Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[CH2:6]([O:13][C:14](Cl)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([O:13][C:14](=[O:15])[N:2]([CH2:3][CH2:4][OH:5])[CH3:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CNCCO
Reactant: O=C(Cl)OCc1ccccc1
Product: CN(CCO)C(=O)OCc1ccccc1

Procedure:
N-methylethanolamine was treated with benzylchloroformate to give (2-hydroxy- ethyl)-methyl-carbamic acid benzyl ester. The product was treated with methanesulfonyl chloride and Et3N in CH2Cl2 to give methanesulfonic acid 2-(benzyloxycarbonyl-methyl-amino)-ethyl ester. The resulting mesylate is used to alklylate 3 as described for the preparation of 4. The isopropenyl group is removed with acid as described for 6. The product is alkylated as described for compound 7 and the benzyloxy group was removed with catalytic hydrogenation (Pd/C) to give compound 99.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].O=O.[C:7]1([CH3:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:4][CH2:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: Cc1ccccc1
Reactant: CC(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=O
Product: CC(=O)OCc1ccccc1

Procedure:
A stainless steel autoclave equipped with a stirrer was charged with 3 parts of toluene, 15 parts of glacial acetic acid, and 0.42 part of palladium acetate [Pd(OAc)2 ], and the toluene was reacted for 4 hours at 90°C. with the introduction of oxygen at a partial pressure of 60 kg/cm2G. A small amount of benzyl acetate and 0.0687 part of dimethyl diphenyl were obtained, and the precipitation of palladium metal was observed. The dimethyl diphenyl so obtained was in an amount of only 20.2 mol % based on the palladium salt fed. The rate of dimerization was slow, and the palladium salt was precipitated as metal. This shows that the palladium catalyst was not regenerated by oxidation, and did not act catalytically.
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:23])[C:9]=1[CH:10]=[C:11]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[C:13](=O)[O:12]1>CO>[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:23])[C:9]=1[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[C:13](=[O:12])[NH:2][N:1]=1
Reactant: NN
Reactant: COc1ccc2c(c1)C(=O)OC2=Cc1c(Cl)cncc1Cl
Solvent: CO
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)n[nH]c(=O)c2c1
Reaction time: 8 h
Yield: 78.6 %

Procedure:
Hydrazine (18.4 ml, 0.378 moles) was added to a suspension of 3-(3,5-dichloro-pyridin-4-ylmethylen)-6-methoxy-3H-isobenzofuran-1-one (24.4 g, 0.126 moles), obtained as described in example 11, in CH3OH (200 ml), under N2. The mixture was heated under reflux for 1 hour, then kept overnight at room temperature, cooled in ice, and the solid was filtered, washed with very cold CH3OH and dried in oven at 50° C. under vacuum, to give 33.3 g of the title compound (yield: 80%). m.p.: 259-262° C.
Reaction SMILES: [Cl:1][CH2:2][CH:3]=O.[SH2:5]>S(=O)(=O)(O)O>[Cl:1][CH2:2][CH:3]1[S:5][CH:3]([CH2:2][Cl:1])[S:5][CH:3]([CH2:2][Cl:1])[S:5]1
Reactant: O=CCCl
Reactant: S
Agent: O=S(=O)(O)O
Product: ClCC1SC(CCl)SC(CCl)S1

