organic compounds

Abstract

Disclosed are TRPM8 modulators as defined by formula (I) for exerting a cooling effect on the skin and mucous membranes.

Description

[Technical Field]

[0001] Technical Field The present invention relates to a particular class of compounds capable of activating the TRPM8 ion channel, and further to the use of said compounds to induce a sensation of coldness, and to consumer products containing these compounds. [Background technology]

[0002] background TRPM8 (transient receptor potential melastatin member 8, also known as Trp-p8 or MCR1) is activated by harmless cool temperatures and thus plays an important role as a thermosensor. The channel is widely distributed in various tissues, including human skin and mucous membranes (such as oral, throat, and nasal mucosa), the male urogenital tract, lung epithelial cells, and arterial muscle cells. They are Ca channels that exhibit a polymodal gating mechanism. 2+ The receptor is a permeable, nonselective cation channel that is activated by harmless cold temperatures, membrane depolarization, and molecules (including natural and synthetic compounds) known as cooling agents. The receptor was first described in 2002 in several publications as the cold receptor.

[0003] The present invention is based on the discovery that a particular class of compounds can be used to promote a cooling response when they come into contact with TRPM8 receptors in vitro and in vivo.

[0004] Compounds that provide a cooling sensation have long played an important role in the flavor / fragrance industry to provide a combination of freshness and cleanliness. Cooling compounds are widely used in a variety of products, such as foodstuffs, tobacco products, beverages, dentifrices, mouthwashes, toothpastes, and toiletries. The cooling sensation they provide has contributed to the appeal and acceptability of consumer products. In particular, oral care products, such as dentifrices and mouthwashes, are formulated with coolants to provide breath freshening benefits and a clean, cool, fresh feeling in the mouth.

[0005] Numerous compounds that provide a cooling sensation have been described. The most well-known naturally occurring compound is menthol, especially L-menthol. Among the synthetic compounds that provide a cooling sensation, many are derivatives of menthol or structurally related to menthol, i.e., those containing a cyclohexane moiety, which are derivatized with functional groups including carboxamide, ketal, ester, ether, and alcohol.

[0006] Applicants have surprisingly discovered a new class of chemical compounds that differ significantly in structure from previously known TRPM8 modulators, and which, as further described herein, have surprisingly been found to be capable of providing long-lasting cooling on human skin and / or mucous membranes at extremely low concentrations. Summary of the Invention

[0007] overview In a first aspect, the compound of formula (I) [ka] During the ceremony X is O and the dotted line represents a single bond; or X is CR 3 and N.R. 3 where R 3 is selected from hydrogen, C1-C6 alkyl, C1-C7 alkyl substituted with one or two OH groups, C3-C7 cycloalkyl, C3-C7 cycloalkyl substituted with one or two OH groups, C5-C7 cycloalkenyl, C5-C7 cycloalkenyl substituted with one, two, or three C1-C3 alkyl groups, and phenyl, and the dotted line represents a single or double bond; R 1 is selected from: hydrogen, C1-C6 alkyl, C1-C7 alkyl substituted with one or two OH groups; C3 to C7 alkenyl, Phenyl (optionally halogen (including Br, Cl, and F), C≡N, NO2, C1-C6 alkyl, C1-C6 alkyl containing up to five halogen atoms (including Br, Cl, and F), C1-C6 alkyloxy, C1-C6 alkyloxy containing up to five halogen atoms (including Br, Cl, and F), C3-C7 cycloalkyl, -C(O)OR 10 (where R 10 is selected from hydrogen and C1-C3 alkyl, and -SR 11 (where R 11 is selected from the group consisting of hydrogen and C1-C3 alkyl (including ethyl and isopropyl), naphthyl (optionally halogen (including Br, Cl, and F), C≡N, NO2, C1-C6 alkyl, C1-C6 alkyl containing up to five halogen atoms (including Br, Cl, and F), C1-C6 alkyloxy, C1-C6 alkyloxy containing up to five halogen atoms (including Br, Cl, and F), C3-C7 cycloalkyl, -C(O)OR 10 (where R 10is selected from hydrogen and C1-C3 alkyl, and -SR 11 (where R 11 is selected from the group consisting of hydrogen and C1-C3 alkyl (including ethyl and isopropyl), and C5~C 10 monocyclic or bicyclic aryl (wherein one or two C atoms are independently replaced by a heteroatom selected from sulfur, nitrogen, and oxygen, and optionally halogen (including Br, Cl, and F), C≡N, NO2, C1-C6 alkyl, C1-C6 alkyl containing up to five halogen atoms (including Br, Cl, and F), C1-C6 alkyloxy, C1-C6 alkyloxy containing up to five halogen atoms (including Br, Cl, and F), C3-C7 cycloalkyl, —C(O)OR 10 (where R 10 is selected from hydrogen and C1-C3 alkyl, and -SR 11 (where R 11 is substituted with up to three (e.g., one or two) substituents selected from the group consisting of hydrogen and C1-C3 alkyl (including ethyl and isopropyl); R 2 , R 4 , R 5 , and R 7 is independently selected from hydrogen and C1-C6 alkyl; R 6 is selected from hydrogen, C1-C6 alkyl (e.g., ethyl, isopropyl), and C3-C7 cycloalkyl; R 8 and R 9 are independently selected from hydrogen and C1-C6 alkyl; or R 8 and R 9 together with the C atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl ring; and n is 0, or n is 1, and R' is selected from hydrogen, C1-C6 alkyl, C2-C6 alkyl substituted with 1 or 2 OH groups, C2-C6 alkenyl, or R' together with the C atom to which it is attached forms a carbonyl group (C=O);

[0010] There is provided a compound represented by the formula:

[0008] According to a second aspect, there is provided a method for modulating (in vitro and in vivo modulation) transient receptor potential channel melastatin member 8 (TRPM8), said method comprising contacting said receptor with a compound of formula (I), or a salt or solvate thereof.

[0009] In a third aspect, there is provided a method of inducing a cooling sensation in a human or animal comprising contacting the human or animal with a compound of formula (I), or a salt or solvate thereof. In a fourth aspect, there is provided a consumer product, particularly a consumer product intended to be contacted with human skin and / or mucous membranes, comprising a compound as defined by formula (I), or a salt or solvate thereof.

[0010] In a fifth aspect, there is provided a composition comprising a cool sensation, wherein the composition comprises at least one compound of formula (I), a salt or solvate thereof, and a further cooling compound. In a sixth aspect, there is provided a pharmaceutical composition comprising one or more compounds as defined by formula (I), or a salt or solvate thereof.

[0011] The details, examples, and preferences provided with respect to any particular one or more of the specified aspects of the invention are further described herein and will apply equally to all aspects of the invention. Any combination of the embodiments, examples, and preferences described herein in all their possible variations is covered by the present invention unless otherwise indicated herein or otherwise clearly contradicted by context. DETAILED DESCRIPTION OF THE INVENTION

[0012] Detailed Description The present invention provides a novel class of chemical compounds that are significantly different in structure from previously known TRPM8 modulators and are capable of activating the TRPM8 ion channel, thereby increasing Ca₂ transport into cold-sensitive neurons. 2+ This is based, at least in part, on the surprising finding that electrical signals produced by the ionizing radiation lead to an influx of electrical signals that are ultimately perceived as a sensation of cold. Applicants have surprisingly found that this class of chemical compounds, as further described herein, can provide long-lasting cooling on human skin and / or mucous membranes at extremely low concentrations.

[0013] Thus, in a first aspect, a compound of formula (I) [ka] During the ceremony X is O and the dotted line represents a single bond; or X is CR 3 and N.R. 3 where R 3 is selected from hydrogen, C1-C6 alkyl, C1-C7 alkyl substituted with one or two OH groups, C3-C7 cycloalkyl, C3-C7 cycloalkyl substituted with one or two OH groups, C5-C7 cycloalkenyl, C5-C7 cycloalkenyl substituted with one, two, or three C1-C3 alkyl groups, and phenyl, and the dotted line represents a single or double bond; R 1 is selected from: hydrogen, C1-C6 alkyl, C1-C7 alkyl substituted with one or two OH groups; C3 to C7 alkenyl, Phenyl (optionally halogen (including Br, Cl, and F), C≡N, NO2, C1-C6 alkyl, C1-C6 alkyl containing up to five halogen atoms (including Br, Cl, and F), C1-C6 alkyloxy, C1-C6 alkyloxy containing up to five halogen atoms (including Br, Cl, and F), C3-C7 cycloalkyl, -C(O)OR 10 (where R 10 is selected from hydrogen and C1-C3 alkyl, and -SR 11 (where R 11 is selected from the group consisting of hydrogen and C1-C3 alkyl (including ethyl and isopropyl), naphthyl (optionally halogen (including Br, Cl, and F), C≡N, NO2, C1-C6 alkyl, C1-C6 alkyl containing up to five halogen atoms (including Br, Cl, and F), C1-C6 alkyloxy, C1-C6 alkyloxy containing up to five halogen atoms (including Br, Cl, and F), C3-C7 cycloalkyl, -C(O)OR 10 (where R 10 is selected from hydrogen and C1-C3 alkyl, and -SR 11 (where R 11 is selected from the group consisting of hydrogen and C1-C3 alkyl (including ethyl and isopropyl), and C5~C 10monocyclic or bicyclic aryl (wherein one or two C atoms are independently replaced by a heteroatom selected from sulfur, nitrogen, and oxygen, and optionally halogen (including Br, Cl, and F), C≡N, NO2, C1-C6 alkyl, C1-C6 alkyl containing up to five halogen atoms (including Br, Cl, and F), C1-C6 alkyloxy, C1-C6 alkyloxy containing up to five halogen atoms (including Br, Cl, and F), C3-C7 cycloalkyl, —C(O)OR 10 (where R 10 is selected from hydrogen and C1-C3 alkyl, and -SR 11 (where R 11 is substituted with up to three (e.g., one or two) substituents selected from the group consisting of hydrogen and C1-C3 alkyl (including ethyl and isopropyl); R 2 , R 4 , R 5 , and R 7 is independently selected from hydrogen and C1-C6 alkyl; R 6 is selected from hydrogen, C1-C6 alkyl (e.g., ethyl, isopropyl), and C3-C7 cycloalkyl; R 8 and R 9 are independently selected from hydrogen and C1-C6 alkyl; or R 8 and R 9 together with the C atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl ring; and n is 0, or n is 1, and R' is selected from hydrogen, C1-C6 alkyl, C2-C6 alkyl substituted with 1 or 2 OH groups, C2-C6 alkenyl, or R' together with the C atom to which it is attached forms a carbonyl group (C=O);

[0010] There is provided a compound represented by the formula:

[0014] A non-limiting example is formula (I), wherein X is CR 3 (where R 3 is selected from hydrogen, C1-C6 alkyl, C1-C7 alkyl substituted with one or two OH groups, C3-C7 cycloalkyl, C3-C7 cycloalkyl substituted with one or two OH groups, C5-C7 cycloalkenyl, C5-C7 cycloalkenyl substituted with one, two, or three C1-C3 alkyl groups, and phenyl); and the dotted line represents a single bond or a double bond; or a salt or solvate thereof.

[0015] Further non-limiting examples include those of formula (I), wherein X is CR 3 (where R 3 is selected from hydrogen, C1-C6 alkyl, C1-C7 alkyl substituted with one or two OH groups, C3-C7 cycloalkyl, C3-C7 cycloalkyl substituted with one or two OH groups, C5-C7 cycloalkenyl, C5-C7 cycloalkenyl substituted with one, two, or three C1-C3 alkyl groups, and phenyl); the dotted line represents a single bond; and n is 0, a salt, or a solvate thereof.

[0016] Further non-limiting examples include those of formula (I), wherein X is NR 3 (where R 3 is selected from hydrogen, C1-C6 alkyl, C1-C7 alkyl substituted with one or two OH groups, C3-C7 cycloalkyl, C3-C7 cycloalkyl substituted with one or two OH groups, C5-C7 cycloalkenyl, C5-C7 cycloalkenyl substituted with one, two, or three C1-C3 alkyl groups, and phenyl); and the dotted line represents a single bond or a double bond, a salt, or a solvate thereof.

[0017] Further non-limiting examples include those of formula (I), wherein X is NR 3 (where R 3 is selected from hydrogen, C1-C6 alkyl, C1-C7 alkyl substituted with one or two OH groups, C3-C7 cycloalkyl, C3-C7 cycloalkyl substituted with one or two OH groups, C5-C7 cycloalkenyl, C5-C7 cycloalkenyl substituted with one, two, or three C1-C3 alkyl groups, and phenyl); the dotted line represents a single bond; and n is 0, a salt, or a solvate thereof.

[0018] Further non-limiting examples include those of formula (I), wherein X is CR 3 (where R 3 is selected from hydrogen, C1-C6 alkyl, C1-C7 alkyl substituted with one or two OH groups, C3-C7 cycloalkyl, C3-C7 cycloalkyl substituted with one or two OH groups, C5-C7 cycloalkenyl, C5-C7 cycloalkenyl substituted with one, two, or three C1-C3 alkyl groups, and phenyl); and the dotted line represents a single bond; n is 0; and R 1 is phenyl (optionally halogen (including Br, Cl, and F), C≡N, NO2, C1-C6 alkyl, C1-C6 alkyl containing up to five halogen atoms (including Br, Cl, and F), C1-C6 alkyloxy, C1-C6 alkyloxy containing up to five halogen atoms (including Br, Cl, and F), C3-C7 cycloalkyl, -C(O)OR 10 (where R 10 is selected from hydrogen and C1-C3 alkyl, and -SR 11 (where R 11 is substituted with up to five (e.g., one, two, or three) substituents selected from the group consisting of hydrogen and C1-C3 alkyl (including ethyl and isopropyl), a salt, or a solvate thereof.

[0019] Further non-limiting examples include compounds of formula (Ia): [ka] During the ceremony X is selected from C and N; R 3 is selected from hydrogen, C1-C6 alkyl, C1-C7 alkyl substituted with one or two OH groups, C3-C7 cycloalkyl, C3-C7 cycloalkyl substituted with one or two OH groups, C5-C7 cycloalkenyl, C5-C7 cycloalkenyl substituted with one, two or three C1-C3 alkyl groups, and phenyl; R 1 is selected from: hydrogen, C1-C6 alkyl, C1-C7 alkyl substituted with one or two OH groups; C3 to C7 alkenyl, Phenyl (optionally halogen (including Br, Cl, and F), C≡N, NO2, C1-C6 alkyl, C1-C6 alkyl containing up to five halogen atoms (including Br, Cl, and F), C1-C6 alkyloxy, C1-C6 alkyloxy containing up to five halogen atoms (including Br, Cl, and F), C3-C7 cycloalkyl, -C(O)OR 10 (where R 10 is selected from hydrogen and C1-C3 alkyl, and -SR 11 (where R 11 is selected from the group consisting of hydrogen and C1-C3 alkyl (including ethyl and isopropyl), naphthyl (optionally halogen (including Br, Cl, and F), C≡N, NO2, C1-C6 alkyl, C1-C6 alkyl containing up to five halogen atoms (including Br, Cl, and F), C1-C6 alkyloxy, C1-C6 alkyloxy containing up to five halogen atoms (including Br, Cl, and F), C3-C7 cycloalkyl, -C(O)OR 10 (where R 10is selected from hydrogen and C1-C3 alkyl, and -SR 11 (where R 11 is selected from the group consisting of hydrogen and C1-C3 alkyl (including ethyl and isopropyl), and C5~C 10 monocyclic or bicyclic aryl (wherein one or two C atoms are independently replaced by a heteroatom selected from sulfur, nitrogen, and oxygen, and optionally halogen (including Br, Cl, and F), C≡N, NO2, C1-C6 alkyl, C1-C6 alkyl containing up to five halogen atoms (including Br, Cl, and F), C1-C6 alkyloxy, C1-C6 alkyloxy containing up to five halogen atoms (including Br, Cl, and F), C3-C7 cycloalkyl, —C(O)OR 10 (where R 10 is selected from hydrogen and C1-C3 alkyl, and -SR 11 (where R 11 is substituted with up to three (e.g., one or two) substituents selected from the group consisting of hydrogen and C1-C3 alkyl (including ethyl and isopropyl); R 2 , R 4 , R 5 , and R 7 is independently selected from hydrogen and C1-C6 alkyl; R 6 is selected from hydrogen, C1-C6 alkyl (e.g., ethyl, isopropyl), and C3-C7 cycloalkyl; R 8 and R 9 are independently selected from hydrogen and C1-C6 alkyl; or R 8 and R 9 form together with the C atom to which they are attached a 3-, 4-, 5-, 6- or 7-membered cycloalkyl ring, or a salt or solvate thereof.

[0020] A further non-limiting example is formula (Ia), wherein X is C; and R 3 is a compound represented by the formula: wherein R is selected from hydrogen, C1-C6 alkyl, C1-C7 alkyl substituted with one or two OH groups, C3-C7 cycloalkyl, C3-C7 cycloalkyl substituted with one or two OH groups, C5-C7 cycloalkenyl, C5-C7 cycloalkenyl substituted with one, two, or three C1-C3 alkyl groups, and phenyl, or a salt or solvate thereof.

[0021] Further non-limiting examples include compounds of formula (Ia): X is C; R 1 is selected from: hydrogen, C1-C6 alkyl, C1-C7 alkyl substituted with 1 or 2 OH groups, C3 to C7 alkenyl, Phenyl (optionally halogen (including Br, Cl, and F), C≡N, NO2, C1-C6 alkyl, C1-C6 alkyl containing up to five halogen atoms (including Br, Cl, and F), C1-C6 alkyloxy, C1-C6 alkyloxy containing up to five halogen atoms (including Br, Cl, and F), C3-C7 cycloalkyl, -C(O)OR 10 (where R 10 is selected from hydrogen and C1-C3 alkyl, and -SR 11 (where R 11 is selected from the group consisting of hydrogen and C1-C3 alkyl (including ethyl and isopropyl), naphthyl (optionally halogen (including Br, Cl, and F), C≡N, NO2, C1-C6 alkyl, C1-C6 alkyl containing up to five halogen atoms (including Br, Cl, and F), C1-C6 alkyloxy, C1-C6 alkyloxy containing up to five halogen atoms (including Br, Cl, and F), C3-C7 cycloalkyl, -C(O)OR 10 (where R 10 is selected from hydrogen and C1-C3 alkyl, and -SR 11 (where R 11 is selected from the group consisting of hydrogen and C1-C3 alkyl (including ethyl and isopropyl), and C5~C 10 monocyclic or bicyclic aryl (wherein one or two C atoms are independently replaced by a heteroatom selected from sulfur, nitrogen, and oxygen, and optionally halogen (including Br, Cl, and F), C≡N, NO2, C1-C6 alkyl, C1-C6 alkyl containing up to five halogen atoms (including Br, Cl, and F), C1-C6 alkyloxy, C1-C6 alkyloxy containing up to five halogen atoms (including Br, Cl, and F), C3-C7 cycloalkyl, —C(O)OR 10 (where R 10 is selected from hydrogen and C1-C3 alkyl, and -SR 11 (where R 11 is substituted with up to three (e.g., one or two) substituents selected from the group consisting of hydrogen and C1-C3 alkyl (including ethyl and isopropyl); R 2 , R 4 , and R 5 is independently selected from hydrogen and C1-C6 alkyl; R 3 is hydrogen; R 6is selected from hydrogen, C1-C6 alkyl (e.g., ethyl, isopropyl), and C3-C7 cycloalkyl; R 7 is hydrogen; R 8 and R 9 are independently selected from hydrogen and C1-C6 alkyl; or R 8 and R 9 form together with the C atom to which they are attached a 3-, 4-, 5-, 6- or 7-membered cycloalkyl ring, or a salt or solvate thereof.

[0022] A further non-limiting example is a compound of formula (Ia), wherein X is C and R 3 is hydrogen; and R 1 is phenyl (optionally halogen (including Br, Cl, and F), C≡N, NO2, C1-C6 alkyl, C1-C6 alkyl containing up to five halogen atoms (including Br, Cl, and F), C1-C6 alkyloxy, C1-C6 alkyloxy containing up to five halogen atoms (including Br, Cl, and F), C3-C7 cycloalkyl, -C(O)OR 10 (where R 10 is selected from hydrogen and C1-C3 alkyl, and -SR 11 (where R 11 is selected from the group consisting of hydrogen and C1-C3 alkyl (including ethyl and isopropyl), and is substituted with up to 5 (for example, 1, 2, or 3) substituents, or a salt or solvate thereof.

[0023] A further non-limiting example is formula (Ia), wherein X is C; R 1is phenyl (optionally halogen (including Br, Cl, and F), C≡N, NO2, C1-C6 alkyl, C1-C6 alkyl containing up to five halogen atoms (including Br, Cl, and F), C1-C6 alkyloxy, C1-C6 alkyloxy containing up to five halogen atoms (including Br, Cl, and F), C3-C7 cycloalkyl, -C(O)OR 10 (where R 10 is selected from hydrogen and C1-C3 alkyl, and -SR 11 (where R 11 is selected from the group consisting of hydrogen and C1-C3 alkyl (including ethyl and isopropyl), which are substituted with up to five (e.g., one, two, or three) substituents; R 3 is hydrogen; and R 7 is hydrogen, a salt or solvate thereof.

[0024] A further non-limiting example is formula (Ia), wherein X is C; R 1 is phenyl (optionally halogen (including Br, Cl, and F), C≡N, NO2, C1-C6 alkyl, C1-C6 alkyl containing up to five halogen atoms (including Br, Cl, and F), C1-C6 alkyloxy, C1-C6 alkyloxy containing up to five halogen atoms (including Br, Cl, and F), C3-C7 cycloalkyl, -C(O)OR 10 (where R 10 is selected from hydrogen and C1-C3 alkyl, and -SR 11 (where R 11 is selected from the group consisting of hydrogen and C1-C3 alkyl (including ethyl and isopropyl), which are substituted with up to five (e.g., one, two, or three) substituents; R 3 is hydrogen; R 4 is hydrogen and R 5 is C1-C3 alkyl; and R 7is hydrogen, a salt or solvate thereof.

[0025] In one specific embodiment, the compound of formula (Ia) (wherein X is C) has the relative stereochemistry as depicted in formula (Ib): [ka] The compound is represented by the formula R 1 is selected from: hydrogen, C1-C6 alkyl, C1-C7 alkyl substituted with one or two OH groups; C3 to C7 alkenyl, Phenyl (optionally halogen (including Br, Cl, and F), C≡N, NO2, C1-C6 alkyl, C1-C6 alkyl containing up to five halogen atoms (including Br, Cl, and F), C1-C6 alkyloxy, C1-C6 alkyloxy containing up to five halogen atoms (including Br, Cl, and F), C3-C7 cycloalkyl, -C(O)OR 10 (where R 10 is selected from hydrogen and C1-C3 alkyl, and -SR 11 (where R 11 is selected from the group consisting of hydrogen and C1-C3 alkyl (including ethyl and isopropyl), naphthyl (optionally halogen (including Br, Cl, and F), C≡N, NO2, C1-C6 alkyl, C1-C6 alkyl containing up to five halogen atoms (including Br, Cl, and F), C1-C6 alkyloxy, C1-C6 alkyloxy containing up to five halogen atoms (including Br, Cl, and F), C3-C7 cycloalkyl, -C(O)OR 10 (where R 10 is selected from hydrogen and C1-C3 alkyl, and -SR 11 (where R11 is selected from the group consisting of hydrogen and C1-C3 alkyl (including ethyl and isopropyl), and C5~C 10 monocyclic or bicyclic aryl (wherein one or two C atoms are independently replaced by a heteroatom selected from sulfur, nitrogen, and oxygen, and optionally halogen (including Br, Cl, and F), C≡N, NO2, C1-C6 alkyl, C1-C6 alkyl containing up to five halogen atoms (including Br, Cl, and F), C1-C6 alkyloxy, C1-C6 alkyloxy containing up to five halogen atoms (including Br, Cl, and F), C3-C7 cycloalkyl, —C(O)OR 10 (where R 10 is selected from hydrogen and C1-C3 alkyl, and -SR 11 (where R 11 is substituted with up to three (e.g., one or two) substituents selected from the group consisting of hydrogen and C1-C3 alkyl (including ethyl and isopropyl); R 3 is selected from hydrogen, C1-C6 alkyl, C1-C7 alkyl substituted with one or two OH groups, C3-C7 cycloalkyl, C3-C7 cycloalkyl substituted with one or two OH groups, C5-C7 cycloalkenyl, C5-C7 cycloalkenyl substituted with one, two or three C1-C3 alkyl groups, and phenyl; R 2 , R 4 , R 5 , and R 7 is independently selected from hydrogen and C1-C6 alkyl; R 6 is selected from hydrogen, C1-C6 alkyl (e.g., ethyl, isopropyl), and C3-C7 cycloalkyl; R 8 and R 9are independently selected from hydrogen and C1-C6 alkyl; or R 8 and R 9 together with the C atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl ring.

[0026] A further non-limiting example is formula (Ib), wherein X is C; R 1 is selected from phenyl and halogen (including Br, Cl, and F), C≡N, NO2, C1-C6 alkyl, C1-C6 alkyl containing up to five halogen atoms (including Br, Cl, and F), C1-C6 alkyloxy, C1-C6 alkyloxy containing up to five halogen atoms (including Br, Cl, and F), C3-C7 cycloalkyl, -C(O)OR 10 (where R 10 is selected from hydrogen and C1-C3 alkyl, and -SR 11 (where R 11 is selected from phenyl substituted with up to five (e.g., 1, 2, or 3) substituents selected from the group consisting of hydrogen and C1-C3 alkyl (including ethyl and isopropyl); and R 3 is hydrogen, a salt or solvate thereof.

[0027] A further non-limiting example is formula (Ib), wherein X is C; R 1 is phenyl (optionally halogen (including Br, Cl, and F), C≡N, NO2, C1-C6 alkyl, C1-C6 alkyl containing up to five halogen atoms (including Br, Cl, and F), C1-C6 alkyloxy, C1-C6 alkyloxy containing up to five halogen atoms (including Br, Cl, and F), C3-C7 cycloalkyl, -C(O)OR 10 (where R 10 is selected from hydrogen and C1-C3 alkyl, and -SR 11 (where R 11is selected from the group consisting of hydrogen and C1-C3 alkyl (including ethyl and isopropyl), which are substituted with up to five (e.g., one, two, or three) substituents; R 3 is hydrogen; and R 7 is hydrogen, a salt or solvate thereof.

[0028] A further non-limiting example is formula (Ib), wherein X is C; R 1 is phenyl (optionally halogen (including Br, Cl, and F), C≡N, NO2, C1-C6 alkyl, C1-C6 alkyl containing up to five halogen atoms (including Br, Cl, and F), C1-C6 alkyloxy, C1-C6 alkyloxy containing up to five halogen atoms (including Br, Cl, and F), C3-C7 cycloalkyl, -C(O)OR 10 (where R 10 is selected from hydrogen and C1-C3 alkyl, and -SR 11 (where R 11 is selected from the group consisting of hydrogen and C1-C3 alkyl (including ethyl and isopropyl), which are substituted with up to five (e.g., one, two, or three) substituents; R 3 is hydrogen; R 4 is hydrogen and R 5 is C1-C3 alkyl; and R 7 is hydrogen, a salt or solvate thereof.

