915095-84-0

Usage

Uses

Used in Pharmaceutical Industry:
(S)-(5-bromo-2-chlorophenyl)(4-(tetrahydrofuran-3-yloxy)phenyl)Methanone is used as a key intermediate in the synthesis of pharmaceuticals for its potential to contribute to the development of new drugs with novel therapeutic properties. Its unique molecular structure allows for the creation of diverse chemical entities with potential medicinal applications.
Used in Agrochemical Industry:
In the agrochemical sector, (S)-(5-bromo-2-chlorophenyl)(4-(tetrahydrofuran-3-yloxy)phenyl)Methanone is utilized as a precursor in the production of agrochemicals, such as pesticides and herbicides. Its reactivity and structural features enable the design of effective compounds targeting specific pests or weeds, thereby enhancing crop protection and yield.
Used in Materials Science:
(S)-(5-bromo-2-chlorophenyl)(4-(tetrahydrofuran-3-yloxy)phenyl)Methanone also finds applications in materials science, where it is employed as a building block for the development of new materials with specific properties. Its incorporation into polymers, for instance, can lead to materials with improved mechanical, thermal, or electrical characteristics, depending on the desired application.
Used in Medicinal Chemistry Research:
As a compound with unique structural features, (S)-(5-bromo-2-chlorophenyl)(4-(tetrahydrofuran-3-yloxy)phenyl)Methanone is used in medicinal chemistry research to explore its potential as a scaffold for the design of new bioactive molecules. Its reactivity allows for the attachment of various functional groups, enabling the synthesis of compounds with specific biological activities and selectivity.
Further research and analysis are required to fully understand the properties and potential uses of this chemical compound, as its applications may extend beyond the current understanding in various industries.

Synthetic route

(2-chloro-5-bromophenyl)(4-fluorophenyl)methanone (915095-85-1) + (S)-3-hydroxytetyrahydrofurane (86087-23-2) → (S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-84-0)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 100 - 110℃;	93%
With potassium tert-butylate In tetrahydrofuran at 7 - 10℃; for 0.5h;	87%
With potassium tert-butylate In tetrahydrofuran at 0 - 10℃; for 2h;	85.3%

(5-bromo-2-chlorophenyl)(4-hydroxyphenyl)methanone (1360568-68-8) + R-3-chloro-tetrahydrofuran → (S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-84-0)

Conditions	Yield
With potassium carbonate; potassium iodide In acetonitrile at 50 - 55℃;	91%

5-bromo-2-chlorobenzoic acid (21739-92-4) → (S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-84-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / fluorobenzene / 2 h / 15 - 25 °C 2: aluminum (III) chloride / 1 h / 0 - 25 °C 3: potassium tert-butylate / tetrahydrofuran / 0.5 h / 7 - 10 °C View Scheme
Multi-step reaction with 3 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / fluorobenzene / 15 - 25 °C / Inert atmosphere 2: aluminum (III) chloride / 25 °C / Inert atmosphere 3: potassium tert-butylate / tetrahydrofuran / 2 - 10 °C View Scheme
Multi-step reaction with 2 steps 1: polyphosphoric acid / 50 - 85 °C 2: potassium iodide; potassium carbonate / acetonitrile / 50 - 55 °C View Scheme

5-bromo-2-chloro-benzoyl chloride (21900-52-7) → (S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-84-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: aluminum (III) chloride / 1 h / 0 - 25 °C 2: potassium tert-butylate / tetrahydrofuran / 0.5 h / 7 - 10 °C View Scheme
Multi-step reaction with 2 steps 1: aluminum (III) chloride / 25 °C / Inert atmosphere 2: potassium tert-butylate / tetrahydrofuran / 2 - 10 °C View Scheme
Multi-step reaction with 2 steps 1: aluminum (III) chloride / dichloromethane / 5 h / 0 - 20 °C 2: potassium tert-butylate / tetrahydrofuran / 2 h / 0 - 10 °C View Scheme
Multi-step reaction with 2 steps 1: aluminum (III) chloride / dichloromethane / 8 h / 0 - 10 °C 2: 18-crown-6 ether; sodium hydroxide / toluene; water / 8 h / 50 - 60 °C View Scheme