Procedure:
One typical example of the method for producing an episulfide compound of the invention, 2,4,6-tris(epithiomethylthiomethyl)-1,3,5-trithiane (a compound of the general formula (1) wherein n is 0), is shown as Scheme 1 mentioned below. An aqueous 40 wt. % chloroacetaldehyde solution is dissolved in 70 wt. % sulfuric acid, and hydrogen sulfide is introduced thereinto at −20 to 40° C. for 2 to 100 hours to give 2,4,6-tris(chloromethyl)-1,3,5-trithiane. Alternatives to sulfuric acid as the acidic solvent include any of 60/40 (v/v) 95 wt. % sulfuric acid-acetic acid, or hydrogen sulfide-saturated acetic acid, ether, or 95 wt. % ethanol. To the resulting methanol solution of the thus-formed chlorine compound is added potassium hydroxide with which the chlorine compound is processed at −10 to 40° C. for 0.5 to 10 hours for removal of hydrogen chloride from it to give 2,4,6-trimethylene-1,3,5-trithiane. This is thermally reacted with 3-mercaptopropene sulfide at 0 to 100° C. for 6 to 100 hours in the presence of a radical generator (described below), to obtain the intended product, 2,4,6-tris(epithiomethylthiomethyl)-1,3,5-trithiane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([OH:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][C:41]([O:47][CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])=[CH:42][CH:43]=2)[CH:38]=1.[H-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:36][C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][C:41]([O:47][CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:53])([CH3:55])[CH3:54])=[CH:42][CH:43]=3)[CH:38]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C[Si](C)(C)CCOCOc1ccc2ccc(CCl)cc2c1
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3ccc(OCOCC[Si](C)(C)C)cc3c2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.2 %

Procedure:
25.4 g (53.86 mmol) of (3R,4R)-3-hydroxy-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butylester and 17.78 g (55.06 mmol) of 2-chloromethyl-7-(2-trimethylsilanyl-ethoxymethoxy)-naphthalene (WO 97/09311) were dissolved in 180 ml of dimethylformamide under argon and then 2.49 g (57.09 mmol) of sodium hydride dispersion (55% in mineral oil) was added. Subsequently, the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured onto ice-water, the product was extracted 3 times with methylene chloride, the organic phases were washed twice with distilled water, then dried over magnesium sulphate, filtered and concentrated in a water-jet vacuum. The resulting crude product was chromatographed on silica gel with methylene chloride and methanol to give 36.43 g (89.2% of theory) of (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-[7-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylic acid tert-butylester as a yellowish oil; MS: 759 (M+H)+.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[NH:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C.O>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([C:9]1[NH:8][CH:12]=[CH:11][CH:10]=1)=[O:4]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: c1cc[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
45 g (247 mmol) of trichloroacetyl chloride and 100 ml of ethyl ether were introduced into a three-necked flask. A solution of 15.4 g (230 mmol) of pyrrole in 100 ml of ethyl ether was added dropwise and the mixture was stirred at room temperature for one hour, then a solution of 20 g of potassium carbonate in 60 ml of water was added slowly. The organic phase was decanted off, dried over magnesium sulfate, evaporated, the residue triturated in hexane and filtered. 42.7 g (87%) of the expected compound of melting point 78°-79° C. were recovered.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].F[C:21]1[C:26]([F:27])=[C:25]([F:28])[CH:24]=[C:23]([F:29])[C:22]=1[N+:30]([O-:32])=[O:31].C(OCC)(=O)C>C1COCC1>[F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]1[C:22]([N+:30]([O-:32])=[O:31])=[C:23]([F:29])[CH:24]=[C:25]([F:28])[C:26]=1[F:27]
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1F
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Temperature: -78 °C
Reaction time: 16 h
Yield: 59.24 %

Procedure:
A stirred solution of 2-fluoro-4-iodoaniline (3.64 gm, 15.37 mmol) in dry THF (100 ml) under nitrogen was cooled to −78° C. and a solution of 1.0 M lithium hexamethyl disilazide (LiN(SiMe3)2) “LHMDS” (15.37 ml, 15.37 mmol) was added slowly. This reaction mixture was stirred at −78° C. for another hour, and then 2,3,4,6-tetrafluoronitrobenzene was added. The reaction mixture was allowed to warm to room temperature, and stirring continued for another 16 hours. Ethyl acetate (200 mL) was added to the reaction mixture, and the mixture was washed with water. The organic layer was dried over sodium sulfate and further purified by column chromatography to provide yellow solid (3.75 gm, yield: 59.24%).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C1COCC1>[N:14]1([C:2]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32 %