[0029] A further non-limiting example is of formula (Ib), wherein R 3 and R 7 are both hydrogen, and R 8 and R 9 are both methyl, a salt or solvate thereof.

[0030] A further non-limiting example is formula (Ib), wherein X is C and R 1is selected from phenyl and halogen (including Br, Cl, and F), C≡N, NO2, C1-C6 alkyl, C1-C6 alkyl containing up to five halogen atoms (including Br, Cl, and F), C1-C6 alkyloxy, C1-C6 alkyloxy containing up to five halogen atoms (including Br, Cl, and F), C3-C7 cycloalkyl, -C(O)OR 10 (where R 10 is selected from hydrogen and C1-C3 alkyl, and -SR 11 (where R 11 is selected from phenyl substituted with up to five (e.g., 1, 2, or 3) substituents selected from the group consisting of hydrogen and C1-C3 alkyl (including ethyl and isopropyl); R 3 and R 7 are both hydrogen; and R 8 and R 9 are both methyl, a salt or solvate thereof.

[0031] A further non-limiting example is formula (Ib), wherein X is C and R 1 is selected from phenyl and halogen (including Br, Cl, and F), C≡N, NO2, C1-C6 alkyl, C1-C6 alkyl containing up to five halogen atoms (including Br, Cl, and F), C1-C6 alkyloxy, C1-C6 alkyloxy containing up to five halogen atoms (including Br, Cl, and F), C3-C7 cycloalkyl, -C(O)OR 10 (where R 10 is selected from hydrogen and C1-C3 alkyl, and -SR 11 (where R 11 is selected from phenyl substituted with up to five (e.g., 1, 2, or 3) substituents selected from the group consisting of hydrogen and C1-C3 alkyl (including ethyl and isopropyl); R 3 and R 7 are both hydrogen; R 6is methyl or isopropyl; and R 8 and R 9 are both methyl, a salt or solvate thereof.

[0032] Further non-limiting examples include compounds of formula (I), (Ia) and (Ib), where R 1 or R 2 is a compound represented by the formula: Further non-limiting examples include compounds of formula (I), (Ia) and (Ib), where R 1 is a compound represented by the formula:

[0033] Further non-limiting examples include compounds of formula (I), (Ia) and (Ib), where R 1 is a compound represented by the formula: wherein the alkyl group is selected from C1 to C6 alkyl, C1 to C7 alkyl substituted with one or two OH groups, and C3 to C7 alkenyl.

[0034] Further non-limiting examples include compounds of formula (I), (Ia) and (Ib), where R 1 is selected from C1-C6 alkyl, C1-C7 alkyl substituted with one or two OH groups, and C3-C7 alkenyl; R 2 is hydrogen or methyl; and R 8 and R 9 is a compound represented by the formula:

[0035] Further non-limiting examples include compounds of formula (I), (Ia) and (Ib), where R 1 is selected from C1-C6 alkyl, C1-C7 alkyl substituted with one or two OH groups, and C3-C7 alkenyl; R 2 is hydrogen or methyl; R 4 is hydrogen and R 5 is C1-C3 alkyl; and R 8 and R 9 is a compound represented by the formula:

[0036] Further non-limiting examples include compounds of formula (I), (Ia) and (Ib), where R 1 is selected from C1-C6 alkyl, C1-C7 alkyl substituted with one or two OH groups, and C3-C7 alkenyl; R 2 is hydrogen or methyl; R 4 is hydrogen and R 5 is C1-C3 alkyl; R 6 is methyl or isopropyl; and R 8 and R 9 is a compound represented by the formula:

[0037] Further non-limiting examples include 1,3,3,5,7-pentamethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole; 1,3,3,5,7-pentamethyl-5-(4-methylpyridin-3-yl)octahydrobenzo[c]isoxazole; 1,3,3,5,7-pentamethyl-5-(pyridin-3-yl)octahydrobenzo[c]isoxazole; 1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole; 1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole; 1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole 1,3,3,6-Tetramethyloctahydrobenzo[c]isoxazole;1,3,3-Trimethyl-6-((R)-4-methylcyclohex-3-en-1-yl)octahydrobenzo[c]isoxazole;1,5,7-Trimethylhexahydro-1H-spiro[benzo[c]isoxazole-3,1'-cyclopentane];1-Ethyl-3,3,5,7-tetramethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole;1-Isopropyl-3,3,5,7-tetramethyl- 1-Isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole;1-Isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole-1-ium chloride;1-Isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole;1-Isopropyl-5,7-dimethylhexahydro-1H-spiro[benzo[c]isoxazole-3,1'-cyclopentane];2-(1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole) 2-Methyl-3-(1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;5-(2,4-dimethoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;5-(2,5-dimethoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;5-(6-Methoxypyridin-2-yl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;5,7-Diethyl-1,3,3-trimethyloctahydrobenzo[c]isoxazole;5-Ethyl-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;6-Isopentyl-1,4,4,8-tetramethyloctahydro-2H-benzo[d][1,3]oxazin-2-one;6-Isopentyl-1,4,4,8-tetramethyloctahydro-2H-benzo[d][1,3]oxazine;rac-(3aR,5R,7aR)-1,3,3-trimethyl-5-pentyloctahydrobenzo[c]isoxazole rac-(3aR,5R,7aR)-1,3,3-trimethyl-5-propyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7aR)-1-ethyl-3,3-dimethyl-5-propyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7aR)-1-isopropyl-3,3-dimethyl-5-propyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7aR)-5-butyl-1,3,3-trimethyloctahydrobenzo[c]isoxazole;rac-( 3aR,5R,7aR)-5-Butyl-1-ethyl-3,3-dimethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7aR)-5-Butyl-1-isopropyl-3,3-dimethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7aR)-5-Ethyl-1-isopropyl-3,3-dimethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7R,7aR)-1,3,3,5,7-pentamethyl-5-(2-(methylthio)phenyl)-octahydrobenzo[c ]isoxazole;rac-(3aR,5R,7R,7aR)-1-ethyl-3,3,5,7-tetramethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole;rac-(3aR,5R,7R,7aR)-1-ethyl-3,3,5,7-tetramethyl-5-(o-tolyl)octahydrobenzo[c]isoxazole;rac-(3aR,5R,7R,7aR)-5-(3-chloro-2-methylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7R,7aR)-5-(4-fluoro-2-methylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7R,7aR)-5-(4-methoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyl-5-(2-(methylthio)phenyl)octahydrobenzo[c]isoxazole;rac-(3aR,5R,7S, 7aR)-1,3,3,5,7-Pentamethyl-5-(2,4,5-trimethylphenyl)octahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-1,3,3,5,7-Pentamethyl-5-(2-methyl-5-(trifluoromethyl)phenyl)octahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-1,3,3,5,7-Pentamethyl-5-(4-(methylthio)phenyl)octahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-1,3,3,5,7-Pentamethyl-5-(4-(methylthio)phenyl)octahydrobenzo[c]isoxazole )-1,3,3,5,7-Pentamethyl-5-(5-methylthiophen-2-yl)octahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-1,3,3,5,7-Pentamethyl-5-(5-methylthiophen-3-yl)octahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-1,3,3,5,7-Pentamethyl-5-(m-tolyl)octahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-1,3,3,5,7-Pentamethyl- 5-(Naphthalen-1-yl)octahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyl-5-(naphthalen-2-yl)octahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyl-5-(o-tolyl)octahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyl-5-(p-tolyl)octahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyl-5-phenyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyl-5-propyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-1,3,3,7-tetramethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-1,3,3,7-tetramethyl-5-(o-trimethyl)octahydrobenzo[c]isoxazole octahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-1,3,3,7-tetramethyl-5-phenyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-1-ethyl-3,3,5,7-tetramethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-1-ethyl-3,3,5,7-tetramethyl-5-(o-tolyl)octahydrobenzo[c]isoxazole;rac-(3aR, rac-(3aR,5R,7S,7aR)-1-Ethyl-3,3,5,7-tetramethyl-5-phenyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-1-Ethyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-1-Ethyl-5-(2-methoxyphenyl)-3,3,7-trimethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-1-Isopropyl-3,3,5,7-tetramethyl-5-(3-methylbutadiene) -2-en-1-yl)octahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-1-isopropyl-3,3,5,7-tetramethyl-5-(o-tolyl)octahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-1-isopropyl-3,3,5,7-tetramethyl-5-phenyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-1-isopropyl-3,3,5,7-tetramethyl-5-propyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-1-Isopropyl-3,3,7-trimethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-1-Isopropyl-3,3,7-trimethyl-5-(o-tolyl)octahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-1-Isopropyl-3,3,7-trimethyl-5-phenyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-1-Isopropyl-3,3,7-trimethyl-5-phenyloctahydrobenzo[c]isoxazole rac-(3aR,5R,7S,7aR)-1-Isopropyl-5-(2-methoxyphenyl)-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-1-Isopropyl-5-(4-methoxyphenyl)-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-1-Isopropyl-5-(6-methoxyphenyl)-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole rac-(3aR,5R,7S,7aR)-5-(2,3-dimethylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(2,4-difluorophenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(2,4-dimethylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole tetramethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(2,4-dimethylphenyl)-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(2,5-difluorophenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(2,5-dimethylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(2,5-dimethylphenyl)-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(2,6-dimethylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(2-ethoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(2-ethoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole )-5-(2-ethylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(2-ethylphenyl)-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(2-ethylphenyl)-1-isopropyl-3,3,7-trimethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(2-fluorophenyl)-1,3,3 ,5,7-Pentamethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(2-methoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(2-methoxyphenyl)-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(3,4-difluorophenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole benzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(3,5-difluorophenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(3,5-dimethoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(3,5-dimethylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(3,5-dimethylphenyl)-1-isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(3-chloro-2-methylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(3-chloro-2-methylphenyl)-1-isopropyl-3,3,7-trimethyloctahydrobenzo[c]isoxazole rac-(3aR,5R,7S,7aR)-5-(3-fluoro-5-(trifluoromethyl)phenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(3-fluorophenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(3-isopropylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole rac-(3aR,5R,7S,7aR)-5-(3-methoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(4-(tert-butyl)phenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(4-(tert-butyl)phenyl)-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole;rac-(3a R,5R,7S,7aR)-5-(4-(tert-butyl)phenyl)-1-isopropyl-3,3,7-trimethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(4-chloro-2-methylphenyl)-1-isopropyl-3,3,7-trimethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(4-fluoro-2-methoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(4-fluoro-2-methylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(4-fluoro-2-methylphenyl)-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(4-fluorophenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(4-fluoro; rac-(3aR,5R,7S,7aR)-5-(4-methoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(5-chloro-2-methylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(5-chloro-2-methylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole -Isopropyl-3,3,7-trimethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(5-fluoro-2-methylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(5-fluoro-2-methylphenyl)-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(benzo[d][1,3]dioxol-5-yl)- 1,3,3,5,7-Pentamethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-(furan-3-yl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5,7-diethyl-1-isopropyl-3,3-dimethyloctahydrobenzo[c]isoxazole;rac-(3aR,5R,7S,7aR)-5-isopentyl-1-isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isooxazole octahydrobenzo[c]isoxazole;rac-(3aR,5S,7aR)-1,3,3,5-tetramethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole;rac-(3aR,7aR)-1,3,3,4,5,7-hexamethyloctahydrobenzo[c]isoxazole;rac-(3aR,7aR)-1,3,3-trimethyl-6-phenyloctahydrobenzo[c]isoxazole;rac-(3aR,7aR)-1,5,7-triethyl-3,3-dimethyloctahydrobenzo[c]isoxazole;rac-(3aR,7aS)-1,3,3,4,5,7-Hexamethyloctahydrobenzo[c]isoxazole;rac-(3aR,7S,7aR)-5,5-Diethyl-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole;rac-(3aS,5R,7S,7aS)-5-(4-Fluorophenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;rac-(3aS,5S,7S,7aS)-1-Ethyl-3,3,7-trimethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole rac-2-chloro-5-((3aS,5R,7R,7aS)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;rac-2-chloro-5-((3aS,5R,7R,7aS)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;rac-2-methyl-5-((3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile )benzonitrile;rac-3-((3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;rac-3-((3aR,5R,7S,7aR)-1-ethyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazol-5-yl)-4-methylbenzonitrile;rac-3-((3aR,5R,7S,7aR)-1-isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazol-5-yl)-4-methylbenzonitrile Tolyl;rac-3-((3aR,5R,7S,7aR)-1-isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;rac-3-((3aR,5R,7S,7aR)-1-isopropyl-3,3,7-trimethyloctahydrobenzo[c]isoxazol-5-yl)-4-methoxybenzonitrile;rac-3-chloro-5-((3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;rac-3-Methyl-4-((3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;rac-4-((3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;rac-4-Methoxy-3-((3aR,5R,7R,7aR)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;rac-4-Methoxy-3-((3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile rac-4-Methyl-2-((3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;rac-4-Methyl-3-((3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;rac-4-Methyl-3-((3aR,5R,7S,7aR)-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;rac-Methyl A compound represented by formula (I), (Ia), or (Ib) selected from the group consisting of 4-methyl-3-((3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzoate; rel-4-methyl-3-((3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile; and rel-4-methyl-3-((3aS,5S,7R,7aS)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;

[0038] As used herein, the prefix "rac" above refers to the relative stereochemistry of each descriptor (R,S), which discloses a racemic mixture of both enantiomers; the prefix "rel" refers to the relative stereochemistry of each descriptor (R,S), which refers to a single unassigned enantiomer. Chemical names without a stereochemical descriptor (i.e., neither R nor S) refer to diastereomeric and enantiomeric mixtures.

[0039] As used with respect to compounds of formula (I) (which encompasses compounds of formulas (Ia) and (Ib)), unless otherwise indicated, "alkyl" refers to linear or branched alkyl, "alkenyl" refers to linear or branched alkyl containing at least one carbon-carbon double bond, for example, two or three double bonds; and "cycloalkenyl" refers to cycloalkyl containing at least one carbon-carbon double bond, provided that the ring is not saturated.

[0040] Compounds as defined by Formula (I), which encompasses compounds represented by Formulas (Ia) and (Ib), contain several chiral centers and may themselves exist as a mixture of stereoisomers, or they may be resolved into isomerically pure forms. Because resolving stereoisomers adds to the complexity of manufacturing and purifying these compounds, it is preferred, solely for economic reasons, to use the compounds as mixtures of their stereoisomers. However, if it is desired to prepare individual stereoisomers, this may be achieved according to methods known in the art (e.g., preparative HPLC and GC, crystallization, or stereoselective synthesis). Consequently, the chemical structures depicted herein encompass all viable stereoisomeric forms of the described compounds.

[0041] It is also noted that compounds as defined by formula (I), which encompasses compounds represented by formulas (Ia) and (Ib), may exist in unsolvated as well as solvated forms (including hydrated forms), and as N-oxides. In general, compounds may be hydrated, solvated, or N-oxides. Certain compounds may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present invention.

[0042] "Solvate" refers to a compound formed by solvation (combination of solvent molecules with solute molecules or ions) or an aggregate consisting of solute ions or molecules, i.e., a compound as defined by Formula (I) with one or more solvent molecules (this encompasses compounds represented by Formulas (Ia) and (Ib)). When water is the solvent, the corresponding solvate is a "hydrate." Further suitable solvents may be, but are not limited to, the following: acetone, acetonitrile, benzene, cyclohexane, dihydrolevoglucosenone, methyl-tetrahydrofuran, pentylene glycol, ethylene glycol, petroleum ether, ethyl lactate, methyl lactate, propyl lactate, diethyl ether, tert-butyl methyl ether, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, ethanol, ethyl acetate, ethylene glycol, diethylene glycol, propylene glycol, heptane, hexane, methanol, toluene, and xylene.

[0043] "Salt" refers to salts of compounds as defined by Formula (I) (which encompasses compounds represented by Formulas (Ia) and (Ib)), which possess the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids, such as amino acids, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion; or salts formed when the acidic proton coordinates with an organic base, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like.

[0044] Compounds as defined by formula (I), which encompasses compounds represented by formulas (Ia) and (Ib), are "TRPM8 agonists" because they inhibit the cellular Ca2+ receptor activity of the TRPM8 channel. 2+It means that it has an agonistic effect on ion permeability. Consequently, "TRPM8 agonist" means any compound that, when it comes into contact with the TRPM8 receptor, causes an increase in fluorescence over background, for example, using the FLIPR method as described by Klein et al., (Chem. Senses 36:649-658, 2011) (which is also described in more detail in the experimental part).

[0045] Accordingly, in a second aspect, there is provided a method for modulating (in vitro and in vivo modulation) transient receptor potential channel melastatin member 8 (TRPM8), said method comprising contacting said receptor with a compound of formula (I), or a salt or solvate thereof. In one embodiment of the second aspect of the invention, the modulating method is an in vitro method.

[0046] In a third aspect, there is provided a non-medical method of inducing a cooling sensation in a human or animal, said method comprising contacting the human or animal with a compound of formula (I) (which encompasses compounds of formula (Ia) and (Ib)), or a salt or solvate thereof. In this regard, it should be noted that with respect to compounds of formula (Ib), some stereoisomers may be more potent than other stereoisomers.

[0047] In some embodiments, the method is a method of exerting a cooling effect on the skin or mucosa, comprising contacting the skin or mucosa with a product comprising one or more compounds of formula (I), which includes compounds of formula (Ia) and (Ib), or a salt or solvate thereof.

[0048] The compounds of formula (I), which encompass compounds of formula (Ia) and (Ib), may be applied directly or as a solution or suspension containing an effective amount of a compound of formula (I). The amount that is effective depends, inter alia, on the target TRPM8 area of ​​the body, but also on the cooling potency of the compound or mixture of compounds.

[0049] In a fourth aspect, there is provided a consumer product comprising a compound as defined by formula (I) (which encompasses compounds of formulae (Ia) and (Ib)), in particular said consumer product intended to be brought into contact with human skin and / or mucous membranes.

[0050] Consumer products that come into contact with mucous membranes include, but are not limited to, food products, beverages, chewing gum, tobacco products and tobacco substitute products, dental care products, personal care products (including lip care products, sexual health and intimate care products).

[0051] In some embodiments, the dental care product is an oral care product, a tooth care product, a dental prosthesis cleaner, a dental prosthesis adhesive, or the like.

[0052] In some embodiments, the food products are iced consumable products such as ice cream, sorbet, etc.; confectioneries such as candies and chocolates; food products, sauces, dairy products containing mint or mint flavors, e.g., milk-based drinks and yogurt; and snacks.

[0053] In some embodiments, the tobacco substitute product is a liquid or solid suitable for consumption by electrical means, such as liquids to vape an electronic cigarette. In some embodiments, the personal care products that are brought into contact with the mucous membrane are lip balms, nasal sprays, and eye drops.

[0054] Consumer products that come into contact with human skin include, but are not limited to, cosmetic products. In some embodiments, cosmetic products are skincare products, particularly bath products, skin washing and cleansing products, skin care products, eye makeup, nail care products, foot care products, etc. In some embodiments, cosmetic products are specific benefit products, particularly sunscreens, insect repellents, tanning products, bleaching products, deodorants, antiperspirants, depilatories, and shaving products. In some embodiments, cosmetic products are haircare products, particularly hair shampoos, haircare products, hair styling products, hair-shaping products, and hair coloring products, as well as scalp care products such as cooling shampoos and creams.

[0055] In some embodiments, the consumer product is selected from air care products, such as air fresheners or "ready-to-use" powdered air fresheners, that can be used in residential spaces (rooms, refrigerators, cupboards, shoes, or cars) and / or in public spaces (hall, hotel, mall, etc.).

[0056] The consumer product can be in any physical form, such as a solid, semi-solid, plaster, solution, suspension, lotion, cream, foam, gel, paste, or combinations thereof. The physical form of a suitable consumer product will depend primarily on the particular function that such consumer product is to accomplish, such as cleaning, softening, caring, cooling, etc.

[0057] In some embodiments, the consumer product that is contacted with human skin is a fabric care product (such as a fabric detergent, fabric conditioner (including tumble dryer sheets), and scent booster (liquid or solid)) that is applied to fabrics in a first step (e.g., when the fabrics are washed), and the treated fabrics are then contacted with human skin.

[0058] The use level of the compounds of the present invention (compounds as defined by formula (I), which includes compounds represented by formulas (Ia) and (Ib)) depends, among other things, on the target TRPM8 area of ​​the body, but also on the cooling efficacy of the compound or mixture of compounds. For example, in oral applications of the compounds of the present invention, such as toothpaste, floss, chewing gum, or white strips, the use level may be from about 0.00001% (0.01 ppm) to about 0.1% (1000 ppm) by weight of the composition; from about 0.00005% (0.5 ppm) to about 0.1% (1000 ppm); from about 0.0001% (1 ppm) to about 0.05% (500 ppm); or from about 0.001% (10 ppm) to about 0.01% (100 ppm). When the compounds of the present invention are used in mouthwashes, the level of use may be from about 0.000001% (10 ppb) to about 0.01% (100 ppm), or from about 0.0001% (1 ppm) to about 0.001% (10 ppm), by weight of the composition. When the compounds of the present invention are delivered topically, for example, in shampoos and lotions, the level may be from about 0.001% (10 ppm) to about 0.5% (5000 ppm), or from about 0.01% (100 ppm) to about 0.4% (4000 ppm), by weight of the composition.

[0059] The cooling potency (strength) of a compound depends on its EC 50 Defined by the value EC 50 EC (half effective concentration) refers to the concentration of a compound that induces a response halfway between baseline and maximum after a specified exposure time. It is commonly used as a measure of efficacy. 50 is a measure of concentration expressed in μM (micromolar concentration), where 1 μM is equivalent to 1 μmol / L.

[0060] EC 50 Compounds with an EC below 10 μM are perceived by humans as cooling. 50 The lower the value, the greater the cooling effect. For example, an EC of approximately 0.1 μM50 Compounds with this value are perceived as strong cooling compounds.

[0061] However, the cooling properties of a compound are defined not only by its strength (potency; EC50), but also by its longevity, which refers to the period (in minutes) over which the cooling effect is perceived. Longevity can range from a few minutes to several hours or even days after rinsing. Another important property of a cooling compound is its speed of onset, which refers to how quickly the cooling effect is perceived after the compound is brought into contact with mucous membranes or skin. Speed ​​of onset can range from immediate, with no noticeable delay in delivering a cooling sensation upon contact, to several seconds or even minutes after rinsing. Compounds of formula (I) (which encompasses compounds of formulas (Ia) and (Ib)) are a class of compounds that deliver a cooling sensation almost immediately upon contact.

[0062] The above-described "speed of onset" is particularly desirable for oral care products, since the cooling sensation is typically already noticeable during use of the respective product (e.g., while brushing teeth with toothpaste or rinsing with mouthwash). This so-called "up-front" cooling sensation enhances the consumer experience during use of the oral care product. It reinforces that the oral care product actively delivers its claimed benefits, thus relating to cleanliness and oral hygiene. Moreover, compounds that deliver this "up-front" cooling sensation can be sufficiently combined with compounds that deliver a long-lasting cooling sensation to create a sustained effect that begins during use of the product and continues for minutes or even hours after use. Depending on the desired effect to be achieved, a skilled flavorist in the art will know how to combine compounds with different cooling properties to create the desired temporal profile of the cooling effect.

[0063] The compounds of formula (I) (which encompasses the compounds of formulas (Ia) and (Ib)) are extremely potent at relatively low concentrations. Therefore, it is preferable to prepare a stock solution, which is further diluted before mixing with the consumer product. In addition to water, specific suitable solvents are triacetin and propylene glycol. Also mentioned are acetone, benzyl alcohol, dihydrolevoglucosenone, methyl-tetrahydrofuran, pentylene glycol, ethylene glycol, ethyl lactate, methyl lactate, propyl lactate, dimethyl sulfoxide, ethanol, ethyl acetate, ethylene glycol, diethylene glycol, propylene glycol, and triacetin, which are suitable solvents for the compounds of formula (I) (which encompasses the compounds of formulas (Ia) and (Ib)). However, other solvent systems containing surfactants may also be used.

[0064] In order to modify the cooling effect of a compound as defined herein by formula (I), which encompasses compounds represented by formulas (Ia) and (Ib), said compound, salt or solvate thereof may be combined with a compound selected from calcium ions and salts, magnesium ions and salts, arginine, or any chelating agent capable of binding calcium or magnesium.

[0065] These compounds are known to be able to modulate the concentrations of such ions in the extracellular space, thus affecting the response of the TRPM8 ion channel and leading to changes in the perceived cooling effect.

[0066] According to Kizilbash et al. (WO2019 / 121193 A1), both cooling intensity and flavor intensity can be enhanced when combined with an agent that has the property of enhancing the effect. Thus, in a specific embodiment, the compound defined by formula (I) herein can be combined with the enhancer disclosed in WO2019 / 121193 (which is incorporated by reference, particularly with respect to the enhancer). Further enhancer agents can include, for example, N-lactoylethanolamine (2-hydroxy-N-(2-hydroxyethyl)propanamide; CAS 5422-34-4), which is known as a cooling agent enhancer in PCT International Publication WO 2008 / 107137 (which is incorporated by reference, particularly with respect to the cooling enhancer as defined by formula (I)).

[0067] For the reasons given above, combinations of cooling compounds possessing different cooling profiles may be desirable depending on the effect desired by the consumer.

[0068] Thus, in a fifth aspect, there is provided a cooling composition, wherein the composition comprises at least one compound of formula (I), a salt or solvate thereof, and a further cooling compound.

[0069] In a specific embodiment, the compound of formula (I) (which encompasses compounds of formula (Ia) and (Ib)) is selected from the group consisting of menthol (e.g., in the form of peppermint oil and / or spearmint oil), menthone, p-menthanecarboxamide, N-2,3-trimethyl-2-isopropyl-butanamide (WS-23), menthyl lactate (Frescolat® ML), menthone glycerol acetal (Frescolat® MGA), 3-(1-menthoxy)-propane-1,2-diol (TK-10), p-menthane-3,8-diol (known as Coolact 38D), isopulegol (Coolact 38D), and the like. P), monomenthyl succinate (Physcool®), monomenthyl glutarate, o-menthylglycerol, menthyl N,N-dimethylsuccinamate, 2-(sec-butyl)cyclohexan-1-one (Freskomenthe), N-(pyrazol-3-yl)-N-(thiophen-2-ylmethyl)-2-(p-tolyloxy)acetamide, 2-(4-ethylphenoxy)-N-(pyrazol-3-yl)-N-(thiophen-2-ylmethyl)acetamide, 3-(benzo[d][1,3]dioxol-5-yl)-N,N-diphenylacrylamide, 4-(2-(4-allyl-2,6-dimethoxyphenoxy)-1-ethoxypropyl)-2-methoxyphenol, 4-(2-(4-allyl) ... N-(4-allyl-2,6-dimethoxyphenoxy)-1-((2-isopropyl-5-methylcyclohexyl)oxy)propyl)-2-methoxyphenol (including 4-(2-(4-allyl-2,6-dimethoxyphenoxy)-1-(((1S,2R,5S)-2-isopropyl-5-methylcyclohexyl)oxy)propyl)-2-methoxyphenol and 4-(2-(4-allyl-2,6-dimethoxyphenoxy)-1-(((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)oxy)propyl)-2-methoxyphenol), N-(2-hydroxy-2-phenylethyl)-2-isopropyl-5,5-dimethylcyclohexane-1-carboxamide, N-(4-(cyanomethyl)phenyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide, and N-(3-hydroxy-4-methoxyphenyl)-2-isopropyl-5,5-dimethylcyclohexanecarboxamide. Further cooling compounds with which the compound of formula (I) may be combined are those described in the applicant's international patent application PCT / EP2020 / 079009.