phenol (108-95-2) → (S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-84-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: polyphosphoric acid / 50 - 85 °C 2: potassium iodide; potassium carbonate / acetonitrile / 50 - 55 °C View Scheme

fluorobenzene (462-06-6) → (S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-84-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: N,N-dimethyl-formamide; oxalyl dichloride / 0 - 25 °C 1.2: 25 °C 2.1: potassium tert-butylate / tetrahydrofuran / 0.5 h / 7 - 10 °C View Scheme

(S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-84-0) → (S)-4-bromo-1-chloro-2-(4-tetrahydrofuran-3-yloxy-benzyl)benzene (915095-89-5)

Conditions	Yield
With aluminum (III) chloride; hydrogen In toluene at 20 - 25℃; for 3h; Temperature;	95%
With aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane In toluene at 0 - 23℃; for 2.5h;	92%
With aluminum (III) chloride; 1,1,3,3-Tetramethyldisiloxane In toluene at 0 - 23℃;	91.28%

(S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-84-0) → C17H16BrClO3

Conditions	Yield
With sodium tetrahydroborate In ethanol at 20 - 25℃;	98 g

(S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-84-0) → C20H24BrClO3Si

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium tetrahydroborate / ethanol / 20 - 25 °C 2: triethylamine / dichloromethane / 0 - 35 °C View Scheme

(S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-84-0) → C18H18BrClO3

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium tetrahydroborate / ethanol / 20 - 25 °C 2: methanesulfonic acid / 20 - 30 °C View Scheme

(S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-84-0) → C38H67ClO9Si5

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium tetrahydroborate / ethanol / 20 - 25 °C 2: triethylamine / dichloromethane / 0 - 35 °C 3: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere View Scheme

(S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-84-0) → C25H31ClO9

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium tetrahydroborate / ethanol / 20 - 25 °C 2: triethylamine / dichloromethane / 0 - 35 °C 3: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 4: methanesulfonic acid / 0 - 35 °C View Scheme

(S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-84-0) → empagliflozin (864070-44-0)

Conditions	Yield
Multi-step reaction with 5 steps 1: sodium tetrahydroborate / ethanol / 20 - 25 °C 2: triethylamine / dichloromethane / 0 - 35 °C 3: n-butyllithium / tetrahydrofuran; hexane / -75 - -70 °C / Inert atmosphere 4: methanesulfonic acid / 0 - 35 °C 5: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / -40 - 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1.1: potassium borohydride; aluminium trichloride / tetrahydrofuran / 0.5 h / 0 - 20 °C 2.1: TurboGrignard / tetrahydrofuran / -10 - 0 °C / Cooling with ice; Inert atmosphere 2.3: 40 - 50 °C / Inert atmosphere 3.1: lithium hydroxide / ethanol; water / 40 - 45 °C View Scheme
Multi-step reaction with 3 steps 1.1: potassium borohydride; aluminium trichloride / tetrahydrofuran / 0.5 h / 0 - 20 °C 2.1: TurboGrignard / tetrahydrofuran / 0.5 h / -10 - 0 °C / Cooling with ice; Inert atmosphere 2.2: 40 - 50 °C / Inert atmosphere 3.1: potassium carbonate / tetrahydrofuran / 40 - 45 °C View Scheme

(S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-84-0) → (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-trityl triacetate

