is washed with water (2×100 ml.), dried over sodium sulphate and evaporated in vacuo. The crude product (8.52 g.) is purified by column chromatography on silica gel (245 g.) using hexane-ethyl acetate (90:10) as the eluting solvent, to yield methyl 6-chloro-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate, an oil having the following physical constants:
Reaction SMILES: N#N.[Li]CCCC.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1([CH3:18])[O:17][CH2:16][CH2:15][O:14]1.CN([CH:22]=[O:23])C>CCCCCC.C1COCC1>[CH3:18][C:13]1([C:9]2[O:8][C:12]([CH:22]=[O:23])=[CH:11][CH:10]=2)[O:14][CH2:15][CH2:16][O:17]1
Reactant: CC1(c2ccco2)OCCO1
Reactant: CN(C)C=O
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(c2ccc(C=O)o2)OCCO1
Temperature: -78 °C
Reaction time: 1 h
Yield: 166.7 %

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of n-BuLi (14.6 mL of a 1.6M solution in hexane, 23.35 mmol) in THF (21 mL) at −78° C. was added dropwise a solution of 2-furan-2-yl-2-methyl-[1,3]dioxolane (3.00 g, 19.46 mmol) in THF (6.0 mL). The reaction mixture was then stirred for 1 h at −78° C. before DMF (4.52 mL, 58.38 mmol) was added dropwise. The reaction mixture was stirred for 1 h at −78° C. Sat. aq. NaH4Cl (50 mL) was added and the mixture was extracted with EA (2×50 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give 5.91 g of crude 5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-carbaldehyde as an orange oil. LC-MS-conditions 02: tR=0.75 min; [M+H]+=183.23. The crude material was dissolved, under inert atmosphere (N2) in MeOH (59.0 mL) and treated at 0° C., portionwise, over 20 min, with NaBH4 (1.53 g, 38.92 mmol in five equal portions). The reaction mixture was stirred at rt for 45 min. The reaction mixture was poured in water (80 mL) and the aq. layer was extracted with EA (2×60 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound. TLC: rf (50:50 hept-EA)=0.27. LC-MS-conditions 02: tR=0.65 min; [M+H]+=185.28.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12][C:13]#[N:14])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].Br[CH2:18][CH2:19]Br.[Cl-].[NH4+]>CS(C)=O>[Cl:1][C:2]1[C:11]([C:12]2([C:13]#[N:14])[CH2:19][CH2:18]2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: BrCCBr
Reactant: COC(=O)c1cccc(CC#N)c1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: COC(=O)c1cccc(C2(C#N)CC2)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
A solution of methyl 2-chloro-3-(cyanomethyl)benzoate (20.0 g, 95.3 mmol) in dimethylsulfoxide (200 mL) was cooled to 15° C., 60% sodium hydride (11.6 g, 289 mmol) was added by small portions, and the mixture was stirred at room temperature for 30 min. To the suspension was dropwise added 1,2-dibromoethane (16.5 mL, 191 mmol) at 15° C. over 10 min, and the mixture was stirred at room temperature for 4 hr. To the reaction mixture was added aqueous ammonium chloride solution (200 mL), and the mixture was extracted with diethyl ether/ethyl acetate (1:1, 3×200 mL). The combined organic layer was washed successively with water (200 mL) and saturated brine (100 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5→65/35) to give the title compound (13.5 g, 60%) as a white powder.