Procedure:
To a solution of 12.2 mmol 2-fluoro-5-nitrobenzoic acid (CAS 7304-32-7; commercially available, e.g. from Fluorochem) in 40 ml THF was added 18.2 mmol morpholine and the mixture was stirred at room temperature for 16 h. The volatiles were removed in vacuo and the residue was resuspended in 25 ml water and acidified to pH 4 by dropwise addition of aqueous HCl. The resulting mixture was stirred at room temperature for 30 min, and the resulting crystals were then collected by filtration and dried in vacuo at 50° C. to afford the title compound as a yellow solid (yield 32%). MS (m/e): 251.0 ([M−H]−, 100%)
Reaction SMILES: F[B-](F)(F)F.C(=O)([O-])[O-].[Na+].[Na+].C(O)CCCCCCC.C(OC(C)=C)(=O)C.C(OCCCCCCCC)(C)=C.[CH2:40]([O:48][C:49]([O:52]CCCCCCCC)(C)[CH3:50])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>C1(C)C=CC=CC=1>[C:49]([O:48][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])(=[O:52])[CH3:50]
Reactant: CCCCCCCCOC(C)(C)OCCCCCCCC
Agent: C=C(C)OC(C)=O
Agent: C=C(C)OCCCCCCCC
Agent: F[B-](F)(F)F
Solvent: CCCCCCCCO
Solvent: Cc1ccccc1
Product: CCCCCCCCOC(C)=O
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a mixture of bis(1,5-cyclooctadiene)iridium tetrafluoroborate [Ir(cod)2]+BF4− (0.01 mmol) and sodium carbonate (0.03 mmol) in toluene (1.0 ml), 1-octanol (130 mg, 1 mmol) and isopropenyl acetate (5 mmol) were added, followed by stirring at 100° C. in an atmosphere of argon gas for 15 hours. The reaction mixture was analyzed by gas chromatography to find that 1-octyl isopropenyl ether, 2,2-bis(1-octyloxy)propane, and octyl acetate were produced in yields of 67%, 6%, and 14%, respectively, with a conversion from 1-octanol of 93%.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[CH3:4][C:5]1([C:8](OC)=[O:9])[CH2:7][CH2:6]1.[H-].[Na+]>O1CCCC1>[CH3:4][C:5]1([C:8]([CH2:2][C:1]#[N:3])=[O:9])[CH2:7][CH2:6]1
Reactant: CC#N
Reactant: COC(=O)C1(C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C(=O)CC#N)CC1

Procedure:
A mixture of 61.1 g of acetonitrile and 108.3 g of methyl 1-methylcyclopropanecarboxylate was added drop-by-drop over a one-hour period to a stirred, refluxing mixture of 35.8 g of sodium hydride and 650 ml of tetrahydrofuran. The resulting mixture was stirred and refluxed for a further 18 hours, then most of the solvent was evaporated in a rotary evaporator. The residue was dissolved in 1 liter of water, and the solution was acidified with hydrochloric acid and extracted with ether. The extract was dried (MgSO4) and concentrated. The residue, a liquid, was fractionally distilled to give (1-methylcyclopropylcarbonyl)acetonitrile (D) as a colorless oil which crystallized on standing, m.p.: 32°-33° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](C(OC)=O)[C:9]([O:11]C)=[O:10])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1>Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: COC(=O)C(C(=O)OC)c1ccc(F)cc1[N+](=O)[O-]
Agent: Cl
Product: O=C(O)Cc1ccc(F)cc1[N+](=O)[O-]
Yield: 89.9 %

Procedure:
Dimethyl 4-fluoro-2-nitrophenylmalonate (5.0 g) was refluxed in 20 ml of 6 N hydrochloric acid for 24 hours. The reaction was cooled and the white solid which formed was collected by vacuum filtration, washed with water and dried to give 3.3 g (87% yield) of 4-fluoro-2-nitrophenylacetic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH3:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:26]Br.CCOC(C)=O.CCCCCCC>COCCOC>[Br:26][C:10]1[C:11]([CH3:25])=[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]([CH3:16])=[C:14]([CH3:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCc2ccccc2)c(C)c(C)c1OCc1ccccc1
Reactant: BrBr
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1c(C)c(OCc2ccccc2)c(Br)c(C)c1OCc1ccccc1
Reaction time: 8 h