[0070] Examples of p-methanecarboxamides are N-ethyl-p-menthane-3-carboxamide (commercially known as WS-3), N-ethoxycarbonylmethyl-p-menthane-3-carboxamide (WS-5), N-(4-methoxyphenyl)-p-menthane-3-carboxamide (WS-12), and N-tert-butyl-p-menthane-3-carboxamide (WS-14), N-(4-(cyanomethyl)phenyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide (commercially known as Evercool 180), 2-isopropyl-5-methyl-N-(2-(pyridin-2-yl)ethyl)cyclohexane-1-carboxamide (commercially known as Evercool 180), and 2-isopropyl-5-methyl-N-(2-(pyridin-2-yl)ethyl)cyclohexane-1-carboxamide (commercially known as Evercool 180). 190), as well as compounds such as (1R,2S,5R)-N-((S)-2-((R)-2-aminopropanamido)-2-phenylethyl)-2-isopropyl-5-methylcyclohexane-1-carboxamide.

[0071] To provide more than just a cooling effect, the compounds of formula (I) (which encompasses compounds of formula (Ia) and (Ib)), salts or solvates thereof may be combined with other actives such as flavors, fragrances and sweeteners.

[0072] Examples of flavor ingredients include natural flavors, artificial flavors, spices, seasonings, etc. Exemplary flavor ingredients include synthetic flavor oils, as well as flavoring aromatic compounds and / or oils, oleoresins, extracts, and distillates, and combinations comprising at least one of the foregoing.

[0073] Flavor oils include peppermint oil, cinnamon oil, oil of wintergreen (methyl salicylate), peppermint oil, Japanese mint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, thuja oil, nutmeg oil, allspice, sage oil, mace, bitter almond oil, and cassia oil; useful flavoring agents include artificial, natural, and synthetic fruit flavors (such as vanilla), as well as citrus oils (including lemon, orange, lime, grapefruit, yuzu, and sudachi), and fruit extracts (including apple, pear, peach, grape, raspberry, blackberry, gooseberry, blueberry, strawberry, cherry, plum, prune, raisin, cola, guarana, neroli, pineapple, apricot, banana, melon, apricot, cherry, tropical fruit, mango, mangosteen, pomegranate, and papaya), and the like.

[0074] Additional exemplary flavors delivered by the flavoring composition include milk flavor, butter flavor, cheese flavor, cream flavor, and yogurt flavor; vanilla flavor; tea or coffee flavor, such as green tea flavor, oolong tea flavor, tea flavor, cocoa flavor, chocolate flavor, and coffee flavor; mint flavor, such as peppermint flavor, spearmint flavor, and mint flavor; agi flavor, ajowan flavor, anise flavor, angelica flavor, fennel flavor, allspice flavor, cinnamon flavor, chamomile flavor, mustard flavor, cardamom flavor, caraway flavor, cumin flavor, clove flavor, pepper flavor, coriander flavor, sassafras flavor, savory flavor, Zanthoxyli Fructus flavor, perilla flavor, juniper berry flavor, ginger flavor, star anise flavor, horseradish flavor, thyme flavor, tarragon flavor, dill flavor, chili pepper flavor, nutmeg flavor, basil flavor, marjoram flavor, rosemary flavor, bay leaf flavor, and wasabi (Japanese horseradish) flavor; nut flavors such as almond flavor, hazelnut flavor, macadamia nut flavor, peanut flavor, pecan flavor, pistachio flavor, and walnut flavor; alcoholic flavors such as wine flavor, whiskey flavor, brandy flavor, rum flavor, gin flavor, and liqueur flavor; floral flavors; and vegetable flavors such as onion flavor, garlic flavor, cabbage flavor, carrot flavor, celery flavor, mushroom flavor, and tomato flavor.

[0075] Generally, any flavoring or food additive (including food colorants) may be used, such as those described in "Essential guide to food additives" by Leatherhead Food International Ltd., Third edition 2008, pages 101-321 (ISBN: 978-1-905224-50-0), which publication is incorporated herein by reference.

[0076] In a specific embodiment, the compound of formula (I) (which encompasses compounds of formulas (Ia) and (Ib)) is selected from the group consisting of anethole, laevomenthol, laevocarvone, ethyl maltol, vanillin, eucalyptol, eugenol, racemic menthol, cis-3-hexenol, linalool, mint oil (e.g., peppermint arvensis oil, peppermint piperita oil, spearmint native oil, spearmint scotch oil, and the like). scotch oil), corylone, ethyl butyrate, cis-3-hexenyl acetate, citral, eucalyptus oil, ethyl vanillin, methyl salicylate, 2'-hydroxypropiophenone, ethyl acetate, methyl dihydrojasmonate, geraniol, lemon oil, isoamyl acetate, thymol, ionone beta, linalyl acetate, decanal, cis-jasmone, ethyl hexanoate, melonal (2,6-dimethylhept-5-enal), citronellol, ethyl acetoacetate, nutmeg oil, and clove oil, or mixtures thereof.

[0077] Examples of sweeteners include, but are not limited to, sucrose, fructose, glucose, high fructose corn syrup, corn syrup, xylose, arabinose, rhamnose, erythritol, xylitol, mannitol, sorbitol, inositol, acesulfame potassium, aspartame, neotame, sucralose, and saccharin, and mixtures thereof; trilobatin, hesperetin dihydrochalcone glucoside, na Lingin dihydrochalcone, mogroside V, Monk fruit extract, rubusoside, Rubus extract, glycyphyllin, isomogroside V, mogroside IV, siamenoside I, neomogroside, mukuroziosid IIb, (+)-hernandulcin, 4β-hydroxyhernandulcin, baionoside, phlomisoside I, bryodulcoside, bryoside, bryonoside, abru Sosides A-E, cyclocarioside A, cyclocaryoside I, albiziasaponins A-E, glycyrrhizin, aboglycyrrhizin, periandrins I-V, pterocaryosides A and B, osladin, polypodosides A and B, telesmosides A8-18, phyllodulcin, huangqioside E, neoasci These compounds include rubin, monatin, 3-acetoxy-5,7-dihydroxy-4'-methoxyflavanone, 2R,3R-(+)-3-acetoxy-5,7,4'-trihydroxyflavanone, (2R,3R)-dihydroquercetin 3-O-acetate, dihydroquercetin 3-O-acetate 4'-methyl ether, brazzein, curculin, mabinlin, monellin, neoculin, pentadin, thaumatin, and combinations thereof. Some of the compounds listed above are known as sweetness enhancers and sweeteners. When used as sweetness enhancers, they are usually used below their sweetness detection threshold.

[0078] In certain embodiments, compounds of Formula (I), which include compounds of Formulas (Ia) and (Ib), may be combined with additional ingredients collectively referred to as orally acceptable carrier materials.

[0079] In some aspects, the orally acceptable carrier may comprise one or more compatible solid or liquid excipients or diluents suitable for topical oral administration. "Compatible," as used herein, means that the components of the composition can be mixed together without interacting in a manner that would substantially reduce stability and / or efficacy. Carriers may include the usual and conventional components of dentifrices, non-abrasive gels, subgingival gels, mouthwashes or rinses, mouth sprays, chewing gum, lozenges, and breath mints. The choice of carrier to be used is primarily determined by the form in which the composition will be introduced into the oral cavity. Carrier materials for toothpastes, tooth gels, or the like, include, for example, abrasives, sudsing agents, binders, humectants, flavoring agents, sweetening agents, and the like, as disclosed in U.S. Patent No. 3,988,433 to Benedict. Carrier materials for two-phase dentifrice formulations are all disclosed in U.S. Patents 5,213,790; 5,145,666; and 5,281,410 to Lukacovic et al., and U.S. Patents 4,849,213 and 4,528,180 to Schaeffer. Carrier materials for mouthwashes, rinses, or mouth sprays typically include water, flavoring agents, and sweeteners, as disclosed, for example, in U.S. Patent 3,988,433 to Benedict. Carrier materials for lozenges typically include a candy base; carrier materials for chewing gums typically include a gum base, flavoring agents, and sweeteners, as disclosed, for example, in U.S. Patent 4,083,955 to Grabenstetter et al. Carrier materials for sachets typically include a sachet bag, flavoring agents, and sweetening agents. For subgingival gels used to deliver active agents to or around the periodontal pocket, a "subgingival gel carrier" is selected, for example, as disclosed in U.S. Patent Nos. 5,198,220 and 5,242,910, both to Damani. Carriers suitable for preparing compositions of the present disclosure are well known in the art.Their choice will depend on secondary considerations such as taste, cost, and shelf life.

[0080] Further suitable types of orally acceptable carrier materials or excipients are listed in WO2010 / 059289, especially on pages 17-31, which are incorporated by reference.

[0081] Scientific literature indicates that activating the TRPM8 channel may be useful for treating most TRPM8-mediated pathological conditions (J.Med.Chem.2016,59(22),10006-10029). Therefore, it can be inferred that the compound of formula (I) may also be suitable for treating prostate cancer, bladder weakness, inflammation, or pain, including contacting a patient with one or more compounds of formula (I) as defined herein. It can also be inferred that the compound of formula (I) as defined herein may be suitable for relieving the symptoms of coughs and colds, irritability, sore throat, or hoarseness, and for treating pharyngeal dysphagia (Int.J.Mol.Sci.2018,19,4113).

[0082] Thus, in a sixth aspect, there is provided a pharmaceutical composition comprising one or more compounds as defined by formula (I) (which encompasses compounds of formulae (Ia) and (Ib)), or a salt or solvate thereof.

[0083] Depending on the particular treatment regimen envisaged, pharmaceutical compositions containing one or more compounds of formula (I) may be administered parenterally, topically, orally, or locally. Pharmaceutical compositions may be liquid, suspension, or solid formulations.

[0084] In some embodiments, the pharmaceutical composition is a nasal spray, a topical cream, a skin spray, a throat spray, or eye drops.

[0085] The compounds of formula (I) are either compounds known per se or compounds that may be prepared by one skilled in the art using known synthetic methods. Compounds of formula (I) (where n is 0) can be prepared from aldehydes 2 by the reaction of these with the respective hydroxylamines R 6 The compound of formula (I) (where n is 0) may be further converted to the compound of formula (I) (where n is 1) by reducing the nitrogen-oxygen bond with a typical reducing agent such as hydrogen under the action of a palladium catalyst (e.g., palladium on charcoal) or zinc powder in a suitable solvent such as ethyl acetate, tetrahydrofuran, or toluene at room temperature or a suitable temperature such as 50°C. The compound of formula (I) (where n is 1) may then be condensed with an appropriate reaction partner such as an aldehyde R'CHO or carbonyldiimidazole to provide the desired substitution in formula (I). [ka] X, R 1 , R 2 , R 4 ~R 9 and R' have the same meaning as provided in formula (I).

[0086] In general, aldehyde 2 may be prepared by standard synthetic methods known to those skilled in the art. For example, aldehyde 2 (wherein X is CHR 3and the dotted line represents a single bond) may be prepared by controlled reduction of α,β-unsaturated aldehydes 3 by reacting them with hydrogen gas in the presence of a catalyst such as Lindlar's catalyst (palladium on calcium carbonate, poisoned by lead) in a suitable solvent such as ethyl acetate at a suitable temperature such as room temperature. Other methods for controlled reduction are known to those skilled in the art, and conditions may vary depending on the substrate.

[0087] Aldehyde 3 may then be prepared by condensing aldehyde 4 with allylic alcohol 5 by reacting them together (as depicted below), optionally in the presence of an acid catalyst such as a protic acid (e.g., triethylamine hydrochloride or p-toluenesulfonic acid) or a Lewis acid. This is done in a suitable solvent such as xylene or toluene, or neat, at elevated temperatures (e.g., 80°C, 120°C, or 140°C), typically with removal of water by a Dean-Stark apparatus. [ka] R 1 ~R 4 and R 7 ~R 9 has the same meaning as provided in formula (I).

[0088] Formula (I), where R 1 is phenyl (optionally substituted as defined above), naphthyl (optionally substituted as defined above), and C-C 10 For compounds represented by the formula: wherein one or two C atoms are independently replaced by a heteroatom selected from sulfur, nitrogen, and oxygen, aldehyde 3 may be prepared from aldehyde 6, which may then be prepared as described above. The conversion of aldehyde 6 to aldehyde 3 can be achieved by reacting aldehyde 6 with the respective aryl bromide R 1 Br (where R 1has the same meaning as provided for formula (I) above) in the presence of a palladium catalyst, such as palladium acetate, and a phosphine ligand, such as tricyclohexylphosphine or tri-tert-butylphosphine. The reaction is typically carried out under an inert atmosphere, such as dinitrogen or argon, in the presence of a base, such as an inorganic base (e.g., cesium carbonate or potassium carbonate or sodium phosphate), in a suitable solvent, such as N,N-dimethylformamide, dimethyl sulfoxide, or N,N-dimethylacetamide, at elevated temperatures (e.g., 100° C. or 120° C.).

[0089] [ka] R 2 ~R 4 and R 7 ~R 9 has the same meaning as provided in formula (I).

[0090] The present invention will now be further described with reference to the following non-limiting examples, which are illustrative only and it will be understood that variations and modifications may occur to those skilled in the art.

[0091] example Example 1: (E)-2,4,7-trimethylocta-2,6-dienal (General Procedure) A mixture of (E)-2-methylpent-2-enal (12.27 g, 125 mmol), 3-methylbut-2-en-1-ol (21.53 g, 250 mmol), and 1.5 g EtN-HCl in xylene was refluxed for 20 h. During this time, water was collected and removed using a Dean-Stark apparatus, and the reaction was monitored by GC. After cooling to room temperature, the reaction mixture was diluted with MTBE (methyl ether tert-butyl ether), washed with water and brine, dried over MgSO, filtered, and then evaporated under reduced pressure to give the crude product, which was purified by distillation to give (E)-2,4,7-trimethylocta-2,6-dienal (14.20 g, 68% yield).

[0092] Example 2: (E)-4-Methyl-3-(2,4,7-trimethyl-1-oxoocta-2,6-dien-4-yl)benzonitrile (General Procedure) A mixture of 3-bromo-4-methylbenzonitrile (25.80 g, 132.00 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (23.51 g, 132.00 mmol), diacetoxypalladium (1.48 g, 6.58 mmol), tri-tert-butylphosphane (2.66 g, 13.15 mmol), and CsCO (42.80 g, 132.00 mmol) in DMF (N,N-dimethylformamide; 120 mL) was heated to 110-120 °C overnight under an Ar atmosphere, and the reaction was monitored by TLC, GC, and GC-MS. After cooling to room temperature, the reaction mixture was diluted with MTBE and filtered through a small pad of silica gel, washing with MTBE. The combined filtrate was concentrated in vacuo to give the crude product, which was purified by distillation or flash chromatography (hexane / MTBE=50:1 to 10:1) to provide the aldehyde (E)-4-methyl-3-(2,4,7-trimethyl-1-oxoocta-2,6-dien-4-yl)benzonitrile (15.27 g, 52.60 mmol, 40% yield) as a pale yellow oil. GC / MS(EI):m / z(%):281(1)[M + ],213(100),198(44),184(24),170(17),154(13),140(11),127(8),115(8),69(83). 1 H NMR(300MHz,CDCl3)δ9.43(s,1H),7.64(s,1H),7.48-7.36(m,1H),7.22(d,J=7.9Hz,1H),6.80(s,1H),4. 89(t,J=7.4Hz,1H),2.60(d,J=10.8Hz,2H),2.30(s,3H),1.67(s,3H),1.54(d,J=7.2Hz,6H),1.16(s,3H). 13C NMR(75MHz,CDCl3)δ195.6(t),160.8(t),145.5(q),142.0(q),138.5(q),136.1(q),132.9(t),130.4(t),1 30.2(t),119.4(q),118.5(t),110.0(q),44.8(q),39.8(d),26.1(s),24.8(s),23.3(s),18.1(s),9.8(s).

[0093] Example 3: (E)-2,4,7-trimethyl-4-(o-tolyl)octa-2,6-dienal Following the general procedure described in Example 2: reaction of 1-bromo-2-methylbenzene (37.60 g, 220.00 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (18.26 g, 110.00 mmol), diacetoxypalladium (1.23 g, 5.49 mmol), tricyclohexylphosphane (3.08 g, 10.98 mmol), CsCO (42.90 g, 132.00 mmol) in DMF (150 mL) gave the title product (22.56 g, 80% yield) as a pale yellow oil. GC / MS(EI):m / z(%):256(1)[M + ],188(93),173(100),159(68),128(34),115(24),105(14),91(17),77(8),69(33). 1 H NMR(300MHz,CDCl3)δ9.45(s,1H),7.38(d,J=9.6,8.0Hz,1H),7.26-7.05(m,3H),6.88(s,1H),5 .01(t,1H),2.67-2.50(m,2H),2.23(s,3H),1.83-1.71(m,1H),1.70-1.51(m,9H),1.20(s,3H). 13 C NMR(75MHz,CDCl3)δ196.1(t),162.8(t),143.9(q),138.1(q),135.8(q),134.9(q),132.0(t),126.6 (t),126.3(t),126.0(t),119.5(t),44.8(q),40.0(d),26.1(s),24.9(s),22.9(s),18.0(s),9.5(s).

[0094] Example 4: (E)-4-(4-fluoro-2-methylphenyl)-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 2: reaction of 1-bromo-4-fluoro-2-methylbenzene (6.82 g, 36.10 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (3.00 g, 18.04 mmol), diacetoxypalladium (0.20 g, 0.90 mmol), tricyclohexylphosphane (0.51 g, 1.80 mmol), CsCO (7.05 g, 21.65 mmol) in DMF (20 mL) gave the title product (0.90 g, 18% yield) as a yellow oil. GC / MS(EI):m / z(%):274(1)[M + ],206(100),191(61),177(72),146(31),133(19),123(20),109(14),77(4),69(53). 1 H NMR(300MHz,CDCl3)δ9.41(s,1H),7.34-7.27(m,1H),6.86-6.80(m,2H),4.95(t,J=7.4Hz,1H),2 .64-2.48(m,2H),2.20(s,3H),1.96(d,1H),1.67(s,3H),1.57(s,3H),1.50(s,3H),1.20(s,3H). 13 C NMR(75MHz,CDCl3)δ196.0(t),163.0(q),162.5(t),159.7(q),139.7(q),139.7(q),138.3(q),138.3(q),135.3(q),128.0(t),1 27.9(t),119.3(t),118.6(t),118.3(t),112.6(t),112.3(t),44.4(q),40.2(d),26.1(s),25.2(s),22.9(s),18.1(s),9.6(s).

[0095] Example 5: (E)-4-(5-chloro-2-methylphenyl)-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 2: reaction of 2-bromo-4-chloro-1-methylbenzene (5.30 g, 25.80 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (2.15 g, 12.90 mmol), diacetoxypalladium (0.15 g, 0.65 mmol), tri-tert-butylphosphane (0.26 g, 1.29 mmol), CsCO (5.04 g, 15.48 mmol) in DMF (20 mL) gave the title product (1.39 g, 37% yield) as a pale yellow oil. GC / MS(EI):m / z(%):290(1)[M + ], 222(100), 207(54), 193(24), 186(18), 172(12), 157(14), 128(23), 115(22), 69(92). 1 H NMR(300MHz,CDCl3)δ9.42-9.37(m,1H),7.32(d,J=2.0Hz,1H),7.14-7.09(m,1H),7.05-7.00(m,1H),6.79(s,1 H),4.97(t,J=7.4Hz,1H),2.69-2.44(m,2H),2.17(s,3H),1.67(s,3H),1.57(s,3H),1.49(s,3H),1.20(s,3H). 13 C NMR(75MHz,CDCl3)δ195.8(t),161.5(t),145.9(q),138.3(q),134.3(q),133.2(q),131.7(q),131.4(q),1 26.6(t),126.5(t),121.5(t),119.0(t),44.8(q),39.8(d),26.1(s),24.8(s),22.3(s),18.1(s),9.7(s).

[0096] Example 6: (E)-3-(2,4,7-trimethyl-1-oxoocta-2,6-dien-4-yl)benzonitrile Following the general procedure described in Example 2: reaction of 3-bromobenzonitrile (6.57 g, 36.10 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (3.00 g, 18.04 mmol), diacetoxypalladium (0.20 g, 0.90 mmol), tri-tert-butylphosphane (0.37 g, 1.80 mmol), CsCO (5.88 g, 18.04 mmol) in DMF (20 mL) gave the title product (1.11 g, 23% yield) as a pale yellow oil. GC / MS(EI):m / z(%):267(1)[M + ],199(87),184(39),170(13),154(14),140(9),127(11),116(10),103(4),69(100). 1 H NMR(300MHz,CDCl3)δ9.42(s,1H),7.56-7.36(m,4H),6.75(s,1H),5.04-4.82(m ,1H),2.49(d,J=7.4Hz,2H),1.65(s,3H),1.53(s,3H),1.46(s,3H),1.25(s,3H). 13 C NMR(75MHz,CDCl3)δ195.7(t),160.7(t),148.0(q),140.3(q),136.2(q),131.5(t),130.3(t),130.0( t),129.2(t),119.0(q),118.3(t),112.4(q),44.9(q),42.8(d),26.0(s),24.5(s),17.9(s),10.7(s).

[0097] Example 7: (E)-4-(2,5-dimethylphenyl)-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 2: reaction of 2-bromo-1,4-dimethylbenzene (6.68 g, 36.10 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (3.00 g, 18.04 mmol), diacetoxypalladium (0.20 g, 0.90 mmol), tri-tert-butylphosphane (0.37 g, 1.80 mmol), CsCO (7.05 g, 21.65 mmol) in DMF (20 mL) gave the title product (2.44 g, 50% yield) as a pale yellow oil. GC / MS(EI):m / z(%):270(1)[M + ],202(93),187(73),173(100),159(28),143(29),128(24),115(17),91(13),69(26). 1 H NMR(300MHz,CDCl3)δ9.41(s,1H),7.17(s,1H),7.06-6.93(m,2H),6.85(s,1H),5.04(t,J=7.4Hz,1H ),2.69-2.45(m,2H),2.33(s,3H),2.15(s,3H),1.72(s,3H),1.60(s,3H),1.52(s,3H),1.21(s,3H). 13 C NMR(75MHz,CDCl3)δ196.2(t),163.0(t),143.9(q),138.1(q),135.2(q),134.9(q),132.6(q),132.0(t), 127.3(t),127.0(t),119.7(t),44.7(q),40.1(d),26.1(s),25.0(s),22.5(s),21.4(s),18.1(s),9.6(s).

[0098] Example 8: (E)-4-(5-fluoro-2-methylphenyl)-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 2: reaction of 2-bromo-4-fluoro-1-methylbenzene (6.34 g, 33.60 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (3.00 g, 16.78 mmol), diacetoxypalladium (0.19 g, 0.84 mmol), tri-tert-butylphosphane (0.34 g, 1.68 mmol), CsCO (5.47 g, 16.78 mmol) in DMF (20 mL) gave the title product (1.00 g, 22% yield) as a pale yellow oil. GC / MS(EI):m / z(%):274(1)[M + ],206(100),191(69),177(29),159(12),146(25),133(15),123(12),109(10),69(69). 1 H NMR(300MHz,CDCl3)δ9.43(s,1H),7.16-6.98(m,2H),6.92-6.74(m,2H),5.13-4.86(m,1 H),2.70-2.48(m,2H),2.18(s,3H),1.67(s,3H),1.58(s,3H),1.50(s,3H),1.21(s,3H). 13 C NMR(75MHz,CDCl3)δ195.9(t),163.0(t),161.8(t),159.8(t),146.2(q),146.1(q),138.4(q),135.5(q),133.3(t),133.2(t),131.4 (q),131.4(q),119.1(t),113.8(t),113.5(t),113.3(t),113.0(t),44.8(q),39.8(d),26.1(s),24.9(s),22.1(s),18.1(s),9.6(s).

[0099] Example 9: (E)-4-(2-methoxyphenyl)-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 2: reaction of 1-bromo-2-methoxybenzene (6.75 g, 36.1 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (3.00 g, 18.04 mmol), diacetoxypalladium (0.20 g, 0.90 mmol), tricyclohexylphosphane (0.51 g, 1.80 mmol), CsCO (7.05 g, 21.65 mmol) in DMF (20 mL) gave the title product (2.50 g, 51% yield) as a pale yellow oil. GC / MS(EI):m / z(%):272(2)[M + ],203(100),188(50),175(40),161(17),145(12),128(14),115(15),91(16),69(9). 1 H NMR(300MHz,CDCl3)δ9.27(s,1H),7.20-7.15(m,1H),7.13-7.05(m,1H),6.83(t,J=7.5Hz,1H),6.76(d,J=0.7Hz,1H),6.70(d ,J=8.1Hz,1H),4.89(t,J=7.4Hz,1H),3.55(s,3H),2.55(d,J=7.6Hz,2H),1.55(s,3H),1.46(s,3H),1.38(s,3H),1.13(s,3H). 13 C NMR(75MHz,CDCl3)δ196.3(t),165.1(t),157.1(q),136.2(q),134.4(q),127.9(t),126.8(t),1 20.6(t),120.1(t),111.5(t),55.1(s),43.0(q),39.1(d),26.0(s),23.4(s),17.9(s),9.3(s).

[0100] Example 10: (E)-2,4,7-trimethyl-4-(p-tolyl)octa-2,6-dienal Following the general procedure described in Example 2: reaction of 1-bromo-4-methylbenzene (6.09 g, 35.6 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (2.96 g, 17.82 mmol), diacetoxypalladium (0.20 g, 0.89 mmol), triphenylphosphine (0.47 g, 1.78 mmol), CsCO (5.81 g, 17.82 mmol) in DMF (20 mL) gave the title product (1.75 g, 38% yield) as a colorless oil. GC / MS(EI):m / z(%):256(1)[M + ],188(70),187(70),172(80),159(100),128(30),115(18),105(14),91(13),69(10). 1 H NMR(300MHz,CDCl3)δ9.40(s,1H),7.17-7.07(m,4H),6.79(d,J=5.7Hz,1H),5.02(t,J=7.3H) z,1H),2.64-2.43(m,2H),2.31(s,3H),1.68(s,3H),1.56(s,3H),1.51(s,3H),1.33(s,3H). 13 C NMR(75MHz,CDCl3)δ196.4(t),163.3(t),143.6(q),139.9(q),135.7(q),135.0(q),129.1( t),126.5(t),119.6(t),44.6(q),42.7(d),26.1(s),25.0(s),21.0(s),18.1(s),10.5(s).