Conditions	Yield
Multi-step reaction with 2 steps 1.1: potassium borohydride; aluminium trichloride / tetrahydrofuran / 0.5 h / 0 - 20 °C 2.1: TurboGrignard / tetrahydrofuran / 0.5 h / -10 - 0 °C / Cooling with ice; Inert atmosphere 2.2: 40 - 50 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1.1: n-butyllithium / toluene; tetrahydrofuran; hexane / 0.5 h / -80 °C / Inert atmosphere 1.2: 2 h / Inert atmosphere 1.3: 12 h / 30 °C / Inert atmosphere 2.1: 4-methyl-morpholine; dmap / ethyl acetate / 4 h / 5 - 30 °C / Inert atmosphere; Large scale 3.1: phenylsilane; aluminum (III) chloride / acetonitrile / 6 h / 45 °C / Inert atmosphere; Large scale View Scheme
Multi-step reaction with 3 steps 1: aluminum (III) chloride; potassium borohydride / tetrahydrofuran / 6 h / 20 °C 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate / 1,4-dioxane / 8 h / 8 °C / Inert atmosphere 3: tetrakis(triphenylphosphine) palladium(0); potassium dihydrogenphosphate / toluene / 12 h / 105 °C View Scheme

(S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-84-0) → C43H59ClO11

Conditions	Yield
Multi-step reaction with 2 steps 1.1: potassium borohydride; aluminium trichloride / tetrahydrofuran / 0.5 h / 0 - 20 °C 2.1: TurboGrignard / tetrahydrofuran / -10 - 0 °C / Cooling with ice; Inert atmosphere 2.3: 40 - 50 °C / Inert atmosphere View Scheme

(S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-84-0) → (4-chloro-3-(4-(3(S)-tetrahydrofuranyloxy)benzyl)phenyl)((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuran[2,3-d][1,3]dioxolan-5-yl)methanone

Conditions	Yield
Multi-step reaction with 2 steps 1.1: aluminum (III) chloride; sodium tetrahydroborate / tetrahydrofuran / 24.5 h / 0 - 60 °C 2.1: n-butyllithium / tetrahydrofuran / 1 h / -80 - -70 °C 2.2: -80 - 0 °C View Scheme

(S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-84-0) → (4-chloro-3-(4-(3(S)-tetrahydrofuryloxy)benzyl)phenyl)((3aS,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuran[2,3-d][1,3]dioxolan-5-yl)methanol

Conditions	Yield
Multi-step reaction with 3 steps 1.1: aluminum (III) chloride; sodium tetrahydroborate / tetrahydrofuran / 24.5 h / 0 - 60 °C 2.1: n-butyllithium / tetrahydrofuran / 1 h / -80 - -70 °C 2.2: -80 - 0 °C 3.1: sodium tetrahydroborate; cerium(III) chloride heptahydrate / methanol / 2 h / -80 - 70 °C View Scheme

(S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-84-0) → C30H33ClO11

Conditions	Yield
Multi-step reaction with 4 steps 1.1: aluminum (III) chloride; sodium tetrahydroborate / tetrahydrofuran / 24.5 h / 0 - 60 °C 2.1: n-butyllithium / tetrahydrofuran / 1 h / -80 - -70 °C 2.2: -80 - 0 °C 3.1: sodium tetrahydroborate; cerium(III) chloride heptahydrate / methanol / 2 h / -80 - 70 °C 4.1: acetic acid / water / 100 °C 4.2: 5 h / 0 - 30 °C View Scheme

(S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-84-0) → C29H32BrClO9

Conditions

Yield

Multi-step reaction with 5 steps 1.1: aluminum (III) chloride; sodium tetrahydroborate / tetrahydrofuran / 24.5 h / 0 - 60 °C 2.1: n-butyllithium / tetrahydrofuran / 1 h / -80 - -70 °C 2.2: -80 - 0 °C 3.1: sodium tetrahydroborate; cerium(III) chloride heptahydrate / methanol / 2 h / -80 - 70 °C 4.1: acetic acid / water / 100 °C 4.2: 5 h / 0 - 30 °C 5.1: potassium fluoride; trimethylsilyl trifluoromethanesulfonate / acetonitrile / -80 - -70 °C View Scheme