Procedure:
A solution of 2,5-bis(benzyloxy)-3,4,6-trimethylbenzene in 100 mL DME (5 g, 15.0 mmol) was treated with a solution of Br2 (0.85 mL, 16.5 mmol, 1.1 equiv.) in 10 mL DME (1.6 M) over ten minutes. The reaction was judged incomplete by HPLC. Additional Br2 in DME (0.42 mL, 1.31 g, 8.19 mmol, 0.55 equiv.) was added and stirred overnight. The reaction was treated with 200 mL EtOAc, which dissolved the crystals, and washed with H2O until the aqueous washings were colorless (3×100 mL). The combined aqueous layers were back extracted with EtOAc (3×50 mL) and the combined organics washed 2×100 mL saturated NaCl, dried over Na2SO4 and concentrated to a brown solid. The solid was adsorbed onto silica and purified by flash chromatography (gradient elution 2-20% EtOAc/heptane) to give a yellow solid. The solid was suspended into heptane, stirred overnight, filtered and the filter cake rinsed with heptane. The resulting white powder was dried in vacuo and yielded 3.31 g of 2-bromo-1,4-bis(benzyloxy)-3,5,6-trimethylbenzene as a white powder. 1H NMR (400 MHz, CDCl3) δ=7.57 (d, 2 H), 7.48 (d, 2 H), 7.44-7.36 (m, 6 H), 4.87 (s, 2 H), 4.74 (s, 2 H), 2.41 (s, 3 H), 2.24 (s, 3 H), 2.20 (s, 3 H) ppm.
Reaction SMILES: [OH-].[Li+].C([O:5][P:6]([CH2:15][C@@H:16]([OH:33])[CH2:17][NH:18][C@H:19]([C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=1)[CH3:20])([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7])C.P(=O)(O)(O)O>O>[CH3:32][O:31][C:23]1[CH:22]=[C:21]([C@@H:19]([NH:18][CH2:17][C@H:16]([OH:33])[CH2:15][P:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:5])[OH:7])[CH3:20])[CH:26]=[C:25]([O:27][CH3:28])[C:24]=1[O:29][CH3:30]
Reactant: CCOP(=O)(Cc1ccccc1)C[C@@H](O)CN[C@@H](C)c1cc(OC)c(OC)c(OC)c1
Agent: O=P(O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: COc1cc([C@H](C)NC[C@H](O)CP(=O)(O)Cc2ccccc2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
10 ml of water and 0.24 g of lithium hydroxide are added to a solution of 2.05 g of 3-{N-[1(S)-(3,4,5- trimethoxyphenyl)ethyl]amino}-2(S)-hydroxy-propyl-(benzyl)-phosphinic acid ethyl ester in 4 ml of water and the mixture is heated at reflux overnight. The then clear solution is cooled to room temperature, adjusted to pH 7 with phosphoric acid and concentrated to dryness by evaporation under reduced pressure. The evaporation residue is made into a slurry in hot methanol and filtered. After concentration of the filtrate by evaporation there remains a foam which, after crystallisation from isopropanol, yields 3-{N-[1(S)-(3,4,5 -trimethoxyphenyl)ethyl]amino}-2(S)-hydroxy-propyl-(benzyl)-phosphinic acid having a melting point of 204°-206°, [α]20D =-35.2°±1.2° (c=0.812 in methanol).
Reaction SMILES: [OH-].[Na+:2].[C:3]([OH:15])(=[O:14])[CH2:4][C:5]([CH2:10][C:11]([OH:13])=[O:12])([C:7]([OH:9])=[O:8])[OH:6]>C(O)(=O)C>[C:3]([O-:15])(=[O:14])[CH2:4][C:5]([CH2:10][C:11]([O-:13])=[O:12])([C:7]([O-:9])=[O:8])[OH:6].[Na+:2].[Na+:2].[Na+:2]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
The procedure of Example 3 was followed except that in lieu of the composition of Example 1 and the sodium hydroxide there was utilized 3.0 lbs of the composition of Example 2 with sufficient citric acid to give a pH of 4.0-4.5 (buffered with sodium citrate) or acetic acid (56%) buffered with sodium acetate at a temperature of 180°-185° F.
Reaction SMILES: [NH4+:1].[OH-].[C:3]([OH:15])(=[O:14])[CH2:4][C:5]([CH2:10][C:11]([OH:13])=[O:12])([C:7]([OH:9])=[O:8])[OH:6]>>[C:3]([O-:15])(=[O:14])[CH2:4][C:5]([CH2:10][C:11]([O-:13])=[O:12])([C:7]([O-:9])=[O:8])[OH:6].[NH4+:1].[NH4+:1].[NH4+:1]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
Ammonium citrate was prepared by mixing 57.4 ml of concentrated NH4OH to 55.149 g of citric acid. Stir to complete the reaction. Add this to the Ca(OH)2 mixture. Stir vigorously to prevent solidification.
Reaction SMILES: [Al+3:1].[Cl-].[Cl-].[Cl-].[C:5]([OH:17])(=[O:16])[CH2:6][C:7]([CH2:12][C:13]([OH:15])=[O:14])([C:9]([OH:11])=[O:10])[OH:8]>>[C:5]([O-:17])(=[O:16])[CH2:6][C:7]([CH2:12][C:13]([O-:15])=[O:14])([C:9]([O-:11])=[O:10])[OH:8].[Al+3:1]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
combining the AlCl3 solution with an aqueous solution of citric acid containing up to about 50 weight % citric acid, while vigorously agitating the resultant solution, to form an aluminum citrate solution having a mole ratio of aluminum ion to citric acid molecule of from about 1.5:1 to 2.0:1, said AlCl3 solution being provided in an amount sufficient to form an aluminum citrate solution containing from 1 up to about 3 weight % aluminum; and
Reaction SMILES: C(=O)([O-])[O-].[Ca+2:5].[C:6]([OH:18])(=[O:17])[CH2:7][C:8]([CH2:13][C:14]([OH:16])=[O:15])([C:10]([OH:12])=[O:11])[OH:9]>>[C:6]([O-:18])(=[O:17])[CH2:7][C:8]([CH2:13][C:14]([O-:16])=[O:15])([C:10]([O-:12])=[O:11])[OH:9].[Ca+2:5].[C:6]([O-:18])(=[O:17])[CH2:7][C:8]([CH2:13][C:14]([O-:16])=[O:15])([C:10]([O-:12])=[O:11])[OH:9].[Ca+2:5].[Ca+2:5]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
It can be advantageous to have some of the calcium carbonate react with citric acid to give calcium citrate.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[C:15](=[O:21])[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:22]([O:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:23])[CH2:3]1.[C:33]([OH:45])(=[O:44])[CH2:34][C:35]([CH2:40][C:41]([OH:43])=[O:42])([C:37]([OH:39])=[O:38])[OH:36]>C(O)C>[OH:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[C:15](=[O:21])[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:22]([O:24][CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)=[O:23])[CH2:3]1.[C:33]([O-:45])(=[O:44])[CH2:34][C:35]([CH2:40][C:41]([O-:43])=[O:42])([C:37]([O-:39])=[O:38])[OH:36]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: C[C@]12CC[C@@H](O)C[C@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)OCCN4CCOCC4)[C@@]3(C)CC(=O)[C@@H]12
Solvent: CCO
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
A solution of 3α-hydroxy-17β-(2'-morpholinoethoxycarbonyl)-5β-androstan-11-one (112 mg., 0.25 mmole) in ethanol (2 ml.) was treated with 0.01 N aqueous citric acid (2.5 ml; 0.25 mmole) and the resulting mixture was evaporated to dryness. The residue was treated with water (1.1 ml) to give an aqueous solution of the title compound (10% with respect to free steroidal base).
Reaction SMILES: [C:1]1([C:10]([NH:12][C:13]([NH2:15])=[NH:14])=[O:11])[N:6]=[C:5]([Cl:7])[C:4]([NH2:8])=[N:3][C:2]=1[NH2:9].O.O.Cl.O.[C:20]([OH:32])(=[O:31])[CH2:21][C:22]([CH2:27][C:28]([OH:30])=[O:29])([C:24]([OH:26])=[O:25])[OH:23].C1(C(NC(N)=N)=O)N=C(Cl)C(N)=NC=1N>O>[C:1]1([C:10]([NH:12][C:13]([NH2:15])=[NH:14])=[O:11])[N:6]=[C:5]([Cl:7])[C:4]([NH2:8])=[N:3][C:2]=1[NH2:9].[C:20]([O-:32])(=[O:31])[CH2:21][C:22]([CH2:27][C:28]([O-:30])=[O:29])([C:24]([O-:26])=[O:25])[OH:23]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: Cl
Agent: N=C(N)NC(=O)c1nc(Cl)c(N)nc1N
Solvent: O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Reaction time: 24 h