[0101] Example 11: (E)-4-(2,4-dimethylphenyl)-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 2: reaction of 1-bromo-2,4-dimethylbenzene (4.78 g, 25.80 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (2.15 g, 12.90 mmol), diacetoxypalladium (0.15 g, 0.65 mmol), tricyclohexylphosphane (0.36 g, 1.29 mmol), CsCO (4.20 g, 12.90 mmol) in DMF (35 mL) gave the title product (2.40 g, 69% yield) as a pale yellow oil. GC / MS(EI):m / z(%):270(2)[M + ],202(53),186(71),173(29),159(21),143(23),128(19),115(14),91(10),69(12). 1 H NMR(300MHz,CDCl3)δ9.42(s,1H),7.23(d,J=8.0Hz,1H),6.97(d,J=8.0Hz,1H),6.91(s,1H),6.83(s,1H),5.01(t,J=7 .4Hz,1H),2.57(qd,J=14.5,7.7Hz,2H),2.26(s,3H),2.18(s,3H),1.67(s,3H),1.58(s,3H),1.49(s,3H),1.18(s,3H). 13 C NMR(75MHz,CDCl3)δ195.9(t),162.9(t),140.9(q),138.1(q),135.9(q),135.5(q),134.7(q),132.8(t), 126.6(t),126.2(t),119.7(t),44.4(q),40.2(d),26.0(s),25.0(s),22.7(s),20.7(s),18.0(s),9.5(s).

[0102] Example 12: (E)-4-(3-chloro-2-methylphenyl)-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 2: reaction of 1-bromo-3-chloro-2-methylbenzene (5.30 g, 25.8 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (2.15 g, 12.90 mmol), diacetoxypalladium (0.145 g, 0.645 mmol), tri-tert-butylphosphane (0.26 g, 1.29 mmol), CsCO (5.04 g, 15.48 mmol) in DMF (20 mL) gave the title product (1.51 g, 40% yield) as a pale yellow oil. GC / MS(EI):m / z(%):290(1)[M + ], 222(100), 207(61), 195(34), 186(36), 157(14), 141(27), 128(27), 115(24), 69(94). 1 H NMR(300MHz,CDCl3)δ9.42(s,1H),7.29(d,J=7.9Hz,2H),7.18-7.10(m,1H),6.86(s,1H),4.97(t,J= 8.0,6.8Hz,1H),2.65-2.50(m,2H),2.23(s,3H),1.67(s,3H),1.57(s,3H),1.51(s,3H),1.17(s,3H). 13 C NMR(75MHz,CDCl3)δ195.8(t),162.1(t),146.3(q),137.8(q),136.4(q),135.3(q),133.9(q),127.8 (t),126.6(t),124.9(t),119.0(t),45.2(q),40.2(d),26.0(s),25.2(s),20.3(s),18.0(s),9.5(s).

[0103] Example 13: (E)-4-(2-fluorophenyl)-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 2: reaction of 1-bromo-2-fluorobenzene (6.32 g, 36.10 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (3.00 g, 18.04 mmol), diacetoxypalladium (0.20 g, 0.90 mmol), tri-tert-butylphosphane (0.37 g, 1.80 mmol), CsCO (7.05 g, 21.65 mmol) in DMF (20 mL) gave the title product (1.4 g, 30% yield) as a pale yellow oil. GC / MS(EI):m / z(%):260(1)[M + ],192(100),177(99),163(31),146(21),133(14),123(14),109(30),77(5),69(59). 1 H NMR(300MHz,CDCl3)δ9.39(s,1H),7.37-7.30(m,1H),7.28-7.19(m,1H),7.17-7.09(m,1H),7.08-6.92(m,2H) ),6.83(s,1H),5.03-4.94(m,1H),2.63(d,J=7.4Hz,2H),1.67(s,3H),1.57(s,3H),1.53(s,3H),1.28(s,3H). 13 C NMR(75MHz,CDCl3)δ196.2(t),162.2(t),138.1(q),138.1(q),135.3(q),133.2(q),133.1(q),128.5(t),128.4(t),127.6(t),1 27.6(t),123.9(t),123.9(t),119.0(t),116.1(t),115.8(t),42.5(d),39.8(d),39.8(d),26.0(s),23.4(s),17.9(s),9.5(s).

[0104] Example 14: (E)-4-(2,4,7-trimethyl-1-oxoocta-2,6-dien-4-yl)benzonitrile Following the general procedure described in Example 2: reaction of 4-bromobenzonitrile (6.57 g, 36.10 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (3.00 g, 18.04 mmol), diacetoxypalladium (0.20 g, 0.90 mmol), tri-tert-butylphosphane (0.37 g, 1.804 mmol), CsCO (5.88 g, 18.04 mmol) in DMF (20 mL) gave the title product (1.00 g, 21% yield) as a pale yellow oil. GC / MS(EI):m / z(%):267(1)[M + ],199(86),184(38),170(11),154(13),140(9),127(11),116(10),103(4),69(100). 1 H NMR(300MHz,CDCl3)δ9.39(s,1H),7.58(d,J=12.8Hz,2H),7.32(d,J=8.2Hz,2H),6.72(s,1H),4 .90(t,J=7.2Hz,1H),2.46(d,J=7.4Hz,2H),1.61(s,3H),1.50(s,3H),1.44(s,3H),1.22(s,3H). 13 C NMR(75MHz,CDCl3)δ195.6(t),160.7(t),152.0(q),140.3(q),136.1(q),132.1(t),127.5( t),118.7(q),118.3(t),110.1(q),45.2(q),42.7(d),25.9(s),24.4(s),17.9(s),10.7(s).

[0105] Example 15: (E)-4-(2,5-dimethoxyphenyl)-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 2: reaction of 2-bromo-1,4-dimethoxybenzene (7.83 g, 36.10 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (3.00 g, 18.04 mmol), diacetoxypalladium (0.20 g, 0.90 mmol), tricyclohexylphosphane (0.51 g, 1.80 mmol), CsCO (7.05 g, 21.65 mmol) in DMF (20 mL) gave the title product (3.25 g, 60% yield) as a yellow oil. GC / MS(EI):m / z(%):274(1)[M + ],206(100),191(69),177(29),159(12),146(25),133(15),123(12),109(10),69(69). 1 H NMR(300MHz,CDCl3)δ9.37(s,1H),6.89(s,1H),6.83(s,1H),6.77-6.69(m,2H),5.01(t,J=15.8,8.4Hz,1 H),3.77(s,3H),3.63(s,3H),2.62(d,J=7.5Hz,2H),1.68(s,3H),1.58(s,3H),1.45(s,3H),1.26(s,3H). 13 C NMR(75MHz,CDCl3)δ196.6(t),165.1(t),153.6(q),151.6(q),136.4(q),136.2(q),134.7(q),120.0(t), 114.6(t),112.4(t),110.8(t),55.8(s),55.7(s),43.1(q),39.2(d),26.1(s),23.4(s),18.0(s),9.5(s).

[0106] Example 16: (E)-2-(2,4,7-trimethyl-1-oxoocta-2,6-dien-4-yl)benzonitrile Following the general procedure described in Example 2: reaction of 2-bromobenzonitrile (4.70 g, 25.80 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (2.15 g, 12.90 mmol), diacetoxypalladium (0.15 g, 0.65 mmol), tri-tert-butylphosphane (0.26 g, 1.29 mmol), CsCO (5.04 g, 15.48 mmol) in DMF (20 mL) gave the title product (1.26 g, 37% yield) as a pale yellow oil. GC / MS(EI):m / z(%):267(1)[M + ],199(43),170(100),156(23),143(7),128(14),116(9),103(4),89(3),69(58). 1 H NMR(300MHz,CDCl3)δ9.48(s,1H),7.67-7.48(m,3H),7.38-7.29(m,1H),6.95(d,J=1.2Hz,1H),4.94 (t,J=7.5Hz,1H),2.73(d,J=11.2Hz,2H),1.66(s,3H),1.58(d,J=3.9Hz,6H),1.17(d,J=1.1Hz,3H). 13 C NMR(75MHz,CDCl3)δ196.0(t),160.7(t),150.7(q),139.0(q),136.3(q),135.2(t),132.7(t),127.1( t),127.0(t),119.4(q),118.3(t),111.7(q),44.7(q),40.8(d),26.1(s),23.8(s),18.1(s),9.9(s).

[0107] Example 17: (E)-4-Methyl-2-(2,4,7-trimethyl-1-oxoocta-2,6-dien-4-yl)benzonitrile Following the general procedure described in Example 2: reaction of 2-bromo-4-methylbenzonitrile (3.28 g, 16.74 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (1.56 g, 8.37 mmol), diacetoxypalladium (0.09 g, 0.42 mmol), tricyclohexylphosphane (0.24 g, 0.84 mmol), CsCO (3.27 g, 10.05 mmol) in DMF (20 mL) gave the title product (0.97 g, 41% yield) as a pale yellow oil. GC / MS(EI):m / z(%):281(1)[M + ],253(2),213(30),184(100),170(30),153(7),142(9),128(6),115(8),69(46). 1 H NMR(300MHz,CDCl3)δ9.46(s,1H),7.50(d,J=7.8Hz,1H),7.29(s,1H),7.12(d,J=7.8Hz,1H),6.92(d,J=1.1Hz,1H), 4.95(t,J=7.5Hz,1H),2.71(d,J=7.5Hz,2H),2.42(s,3H),1.66(s,3H),1.56(d,J=5.9Hz,6H),1.18(d,J=1.0Hz,3H). 13 C NMR(75MHz,CDCl3)δ196.0(t),160.8(t),150.6(q),143.5(q),138.8(q),136.1(q),135.0(t),127.8(t),1 27.7(t),119.7(q),118.4(t),108.6(q),44.5(q),40.8(d),26.1(s),23.8(s),22.1(s),18.1(s),9.9(s).

[0108] Example 18: (E)-4-(3-methoxyphenyl)-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 2: reaction of 1-bromo-3-methoxybenzene (6.75 g, 36.10 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (3.00 g, 18.04 mmol), diacetoxypalladium (0.20 g, 0.90 mmol), tricyclohexylphosphane (0.51 g, 1.80 mmol), CsCO (7.05 g, 21.65 mmol) in DMF (20 mL) gave the title product (1.20 g, 24% yield) as a pale yellow oil. GC / MS(EI):m / z(%):272(2)[M + ],204(82),188(100),175(72),161(18),145(21),128(20),115(21),91(20),69(22). 1 H NMR(300MHz,CDCl3)δ9.42(s,1H),7.25-7.18(m,1H),6.87-6.79(m,2H),6.78-6.71(m,2H),5. 00(t,1H),3.79(s,3H),2.61-2.44(m,2H),1.66(s,3H),1.55(s,3H),1.50(s,3H),1.32(s,3H). 13 C NMR(75MHz,CDCl3)δ196.3(t),162.8(t),159.6(q),148.3(q),140.0(q),135.1(q),129.3(t),119.5( t),119.3(t),113.3(t),110.7(t),55.2(s),44.9(q),42.6(d),26.1(s),24.9(s),18.1(s),10.4(s).

[0109] Example 19: (E)-2,4,7-trimethyl-4-(naphthalen-2-yl)octa-2,6-dienal Following the general procedure described in Example 2: reaction of 2-bromonaphthalene (6.23 g, 30.10 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (2.50 g, 15.04 mmol), diacetoxypalladium (0.17 g, 0.752 mmol), tri-tert-butylphosphine (0.30 g, 1.50 mmol), CsCO (4.90 g, 15.04 mmol) in DMF (20 mL) gave the title product (1.00 g, 23% yield) as a yellow oil. GC / MS(EI):m / z(%):292(1)[M + ],224(100),208(69),195(29),179(12),165(25),153(15),141(12),128(10),69(69). 1 H NMR(300MHz,CDCl3)δ9.38(s,1H),7.76-7.69(m,3H),7.63(s,1H),7.41-7.35(m,2H),7.31-7.24(m,1H),6.7 7(d,J=1.1Hz,1H),4.94(t,J=7.4Hz,1H),2.63-2.45(m,2H),1.56(d,J=9.8Hz,6H),1.47(s,3H),1.20(s,3H). 13 C NMR(75MHz,CDCl3)δ196.4(t),162.7(t),144.0(q),140.2(q),135.2(q),133.3(q),132.0(q),128.1(t),128.0(t),12 7.5(t),126.1(t),125.9(t),125.8(t),124.6(t),119.4(t),45.1(q),42.6(d),26.1(s),24.9(s),18.1(s),10.5(s).

[0110] Example 20: (E)-4-(2-ethylphenyl)-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 2: reaction of 1-bromo-2-ethylbenzene (5.00 g, 27.00 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (2.25 g, 13.51 mmol), diacetoxypalladium (0.15 g, 0.68 mmol), tri-tert-butylphosphane (0.27 g, 1.35 mmol), CsCO (5.28 g, 16.21 mmol) in DMF (20 mL) gave the title product (1.52 g, 42% yield) as a pale yellow oil. GC / MS(EI):m / z(%):270(1)[M + ],202(66),187(16),173(100),145(27),128(30),115(19),91(14),69(29). 1 H NMR(300MHz,CDCl3)δ9.41(s,1H),7.36(d,J=7.3Hz,1H),7.24-7.14(m,3H),6.95(d,J=1.2Hz,1H),5.02(t,J= 6.7,1.3Hz,1H),2.71-2.43(m,4H),1.70(s,3H),1.59(s,3H),1.52(s,3H),1.21(s,3H),1.09(t,J=7.6Hz,3H). 13 C NMR(75MHz,CDCl3)δ196.1(t),163.4(t),143.8(q),142.0(q),137.8(q),135.0(q),130.1(t),126.8(t), 126.0(t),125.8(t),119.6(t),44.5(q),41.1(d),27.6(d),26.1(s),25.1(s),18.1(s),15.5(s),9.7(s).

[0111] Example 21: (E)-2,4,7-trimethyl-4-(m-tolyl)octa-2,6-dienal Following the general procedure described in Example 2: reaction of 1-bromo-3-methylbenzene (4.41 g, 25.80 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (2.15 g, 12.90 mmol), diacetoxypalladium (0.15 g, 0.65 mmol), tricyclohexylphosphine (0.36 g, 1.29 mmol), CsCO (4.20 g, 12.90 mmol) in DMF (15 mL) gave the title product (2.04 g, 62% yield) as a pale yellow oil. GC / MS(EI):m / z(%):256(1)[M + ],188(100),173(84),159(89),143(20),128(34),115(21),91(17),69(22). 1 H NMR(300MHz,CDCl3)δ9.43(s,1H),7.23-7.13(m,1H),7.10-6.98(m,3H),6.79(d,J=1.1Hz,1H), 5.05(t,1H),2.61-2.46(m,2H),2.34(s,3H),1.69(s,3H),1.54(d,J=12.8Hz,6H),1.34(s,3H). 13 C NMR(75MHz,CDCl3)δ196.3(t),163.2(t),146.5(q),139.8(q),137.7(q),134.9(q),128.1(t),127.3( t),126.9(t),123.6(t),119.6(t),44.8(q),42.6(d),26.0(s),24.9(s),21.7(s),18.0(s),10.4(s).

[0112] Example 22: (E)-4-(benzo[d][1,3]dioxol-5-yl)-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 2: reaction of 5-bromobenzo[d][1,3]dioxole (3.89 g, 19.35 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (2.15 g, 12.90 mmol), diacetoxypalladium (0.15 g, 0.65 mmol), tricyclohexylphosphane (0.36 g, 1.29 mmol), CsCO (5.04 g, 15.48 mmol) in DMF (20 mL) gave the title product (1.26 g, 34% yield) as a pale yellow oil. GC / MS(EI):m / z(%):286(3)[M + ],217(29),202(33),189(100),159(45),115(29),91(19),69(11). 1 H NMR(300MHz,CDCl3)δ9.41(s,1H),6.78-6.70(m,4H),5.94(s,2H),5.00(t,J=7. 3Hz,1H),2.55-2.41(m,2H),1.68(s,3H),1.56(s,3H),1.47(s,3H),1.36(s,3H). 13 C NMR(75MHz,CDCl3)δ196.3(t),163.0(t),147.8(q),145.8(q),140.6(q),139.9(q),135.1(q),119.6( t),119.4(t),107.9(t),107.5(t),101.0(d),44.7(q),42.9(d),26.1(s),25.0(s),18.1(s),10.4(s).

[0113] Example 23: (E)-4-(6-methoxypyridin-2-yl)-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 2: reaction of 2-bromo-6-methoxypyridine (5.11 g, 27.20 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (2.26 g, 13.59 mmol), diacetoxypalladium (0.15 g, 0.68 mmol), tri-tert-butylphosphane (0.28 g, 1.36 mmol), CsCO (5.32 g, 16.31 mmol) in DMF (20 mL) gave the title product (2.12 g, 57% yield) as a pale yellow oil. GC / MS(EI):m / z(%):273(2)[M + ],244(16),188(100),176(49),162(53),146(27),137(28),69(39). 1 H NMR(300MHz,CDCl3)δ9.39(s,1H),7.45(q,J=7.7Hz,1H),6.83-6.67(m,2H),6.53(d,J=9.3Hz,1H ),5.01(t,J=7.4Hz,1H),3.88(s,3H),2.67-2.54(m,2H),1.65(s,3H),1.53(s,6H),1.34(s,3H). 13 C NMR(75MHz,CDCl3)δ196.4(t),163.1(q),162.8(q),162.5(t),139.4(q),138.6(t),134.8(q),1 19.6(t),113.8(t),107.9(t),53.1(s),47.5(q),41.0(d),26.0(s),24.1(s),18.0(s),10.2(s).

[0114] Example 24: (E)-4-(2,4-dimethoxyphenyl)-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 2: reaction of 1-bromo-2,4-dimethoxybenzene (7.83 g, 36.10 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (3.00 g, 18.04 mmol), diacetoxypalladium (0.20 g, 0.90 mmol), tri-tert-butylphosphine (0.37 g, 1.80 mmol), CsCO (7.05 g, 21.65 mmol) in DMF (20 mL) gave the title product (3.40 g, 62% yield) as a pale yellow oil. GC / MS(EI):m / z(%):302(1)[M + ],233(100),218(34),205(97),191(26),175(18),115(9),91(8). 1 H NMR(300MHz,CDCl3)δ9.43(d,J=52.8Hz,1H),7.15(d,J=8.5Hz,1H),6.81(s,1H),6.45(dd,J=8.5,2.4Hz,1H),6.41-6.37(m,1H),4.97 (t,J=6.1Hz,1H),3.75(d,J=5.2Hz,3H),3.65(d,J=7.6Hz,3H),2.65-2.55(m,2H),1.64(s,3H),1.54(s,3H),1.43(s,3H),1.24(s,3H). 13 C NMR(75MHz,CDCl3)δ196.5(t),165.5(t),159.6(q),158.0(q),136.2(q),134.2(q),127.2(t),126.8(q), 120.1(t),103.8(t),99.3(t),55.1(s),55.1(s),42.5(q),39.2(d),25.9(s),23.5(s),17.9(s),9.2(s).

[0115] Example 25: (E)-4-(3,5-dimethylphenyl)-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 2: reaction of 1-bromo-3,5-dimethylbenzene (4.78 g, 25.8 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (2.15 g, 12.90 mmol), diacetoxypalladium (0.15 g, 0.65 mmol), tricyclohexylphosphane (0.36 g, 1.29 mmol), CsCO (4.20 g, 12.90 mmol) in DMF (15 mL) gave the title product (2.15 g, 62% yield) as a colorless oil. GC / MS(EI):m / z(%):270(1)[M + ],202(57),186(100),173(89),159(22),143(27),128(17),115(12),91(9),69(10). 1 H NMR(300MHz,CDCl3)δ9.45(s,1H),6.88(s,3H),6.78(d,J=1.0Hz,1H),5.06(t,J=7.3Hz, 1H),2.63-2.45(m,2H),2.32(s,6H),1.71(s,3H),1.60(s,3H),1.51(s,3H),1.38(s,3H). 13 C NMR(75MHz,CDCl3)δ196.6(t),163.4(t),146.6(q),139.8(q),137.6(q),134.9(q),127.8(t),1 24.4(t),119.7(t),44.8(q),42.6(d),26.1(s),25.1(s),21.6(s),21.4(s),18.1(s),10.5(s).

[0116] Example 26: (E)-4-(4-methoxyphenyl)-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 2: reaction of 1-bromo-4-methoxybenzene (4.50 g, 24.06 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (2.00 g, 12.03 mmol), bis(tri-tert-butylphosphine)palladium(0) (0.31 g, 0.60 mmol), CsCO (4.70 g, 14.44 mmol) in DMF (20 mL) gave the title product (2.81 g, 86% yield) as a pale yellow oil. GC / MS(EI):m / z(%):272(2)[M + ],203(100),188(62),175(83),160(11),145(11),115(12),91(9). 1 H NMR(300MHz,CDCl3)δ9.40(s,1H),7.19-7.12(m,2H),6.83(d,2H),6.77(s,1H),5.00(t ,1H),3.79(s,3H),2.58-2.39(m,2H),1.67(s,3H),1.52(d,J=14.9Hz,6H),1.31(s,3H). 13 C NMR(75MHz,CDCl3)δ196.4(t),163.5(t),157.8(q),139.8(q),138.6(q),135.0(q),127.8(t),127.7(t),1 19.6(t),114.2(t),113.6(t),55.4(t),55.2(t),44.3(q),42.8(d),26.1(s),25.0(s),18.1(s),10.4(s).

[0117] Example 27: (E)-2,4,7-trimethyl-4-(naphthalen-1-yl)octa-2,6-dienal Following the general procedure described in Example 2: reaction of 1-bromonaphthalene (7.47 g, 36.10 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (3.00 g, 18.04 mmol), diacetoxypalladium (0.20 g, 0.902 mmol), tricyclohexylphosphane (0.51 g, 1.80 mmol), CsCO (7.05 g, 21.65 mmol) in DMF (20 mL) gave the title product (2.1 g, 40% yield) as a pale yellow oil. GC / MS(EI):m / z(%):292(4)[M + ],224(59),209(27),195(100),179(46),165(58),153(24),69(13). 1H NMR(300MHz,CDCl3)δ9.44(s,1H),7.96-7.71(m,3H),7.57-7.35(m,4H),7.14(s,1H),4 .97(s,1H),2.79(s,2H),1.64(d,J=4.4Hz,3H),1.50(s,3H),1.19(s,3H),1.00(s,3H). 13 C NMR(75MHz,CDCl3)δ195.8(t),162.9(t),142.3(q),138.5(q),135.0(q),134.6(q),130.5(q),129.4(t),128.0( t),126.0(t),125.2(t),124.9(t),124.1(t),119.4(t),45.0(q),40.9(d),26.0(s),25.5(s),18.0(s),9.3(s).

[0118] Example 28: (E)-4-(3,5-dimethoxyphenyl)-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 2: reaction of 1-bromo-3,5-dimethoxybenzene (7.83 g, 36.1 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (3.00 g, 18.04 mmol), diacetoxypalladium (0.20 g, 0.90 mmol), tricyclohexylphosphane (0.51 g, 1.804 mmol), CsCO (7.05 g, 21.65 mmol) in DMF (20 mL) gave the title product (2.00 g, 29% yield) as a yellow oil. GC / MS(EI):m / z(%):302(6)[M + ],233(100),218(86),205(49),191(34),175(27),115(12),69(19). 1 H NMR(300MHz,CDCl3)δ9.41(s,1H),6.47(t,J=2.2Hz,1H),6.42(d,J=2.1Hz,2H),6.33(t,J=2.1Hz,1H) ,5.03(t,J=7.3Hz,1H),3.77(s,6H),2.50(t,2H),1.69(s,3H),1.57(s,3H),1.49(s,3H),1.39(s,3H). 13C NMR(75MHz,CDCl3)δ196.2(t),162.5(t),161.0(q),160.7(q),149.1(q),143.5(q),135.0(q),119.5(t), 105.5(t),105.5(t),99.5(t),55.4(s),55.3(q),45.0(d),42.5(s),26.0(s),24.8(s),18.0(s),10.4(s).

[0119] Example 29: (E)-4-(3-isopropylphenyl)-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 2: reaction of 1-bromo-3-isopropylbenzene (7.18 g, 36.1 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (3.00 g, 18.04 mmol), diacetoxypalladium (0.20 g, 0.90 mmol), tri-tert-butylphosphine (0.37 g, 1.80 mmol), CsCO (7.05 g, 21.65 mmol) in DMF (20 mL) gave the title product (5.00 g, 97% yield) as a yellow oil. GC / MS(EI):m / z(%):284(1)[M + ],216(44),187(26),173(100),158(21),145(46),128(20),115(12),91(11),69(14). 1 H NMR(300MHz,CDCl3)δ9.41(s,1H),7.26-7.18(m,1H),7.08(d,3H),6.79(s,1H),5.04(t,J=7.4Hz, 1H),2.97-2.79(m,1H),2.52(d,2H),1.68(s,3H),1.53(s,6H),1.31(s,3H),1.22(d,J=6.9Hz,6H). 13C NMR(75MHz,CDCl3)δ196.4(t),163.3(t),148.8(q),146.3(q),139.8(q),135.0(q),128.2(t),125.2(t),124.1 (t),124.0(t),119.6(t),45.1(q),42.7(d),34.3(t),26.1(s),25.1(s),24.2(s),24.1(s),18.0(s),10.5(s).

[0120] Example 30: (E)-2,4,7-trimethyl-4-(pyridin-3-yl)octa-2,6-dienal Following the general procedure described in Example 2: reaction of 3-bromopyridine (5.70 g, 36.1 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (3.00 g, 18.04 mmol), diacetoxypalladium (0.20 g, 0.90 mmol), tricyclohexylphosphane (0.51 g, 1.80 mmol), CsCO (7.05 g, 21.65 mmol) in DMF (20 mL) gave the title product (0.6 g, 14% yield) as a pale yellow oil. GC / MS(EI):m / z(%):243(2)[M + ],214(10),200(11),175(55),158(39),146(100),132(61),69(47). 1 H NMR(300MHz,CDCl3)δ9.42(s,1H),8.52(d,J=2.3Hz,1H),8.46(dd,J=4.7,1.3Hz,1H),7.58-7.49(m,1H),7.25-7.20( m,1H),6.77(s,1H),4.99(t,J=7.4Hz,1H),2.52(d,J=7.4Hz,2H),1.66(s,3H),1.56(s,3H),1.47(s,3H),1.30(s,3H). 13 C NMR(75MHz,CDCl3)δ195.9(t),161.0(t),148.5(t),147.7(t),141.8(q),140.3(q),136.1( q),134.3(t),123.2(t),118.5(t),43.7(q),42.8(d),26.1(s),24.5(s),18.0(s),10.8(s).