(S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-84-0) → C32H35ClO13

Conditions	Yield
Multi-step reaction with 2 steps 1.1: n-butyllithium / toluene; tetrahydrofuran; hexane / 0.5 h / -80 °C / Inert atmosphere 1.2: 2 h / Inert atmosphere 1.3: 12 h / 30 °C / Inert atmosphere 2.1: 4-methyl-morpholine; dmap / ethyl acetate / 4 h / 5 - 30 °C / Inert atmosphere; Large scale View Scheme

methanol (67-56-1) + (S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-84-0) + (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (32469-28-6, 55515-28-1, 55515-29-2, 32384-65-9) → [2-chloro-5-[(3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-2 methoxy-tetrahydropyran-2-yl]phenyl]-[4-[(3S)-tetrahydrofuran-3-yl]oxyphenyl]methanone

Conditions

Yield

Stage #1: (S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone With n-butyllithium In tetrahydrofuran; hexane; toluene at -80℃; for 0.5h; Inert atmosphere; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran; hexane; toluene for 2h; Inert atmosphere; Stage #3: methanol With methanesulfonic acid In tetrahydrofuran; hexane; toluene at 30℃; for 12h; Inert atmosphere;

(S)-(5-bromo-2-chlorophenyl)(4-((tetrahydrofuran-3-yl)oxy)phenyl)methanone (915095-84-0) → 2-[4-chloro-3-({4-[(3S)-oxolan-3-yloxy]phenyl}methyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Conditions	Yield
Multi-step reaction with 2 steps 1: aluminum (III) chloride; potassium borohydride / tetrahydrofuran / 6 h / 20 °C 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate / 1,4-dioxane / 8 h / 8 °C / Inert atmosphere View Scheme

Upstream product

• 915095-85-1 (5-bromo-2-chlorophenyl)(4-fluorophenyl)methanone 
• 86087-23-2 (S)-3-hydroxytetyrahydrofurane 
• 21739-92-4 5-bromo-2-chlorobenzoic acid 
• 21900-52-7 5-bromo-2-chloro-benzoyl chloride 
• 1360568-68-8 (5-bromo-2-chlorophenyl)(4-hydroxyphenyl)methanone 
• 108-95-2 phenol 
• 462-06-6 fluorobenzene 
• 106-39-8 bromochlorobenzene 
• 27522-79-8 p-hydroxybenzoylethylamine 
• 25804-49-3 tert-butyl 4-hydroxybenzoate 
• 17696-62-7 Phenyl 4-hydroxybenzoate 

Downstream Products

• 915095-99-7 (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-trityl triacetate 
• 864070-44-0 empagliflozin 
• 915095-89-5 (S)-4-bromo-1-chloro-2-(4-tetrahydrofuran-3-yloxy-benzyl)benzene 

Relevant academic research and scientific papers

A NEW HETEROCYCLIC COMPOUND: CRYSTAL STRUCTURE AND ANTICANCER ACTIVITY AGAINST HUMAN LUNG ADENOCARCINOMA CELLS

Abstract: New heterocyclic compound (S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran (1), designed by utilizing 5-bromo-2-chlorobenzoic acid (2) as the starting material, is obtained by the organic synthesis and then characterized by single crystal X-ray crystallography, 1H NMR and IR spectroscopy. In the biological study, the CCK-8 assay is performed to evaluate the inhibitory effect of the compound on SPC-A-1 human lung adenocarcinoma cells in vitro by measuring the cancer cell viability. Then, the anticancer activity of the compound is also confirmed by the in vivo xenograft experiment by measuring the mice body weight and the cancer volume.

Preparation process of empagliflozin intermediate

The invention discloses a preparation process of an empagliflozin intermediate, and relates to the technical field of biological pharmacy, the process comprises the following steps: taking a compound of a formula d structure and s-3-hydroxytetrahydrofuran (namely a compound e) as initial raw materials, dehydrating to obtain a compound of a formula c structure; sequentially adding alkali metal and a chlorination reagent to obtain a compound b; further performing Friedel-Crafts reaction with a compound with a structure as shown in a formula f under the catalytic action of Lewis acid to synthesize a compound with a structure as shown in a formula a; and finally, carrying out reduction reaction to obtain a target compound with a structure shown in a formula g. The preparation method is low in cost, easy to operate, less in wastewater, easy in post-treatment, high in yield, high in product purity and suitable for industrial production.