Procedure:
Two millimoles of amiloride hydrochloride (604.0 mg) are dissolved in 150 ml of water, with gentle heating and filtered. One millimole of citric acid monohydrate (210.0 mg) is dissolved in 10 ml of water and added to the amiloride solution. The pH of this solution is pH 2.7. `The solution is stored at 5° C. for about 24 hours. The precipitate is washed with 2 ten milliter portions of water and then dried in vacuo at 40° C. After being further dried at 65° C. for 8 hours, the resulting amiloride citrate weighed 330 mg.
Reaction SMILES: [O-2].[Ca+2:2].O.[C:4]([OH:16])(=[O:15])[CH2:5][C:6]([CH2:11][C:12]([OH:14])=[O:13])([C:8]([OH:10])=[O:9])[OH:7]>O>[C:4]([O-:16])(=[O:15])[CH2:5][C:6]([CH2:11][C:12]([O-:14])=[O:13])([C:8]([O-:10])=[O:9])[OH:7].[Ca+2:2].[C:4]([O-:16])(=[O:15])[CH2:5][C:6]([CH2:11][C:12]([O-:14])=[O:13])([C:8]([O-:10])=[O:9])[OH:7].[Ca+2:2].[Ca+2:2]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Ca+2]
Agent: [O-2]
Solvent: O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Temperature: 90 °C
Reaction time: 0.03 h