[0121] Example 31: (E)-4-Methoxy-3-(2,4,7-trimethyl-1-oxoocta-2,6-dien-4-yl)benzonitrile Following the general procedure described in Example 2: reaction of 3-bromo-4-methoxybenzonitrile (5.04 g, 23.77 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (2.16 g, 11.89 mmol), diacetoxypalladium (0.13 g, 0.594 mmol), tri-tert-butylphosphane (0.24 g, 1.19 mmol), CsCO (7.75 g, 23.77 mmol) in DMF (50 mL) gave the title product (1.91 g, 54% yield) as a pale yellow oil. GC / MS(EI):m / z(%):297(1)[M + ],229(100),214(15),200(33),186(28),170(11),160(9),146(10),116(11),69(48). 1 H NMR(300MHz,CDCl3)δ9.33(s,1H),7.64-7.45(m,2H),6.87(d,J=7.7Hz,1H),6.75(s,1H),4.86(t ,J=7.4Hz,1H),3.74(s,3H),2.78-2.46(m,2H),1.61(s,3H),1.48(d,J=11.8Hz,6H),1.17(s,3H). 13 C NMR(75MHz,CDCl3)δ196.0(t),162.8(t),160.3(q),136.6(q),135.6(q),135.4(q),132.8(t),131.0(t),1 19.4(q),119.0(t),111.6(t),103.9(q),55.5(s),43.0(q),38.6(d),25.9(s),23.2(s),17.9(s),9.5(s).

[0122] Example 32: (E)-4-(2,5-difluorophenyl)-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 2: reaction of 2-bromo-1,4-difluorobenzene (5.00 g, 25.90 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (2.32 g, 12.95 mmol), diacetoxypalladium (0.09 g, 0.39 mmol), tri-tert-butylphosphane (0.16 g, 0.78 mmol), CsCO (8.44 g, 25.90 mmol) in DMF (30 mL) gave the title product (1.19 g, 33% yield) as a pale yellow oil. GC / MS(EI):m / z(%):278(1)[M + ],210(100),195(15),181(11),164(15),147(10),127(20),119(4),101(5),69(71). 1 H NMR(300MHz,CDCl3)δ9.37(s,1H),7.08-6.84(m,3H),6.76(d,J=1.9Hz,1H),4.95(t,J= 7.3Hz,1H),2.57(d,J=11.2Hz,2H),1.65(s,3H),1.54(s,3H),1.48(s,3H),1.28(s,3H). 13 C NMR(75MHz,CDCl3)δ195.9(t),161.0(t),138.3(q),138.3(q),135.8(q),118.6(t),117.2(t),117.0(t),116.8(t),116.7(t),1 14.8(t),114.8(t),114.6(t),114.5(t),114.4(t),114.3(t),42.6(q),39.7(d),39.7(d),26.0(s),23.4(s),17.9(s),9.6(s).

[0123] Example 33: (E)-4-(3,5-difluorophenyl)-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 2: reaction of 1-bromo-3,5-difluorobenzene (5.00 g, 25.9 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (2.32 g, 12.95 mmol), diacetoxypalladium (0.09 g, 0.39 mmol), tri-tert-butylphosphane (0.18 g, 0.78 mmol), CsCO (8.44 g, 25.90 mmol) in DMF (30 mL) gave the title product (1.48 g, 41% yield) as a pale yellow oil. GC / MS(EI):m / z(%):278(1)[M + ],210(80),192(46),181(13),164(19),151(13),127(13),119(4),101(4),69(100). 1 H NMR(300MHz,CDCl3)δ9.42(s,1H),6.92-6.54(m,4H),4.96(t,J=10.6,4.3Hz,1H),2 .48(d,J=7.5Hz,2H),1.67(s,3H),1.53(s,3H),1.49(s,3H),1.33(d,J=1.1Hz,3H). 13 C NMR(75MHz,CDCl3)δ195.8(t),164.8(q),164.6(q),161.5(q),161.3(q),160.8(t),150.9(q),140.5(q),136.0(q),118.5(t),11 0.0(t),109.9(t),109.8(t),109.7(t),102.2(t),101.8(t),101.5(t),45.0(q),42.7(d),26.1(s),24.6(s),18.0(s),10.6(s).

[0124] Example 34: (E)-2-chloro-5-(2,4,7-trimethyl-1-oxoocta-2,6-dien-4-yl)benzonitrile Following the general procedure described in Example 2: reaction of 5-bromo-2-chlorobenzonitrile (5.00 g, 23.10 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (3.00 g, 18.04 mmol), diacetoxypalladium (0.20 g, 0.90 mmol), tri-tert-butylphosphane (0.37 g, 1.80 mmol), CsCO (7.05 g, 21.65 mmol) in DMF (20 mL) gave the title product (1.00 g, 18% yield) as a yellow oil. GC / MS(EI):m / z(%):301(1)[M + ],233(45),218(13),198(6),190(5),166(5),153(9),140(6),127(5),69(100). 1 H NMR(300MHz,CDCl3)δ9.43(s,1H),7.55(d,J=1.7Hz,1H),7.47-7.37(m,2H),6.72(d,J=1.0Hz,1H) ,4.93(t,J=7.4Hz,1H),2.48(d,J=7.4Hz,2H),1.67(s,3H),1.53(s,3H),1.48(s,3H),1.30(s,3H). 13 C NMR(75MHz,CDCl3)δ195.5(t),160.0(t),146.4(q),140.5(q),136.7(q),134.7(q),132.7(t),132.1( t),129.9(t),118.0(t),116.2(q),113.3(q),44.7(q),42.8(d),26.1(s),24.6(s),18.1(s),10.9(s).

[0125] Example 35: (E)-3-chloro-5-(2,4,7-trimethyl-1-oxoocta-2,6-dien-4-yl)benzonitrile Following the general procedure described in Example 2: reaction of 3-bromo-5-chlorobenzonitrile (5.00 g, 23.10 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (3.00 g, 18.04 mmol), diacetoxypalladium (0.20 g, 0.90 mmol), tri-tert-butylphosphane (0.37 g, 1.80 mmol), CsCO (7.05 g, 21.65 mmol) in DMF (20 mL) gave the title product (0.23 g, 4% yield) as a yellow oil. GC / MS(EI):m / z(%):301(1)[M + ],233(35),215(6),204(5),190(3),166(4),153(8),140(5),127(4),69(100). 1 H NMR(300MHz,CDCl3)δ9.41(s,1H),7.52-7.37(m,3H),6.70(s,1H),4.93(t,J=7.4H z,1H),2.46(d,J=7.4Hz,2H),1.65(s,3H),1.51(s,3H),1.45(s,3H),1.28(s,3H). 13 C NMR(75MHz,CDCl3)δ195.4(t),159.4(t),150.2(q),140.5(q),136.7(q),135.2(q),131.7(t),129.6( t),128.6(t),117.9(t),117.5(q),113.7(q),44.9(q),42.6(d),26.0(s),24.4(s),17.9(s),10.8(s).

[0126] Example 36: (E)-4-(3,4-difluorophenyl)-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 2: reaction of 4-bromo-1,2-difluorobenzene (5.00 g, 25.9 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (2.32 g, 12.95 mmol), diacetoxypalladium (0.09 g, 0.39 mmol), tri-tert-butylphosphane (0.16 g, 0.78 mmol), CsCO (8.44 g, 25.90 mmol) in DMF (30 mL) gave the title product (1.27 g, 35% yield) as a pale yellow oil. GC / MS(EI):m / z(%):278(1)[M + ],210(88),195(36),181(28),164(21),151(14),141(11),127(24),101(5),69(100). 1 H NMR(300MHz,CDCl3)δ9.41(s,1H),7.15-6.89(m,3H),6.72(d,J=1.0Hz,1H),4.96(t,J=7. 4Hz,1H),2.47(d,J=7.4Hz,2H),1.67(s,3H),1.50(d,J=6.0Hz,6H),1.31(d,J=0.8Hz,3H). 13 C NMR(75MHz,CDCl3)δ195.9(t),161.5(t),151.9(q),151.7(q),150.5(q),150.3(q) ,148.6(q),148.4(q),147.2(q),147.0(q),143.8(q),143.7(q),143.7(q),140.3( q),135.8(q),122.9(t),122.8(t),122.7(t),122.6(t),118.7(t),117.1(t),116. 9(t),116.0(t),115.7(t),44.5(q),42.9(d),26.1(s),24.8(s),18.0(s),10.6(s).

[0127] Example 37: (E)-2-Methyl-5-(2,4,7-trimethyl-1-oxoocta-2,6-dien-4-yl)benzonitrile Following the general procedure described in Example 2: reaction of 5-bromo-2-methylbenzonitrile (5.00 g, 25.5 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (3.00 g, 18.04 mmol), diacetoxypalladium (0.20 g, 0.90 mmol), tri-tert-butylphosphane (0.37 g, 1.804 mmol), CsCO (7.05 g, 21.65 mmol) in DMF (20 mL) gave the title product (2.10 g, 41% yield) as a yellow oil. GC / MS(EI):m / z(%):281(1)[M + ],213(100),198(74),184(26),170(24),154(14),140(9),130(10),115(10),69(100). 1 H NMR(300MHz,CDCl3)δ9.41(s,1H),7.47(d,J=1.6Hz,1H),7.34(dd,J=8.2,1.8Hz,1H),7.23(d,J=8.2Hz,1H ),6.73(s,1H),4.93(t,J=7.3Hz,1H),2.55-2.41(m,5H),1.66(s,3H),1.50(d,J=5.4Hz,6H),1.27(s,3H). 13 C NMR(75MHz,CDCl3)δ195.8(t),161.1(t),145.0(q),140.2(q),139.9(q),136.0(q),131.4(t),130.5(t),1 30.3(t),118.5(t),118.3(q),112.7(q),44.5(q),42.7(d),26.0(s),24.6(s),20.0(s),18.0(s),10.7(s).

[0128] Example 38: (E)-2,4,7-trimethyl-4-(2-(methylthio)phenyl)octa-2,6-dienal Following the general procedure described in Example 2: reaction of (2-bromophenyl)(methyl)-sulfane (5.71 g, 28.1 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (2.51 g, 14.05 mmol), diacetoxypalladium (0.16 g, 0.70 mmol), tri-tert-butylphosphane (0.28 g, 1.41 mmol), CsCO (4.58 g, 14.05 mmol) in DMF (80 mL) gave the title product (2.31 g, 57% yield) as a pale yellow oil. GC / MS(EI):m / z(%):288(1)[M + ],273(29),245(28),217(80),205(35),172(89),163(80),144(100),129(73),69(61). 1 H NMR(300MHz,CDCl3)δ9.46(s,1H),7.42-7.34(m,2H),7.26-7.20(m,2H),6.99(d,J=0.9Hz,1H),5.02(t,J= 7.5Hz,1H),2.87-2.68(m,2H),2.33(s,3H),1.69(s,3H),1.60(s,3H),1.55(s,3H),1.20(d,J=0.7Hz,3H). 13 C NMR(75MHz,CDCl3)δ196.3(t),162.6(t),146.4(q),136.7(q),136.3(q),134.9(q),131.0(t),127.2 (t),126.4(t),126.1(t),119.6(t),45.1(q),39.6(d),26.0(s),24.0(s),19.2(s),18.0(s),9.5(s).

[0129] Example 39: (E)-4-(3-fluoro-5-(trifluoromethyl)phenyl)-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 2: reaction of 1-bromo-3-fluoro-5-(trifluoromethyl)benzene (8.77 g, 36.10 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (3.00 g, 18.04 mmol), diacetoxypalladium (0.20 g, 0.90 mmol), tri-tert-butylphosphane (0.37 g, 1.81 mmol), CsCO (7.05 g, 21.65 mmol) in DMF (20 mL) gave the title product (1.75 g, 30% yield) as a pale yellow oil. GC / MS(EI):m / z(%):328(1)[M + ],309(3),260(100),242(15),231(9),195(6),177(6),146(6),133(3),69(41). 1 H NMR(300MHz,CDCl3)δ9.44(s,1H),7.28(s,1H),7.17(t,J=10.4Hz,2H),6.74(s,1H),4.98( t,J=7.5Hz,1H),2.50(d,J=7.5Hz,2H),1.67(s,3H),1.54(s,3H),1.47(s,3H),1.31(s,3H). 13 C NMR(75MHz,CDCl3)δ195.7(t),164.2(q),160.9(q),160.3(t),150.7(q),150.6(q),140.6(q),136.5(q),119.5(t),119.4(t),11 8.3(t),117.6(t),117.3(t),111.0(t),110.9(t),110.6(t),110.6(t),45.2(q),42.8(d),26.0(s),24.8(s),18.0(s),10.8(s).

[0130] Example 40: (E)-4-(2,3-dimethylphenyl)-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 2: reaction of 1-bromo-2,3-dimethylbenzene (6.68 g, 36.10 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (3.00 g, 18.04 mmol), diacetoxypalladium (0.20 g, 0.90 mmol), tricyclohexylphosphane (0.51 g, 1.80 mmol), CsCO (7.05 g, 21.65 mmol) in DMF (20 mL) gave the title product (1.65 g, 34% yield) as a pale yellow oil. GC / MS(EI):m / z(%):270(1)[M + ],202(88),201(26),187(100),186(82),173(89),171(21),159(31),157(28),143(35),141(26),69(29). 1 H NMR(300MHz,CDCl3)δ9.55(s,1H),7.37(d,J=6.7Hz,1H),7.25-7.17(m,2H),7.04(s,1H),5.16(t,J=7.4H z,1H),2.86-2.60(m,2H),2.35(s,3H),2.21(s,3H),1.83(s,3H),1.70(s,3H),1.64(s,3H),1.28(s,3H). 13 C NMR(75MHz,CDCl3)δ196.2(t),163.5(t),144.3(q),138.0(q),137.6(q),134.9(q),134.4(q),128.5(t), 125.6(t),124.1(t),119.7(t),44.9(q),40.5(d),26.1(s),25.4(s),21.2(s),19.6(s),18.1(s),9.5(s).

[0131] Example 41: (E)-2,4,7-trimethyl-4-(2-methyl-5-(trifluoromethyl)phenyl)octa-2,6-dienal Following the general procedure described in Example 2: reaction of 2-bromo-1-methyl-4-(trifluoromethyl)benzene (5.00 g, 20.92 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (1.74 g, 10.46 mmol), diacetoxypalladium (0.12 g, 0.52 mmol), tri-tert-butylphosphane (0.21 g, 1.05 mmol), CsCO (4.09 g, 12.55 mmol) in DMF (20 mL) gave the title product (1.50 g, 44% yield) as a yellow oil. GC / MS(EI):m / z(%):324(1)[M + ],305(88),256(100),241(55),236(6),22(19),225(21),159(31),221(28),191(3),177(4),69(57). 1 H NMR(300MHz,CDCl3)δ9.44(s,1H),7.59(s,1H),7.41(d,J=7.9Hz,1H),7.22(d,J=7.9Hz,1H),6.83(s ,1H),4.96(t,J=7.3Hz,1H),2.70-2.49(m,2H),2.29(s,3H),1.67(s,3H),1.56(s,6H),1.18(s,3H). 13 C NMR(75MHz,CDCl3)δ195.8(t),161.4(t),144.9(q),140.2(q),138.4(q),135.8(q),132.4(t),128.6(q),128.2(q),1 23.4(t),123.4(t),123.2(t),123.2(t),118.8(t),44.9(q),39.9(d),26.0(s),24.9(s),22.9(s),18.0(s),9.7(s).

[0132] Example 42: (E)-4-(2-ethoxyphenyl)-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 2: reaction of 1-bromo-2-ethoxybenzene (7.26 g, 36.10 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (3.00 g, 18.04 mmol), diacetoxypalladium (0.20 g, 0.90 mmol), tricyclohexylphosphane (0.51 g, 1.80 mmol), CsCO (7.05 g, 21.65 mmol) in DMA (20 mL) gave the title product (2.16 g, 42% yield) as a pale yellow oil. GC / MS(EI):m / z(%):286(5)[M + ],218(37),217(100),189(60),188(25),161(42),147(30),133(21),91(17),69(13). 1 H NMR(300MHz,CDCl3)δ9.38(s,1H),7.32-7.27(m,1H),7.24-7.16(m,1H),6.97-6.87(m,2H),6.80(d,J=8.1Hz,1H),5.01(t,J= 7.5Hz,1H),4.07-3.72(m,2H),2.76-2.56(m,2H),1.67(s,3H),1.59(s,3H),1.49(s,3H),1.31(t,J=7.0Hz,3H),1.23(s,3H). 13 C NMR(75MHz,CDCl3)δ196.7(t),165.8(t),156.4(q),136.1(q),134.6(q),134.4(q),127.8(t),126.9(t), 120.4(t),120.2(t),111.8(t),63.4(d),43.1(q),39.2(d),26.1(s),23.4(s),18.0(s),15.0(s),9.5(s).

[0133] Example 43: (E)-2,4,7-trimethyl-4-(4-methylpyridin-3-yl)octa-2,6-dienal Following the general procedure described in Example 2: reaction of 3-bromo-4-methylpyridine (5.00 g, 29.1 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (2.42 g, 14.53 mmol), diacetoxypalladium (0.16 g, 0.73 mmol), tri-tert-butylphosphane (0.29 g, 1.45 mmol), CsCO (5.68 g, 17.44 mmol) in DMF (20 mL) gave the title product (1.18 g, 30% yield) as a pale yellow oil. GC / MS(EI):m / z(%):257(5)[M + ],228(5),214(8),189(65),174(28),160(100),146(71),130(14),121(10),69(45). 1 H NMR(300MHz,CDCl3)δ9.36(s,1H),8.51(s,1H),8.30(d,J=4.9Hz,1H),6.96(d,J=4.8Hz,1H),6.74(s,1H),4 .88(t,J=6.9Hz,1H),2.54(d,J=7.4Hz,2H),2.17(s,3H),1.59(s,3H),1.50(d,J=10.2Hz,6H),1.14(s,3H). 13 C NMR(75MHz,CDCl3)δ195.5(t),160.9(t),147.9(t),147.7(q),145.0(q),139.1(q),138.5(q),1 35.6(q),126.4(t),118.6(t),43.5(q),39.8(d),25.9(s),24.3(s),22.1(s),18.0(s),9.7(s).

[0134] Example 44: (E)-2,4,7-trimethyl-4-(5-methylthiophen-3-yl)octa-2,6-dienal Following the general procedure described in Example 2: reaction of 4-bromo-2-methylthiophene e (5.00 g, 28.20 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (2.52 g, 14.12 mmol), diacetoxypalladium (0.10 g, 0.42 mmol), tri-tert-butylphosphane (0.17 g, 0.85 mmol), Cs2CO3 (9.20 g, 28.20 mmol) in DMF (30 mL) gave the title product (1.80 g, 49% yield) as a pale yellow oil. GC / MS(EI):m / z(%):262(1)[M + ],193(43),178(65),165(100),149(11),135(7),111(7),69(9). 1 H NMR(300MHz,CDCl3)δ9.36(s,1H),6.71(d,J=1.4Hz,1H),6.64(d,J=1.2Hz,1H),6.54(s,1H),5.04(t,J=7.3Hz ,1H),2.56-2.44(m,2H),2.41(d,J=0.7Hz,3H),1.68(s,3H),1.56(s,3H),1.46(s,3H),1.42(d,J=1.1Hz,3H). 13 C NMR(75MHz,CDCl3)δ196.2(t),161.9(t),147.4(q),139.8(q),139.7(q),134.8(q),125.3 (t),119.5(t),117.3(t),42.9(q),41.7(d),26.0(s),25.3(s),18.0(s),15.4(s),9.7(s).

[0135] Example 45: (E)-4-(furan-3-yl)-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 2: reaction of 3-bromofuran (3.31 g, 22.51 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (2.01 g, 11.25 mmol), diacetoxypalladium (0.08 g, 0.34 mmol), tri-tert-butylphosphane (0.14 g, 0.68 mmol), CsCO (7.33 g, 22.51 mmol) in DMF (30 mL) gave the title product (1.12 g, 43% yield) as a pale yellow oil. GC / MS(EI):m / z(%):232(2)[M + ],164(46),163(30),148(7),135(100),121(7),107(12),91(40),69(24). 1 H NMR(300MHz,CDCl3)δ9.36(s,1H),7.35(t,J=1.4Hz,1H),7.20(s,1H),6.58(d,J=1.1Hz,1H),6.21(d, J=0.7Hz,1H),5.06(t,J=7.3Hz,1H),2.55-2.33(m,2H),1.68(s,3H),1.61-1.49(m,6H),1.44(s,3H). 13 C NMR(75MHz,CDCl3)δ196.2(t),161.0(t),143.1(t),139.7(q),138.4(t),134.9(q),1 31.3(q),119.3(t),109.7(t),41.4(d),39.4(q),25.9(s),25.3(s),18.0(s),9.9(s).

[0136] Example 46: (E)-4-(2,4-difluorophenyl)-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 2: reaction of 1-bromo-2,4-difluorobenzene (5.44 g, 28.20 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (2.52 g, 14.10 mmol), diacetoxypalladium (0.10 g, 0.42 mmol), tri-tert-butylphosphane (0.17 g, 0.85 mmol), CsCO (9.19 g, 28.20 mmol) in DMF (30 mL) gave the title product (1.35 g, 35% yield) as a pale yellow oil. GC / MS(EI):m / z(%):278(1)[M + ],276(3),210(98),195(41),181(27),164(22),141(21),127(45),69(100). 1 H NMR(300MHz,CDCl3)δ9.41(s,1H),7.36-7.24(m,1H),6.92-6.83(m,1H),6.82-6.78(m,1H),6.77-6.69( m,1H),4.97(t,J=7.3Hz,1H),2.61(d,J=7.6Hz,2H),1.67(s,3H),1.56(s,3H),1.53(s,3H),1.31(s,3H). 13 C NMR(75MHz,CDCl3)δ196.0(t),163.6(q),163.4(q),162.5(q),162.3(q),161.6(t),160.3(q),160.2 (q),159.2(q),159.0(q),138.3(q),138.2(q),135.6(q),129.3(q),129.3(q),129.2(q),129.1(q),1 28.5(t),128.5(t),128.4(t),128.3(t),118.8(t),110.9(t),110.9(t),110.7(t),110.6(t),104.8 (t),104.4(t),104.4(t),104.1(t),42.3(q),42.3(q),39.9(d),26.0(s),23.6(s),17.9(s),9.6(s).

[0137] Example 47: (E)-4-(4-chloro-2-methylphenyl)-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 2: reaction of 1-bromo-4-chloro-2-methylbenzene (4.94 g, 24.06 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (2.00 g, 12.03 mmol), diacetoxypalladium (0.14 g, 0.60 mmol), tricyclohexylphosphane (0.34 g, 1.20 mmol), CsCO (4.70 g, 14.43 mmol) in DMF (20 mL) gave the title product (0.86 g, 25% yield) as a yellow oil. GC / MS(EI):m / z(%):290(1)[M + ], 222(100), 207(69), 193(50), 186(63), 158(26), 141(34), 128(32), 115(32), 69(98). 1 H NMR(300MHz,CDCl3)δ9.42(s,1H),7.34-7.23(m,1H),7.20-7.05(m,2H),6.80(s,1H),4. 93(s,1H),2.55(s,2H),2.20(s,3H),1.66(s,3H),1.56(s,3H),1.49(s,3H),1.20(s,3H). 13 C NMR(75MHz,CDCl3)δ196.0(t),162.2(t),142.6(q),138.4(q),138.0(q),135.5(q),132.3(q),131.8 (t),128.0(t),126.1(t),119.2(t),44.6(q),40.1(d),26.2(s),25.1(s),22.8(s),18.2(s),9.8(s).

[0138] Example 48: (E)-4-(4-fluorophenyl)-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 2: reaction of 1-bromo-4-fluorobenzene (2.93 g, 16.74 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (1.56 g, 8.37 mmol), diacetoxypalladium (0.09 g, 0.42 mmol), tricyclohexylphosphane (0.24 g, 0.84 mmol), CsCO (3.27 g, 10.05 mmol) in DMF (20 mL) gave the title product (1.20 g, 55% yield) as a yellow oil. GC / MS(EI):m / z(%):260(1)[M + ],192(100),177(57),163(25),146(22),133(14),109(16),95(2),83(2),69(65). 1 H NMR(300MHz,CDCl3)δ9.40(s,1H),7.23-7.14(m,2H),6.95(t,J=8.7Hz,2H),6.75(d,J=1.0Hz,1H ),4.97(t,J=7.4Hz,1H),2.48(d,J=7.4Hz,2H),1.64(s,3H),1.49(s,6H),1.28(d,J=0.9Hz,3H). 13 C NMR(75MHz,CDCl3)δ196.0(t),162.8(q),162.5(t),159.6(q),142.2(q),142.1(q),139.9(q),135.3(q),12 8.2(t),128.1(t),119.1(t),115.1(t),114.8(t),44.4(q),42.9(d),26.0(s),24.8(s),17.9(s),10.4(s).

[0139] Example 49: (E)-4-(3-fluorophenyl)-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 2: reaction of 1-bromo-3-fluorobenzene (2.93 g, 16.74 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (1.56 g, 8.37 mmol), diacetoxypalladium (0.094 g, 0.419 mmol), tricyclohexylphosphane (0.24 g, 0.84 mmol), CsCO (3.27 g, 10.05 mmol) in DMF (20 mL) gave the title product (1.18 g, 54% yield) as a yellow oil. GC / MS(EI):m / z(%):260(1)[M + ],192(100),177(59),163(65),146(27),133(17),109(23),96(3),83(3),69(45). 1 H NMR(300MHz,CDCl3)δ9.43(s,1H),7.31-7.21(m,1H),7.07-6.86(m,3H),6.76(d,J=1.1Hz,1H),5. 00(t,J=7.4Hz,1H),2.60-2.40(m,2H),1.68(s,3H),1.52(d,J=5.0Hz,6H),1.32(d,J=1.0Hz,3H). 13 C NMR(75MHz,CDCl3)δ196.0(t),164.5(q),161.9(t),161.3(q),149.3(q),149.3(q),140.1(q),135.5(q),129.8(t),129.7(t),122.5( t),122.4(t),119.0(t),113.9(t),113.6(t),113.2(t),112.9(t),44.9(q),44.8(q),42.7(d),26.0(s),24.7(s),18.0(s),10.5(s).

[0140] Example 50: (E)-2,4,7-trimethyl-4-phenylocta-2,6-dienal To a three-necked round-bottom flask equipped with a magnetic stirrer, Dean-Stark filter, and water condenser, 3-methylbut-2-en-1-ol (9.69 g, 110.00 mmol), (E)-2-methyl-4-phenylpent-2-enal (11.71 g, 55.10 mmol), and triethylamine hydrochloride (0.38 g, 2.76 mmol) in xylene (30 mL) were added to give a pale colorless solution. The reaction mixture was stirred and heated to reflux at 150 °C. Water was collected from the Dean-Stark filter. The reaction mixture was heated at reflux for 16 h. It was then cooled to room temperature and filtered through a short pad of silica gel, washing with MTBE (150 mL). The crude product was concentrated on a rotary evaporator to remove excess xylene and alcohol. Subsequent purification by Kugelrohr distillation (0.03 mbar / 155° C.) afforded the title product (5.691 g, 22.07 mmol, 40.0% yield) as a pale yellow oil. GC / MS(EI):m / z(%):242(1)[M + ],174(100),159(57),145(49),128(27),115(20),105(11),91(19),77(10),69(22). 1 H NMR(300MHz,CDCl3)δ9.42(s,1H),7.30-7.23(m,5H),6.79(d,J=1.1Hz,1H),5.09-4.9 3(m,1H),2.60-2.44(m,2H),1.67(s,3H),1.53(d,J=3.5Hz,6H),1.31(d,J=1.1Hz,3H). 13 C NMR(75MHz,CDCl3)δ196.3(t),163.0(t),146.5(q),139.9(q),135.1(q),128.3(t),12 6.6(t),126.2(t),119.4(t),44.9(q),42.7(d),26.0(s),24.8(s),18.0(s),10.4(s).