Synthetic method of empagliflozin

The invention provides a brand-new synthesis process of empagliflozin. According to the process, a boric acid ester is used for halogen removal, and specific reaction conditions are combined, so thatempagliflozin can be prepared with high yield and simplicity and convenience in operation. The synthesis method of empagliflozin has the advantages of mild reaction conditions, high total yield, few side reactions and convenience in operation, thereby being beneficial to industrial production and cost control.

Synthetic method for preparing empagliflozin intermediate

The invention discloses a synthetic method for preparing an empagliflozin intermediate. The method comprises the following specific steps: 1) mixing a compound I with a solvent, preparing a compound II by using an acylation reagent, adding the compound II into a system of fluorobenzene and aluminum trichloride, carrying out a Friedel-Crafts reaction at room temperature, performing quenching with water, conducting liquid separation and washing successively, and concentrating an organic matter to obtain a compound III; 2) adding the compound III into a reaction kettle, adding a solvent, an alkali and a catalyst, then adding a compound IV, carrying out heating for a reaction, performing washing with water after the reaction, and conducting concentrating and crystallizing to obtain a solid compound V; and 3) adding the compound V into the reaction kettle, adding a solvent, an acid and a reducing agent, carrying out quenching with water after a reaction, conducting liquid separation and washing successively, concentrating an organic matter, and carrying out crystallizing to obtain a solid compound V. The method is simple and safe in process, high in product yield, easy in impurity control and suitable for industrial production.

6-halogenated glucose C-glycoside as well as preparation method and application thereof

The invention discloses a 6-halogenated glucose C-glycoside as well as a preparation method and application thereof. A structure of 6-halogenated glucose C-glycoside is shown in formula I; an intermediate can be synthesized efficiently with cheap and easily available raw materials; meanwhile, when the raw material is used for synthesizing Jardiance, dapagliflozin and the like, a reaction yield ishigh, and an obtained product has high purity and relatively high industrial application prospect.

Preparation method of Jardiance

The invention discloses a preparation method of Jardiance. The preparation method comprises the following steps: (1) performing a Grignard exchange reaction on a compound 5, then enabling the compound 5 after the Grignard exchange reaction to react with a glucose lactone derivative 6 so as to obtain a compound 7 (as shown in the description), wherein X is bromine or iodine, LG is chlorine, bromine, mesyloxy or tosyl, and PG is acetyl, tert- butanoyl or benzoyl; (2) under the action of alkali, performing deprotection on the compound 7 so as to obtain a finished product namely an Jardiance type compound 8 (as shown in the description). The preparation route is simple to operate, the reaction steps are reduced, the yield is high, the obtained product is high in purity, and the preparation method is suitable for scaled production.

PROCESS FOR THE PREPARATION OF EMPAGLIFLOZIN

An improved process for the preparation of empagliflozin is disclosed. Novel intermediates of formulas (13) and (14) for the preparation of empagliflozin are also disclosed, wherein R1 and R2 are independently hydrogen or hydroxyl protecting groups.

Efficient synthesis of empagliflozin, an inhibitor of SGLT-2, utilizing an AlCl3-promoted silane reduction of a β-glycopyranoside

An efficient production synthesis of the SGLT-2 inhibitor Empagliflozin (5) from acid 1 is described. The key tactical stage involves I/Mg exchange of aryl iodide 2 followed by addition to glucono lactone 3 in THF. Subsequent in situ treatment of the resulting lactol with HCl in MeOH produces β-anomeric methyl glycopyranoside 4 which is, without isolation, directly reduced with Et3SiH mediated by AlCl3 as a Lewis acid in CH 2Cl2/MeCN to afford 5 in 50% overall yield. The process was implemented for production on a metric ton scale for commercial launch.

Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein

The present invention relates to processes for preparing the compounds of general formula I, wherein the groups R1 and R3 are defined according to claim 1. Furthermore this inventions relates to intermediates obtained in these processes.