Procedure:
An aqueous calcium citrate mixture was prepared by adding 28 grams of calcium oxide to 210 grams of citric acid monohydrate in 476 grams of distilled water. To this, 11.0 grams of acetaldehyde/diacetyl flavorant was added. Some of the mixture precipitated out of solution. The mixture was then blended at high speed in a Waring blender for approximately two minutes, and then transferred to a Niro dryer. The dryer was maintained with an inlet temperature of 120° C. and an outlet temperature of 90° C. Gas chromographic analysis of the resultant powder indicates that there was no fixation or retention of the acetaldehyde/diacetyl flavorant after spray-drying.
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:26]=[CH:25][C:12]([C:13]([N:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH3:16])=[O:14])=[CH:11][C:10]=1B1OC(C)(C)C(C)(C)O1.Br[C:37]1[CH:38]=[CH:39][C:40]([Cl:43])=[N:41][CH:42]=1.C([O-])([O-])=O.[Na+].[Na+]>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.O>[Cl:8][C:9]1[CH:26]=[CH:25][C:12]([C:13]([N:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH3:16])=[O:14])=[CH:11][C:10]=1[C:37]1[CH:42]=[N:41][C:40]([Cl:43])=[CH:39][CH:38]=1
Reactant: Clc1ccc(Br)cn1
Reactant: COc1ccccc1N(C)C(=O)c1ccc(Cl)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccccc1N(C)C(=O)c1ccc(Cl)c(-c2ccc(Cl)nc2)c1
Temperature: 100 °C
Yield: 38.9 %

Procedure:
A mixture of toluene (1.5 mL) and water (0.5 mL) containing 4-chloro-N-(2-methoxy-phenyl)-N-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (60 mg, 0.15 mmol), 5-bromo-2-chloro-pyridine (29 mg, 0.15 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol), Na2CO3 (2N, 0.15 mL, 0.3 mmol), was bubbled with N2 for 5 min, then heated at 100° C. for 12 hrs. The mixture was filtered and purified by prep. LCMS to yield 4-chloro-3-(6-chloro-pyridin-3-yl)-N-(2-methoxy-phenyl)-N-methyl-benzamide 2-1 (22.6 mg). MS: 386.7 (M+H)+; tR=7.77 min (method 2).