[0141] Example 51: (E)-2-Methyl-3-(2,4,7-trimethyl-1-oxoocta-2,6-dien-4-yl)benzonitrile Following the general procedure described in Example 2: reaction of 3-iodo-2-methylbenzonitrile (2.00 g, 8.23 ​​mmol), (E)-2,4,7-trimethylocta-2,6-dienal (2.74 g, 16.46 mmol), diacetoxypalladium (0.09 g, 0.41 mmol), tri-tert-butylphosphane (0.17 g, 0.82 mmol), CsCO (3.22 g, 9.87 mmol) in DMF (60 mL) gave the title product (0.42 g, 18% yield) as a pale yellow oil. GC / MS(EI):m / z(%):281(1)[M + ],213(62),198(38),184(13),170(10),154(11),140(8),69(100)

[0142] Example 52: (E)-2,4,7-trimethyl-4-(5-methylthiophen-2-yl)octa-2,6-dienal Following the general procedure described in Example 2: reaction of 2-bromo-5-methylthiophene e (1.75 g, 9.88 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (4.93 g, 29.7 mmol), diacetoxypalladium (0.11 g, 0.49 mmol), tricyclohexylphosphane (0.28 g, 0.99 mmol), Cs2CO3 (6.44 g, 19.77 mmol) in DMF (35 mL) gave the title product (0.54 g, 21% yield) as a pale yellow oil. GC / MS(EI):m / z(%):262(1)[M + ],193(73),178(54),165(100),149(10),135(8),125(8),111(10),91(9),59(13).

[0143] Example 53: (E)-2,4,7-trimethyl-4-(2,4,5-trimethylphenyl)octa-2,6-dienal Following the general procedure described in Example 2: reaction of 1-bromo-2,4,5-trimethylbenzene (5.00 g, 25.10 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (2.25 g, 12.56 mmol), diacetoxypalladium (0.09 g, 0.38 mmol), tri-tert-butylphosphane (0.15 g, 0.75 mmol), CsCO (8.18 g, 25.10 mmol) in DMF (30 mL) gave the title product (1.51 g, 42% yield) as a pale yellow oil. GC / MS(EI):m / z(%):284(1)[M + ],215(54),200(68),187(100),173(31),157(26),141(15),128(10),115(9),69(11).

[0144] Example 54: (E)-4-(2,6-dimethylphenyl)-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 2: reaction of 2-bromo-1,3-dimethylbenzene (6.68 g, 36.1 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (3.00 g, 18.0 mmol), diacetoxypalladium (0.20 g, 0.90 mmol), tri-tert-butylphosphane (0.37 g, 1.80 mmol), CsCO (7.05 g, 21.7 mmol) in DMF (20 mL) gave the title product (1.02 g, 21% yield) as a yellow oil. GC / MS(EI):m / z(%):270(1)[M + ],202(48),186(90),173(100),159(51),143(49),129(56),109(51).

[0145] Example 55: (E)-2,4,7-trimethylocta-2,6-dienal A mixture of (E)-2-methylbut-2-enal (100 g, 1161 mmol), 3-methylbut-2-en-1-ol (195 g, 2322 mmol), and 7.99 g EtN-HCl in xylene was refluxed for 36 h. During this time, water was collected and removed from the Dean-Stark apparatus, and the reaction was monitored by GC. After cooling to room temperature, the reaction mixture was diluted with MTBE, washed with water and brine, dried over MgSO, filtered, and then evaporated under reduced pressure to give the crude product, which was purified by distillation to give (E)-2,7-dimethylocta-2,6-dienal (77.5 g, 44% yield) as a colorless oil.

[0146] Example 56: (E)-4-Methyl-3-(2,4,7-trimethyl-1-oxoocta-2,6-dien-4-yl)benzonitrile (General Procedure) A mixture of 3-bromo-4-methylbenzonitrile (4.62 g, 23.55 mmol), (E)-2,7-dimethylocta-2,6-dienal (1.82 g, 11.77 mmol), diacetoxypalladium (0.13 g, 0.59 mmol), tri-tert-butylphosphane (0.24 g, 1.18 mmol), and CsCO (3.84 g, 11.77 mmol) in DMF (20 mL) was heated to 110–120 °C under an Ar atmosphere overnight, and the reaction was monitored by TLC, GC, and GC-MS. After cooling to room temperature, the reaction mixture was diluted with MTBE and filtered through a small pad of silica gel, which was then washed with MTBE. The combined filtrate was then concentrated in vacuo to give the crude product, which was purified by distillation or flash chromatography (hexane / MTBE=50:1 to 10:1) to afford (E)-3-(2,7-dimethyl-1-oxoocta-2,6-dien-4-yl)-4-methylbenzonitrile (1.03 g, yield: 31%) as a pale yellow oil. GC / MS(EI):m / z(%):267(1)[M + ],199(100),184(21),170(11),154(11),140(13),127(9),115(8),103(5),69(83). 1H NMR(300MHz,CDCl3)δ9.44(s,1H),7.55(s,1H),7.47-7.40(m,1H),7.27(d,J=8.0Hz,1H),6.50(d,J=9.6Hz,1H),5.02(t ,J=7.1Hz,1H),4.04(q,J=16.7,7.4Hz,1H),2.49(t,J=7.2Hz,2H),2.40(s,3H),1.76(s,3H),1.67(s,3H),1.58(s,3H). 13 C NMR(75MHz,CDCl3)δ194.9(t),154.8(t),142.5(q),141.7(q),139.5(q),134.9(q),131.4(t),130.3( t),130.1(t),120.0(t),119.0(q),110.4(q),40.8(t),33.9(d),25.7(s),20.1(s),17.9(s),9.8(s).

[0147] Example 57: (E)-2,7-dimethyl-4-phenylocta-2,6-dienal Following the general procedure described in Example 56: reaction of bromobenzene (4.07 g, 25.90 mmol), (E)-2,7-dimethylocta-2,6-dienal (2.15 g, 12.96 mmol), diacetoxypalladium (0.15 g, 0.65 mmol), tricyclohexylphosphine (0.36 g, 1.30 mmol), CsCO (5.07 g, 15.56 mmol) in DMF (20 mL) gave the title product (2.04 g, 69% yield) as a pale yellow oil. GC / MS(EI):m / z(%):228(1)[M + ],160(100),145(41),131(30),115(28),91(40),77(12),69(71),53(12). 1 H NMR(300MHz,CDCl3)δ9.42(s,1H),7.36-7.28(m,2H),7.26-7.21(m,3H),6.59(d,J=9.9Hz,1H),5.03(t ,J=7.1Hz,1H),3.82(dd,J=16.9,7.7Hz,1H),2.59-2.42(m,2H),1.78(s,3H),1.65(s,3H),1.58(s,3H). 13 C NMR(75MHz,CDCl3)δ195.4(t),156.9(t),142.6(q),138.8(q),134.1(q),128.9( t),127.6(t),127.0(t),121.0(t),45.6(t),34.8(d),25.9(s),18.1(s),9.7(s).

[0148] Example 58: (E)-4-(2,4-dimethylphenyl)-2,7-dimethylocta-2,6-dienal Following the general procedure described in Example 56: reaction of 1-bromo-2,4-dimethylbenzene (7.29 g, 39.4 mmol), (E)-2,7-dimethylocta-2,6-dienal (3.00 g, 19.71 mmol), diacetoxypalladium (0.22 g, 0.99 mmol), tricyclohexylphosphane (0.55 g, 1.971 mmol), CsCO (7.70 g, 23.65 mmol) in DMF (20 mL) gave the title product (1.60 g, 32% yield) as a yellow oil. GC / MS(EI):m / z(%):256(2)[M + ],188(72),173(43),172(50),159(100),144(22),129(14),69(15). 1 H NMR(300MHz,CDCl3)δ9.41(s,1H),7.17(d,J=7.8Hz,1H),7.06-6.98(m,2H),6.53(d,J=13.2,6.6Hz,1H),5.07(t,J=7.1Hz,1H),4 .00(q,J=17.0,7.5Hz,1H),2.46(t,J=18.9,11.5Hz,2H),2.30(d,J=1.9Hz,6H),1.78(d,J=0.9Hz,3H),1.67(s,3H),1.61(s,3H). 13C NMR(75MHz,CDCl3)δ195.5(t),157.5(t),138.5(q),137.9(q),136.2(q),135.7(q),133.9(q),131.5 (t),127.3(t),126.3(t),121.2(t),40.9(t),34.3(d),25.8(s),21.0(s),19.7(s),18.0(s),9.7(s).

[0149] Example 59: (E)-4-(4-chloro-2-methylphenyl)-2,7-dimethylocta-2,6-dienal Following the general procedure described in Example 56: reaction of 1-bromo-4-chloro-2-methylbenzene (8.10 g, 39.40 mmol), (E)-2,7-dimethylocta-2,6-dienal (3.00 g, 19.71 mmol), diacetoxypalladium (0.22 g, 0.99 mmol), tricyclohexylphosphane (0.55 g, 1.97 mmol), CsCO (7.70 g, 23.65 mmol) in DMF (20 mL) gave the title product (1.00 g, 18% yield) as a yellow oil. GC / MS(EI):m / z(%):276(1)[M + ],208(88),193(37),179(30),172(40),144(27),129(18),69(100). 1 H NMR(300MHz,CDCl3)δ9.41(s,1H),7.22-7.10(m,3H),6.51(d,J=9.5Hz,1H),5.03(t,J=7.1Hz,1H),3. 97(q,J=16.7,7.5Hz,1H),2.45(t,J=7.2Hz,2H),2.30(s,3H),1.75(s,3H),1.66(s,3H),1.58(s,3H). 13 C NMR(75MHz,CDCl3)δ195.2(t),156.3(t),139.5(q),139.0(q),137.8(q),134.4(q),132.1(q),1 30.5(t),127.9(t),126.6(t),120.6(t),40.7(t),34.2(d),25.8(s),19.6(s),18.0(s),9.8(s).

[0150] Example 60: (E)-4-(2,5-dimethylphenyl)-2,7-dimethylocta-2,6-dienal Following the general procedure described in Example 56: reaction of 2-bromo-1,4-dimethylbenzene (7.29 g, 39.4 mmol), (E)-2,7-dimethylocta-2,6-dienal (3.00 g, 19.71 mmol), diacetoxypalladium (0.22 g, 0.99 mmol), tricyclohexylphosphane (0.55 g, 1.97 mmol), CsCO (7.70 g, 23.65 mmol) in DMF (20 mL) gave the title product (1.44 g, 28% yield) as a yellow oil. GC / MS(EI):m / z(%):256(2)[M + ],188(100),173(86),172(52),159(76),144(23),115(10),69(36). 1 H NMR(300MHz,CDCl3)δ9.41(s,1H),7.06(d,J=8.5Hz,2H),6.96(d,J=7.5Hz,1H),6.55(d,J=11.8Hz,1H),5.07(t,J=7.1Hz ,1H),4.08-3.94(m,1H),2.47(t,J=17.3,10.1Hz,2H),2.34(s,3H),2.29(s,3H),1.78(s,3H),1.67(s,3H),1.61(s,3H). 13 C NMR(75MHz,CDCl3)δ195.4(t),157.3(t),140.7(q),138.5(q),135.9(q),133.9(q),132.5(q),130.5 (t),127.2(t),127.0(t),121.1(t),41.1(t),34.3(d),25.7(s),21.1(s),19.2(s),17.9(s),9.7(s).

[0151] Example 61: (E)-4-(5-chloro-2-methylphenyl)-2,7-dimethylocta-2,6-dienal Following the general procedure described in Example 56: reaction of 2-bromo-4-chloro-1-methylbenzene (8.10 g, 39.4 mmol), (E)-2,7-dimethylocta-2,6-dienal (3.00 g, 19.71 mmol), diacetoxypalladium (0.22 g, 0.99 mmol), tricyclohexylphosphane (0.55 g, 1.97 mmol), CsCO (7.70 g, 23.65 mmol) in DMF (20 mL) gave the title product (0.62 g, 11% yield) as a yellow oil. GC / MS(EI):m / z(%):276(1)[M + ],210(25),208(78),173(28),141(12),128(13),115(8),69(100). 1 H NMR(300MHz,CDCl3)δ9.42(s,1H),7.21(s,1H),7.14-7.04(m,2H),6.48(d,J=11.3Hz,1H),5.03(t,J=7.2Hz, 1H),3.97(q,J=16.9,7.4Hz,1H),2.46(t,J=7.3Hz,2H),2.28(s,3H),1.76(s,3H),1.66(s,3H),1.59(s,3H). 13 C NMR(75MHz,CDCl3)δ195.2(t),155.9(t),142.8(q),139.2(q),134.5(q),134.2(q),132.2( q),131.9(t),126.6(t),120.5(t),41.2(t),34.2(d),25.8(s),19.2(s),18.0(s),9.8(s).

[0152] Example 62: (E)-4-(4-fluoro-2-methylphenyl)-2,7-dimethylocta-2,6-dienal Following the general procedure described in Example 56: reaction of 1-bromo-4-fluoro-2-methylbenzene (7.45 g, 39.4 mmol), (E)-2,7-dimethylocta-2,6-dienal (3.00 g, 19.71 mmol), diacetoxypalladium (0.22 g, 0.99 mmol), tricyclohexylphosphane (0.553 g, 1.971 mmol), CsCO (7.70 g, 23.65 mmol) in DMF (20 mL) gave the title product (1.03 g, 20% yield) as a yellow oil. GC / MS(EI):m / z(%):260(1)[M + ],192(100),177(46),163(59),146(26),133(19),123(26),109(10),77(5),69(50). 1 H NMR(300MHz,CDCl3)δ9.41(s,1H),7.24-7.16(m,1H),6.94-6.82(m,2H),6.51(dd,J=9.6,1.0Hz,1H),5.03(t,J=7 .2Hz,1H),3.97(q,J=16.9,7.4Hz,1H),2.45(t,J=7.2Hz,2H),2.31(s,3H),1.75(s,3H),1.65(s,3H),1.57(s,3H). 13 C NMR(75MHz,CDCl3)δ195.3(t),162.8(q),159.6(q),156.7(t),138.8(q),138.2(q),138.1(q),136.6(q),134.3(q),128.0( t),127.9(t),120.7(t),117.3(t),117.1(t),113.4(t),113.1(t),40.6(t),34.3(d),25.8(s),19.8(s),17.9(s),9.7(s).

[0153] Example 63: (E)-4-(3-chloro-2-methylphenyl)-2,7-dimethylocta-2,6-dienal Following the general procedure described in Example 56: reaction of 1-bromo-3-chloro-2-methylbenzene (5.00 g, 24.33 mmol), (E)-2,7-dimethylocta-2,6-dienal (1.85 g, 12.17 mmol), diacetoxypalladium (0.14 g, 0.61 mmol), tricyclohexylphosphane (0.34 g, 1.22 mmol), CsCO (4.76 g, 14.60 mmol) in DMF (20 mL) gave the title product (0.40 g, 12% yield) as a yellow oil. GC / MS(EI):m / z(%):276(1)[M + ],210(22),208(66),173(55),141(12),128(13),115(9),69(100). 1 H NMR(300MHz,CDCl3)δ9.43(s,1H),7.31-7.26(m,1H),7.21-7.11(m,2H),6.54(d,J=9.3Hz,1H),5.05(t,J= 6.5Hz,1H),4.22-3.96(m,1H),2.48(t,J=7.1Hz,2H),2.39(s,3H),1.76(s,3H),1.68(s,3H),1.60(s,3H). 13 C NMR(75MHz,CDCl3)δ195.2(t),156.3(t),143.1(q),139.2(q),135.3(q),134.5(q),133.9(q),1 27.7(t),127.1(t),125.1(t),120.7(t),41.9(t),34.4(d),25.8(s),18.0(s),16.0(s),9.8(s).

[0154] Example 64: (E)-4-(2-methoxyphenyl)-2,7-dimethylocta-2,6-dienal Following the general procedure described in Example 56: reaction of 1-bromo-2-methoxybenzene (7.37 g, 39.4 mmol), (E)-2,7-dimethylocta-2,6-dienal (3.00 g, 19.71 mmol), diacetoxypalladium (0.22 g, 0.99 mmol), tricyclohexylphosphane (0.55 g, 1.97 mmol), CsCO (7.70 g, 23.65 mmol) in DMF (20 mL) gave the title product (1.90 g, 37% yield) as a yellow oil. GC / MS(EI):m / z(%):258(3)[M + ],189(100),174(64),161(51),145(13),128(19),115(25),107(8),91(40),69(19). 1 H NMR(300MHz,CDCl3)δ9.41(s,1H),7.26-7.16(m,2H),6.99-6.83(m,2H),6.61(dd,J=9.8,1.1Hz,1H),5.06(t,J= 7.1Hz,1H),4.30-4.13(m,1H),3.83(s,3H),2.60-2.41(m,2H),1.77(d,J=1.1Hz,3H),1.66(s,3H),1.60(s,3H). 13 C NMR(75MHz,CDCl3)δ195.8(t),157.4(t),157.1(q),138.9(q),133.6(q),130.7(q),128.0(t),1 27.8(t),121.5(t),120.8(t),110.8(t),55.4(s),39.4(t),33.1(d),25.8(s),18.0(s),9.5(s).

[0155] Example 65: (E)-4-(5-fluoro-2-methylphenyl)-2,7-dimethylocta-2,6-dienal Following the general procedure described in Example 56: reaction of 2-bromo-4-fluoro-1-methylbenzene (7.45 g, 39.40 mmol), (E)-2,7-dimethylocta-2,6-dienal (3.00 g, 19.71 mmol), diacetoxypalladium (0.22 g, 0.99 mmol), tricyclohexylphosphane (0.55 g, 1.97 mmol), CsCO (7.70 g, 23.65 mmol) in DMF (20 mL) gave the title product (1.45 g, 28% yield) as a yellow oil. GC / MS(EI):m / z(%):260(1)[M + ],192(100),177(23),163(18),146(23),133(17),123(15),109(8),69(82). 1 H NMR(300MHz,CDCl3)δ9.42(s,1H),7.10(dd,J=8.1,6.2Hz,1H),6.96(dd,J=10.2,2.6Hz,1H),6.83(td,J=8.3,2.7Hz,1H),6.49(dd,J=9.6,1.0H z,1H),5.04(t,J=7.2Hz,1H),3.99(dd,J=15.9,7.7Hz,1H),2.46(t,J=7 .3Hz,2H),2.28(s,3H),1.76(d,J=1.0Hz,3H),1.66(s,3H),1.59(s,3H). 13 C NMR(75MHz,CDCl3)δ195.2(t),163.3(q),160.1(q),156.0(t),142.9(q),142.9(q),139.1(q),134.4(q),131.8(t),131.7(t),131.3( q),131.3(q),120.6(t),113.5(t),113.4(t),113.2(t),113.1(t),41.34(t),41.3(t),34.1(d),25.8(s),19.0(s),17.9(s),9.8(s).

[0156] Example 66: (E)-2,7-dimethyl-4-(o-tolyl)octa-2,6-dienal Following the general procedure described in Example 56: reaction of 1-bromo-2-methylbenzene (4.43 g, 25.9 mmol), (E)-2,7-dimethylocta-2,6-dienal (2.15 g, 12.96 mmol), diacetoxypalladium (0.15 g, 0.65 mmol), tricyclohexylphosphine (0.36 g, 1.30 mmol), CsCO (5.07 g, 15.56 mmol) in DMF (20 mL) gave the title product (1.89 g, 60% yield) as a pale yellow oil. GC / MS(EI):m / z(%):242(1)[M + ],174(100),159(81),145(70),128(58),115(45),105(26),91(20),69(52). 1 H NMR(300MHz,CDCl3)δ9.40(s,1H),7.25-7.09(m,4H),6.54(d,J=9.7,1.1Hz,1H),5.04(t,J=7.2Hz,1H),4. 01(q,J=9.5,7.4Hz,1H),2.53-2.42(m,2H),2.31(s,3H),1.75(d,J=1.1Hz,3H),1.64(s,3H),1.57(s,3H). 13 C NMR(75MHz,CDCl3)δ195.4(t),157.2(t),140.9(q),138.6(q),135.7(q),134.0(q),130.6( t),126.6(t),126.4(t),121.0(t),41.1(t),34.2(d),25.8(s),19.7(s),17.9(s),9.7(s).

[0157] Example 67: (E)-4-(2-ethylphenyl)-2,7-dimethylocta-2,6-dienal Following the general procedure described in Example 56: reaction of 1-bromo-2-ethylbenzene (5.00 g, 27.0 mmol), (E)-2,7-dimethylocta-2,6-dienal (2.36 g, 13.51 mmol), diacetoxypalladium (0.15 g, 0.68 mmol), tricyclohexylphosphane (0.38 g, 1.35 mmol), CsCO (5.28 g, 16.21 mmol) in DMF (20 mL) gave the title product (2.01 g, 58% yield) as a yellow oil. GC / MS(EI):m / z(%):256(1)[M + ],188(73),173(10),159(100),141(17),131(30),115(25),103(4),91(20),69(24).

[0158] Example 68: (E)-4-(4-fluoro-2-methoxyphenyl)-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 56: reaction of 1-bromo-4-fluoro-2-methoxybenzene (3.43 g, 16.7 mmol), (E)-2,4,7-trimethylocta-2,6-dienal (1.56 g, 8.37 mmol), diacetoxypalladium (0.094 g, 0.42 mmol), tricyclohexylphosphane (0.235 g, 0.84 mmol), CsCO (3.27 g, 10.1 mmol) in DMF (20 mL) gave the title product (1.86 g, 73% yield) as a pale yellow oil. GC / MS(EI):m / z(%):290(1)[M + ],221(100),206(35),193(46),179(18),139(19),109(18),69(10).

[0159] Example 69: (E)-2,4,7-trimethyl-4-(3-methylbut-2-en-1-yl)octa-2,6-dienal Following the general procedure described in Example 1: 2,4,7-trimethylocta-2,6-dienal, 3-methylbut-2-en-1-ol, and Et3N-HCl were reacted in xylene to give the title product as a colorless oil. GC / MS(EI):m / z(%):234(1)[M +],166(82),151(9),137(22),123(56),108(61),95(58),81(21),69(100),55(17). 1 H NMR(300MHz,CDCl3)δ9.31(s,1H),6.33(s,1H),5.07(t,J=7.1Hz,2H),2.33-2.06(m,4H),1.84(s,3H),1.69(s,6H),1.59(s,6H),1.18(s,3H). 13 C NMR(75MHz, CDCl3)δ196.8(t),163.6(t),138.6(q),134.2(q),120.1(t),42.5(q),39.4(d),26.1(s),24.4(s),18.1(s),10.1(s).

[0160] Example 70: (E)-2,7-dimethyl-4-(3-methylbut-2-en-1-yl)octa-2,6-dienal Following the general procedure described in Example 1: 2,7-dimethylocta-2,6-dienal, 3-methylbut-2-en-1-ol, and Et3N-HCl were reacted in xylene to give the title product as a colorless oil. GC / MS(EI):m / z(%):220(4)[M + ],205(3),177(3),152(55),137(7),109(38),95(20),82(44),77(10),69(100). 1 H NMR(300MHz,CDCl3)δ9.39(s,1H),6.26(d,J=10.2Hz,1H),5.04(t,J=9.0,4.3Hz,2H),2.7 4-2.53(m,1H),2.30-2.12(m,2H),2.09-1.94(m,2H),1.69(d,J=14.5Hz,9H),1.58(s,6H). 13 C NMR(75MHz, CDCl3)δ195.7(t),159.2(t),139.0(q),133.5(q),121.4(t),40.4(t),32.8(d),25.8(s),17.9(s),9.7(s).

[0161] Example 71: 4-Ethyl-2-methylhex-2-enal A solution of 2-ethylbutanal (50 g, 0.5 mol) in methanol (100 mL) was treated with a solution of sodium hydroxide (3.99 g, 100 mmol) in water (5 mL) at room temperature. The resulting solution was cooled to 0 °C and then treated with propionaldehyde (72.5 g, 1.25 mol) dropwise over 3 h with vigorous stirring, then allowed to warm to rt overnight. The resulting mixture was neutralized by the addition of acetic acid and concentrated under reduced pressure. The residue was extracted with MTBE (3 × 150 mL), and the combined extracts were washed with brine, dried over MgSO4, and concentrated under reduced pressure to give an oil that was subjected to Kugelrohr distillation (0.9 mbar, 80 °C) to give 4-ethyl-2-methylhex-2-enal (25 g, 36% yield) as a colorless oil. GC / MS(EI):m / z(%):140(13)[M + ],125(12),111(100),97(19),83(22),69(28),55(71).

[0162] Example 72: (E)-4,4-Diethyl-2,7-dimethylocta-2,6-dienal Following the general procedure described in Example 1: reaction of 4-ethyl-2-methylhex-2-enal, 3-methylbut-2-en-1-ol and Et3N-HCl in xylene gave the title product as a colorless oil. GC / MS(EI):m / z(%):208(1)[M + ],140(100),125(20),111(79),95(22),81(19),69(66),55(31).

[0163] Example 73: (E)-4-Ethyl-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 1: reaction of 2,4-dimethylhept-2-enal, 3-methylbut-2-en-1-ol and Et3N-HCl in xylene gave the title product as a colorless oil. GC / MS(EI):m / z(%):208(1)[M + ],140(100),125(9),111(40),97(42),83(10),69(66),55(17).

[0164] Example 74: (E)-4-(3-methylbut-2-en-1-yl)non-2-enal Following the general procedure described in Example 1: reaction of non-2-enal, 3-methylbut-2-en-1-ol, and Et3N-HCl in xylene gave the title product as a colorless oil. GC / MS(EI):m / z(%):208(1)[M + ],140(48),111(2),96(25),83(26),69(100),55(10).

[0165] Example 75: (E)-4-Butyl-7-methylocta-2,6-dienal Following the general procedure described in Example 1: reaction of oct-2-enal, 3-methylbut-2-en-1-ol, and Et3N-HCl in xylene gave the title product as a colorless oil. GC / MS(EI):m / z(%):194(2)[M + ],126(67),95(6),83(34),69(17),55(10).

[0166] Example 76: (E)-4-Ethyl-2,4,7-trimethylocta-2,6-dienal Following the general procedure described in Example 1: 2,4-dimethylhex-2-enal, 3-methylbut-2-en-1-ol, and Et3N-HCl were reacted in xylene to give the title product as a pale yellow oil. GC / MS(EI):m / z(%):194(1)[M + ],165(2),126(100),111(22),109(22),97(53),69(54),55(25).

[0167] Example 77: (E)-4,7-dimethyl-4-(3-methylbut-2-en-1-yl)octa-2,6-dienal Following the general procedure described in Example 1: 4,7-dimethylocta-2,6-dienal, 3-methylbut-2-en-1-ol, and Et3N-HCl were reacted in xylene to give the title product as a colorless oil. GC / MS(EI):m / z(%):220(1)[M +],152(67),137(14),123(25),109(54),94(47),81(42),69(100),59(18),53(16).

[0168] Example 78: 7-Methyl-3-phenyloct-6-enal A mixture of phenylboronic acid (1.76 g, 14.47 mmol), (E)-7-methylocta-2,6-dienal (1.00 g), and diacetoxypalladium (0.041 g, 0.18 mmol) was stirred in 50 mL of toluene to give a red solution. Tri-phenylphosphane (0.19 g, 0.72 mmol), K2CO3 (2.00 g, 14.47 mmol), and Cs2CO3 (0.24 g, 0.72 mmol) were then added, and the mixture was stirred overnight at 80 °C under an Ar atmosphere while the reaction was monitored by GC and GC-MS. The reaction was then quenched with water and extracted with MTBE. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give the crude product as a brown oil, which was purified by distillation (180 °C, 0.12 mbar) to give 7-methyl-3-phenyloct-6-enal (1.20 g, 4.27 mmol, 59.0% yield) as a colorless oil. GC / MS(EI):m / z(%):216(18)[M + ],198(29),183(24),157(38),142(34),129(78),118(74),105(100),91(71),77(44),69(51),55(52).

[0169] Example 79: 7-methyl-3-((R)-4-methylcyclohex-3-en-1-yl)oct-6-enal A mixture of [carbonyl(hydrido)tris(triphenylphosphane)rhodium(I)] ([RhH(CO)(PPh3)3]) (1.40 g, 1.52 mmol), triphenylphosphane (1.28 g, 4.89 mmol), and (R)-1-methyl-4-(6-methylhepta-1,5-dien-2-yl)cyclohex-1-ene (50.00 g, 245.00 mmol) was stirred in a 100 mL autoclave and heated to 80 °C under a synthesis gas atmosphere at 4 MPa pressure for approximately 36 h until the internal pressure no longer decreased. The mixture was purified by distillation (0.068 mbar, 175° C.) to give (S)-7-methyl-3-((R)-4-methylcyclohex-3-en-1-yl)oct-6-enal (35.00 g, 149.33 mmol) as a colorless oil. GC / MS(EI):m / z(%):216(38)[M + ],201(16),159(23),137(38),121(40),105(60),95(100),79(96),67(90),55(64).

[0170] Example 80: 4-Isopentyl-2,4,7-trimethyloct-6-enal A mixture of Lindlar catalyst (Pd / CaCO, lead-poisoned, 5 wt%, 0.1 g), (E)-2,4,7-trimethyl-4-(3-methylbut-2-en-1-yl)octa-2,6-dienal (4.12 g, 17.01 mmol), and ethyl acetate (40 mL) was stirred under a hydrogen atmosphere at room temperature overnight, and the reaction was monitored by GC and GC-MS. The mixture was filtered through a small pad of MgSO, and the filtrate was washed with MTBE. The combined filtrate was concentrated in vacuo to give the crude product, 4-isopentyl-2,4,7-trimethyloct-6-enal, as a colorless oil (3.08 g, 12.9 mmol, 76% yield), which was used in the next step without further purification. GC / MS(EI):m / z(%):238(1)[M + ],220(2),169(15),151(20),109(30),95(100),81(28),69(98),55(49).

[0171] Example 81: 4-Methyl-3-(1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile (General Procedure) Example 81a: 4-methyl-3-(2,4,7-trimethyl-1-oxooct-6-en-4-yl)benzonitrile A mixture of Lindlar catalyst (Pd / CaCO, lead-poisoned, 5 wt%, 0.2 g), (E)-4-methyl-3-(2,4,7-trimethyl-1-oxoocta-2,6-dien-4-yl)benzonitrile (10.3 g, 35.4 mmol), and ethyl acetate (40 mL) was stirred under a hydrogen atmosphere at rt, and the reaction was monitored by GC and GC-MS until >85% conversion was observed. The mixture was then filtered through a small pad of MgSO, and the filtrate was washed with MTBE. The combined filtrate was concentrated in vacuo to give the crude product, 4-methyl-3-(2,4,7-trimethyl-1-oxooct-6-en-4-yl)benzonitrile (7.1 g, 24.9 mmol, 70% yield), which was used in the next step without further purification.

[0172] Example 81b: 4-methyl-3-(1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile A mixture of N-methylhydroxylamine hydrochloride (5.06 g, 60.60 mmol) and K2CO3 (4.46 g, 32.30 mmol) in toluene (50 mL) was stirred at room temperature under Ar for 15 min, then 4-methyl-3-(2,4,7-trimethyl-1-oxooct-6-en-4-yl)benzonitrile (13.95 g, 40.4 mmol) was added and stirred at room temperature for 5 min. The mixture was heated to reflux under Ar overnight, and the reaction was monitored by GC and GC-MS. During this time, water was collected and removed using a Dean-Stark apparatus. After cooling to room temperature, excess K2CO3 was added, the reaction mixture was filtered, and the filter was washed with MTBE. The combined filtrate was collected in Concentration in vacuo gave the crude product, which was purified by flash chromatography (hexane / MTBE = 4:1 to 1:3) to afford rac-4-methyl-3-((3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile (2.72 g, 8.52 mmol, 21% yield) as a yellow wax. (7S,7aS)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile (0.41 g, 1.33 mmol, 21% yield) was obtained as a yellow oil, and rac-4-methyl-3-((3aS,5R,7R,7aS)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile (2.52 g, 8.08 mmol, 20% yield) was obtained as a yellow oil. The obtained rac-4-methyl-3-((3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile was further recrystallized from a mixture of ether and CHCl to give rac-4-methyl-3-((3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile as a white solid.

[0173] rac-4-methyl-3-((3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile: GC / MS(EI):m / z(%):312(37)[M + ],297(4),266(20),196(6),182(6),144(14),126(100),100(47),87(55),70(17). 1 H NMR(300MHz,CDCl3)δ7.67(s,1H),7.50-7.35(m,1H),7.23(s,1H),2.99-2.53(m,6H),2.32(t,J=10 .7Hz,1H),2.19-1.85(m,4H),1.69-1.55(m,1H),1.53-1.39(m,4H),1.28(s,3H),1.22-1.00(m,6H). 13 C NMR(75MHz,CDCl3)δ149.8(q),142.3(q),134.2(t),129.7(t),129.6(t),119.7(q),109.9(q),79.5(q),77.4 (t),53.8(t),49.0(s),45.2(d),40.0(q),35.9(d),33.3(t),27.0(s),25.1(s),24.5(s),24.2(s),20.4(s). rac-4-Methyl-3-((3aS,5R,7S,7aS)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile: GC / MS (EI): m / z (%): 312 (37) [M + ],297(6),266(4),196(3),182(4),144(9),126(100),113(44),98(95),87(21). rac-4-Methyl-3-((3aS,5R,7R,7aS)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile: GC / MS (EI): m / z (%): 312 (58) [M +],297(6),266(22),196(7),182(7),144(17),126(89),113(25),100(38),98(45),87(100),70(20).

[0174] A sample of rac-4-methyl-3-((3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile was purified by chiral HPLC (Phenomenex Lux). Further separation by Cellulose-1, 4.6 x 150 mm, 3 µm hexane / isopropanol, 96:4% v / v, isocratic for 20 min gave two enantiomerically pure fractions: rel-4-methyl-3-((3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile (first peak, elution-retention time ca. 9 min) and rel-4-methyl-3-((3aS,5S,7R,7aS)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile (second peak, elution-retention time ca. 12 min).

[0175] In the preparation of similar examples in which N-methylhydroxylamine hydrochloride was replaced by N-ethylhydroxylamine or N-isopropylhydroxylamine, the same procedure was used, except that the base (K2CO3) was omitted and toluene was occasionally replaced with xylene as the indicated reaction solvent.

[0176] Example 82: rac-(3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyl-5-(o-tolyl)octahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,4,7-trimethyl-4-(o-tolyl)oct-6-enal (3.15 g, 10.59 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (1.33 g, 15.88 mmol), KCO (1.17 g, 8.47 mmol) in toluene (50 mL) gave the title product (0.70 g, 23% yield) as a pale yellow oil. GC / MS(EI):m / z(%):287(64)[M + ],272(5),171(12),157(14),126(100),119(23),100(47),87(56),70(12). 1 H NMR(300MHz,CDCl3)δ7.46-7.35(m,1H),7.22-7.09(m,3H),2.84(s,3H),2.58(s,3H),2.41-2.25(m,1H),2.19-2.06 (m,1H),2.05-1.90(m,3H),1.67(t,J=12.9Hz,1H),1.59-1.49(m,1H),1.46(s,3H),1.28(s,3H),1.18-1.01(m,6H). 13 C NMR(75MHz,CDCl3)δ148.3(q),136.0(q),133.5(t),126.2(t),126.0(t),125.5(t),79.5(q),77.2(t), 53.9(t),48.9(s),45.3(d),39.7(q),35.9(d),33.3(t),27.0(s),25.1(s),24.6(s),23.8(s),20.4(s).

[0177] Example 83: rac-(3aR,5R,7S,7aR)-1-isopropyl-3,3,5,7-tetramethyl-5-(o-tolyl)octahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,4,7-trimethyl-4-(o-tolyl)oct-6-enal (520 mg, 1.51 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-isopropylhydroxylamine hydrochloride, KCO (170 mg, 1.21 mmol) in toluene (50 mL) gave the title product (320 mg, 67% yield) as a pale yellow oil. GC / MS(EI):m / z(%):315(44)[M + ],300(100),241(1),185(9),171(8),154(69),128(22),126(25),115(24),98(3). 1H NMR(300MHz,CDCl3)δ7.40(d,J=7.7Hz,1H),7.21-7.06(m,3H),3.31-3.09(m,1H),2.57(s,3H),2.48-2.26(m,2H),1.98(dd,J =10.3,3.2Hz,3H),1.69-1.51(m,2H),1.47(s,3H),1.31(s,3H),1.26(d,J=6.7Hz,3H),1.11-1.01(m,8H),0.99-0.92(m,1H). 13 C NMR(75MHz,CDCl3)δ148.4(q),136.0(q),133.4(t),126.1(t),125.9(t),125.4(t),78.0(q),68.5(t),55.0(t), 53.0(t),45.7(d),39.5(t),35.9(d),33.6(t),27.1(s),24.6(s),24.3(s),23.8(s),22.6(s),20.5(s),13.4(s).

[0178] Example 84: rac-(3aR,5R,7S,7aR)-1-ethyl-3,3,5,7-tetramethyl-5-(o-tolyl)octahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,4,7-trimethyl-4-(o-tolyl)oct-6-enal (298 mg, 0.81 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-ethylhydroxylamine hydrochloride (118 mg, 1.21 mmol), KCO (89 mg, 0.65 mmol) in toluene (50 mL) gave the title product (95 mg, 39% yield) as a pale yellow oil. GC / MS(EI):m / z(%):301(2)[M + ],300(8),286(77),185(10),171(12),132(100),117(20),105(20),91(15),68(9). 1H NMR(300MHz,CDCl3)δ7.40(d,J=7.7Hz,1H),7.21-7.06(m,3H),3.09-2.92(m,1H),2.88-2.73(m,1H),2.57(s,3H),2.36 -2.22(m,2H),2.07-1.90(m,3H),1.73-1.51(m,2H),1.46(s,3H),1.31-1.21(m,6H),1.11(s,3H),1.02(d,J=6.2Hz,3H). 13 C NMR(75MHz,CDCl3)δ148.3(q),136.0(q),133.4(t),126.1(t),126.0(t),125.5(t),79.5(q),74.8(t),56.5 (d),53.2(t),45.4(d),39.7(q),36.0(d),33.9(t),31.0(s),26.6(s),24.8(s),23.8(s),20.5(s),13.9(s).

[0179] Example 85: rac-(3aR,5R,7S,7aR)-5-(4-fluoro-2-methylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(4-fluoro-2-methylphenyl)-2,4,7-trimethyloct-6-enal (400 mg, 1.45 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (181 mg, 2.17 mmol), KCO (160 mg, 1.16 mmol) in toluene (50 mL) gave the title product (110 mg, 25% yield) as a yellow oil. GC / MS(EI):m / z(%):305(100)[M + ],150(42),137(38),126(85),123(22),100(42),98(28),87(48). 1 H NMR(300MHz,CDCl3)δ7.49-7.21(m,1H),7.01-6.65(m,2H),3.27-2.67(m,3H),2.60- 2.51(m,2H),2.31(s,1H),2.21-1.81(m,4H),1.65-1.38(m,5H),1.36-0.99(m,10H). 13 C NMR(75MHz,CDCl3)δ162.5(q),159.2(q),144.1(q),138.7(q),127.3(t),119.7(t),112.1(t),79.4(q),73.8 (t),53.9(t),48.9(s),45.5(d),39.4(q),36.1(d),33.3(t),26.9(s),25.0(s),24.8(s),23.7(s),20.3(s).

[0180] From the same reaction, an additional diastereomer was isolated: rac-(3aR,5R,7R,7aR)-5-(4-fluoro-2-methylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole (138 mg, 31% yield) as a yellow oil. GC / MS(EI):m / z(%):305(71)[M + ],150(30),126(100),113(29),100(52),98(49),87(96),70(25).

[0181] Example 86: rac-(3aR,5R,7S,7aR)-5-(5-chloro-2-methylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(5-chloro-2-methylphenyl)-2,4,7-trimethyloct-6-enal (412 mg, 1.15 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (145 mg, 1.73 mmol), KCO (128 mg, 0.92 mmol) in toluene (50 mL) gave the title product (120 mg, 32% yield) as a pale yellow oil. GC / MS(EI):m / z(%):321(46)[M + ],306(3),275(2),205(4),191(5),153(26),126(100),100(44),87(56),70(12). 1H NMR(300MHz,CDCl3)δ7.33(s,1H),7.15-7.00(m,2H),2.83(s,3H),2.52(s,3H),2.38-2.21(m,1H),2.14-2.05(m,1 H),1.95(d,J=12.8Hz,3H),1.60(t,J=12.8Hz,1H),1.48-1.39(m,4H),1.29(s,3H),1.17(s,3H),1.09-1.01(m,3H). 13 C NMR(75MHz,CDCl3)δ150.2(q),134.6(t),134.5(t),131.7(q),126.0(t),125.9(t),79.5(q),77.1(t), 53.8(t),49.1(s),45.1(d),39.8(q),35.7(d),33.3(t),27.0(s),25.0(s),24.4(s),23.2(s),20.4(s).

[0182] Example 87: rac-3-((3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile Following the general procedure described in Example 81b: reaction of 3-(2,4,7-trimethyl-1-oxooct-6-en-4-yl)benzonitrile (6.00 g, 13.48 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (1.69 g, 20.23 mmol), KCO (1.49 g, 10.79 mmol) in toluene (50 mL) gave the title product (1.20 g, 30% yield) as a yellow oil. GC / MS(EI):m / z(%):298(36)[M + ],283(6),252(11),182(10),168(9),126(100),100(41),87(50),70(16). 1H NMR(300MHz,CDCl3)δ7.72-7.57(m,2H),7.53-7.35(m,2H),2.90-2.59(m,3H),2.43-2.21(m,1H),2.14-1.90(m, 2H),1.89-1.71(m,2H),1.58-1.45(m,1H),1.40(d,J=12.7Hz,1H),1.34(s,3H),1.25(s,3H),1.19-0.96(m,6H). 13 C NMR(75MHz,CDCl3)δ152.5(q),129.9(t),129.7(t),129.2(t),129.1(t),119.2(q),112.4(q),79.3(q), 77.4(t),53.7(t),48.9(s),45.8(d),38.8(q),36.8(d),33.1(t),26.9(s),26.4(s),24.9(s),20.1(s).

[0183] Example 88: rac-(3aR,5R,7S,7aR)-5-(2,5-dimethylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(2,5-dimethylphenyl)-2,4,7-trimethyloct-6-enal (500 mg, 1.84 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (230 mg, 2.75 mmol), KCO (203 mg, 1.47 mmol) in toluene (50 mL) gave the title product (168 mg, 30% yield) as a yellow oil. GC / MS(EI):m / z(%):301(68)[M + ],286(3),255(2),171(20),126(100),119(19),100(38),87(47),70(11). 1H NMR(300MHz,CDCl3)δ7.20(s,1H),7.06(d,J=7.6Hz,1H),6.96(d,J=7.6Hz,1H),2.91-2.67(m,3H),2.53(s,3H),2.39-2.25(m,4H),2.18-2.06(m, 1H),1.97(d,J=12.8Hz,3H),1.68(d,J=12.8Hz,1H),1.59-1.48(m,1H),1 .45(s,3H),1.34-1.22(m,4H),1.18-1.13(m,2H),1.06(d,J=6.0Hz,3H). 13 C NMR(75MHz,CDCl3)δ148.0(q),135.2(q),133.4(t),132.7(q),126.7(t),126.3(t),79.5(q),77.2(t),53.9(t), 48.9(s),45.3(d),39.5(s),35.8(d),33.3(t),27.1(s),27.0(s),25.0(s),24.6(s),23.4(s),21.4(s),20.4(s).

[0184] Example 89: rac-3-((3aR,5R,7S,7aR)-1-ethyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazol-5-yl)-4-methylbenzonitrile Following the general procedure described in Example 81b: reaction of 4-methyl-3-(2,4,7-trimethyl-1-oxooct-6-en-4-yl)benzonitrile (300 mg, 0.79 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a) with N-ethylhydroxylamine (73 mg, 1.19 mmol) in toluene (50 mL) gave the title product (50 mg, 19% yield) as a yellow oil. GC / MS(EI):m / z(%):326(24)[M + ],311(23),266(14),196(5),182(5),140(100),114(37),101(38). 1H NMR(300MHz,CDCl3)δ7.64(s,1H),7.39(d,J=7.9Hz,1H),7.22(d,J=7.9Hz,1H),3.07-2.91(m,1H),2.87-2.72(m,1H),2.59(s,3H),2. 33-2.22(m,2H),2.04-1.87(m,3H),1.62-1.51(m,1H),1.45-1.37(m,4H),1.30-1.21(m,6H),1.18-1.07(m,3H),1.02(d,J=6.1Hz,3H). 13 C NMR(75MHz,CDCl3)δ149.5(q),142.1(q),133.9(t),129.5(t),129.4(t),119.5(q),109.7(q),79.3(q),74.5(t), 56.4(d),52.8(t),45.0(d),39.8(q),35.8(d),33.6(t),26.5(s),24.6(s),24.3(s),24.0(s),20.3(s),13.7(s).

[0185] Example 90: rac-(3aR,5R,7S,7aR)-5-(5-fluoro-2-methylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(5-fluoro-2-methylphenyl)-2,4,7-trimethyloct-6-enal (400 mg, 1.45 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (181 mg, 2.17 mmol), KCO (160 mg, 1.16 mmol) in toluene (50 mL) gave the title product (60 mg, 14% yield) as a yellow oil. GC / MS(EI):m / z(%):305(71)[M + ],150(11),137(30),126(100),123(23),100(45),98(34),87(57). 1H NMR(300MHz,CDCl3)δ7.16-6.96(m,2H),6.79(td,J=8.1,2.6Hz,1H),2.93-2.64(m,3H),2.51(s,3H),2.36-2.21(m,1H) ,2.09(t,J=10.3Hz,1H),2.03-1.84(m,3H),1.60(t,J=12.9Hz,1H),1.51-1.39(m,4H),1.25(s,3H),1.19-0.96(m,6H). 13 C NMR(75MHz,CDCl3)δ162.8(q),159.6(q),150.5(q),150.4(q),134.4(t),134.3(t),131.4(q),131.3(q),112.9(t),112.6(t),112.5(t ),112.2(t),79.4(q),77.1(t),53.8(t),48.9(s),45.0(d),39.7(q),35.6(d),33.2(t),26.9(s),25.0(s),24.3(s),23.0(s),20.3(s).

[0186] Example 91: rac-3-((3aR,5R,7S,7aR)-1-isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile Following the general procedure described in Example 81b: reaction of 3-(2,4,7-trimethyl-1-oxooct-6-en-4-yl)benzonitrile (200 mg, 0.74 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a) with N-isopropylhydroxylamine (167 mg, 2.23 mmol) in xylene (70 mL) gave the title product (55 mg, 23% yield) as a yellow oil. GC / MS(EI):m / z(%):326(24)[M + ],311(100),252(4),196(10),182(5),154(51),126(20),115(9). 1H NMR(300MHz,CDCl3)δ7.69-7.58(m,2H),7.52-7.36(m,2H),3.27-3.10(m,1H),2.46-2.25(m,2H),2.06-1. 91(m,1H),1.86-1.72(m,2H),1.54-1.39(m,2H),1.34(s,3H),1.30(s,3H),1.23(s,3H),1.10-0.98(m,9H). 13 C NMR(75MHz,CDCl3)δ152.7(q),130.0(t),129.6(t),129.2(t),129.1(t),119.3(q),112.4(q),77.9(q),68.8(t), 55.0(t),52.9(t),46.1(d),38.7(q),36.7(d),33.5(t),27.2(s),26.5(s),24.3(s),22.6(s),20.3(s),13.7(s).

[0187] Example 92: rac-3-((3aR,5R,7S,7aR)-1-isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazol-5-yl)-4-methylbenzonitrile Following the general procedure described in Example 81b: reaction of 4-methyl-3-(2,4,7-trimethyl-1-oxooct-6-en-4-yl)benzonitrile (3.534 g, 12.38 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-isopropylhydroxylamine (2.79 g, 37.10 mmol) in xylene (70 mL) gave the title product rac-3-((3aR,5R,7S,7aR)-1-isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazol-5-yl)-4-methylbenzonitrile (589 mg, 14% yield) as a white solid. GC / MS(EI):m / z(%):340(23)[M + ],325(89),266(7),196(5),182(5),154(100),126(37),115(30). 1H NMR(300MHz,CDCl3)δ7.65(s,1H),7.40(d,J=7.8Hz,1H),7.23(d,J=7.8Hz,1H),3.35-3.05(m,1H),2.62(s,3H), 2.48-2.22(m,2H),2.05-1.85(m,3H),1.61-1.37(m,5H),1.31(s,3H),1.25(d,J=6.6Hz,3H),1.14-0.94(m,9H). 13 C NMR(75MHz,CDCl3)δ149.8(q),142.2(q),134.0(t),129.5(t),129.4(t),119.5(q),109.7(q),77.9(q),68.3(t), 55.0(t),52.8(t),45.4(d),39.7(q),35.7(d),33.5(t),27.1(s),24.2(s),24.1(s),22.6(s),20.4(s),13.4(s).

[0188] From the same reaction, two additional isomers were isolated as pale yellow oils: rac-3-((3aS,5R,7S,7aS)-1-isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazol-5-yl)-4-methylbenzonitrile (234 mg, 6% yield) and rac-3-((3aS,5R,7R,7aS)-1-isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazol-5-yl)-4-methylbenzonitrile (765 mg, 18% yield). rac-3-((3aS,5R,7S,7aS)-1-isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazol-5-yl)-4-methylbenzonitrile: GC / MS(EI):m / z(%):340(11)[M + ],325(24),247(27),154(63),141(43),126(100),115(24),84(30). rac-3-((3aS,5R,7R,7aS)-1-isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazol-5-yl)-4-methylbenzonitrile: GC / MS(EI):m / z(%):340(20)[M + ],325(100),266(6),210(9),154(52),141(23),126(45),115(43).

[0189] Example 93: rac-(3aR,5R,7S,7aR)-5-(2-methoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(2-methoxyphenyl)-2,4,7-trimethyloct-6-enal (500 mg, 1.82 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (228 mg, 2.73 mmol), KCO (201 mg, 1.46 mmol) in toluene (50 mL) gave the title product (123 mg, 22% yield) as a yellow oil. GC / MS(EI):m / z(%):303(92)[M + ],288(5),257(9),201(15),180(17),135(31),126(100),100(37),87(44). 1 H NMR(300MHz,CDCl3)δ7.31(d,J=7.8Hz,1H),7.25-7.16(m,1H),6.99-6.83(m,2H),3.84(s,3H),2.93-2.61(m,3H),2.40-2.26(m,1H),2 .17-1.84(m,4H),1.73(t,J=12.7Hz,1H),1.57(t,J=12.7Hz,1H),1.43(s,3H),1.30-1.25(m,3H),1.19-1.11(m,3H),1.07-0.98(m,3H). 13 C NMR(75MHz,CDCl3)δ158.3(q),138.3(q),127.3(t),126.0(t),120.5(t),111.9(t),79.5(q),77.5(t), 55.0(s),53.7(t),48.9(s),44.1(d),38.7(q),34.6(d),33.0(t),26.9(s),25.0(s),23.6(s),20.3(s).

[0190] Example 94: rac-(3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyl-5-phenyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,4,7-trimethyl-4-phenyloct-6-enal (2.11 g, 8.04 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (1.01 g, 12.06 mmol), KCO (0.89 mg, 6.43 mmol) in toluene (50 mL) gave the title product (0.78 g, 35% yield) as a pale yellow oil. GC / MS(EI):m / z(%):273(52)[M + ],258(5),227(3),171(11),180(9),157(15),126(100),100(40),87(44). 1 H NMR(300MHz,CDCl3)δ7.45-7.38(m,2H),7.37-7.29(m,2H),7.24-7.16(m,1H),2.90-2.66(m,3H),2.43-2.25(m,1H),2.13-2.02( m,1H),2.01-1.90(m,1H),1.87-1.75(m,2H),1.65-1.52(m,1H),1.50-1.42(m,1H),1.36(s,3H),1.27(s,3H),1.19-0.99(m,6H). 13 C NMR(75MHz,CDCl3)δ151.2(q),128.3(t),125.9(t),125.1(t),79.4(q),77.7(t),53.9( t),48.9(s),46.1(d),38.6(q),37.0(d),33.2(t),27.0(s),26.6(s),25.0(s),20.2(s).

[0191] Example 95: rac-(3aR,5R,7S,7aR)-5-(2,4-dimethylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(2,4-dimethylphenyl)-2,4,7-trimethyloct-6-enal (1.02 g, 1.88 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (0.24 g, 2.82 mmol), KCO (0.21 g, 1.50 mmol) in toluene (50 mL) gave the title product (0.15 g, 27% yield) as a pale yellow oil. GC / MS(EI):m / z(%):301(54)[M + ],286(6),255(3),185(12),171(14),126(100),119(23),100(42),87(58),70(12). 1 H NMR(300MHz,CDCl3)δ7.34-7.22(m,1H),7.04-6.92(m,2H),2.89-2.65(m,3H),2.54(s,3H),2.35-2.24(m,4H),2.14-2.05(m ,1H),2.05-1.85(m,3H),1.65(t,J=12.9Hz,1H),1.56-1.48(m,1H),1.44(s,3H),1.27(d,J=10.0Hz,3H),1.18-0.96(m,6H). 13 C NMR(75MHz,CDCl3)δ145.3(q),135.8(q),135.5(q),134.3(t),126.6(t),125.5(t),79.5(q),77.2(t),53.9 (t),48.9(s),45.5(d),39.4(q),36.0(d),33.3(t),27.0(s),25.0(s),24.7(s),23.6(s),20.5(s),20.4(s).

[0192] Example 96: rac-(3aR,5R,7S,7aR)-1-ethyl-3,3,5,7-tetramethyl-5-phenyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,4,7-trimethyl-4-phenyloct-6-enal (1.03 g, 2.93 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-ethylhydroxylamine hydrochloride (0.43 g, 4.39 mmol), KCO (0.32 g, 2.34 mmol) in toluene (50 mL) gave the title product (0.34 g, 40% yield) as a pale yellow oil. GC / MS(EI):m / z(%):287(28)[M + ],272(94),171(19),157(24),140(87),129(20),118(100),105(37),91(51). 1 H NMR(300MHz,CDCl3)δ7.44-7.38(m,2H),7.37-7.29(m,2H),7.24-7.16(m,1H),3.10-2.71(m,2H),2.38-2.16(m,2H),2.05-1.92(m,1 H),1.90-1.77(m,2H),1.56(t,J=12.4Hz,1H),1.50-1.37(m,1H),1.36(s,3H),1.32-1.18(m,6H),1.12(s,3H),1.02(d,J=6.4Hz,3H). 13 C NMR(75MHz,CDCl3)δ151.3(q),128.3(t),125.9(t),125.1(t),79.4(q),75.3(t),56.5(d),5 3.2(t),46.2(d),38.6(q),37.1(d),33.7(t),26.7(s),26.6(s),24.7(s),20.4(s),13.9(s).

[0193] Example 97: rac-(3aR,5R,7S,7aR)-5-(3-chloro-2-methylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(3-chloro-2-methylphenyl)-2,4,7-trimethyloct-6-enal (289 mg, 0.83 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (104 mg, 1.24 mmol), KCO (92 mg, 0.66 mmol) in toluene (50 mL) gave the title product (121 mg, 45% yield) as a pale yellow oil. GC / MS(EI):m / z(%):321(10)[M + ],320(21),306(7),234(31),195(22),180(21),166(100),126(53),115(13),96(15),68(16). 1 H NMR(300MHz,CDCl3)δ7.38-7.22(m,2H),7.15-7.05(m,1H),2.90-2.67(m,3H),2.57(s,3H),2.40-2.26(m,1H),2.21-2.08( m,1H),2.05-1.84(m,3H),1.68(t,J=12.9Hz,1H),1.52-1.45(m,4H),1.27(s,3H),1.20-1.14(m,3H),1.05(d,J=6.2Hz,3H). 13 C NMR(75MHz,CDCl3)δ150.2(q),137.4(q),134.2(q),127.5(t),126.4(t),123.9(t),79.4(q),76.9(t),53.8 (t),48.9(s),45.6(d),40.0(s),36.3(d),33.3(t),27.0(s),26.9(s),25.1(s),25.0(s),20.3(s),20.2(s).

[0194] Example 98: rac-(3aR,5R,7S,7aR)-5-(2-fluorophenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(2-fluorophenyl)-2,4,7-trimethyloct-6-enal (500 mg, 1.91 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (240 mg, 2.86 mmol), KCO (211 mg, 1.53 mmol) in toluene (50 mL) gave the title product (120 mg, 22% yield) as a pale yellow oil. GC / MS(EI):m / z(%):291(41)[M + ],276(7),136(35),126(100),123(29),109(41),98(35),87(40). 1 H NMR(300MHz,CDCl3)δ7.26(td,J=8.2,1.5Hz,1H),7.18-7.08(m,1H),7.06-6.88(m,2H),2.85-2.56(m,3H),2.34-2.14(m,1H),2.04(t,J=10.3Hz, 1H),1.85(d,J=12.6Hz,3H),1.59(t,J=12.6Hz,1H),1.52-1.41(m,1H),1 .36(s,3H),1.26-1.16(m,3H),1.14-1.03(m,3H),0.96(d,J=6.1Hz,3H). 13 C NMR(75MHz,CDCl3)δ163.4(q),160.2(q),137.3(q),137.1(q),127.9(t),1 27.8(t),126.6(t),126.5(t),124.1(t),124.0(t),116.8(t),116.5(t),7 9.4(q),77.4(t),53.5(t),48.9(s),44.5(d),44.4(d),38.3(q),38.2(q), 35.2(d),35.1(d),33.0(t),26.9(s),24.9(s),24.2(s),24.1(s),20.2(s).

[0195] Example 99: rac-(3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyl-5-(p-tolyl)octahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,4,7-trimethyl-4-(p-tolyl)oct-6-enal (284 mg, 1.01 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (127 mg, 1.52 mmol), KCO (112 mg, 0.81 mmol) in toluene (50 mL) gave the title product (112 mg, 40% yield) as a pale yellow oil. GC / MS(EI):m / z(%):287(1)[M + ],286(3),195(35),180(22),171(4),132(100),126(28),117(14),105(13),98(12),91(10). 1 H NMR(300MHz,CDCl3)δ7.30(d,J=8.2Hz,2H),7.15(d,J=8.2Hz,2H),2.89-2.65(m,3H),2.39-2.26(m,4H),2.08(t,J=10.3Hz,1H),2.0 1-1.90(m,1H),1.88-1.74(m,2H),1.55(t,J=12.9Hz,1H),1.48-1.40(s,1H),1.37(d,J=12.9Hz,3H),1.27(s,3H),1.16-1.01(m,6H). 13 C NMR(75MHz,CDCl3)δ148.4(q),135.5(q),129.1(t),125.0(t),79.5(q),77.7(t),54.0(t),4 9.0(s),46.2(d),38.3(q),37.2(d),33.2(t),27.0(s),26.6(s),25.0(s),20.9(s),20.3(s).

[0196] Example 100: rac-(3aR,5R,7S,7aR)-1-isopropyl-3,3,5,7-tetramethyl-5-phenyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,4,7-trimethyl-4-phenyloct-6-enal (258 mg, 0.91 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a) with N-isopropylhydroxylamine (102 mg, 1.36 mmol) in xylene (50 mL) gave the title product rac-(3aR,5R,7S,7aR)-1-isopropyl-3,3,5,7-tetramethyl-5-phenyloctahydrobenzo[c]isoxazole (92 mg, 34% yield) as a pale yellow oil. GC / MS(EI):m / z(%):301(35)[M + ],286(100),171(11),154(71),126(28),115(24),105(20),91(23). 1 H NMR(300MHz,CDCl3)δ7.45-7.37(m,2H),7.33(t,J=7.7Hz,2H),7.24-7.16(m,1H),3.32-3.08(m,1H),2.48-2.26(m,2H),2. 05-1.90(m,1H),1.87-1.72(m,2H),1.62-1.41(m,2H),1.36(s,3H),1.31(s,3H),1.26(d,J=6.7Hz,3H),1.13-0.97(m,9H). 13 C NMR(75MHz,CDCl3)δ151.4(q),128.3(t),125.9(t),125.1(t),78.0(q),69.0(t),55.0(t),5 3.1(t),46.5(d),38.5(q),37.0(d),33.6(t),27.2(s),26.7(s),24.3(s),22.6(s),20.4(s).

[0197] From the same reaction, additional isomers were also isolated as pale yellow oils: rac-(3aS,5R,7S,7aS)-1-isopropyl-3,3,5,7-tetramethyl-5-phenyloctahydrobenzo[c]isoxazole (19 mg, 6% yield) and rac-(3aS,5R,7R,7aS)-1-isopropyl-3,3,5,7-tetramethyl-5-phenyloctahydrobenzo[c]isoxazole (68 mg, 24% yield). rac-(3aS,5R,7S,7aS)-1-isopropyl-3,3,5,7-tetramethyl-5-phenyloctahydrobenzo[c]isoxazole: GC / MS(EI):m / z(%):301(24)[M + ],286(38),169(14),154(80),141(37),126(100),115(25),105(38),91(44). rac-(3aS,5R,7R,7aS)-1-isopropyl-3,3,5,7-tetramethyl-5-phenyloctahydrobenzo[c]isoxazole: GC / MS(EI):m / z(%):301(35)[M + ],286(100),171(11),154(71),126(28),115(24),105(20),91(23).

[0198] Example 101: rac-(3aR,5R,7S,7aR)-1-isopropyl-5-(2-methoxyphenyl)-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(2-methoxyphenyl)-2,4,7-trimethyloct-6-enal (700 mg, 2.55 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a) with propan-2-ol (460 mg, 7.65 mmol) in toluene (50 mL) gave the title product (183 mg, 22% yield) as a pale yellow oil. GC / MS(EI):m / z(%):331(45)[M + ],316(94),257(4),201(12),154(100),135(23),126(33),115(24),91(16). 1H NMR(300MHz,CDCl3)δ7.30(d,J=7.7Hz,1H),7.25-7.16(m,1H),6.97-6.87(m,2H),3.84(s,3H),2.49-2.26(m,2H),1.98(d,J= 12.1Hz,3H),1.74-1.48(m,3H),1.43(s,3H),1.30(s,3H),1.26(d,J=6.7Hz,3H),1.08(d,J=7.2Hz,6H),1.01(d,J=6.2Hz,3H). 13 C NMR(75MHz,CDCl3)δ158.4(q),138.6(q),127.3(t),126.0(t),120.6(t),112.0(t),78.2(q),68.9(t),55.1(t), 54.9(s),52.8(t),44.6(d),38.7(q),34.7(d),27.2(s),27.0(s),24.3(s),23.6(s),22.6(s),20.5(s),13.7(s).

[0199] Example 102: rac-4-((3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile Following the general procedure described in Example 81b: reaction of 4-(2,4,7-trimethyl-1-oxooct-6-en-4-yl)benzonitrile (300 mg, 1.11 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (140 mg, 1.67 mmol), KCO (123 mg, 0.89 mmol) in toluene (50 mL) gave the title product (75 mg, 23% yield) as a pale yellow oil. GC / MS(EI):m / z(%):298(5)[M + ],297(20),283(6),240(13),195(21),180(18),143(35),126(70),116(31),98(37),68(100). 1H NMR(300MHz,CDCl3)δ7.60(d,J=8.4Hz,2H),7.48(d,J=8.4Hz,2H),2.88-2.61(m,3H),2.39-2.21(m,1H),2.13-2.01(m,1H),1.91-1.7 3(m,2H),1.51(t,J=12.9Hz,1H),1.41(d,J=12.2Hz,1H),1.34(s,3H),1.29-1.17(m,4H),1.14(d,J=9.7Hz,3H),1.03(d,J=6.0Hz,3H). 13 C NMR(75MHz,CDCl3)δ156.5(q),132.2(t),126.1(t),119.0(q),109.8(q),79.3(q),77.3(t),5 3.6(t),48.9(s),45.6(d),39.2(q),36.6(d),33.1(t),26.9(s),26.3(s),24.9(s),20.2(s).

[0200] Example 103: rac-(3aR,5R,7S,7aR)-5-(3-methoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(3-methoxyphenyl)-2,4,7-trimethyloct-6-enal (700 mg, 2.55 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (320 mg, 3.83 mmol), KCO (282 mg, 2.04 mmol) in toluene (50 mL) gave the title product (238 mg, 31% yield) as a yellow oil. GC / MS(EI):m / z(%):303(5)[M + ],302(8),288(3),216(20),195(28),180(18),148(100),126(38),98(12),96(13). 1H NMR(300MHz,CDCl3)δ7.18(t,J=8.0Hz,1H),6.89(dd,J=11.6,5.0Hz,2H),6.66(dd,J=8. 0,2.2Hz,1H),3.72(s,3H),2.82-2.55(m,3H),2.33-2.11(m,1H),1.99(t,J=10.2Hz,1H) ,1.91-1.81(m,1H),1.72(dd,J=15.2,7.1Hz,2H),1.48(t,J=12.9Hz,1H),1.36(dd,J=20 .6,8.2Hz,1H),1.26(s,3H),1.19(d,J=8.7Hz,3H),1.12-1.02(m,3H),0.99-0.90(m,3H). 13 C NMR(75MHz,CDCl3)δ159.5(q),153.0(q),129.2(t),117.5(t),112.1(t),110.0(t),79.3(q),77.6(t), 55.1(q),53.8(t),48.9(s),46.0(d),38.6(q),36.9(d),33.1(t),26.9(s),26.5(s),24.9(s),20.2(s).

[0201] Example 104: rac-(3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyl-5-(naphthalen-2-yl)octahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,4,7-trimethyl-4-(naphthalen-2-yl)oct-6-enal (500 mg, 1.70 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (213 mg, 2.55 mmol), KCO (188 mg, 1.36 mmol) in toluene (50 mL) gave the title product (160 mg, 29% yield) as a pale yellow oil. GC / MS(EI):m / z(%):323(14)[M + ],308(5),236(12),195(72),180(70),168(100),126(35),98(14),96(19). 1H NMR(300MHz,CDCl3)δ7.87-7.68(m,4H),7.56(dd,J=8.7,1.5Hz,1H),7.49-7.37(m,2H),2.93-2.63(m,3H),2.37(dd,J=16.9,6.5H z,1H),2.16-1.84(m,4H),1.66(s,1H),1.56(d,J=12.4Hz,1H),1.44(s,3H),1.32(s,3H),1.20-1.14(m,3H),1.07(d,J=5.8Hz,3H). 13 C NMR(75MHz,CDCl3)δ148.5(q),133.4(q),131.8(q),128.0(t),127.9(t),127.4(t),126.0(t),125.6(t),124.4(t),122 .8(t),79.5(q),77.7(t),53.6(t),48.9(s),46.1(d),38.7(q),37.0(d),33.2(t),27.0(s),26.4(s),25.0(s),20.3(s).

[0202] Example 105: rac-(3aR,5R,7S,7aR)-5-(2-ethylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(2-ethylphenyl)-2,4,7-trimethyloct-6-enal (500 mg, 1.84 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (230 mg, 2.75 mmol), KCO (203 mg, 1.47 mmol) in toluene (50 mL) gave the title product (146 mg, 26% yield) as a pale yellow oil. GC / MS(EI):m / z(%):301(82)[M + ],286(5),185(10),171(13),147(20),126(100),100(47),87(52). 1H NMR(300MHz,CDCl3)δ7.45-7.33(m,1H),7.28-7.09(m,3H),3.00-2.67(m,5H),2.35(s,1H),2.14(dd,J=13.8,6.8Hz,1H),1.94(ddd,J=23.8,8. 1,2.6Hz,3H),1.72(d,J=12.9Hz,1H),1.56(d,J=12.5Hz,1H),1.47(s,3H),1.29(t,J=7.4Hz,6H),1.17(d,J=10.4Hz,3H),1.05(d,J=6.2Hz,3H). 13 C NMR(75MHz,CDCl3)δ147.4(q),142.7(q),131.9(t),126.3(t),125.6(t),125.2(t),79.4(q),77.0(t),53.9 (t),48.8(s),46.1(d),39.6(q),36.6(d),33.3(t),27.5(d),26.9(s),25.4(s),25.0(s),20.3(s),17.1(s).

[0203] Example 106: rac-(3aR,5R,7S,7aR)-5-(benzo[d][1,3]dioxol-5-yl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(benzo[d][1,3]dioxol-5-yl)-2,4,7-trimethyloct-6-enal (259 mg, 0.90 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (113 mg, 1.35 mmol), KCO (99 mg, 0.72 mmol) in toluene (50 mL) gave the title product (87 mg, 31% yield) as a pale yellow oil. GC / MS(EI):m / z(%):317(5)[M + ],302(4),258(6),230(10),195(73),180(79),162(100),138(10),126(26),98(10),96(14). 1H NMR(300MHz,CDCl3)δ6.91(d,J=1.4Hz,1H),6.84(dd,J=8.2,1.6Hz,1H),6.76(d,J=8 .2Hz,1H),5.93(s,2H),2.86-2.58(m,3H),2.36-2.19(m,1H),2.06(t,J=10.3Hz,1H), 1.99-1.85(m,1H),1.76(t,J=11.3Hz,2H),1.51(t,J=12.9Hz,1H),1.40(d,J=12.7Hz, 1H),1.32(d,J=7.6Hz,3H),1.26(d,J=8.6Hz,3H),1.15(s,3H),1.02(d,J=6.2Hz,3H). 13 C NMR(75MHz,CDCl3)δ147.7(q),145.6(q),145.5(q),117.8(t),107.9(t),106.2(t),101.0(d),79.4(q), 77.7(t),54.0(t),49.0(d),46.5(d),38.6(q),37.4(d),33.2(t),27.0(d),26.9(d),25.0(d),20.3(d).

[0204] Example 107: rac-(3aR,5R,7S,7aR)-5-(3,5-dimethylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(3,5-dimethylphenyl)-2,4,7-trimethyloct-6-enal (311 mg, 1.14 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (143 mg, 1.71 mmol), KCO (126 mg, 0.91 mmol) in toluene (50 mL) gave the title product (124 mg, 36% yield) as a pale yellow oil. GC / MS(EI):m / z(%):301(97)[M + ],286(5),255(5),185(19),171(23),126(100),119(16),100(38),87(45),70(10). 1H NMR(300MHz,CDCl3)δ7.01(s,2H),6.87(s,1H),2.95-2.57(m,3H),2.44-2.22(m,7H),2.08(t,J=10.3Hz,1H),2.01-1.89(m,1H),1. 81(dd,J=14.8,7.1Hz,2H),1.55(t,J=12.9Hz,1H),1.47(d,J=12.1Hz,1H),1.35(s,3H),1.28(d,J=11.5Hz,3H),1.18-1.02(m,6H). 13 C NMR(75MHz,CDCl3)δ151.3(q),137.7(q),127.6(t),122.9(t),79.5(q),77.7(t),54.0(t),4 9.0(s),46.1(d),38.4(q),37.1(d),33.2(t),27.0(s),26.6(s),25.0(s),21.7(s),20.3(s).

[0205] Example 108: rac-(3aR,5R,7R,7aR)-1-ethyl-3,3,5,7-tetramethyl-5-(o-tolyl)octahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,4,7-trimethyl-4-(o-tolyl)oct-6-enal (300 mg, 0.81 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-ethylhydroxylamine hydrochloride (120 mg, 1.21 mmol), KCO (90 mg, 0.65 mmol) in toluene (50 mL) gave the title product (80 mg, 33% yield) as a pale yellow oil. GC / MS(EI):m / z(%):301(27)[M + ],286(100),243(10),185(10),171(10),140(25),132(38),119(14),101(18),91(10). 1H NMR(300MHz,CDCl3)δ7.17(d,J=8.7Hz,1H),7.00(t,J=8.7Hz,3H),2.99-2.62(m,2H),2.61-2.48(m,1H),2.4 0(d,J=12.3Hz,3H),2.24(dd,J=14.2,6.1Hz,1H),2.13-1.93(m,1H),1.90-1.59(m,2H),1.41-0.69(m,17H). 13 C NMR(75MHz,CDCl3)δ143.6(q),135.6(q),133.6(t),127.9(t),126.2(t),126.0(t),78.8(q),75.8(t),56.2 (d),53.4(t),47.7(d),41.8(q),37.0(d),33.8(t),30.4(s),26.5(s),24.5(s),24.0(s),20.2(s),13.7(s).

[0206] Example 109: rac-(3aR,5R,7S,7aR)-5-(3,5-dimethylphenyl)-1-isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(3,5-dimethylphenyl)-2,4,7-trimethyloct-6-enal (260 mg, 0.95 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-isopropylhydroxylamine (210 mg, 2.84 mmol), KCO (90 mg, 0.65 mmol) in xylene (80 mL) gave the title product (220 mg, 69% yield) as a pale yellow oil. GC / MS(EI):m / z(%):329(58)[M + ],314(100),199(8),185(10),171(11),154(88),126(28),115(22),112(18),91(9). 1H NMR(300MHz,CDCl3)δ7.02(s,2H),6.87(s,1H),3.41-2.90(m,1H),2.48-2.24(m,8H),2.08-1.90(m,1H),1.81 (ddd,J=12.2,5.6,2.7Hz,2H),1.50(dt,J=17.9,12.7Hz,2H),1.39-1.22(m,9H),1.08(dd,J=13.7,5.8Hz,9H). 13 C NMR(75MHz,CDCl3)δ151.3(q),137.5(q),127.4(t),122.8(t),77.9(q),68.9(t),54.8(t),53.0(t), 46.3(d),38.1,36.9(d),33.4(t),27.1(s),26.6(s),24.2(s),22.5(s),21.5(s),20.4(s),13.6(s).

[0207] Example 110: rac-(3aR,5R,7S,7aR)-5-(4-methoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(4-methoxyphenyl)-2,4,7-trimethyloct-6-enal (500 mg, 1.82 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (230 mg, 2.73 mmol), KCO (200 mg, 1.46 mmol) in toluene (50 mL) gave the title product (130 mg, 24% yield) as a pale yellow oil. GC / MS(EI):m / z(%):303(1)[M + ],302(3),288(5),244(5),216(6),195(61),180(53),148(100),126(20),96(10). 1H NMR(300MHz,CDCl3)δ7.32(d,J=8.8Hz,2H),6.87(d,J=8.8Hz,2H),3.79(s,3H),2.88-2.64(m,3H),2.42-2.20(m,1H),2.07(t,J=10.3Hz,1H),2.00 -1.89(m,1H),1.79(dd,J=14.9,6.9Hz,2H),1.55(t,J=12.9Hz,1H),1.48- 1.39(m,1H),1.38-1.23(m,6H),1.20-1.11(m,3H),1.04(d,J=6.2Hz,3H). 13 C NMR(75MHz,CDCl3)δ157.5(q),143.4(q),126.0(t),113.5(t),79.3(q),77.6(t),55.1(s),53.9( t),48.9(s),46.3(d),37.9(q),37.2(d),33.1(t),26.9(s),26.9(s),26.6(s),24.9(s),20.2(s).

[0208] Example 111: rac-(3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyl-5-(naphthalen-1-yl)octahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,4,7-trimethyl-4-(naphthalen-1-yl)oct-6-enal (500 mg, 1.70 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (210 mg, 2.55 mmol), KCO (190 mg, 1.36 mmol) in toluene (50 mL) gave the title product (170 mg, 31% yield) as a pale yellow oil. GC / MS(EI):m / z(%):323(2)[M + ],322(5),308(4),236(6),195(82),180(100),168(64),153(49),126(19),98(12),96(11). 1H NMR(300MHz,CDCl3)δ8.44(d,J=8.5Hz,1H),7.90(dd,J=7.9,1.3Hz,1H),7.75(d,J=8.0Hz,1H),7.62-7.36(m,4H),3.01-2.68(m,3H),2.49( d,J=10.5Hz,1H),2.32-2.12(m,3H),1.92(t,J=12.9Hz,1H),1.76-1.69(m,3H),1.39-1.26(m,5H),1.20(d,J=8.5Hz,3H),1.14-1.06(m,3H). 13 C NMR(75MHz,CDCl3)δ146.0(q),135.3(q),131.1(q),130.0(t),127.9(t),126.4(t),125.2(t),124.7(t),124.7(t),122 .8(t),79.4(q),77.3(t),53.9(t),48.8(s),46.5(d),39.9(q),37.1(d),33.3(t),26.9(s),25.7(s),24.9(s),20.2(s).

[0209] Example 112: rac-(3aR,5R,7R,7aR)-5-(3-chloro-2-methylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(3-chloro-2-methylphenyl)-2,4,7-trimethyloct-6-enal (290 mg, 0.83 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (100 mg, 1.24 mmol), KCO (90 mg, 0.66 mmol) in toluene (50 mL) gave the title product (100 mg, 39% yield) as a pale yellow oil. GC / MS(EI):m / z(%):321(12)[M + ],320(44),306(7),263(44),234(20),166(100),153(14),126(23),108(21),98(18),68(12). 1H NMR(300MHz,CDCl3)δ7.30-7.21(m,1H),7.18(d,J=7.8Hz,1H),7.05(t,J= 8.0Hz,1H),2.92-2.65(m,3H),2.59-2.49(m,3H),2.47-2.34(m,1H),2.16( dd,J=12.1,8.1Hz,1H),1.81(t,J=11.0Hz,2H),1.36(d,J=12.8Hz,3H),1. 30(d,J=6.3Hz,1H),1.26(s,1H),1.23-1.09(m,6H),1.03(t,J=7.3Hz,4H). 13 C NMR(75MHz,CDCl3)δ145.7(q),137.4(q),133.9(q),127.5(t),126.6(t),126.4(t),79.0(q),78.1(t), 54.2(t),48.7(s),48.2(d),42.0(q),37.2(d),33.4(t),30.6(s),26.8(s),24.7(s),20.1(s),19.9(s).

[0210] Example 113: rac-(3aR,5R,7S,7aR)-1-isopropyl-5-(4-methoxyphenyl)-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(4-methoxyphenyl)-2,4,7-trimethyloct-6-enal (700 mg, 2.55 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-isopropylhydroxylamine (290 mg, 3.83 mmol), KCO (280 mg, 2.04 mmol) in toluene (50 mL) gave the title product (150 mg, 18% yield) as a pale yellow oil. GC / MS(EI):m / z(%):331(50)[M + ],316(100),208(12),187(7),154(69),126(22),115(17). 1H NMR(300MHz,CDCl3)δ7.24(d,J=8.8Hz,2H),6.79(d,J=8.8Hz,2H),3.71(s,3H),3.22-2.94(m,1H),2.27(dd,J=17.7,5.9Hz,2H),1.95-1 .77(m,1H),1.75-1.62(m,2H),1.39(dt,J=25.8,12.7Hz,2H),1.24(d,J=8.6Hz,6H),1.18(d,J=6.7Hz,3H),0.97(dd,J=16.1,6.3Hz,9H). 13 C NMR(75MHz,CDCl3)δ157.5(q),143.6(q),126.0(t),113.5(t),77.9(q),68.9(t),55.2,54.9(t),53. 0(t),46.7(d),37.8(q),37.1(d),33.5(t),27.1(s),26.6(s),24.2(s),22.5(s),20.3(s),13.6(s).

[0211] Example 114: rac-(3aR,5R,7S,7aR)-5-(3-isopropylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(3-isopropylphenyl)-2,4,7-trimethyloct-6-enal (500 mg, 1.75 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (220 mg, 2.62 mmol), KCO (190 mg, 1.40 mmol) in toluene (50 mL) gave the title product (130 mg, 24% yield) as a pale yellow oil. GC / MS(EI):m / z(%):315(62)[M + ],180(13),161(14),126(100),100(38),87(40). 1H NMR(300MHz,CDCl3)δ7.23-7.08(m,3H),7.00(d,J=6.9Hz,1H),2.91-2.78(m,1H),2.77-2.57(m,3H),2.34-2.17(m,1H) ,2.08-1.67(m,4H),1.49(t,J=12.9Hz,1H),1.37(t,J=12.6Hz,1H),1.28(s,3H),1.23-1.10(m,9H),1.09-0.91(m,6H). 13 C NMR(75MHz,CDCl3)δ151.1(q),148.6(q),128.1(t),123.6(t),123.3(t),122.5(t),79.3(q),77.6(t),53.9(t), 48.9(s),46.0(d),38.5(q),37.0(d),34.4(t),33.1(t),26.9(s),26.6(s),24.9(s),24.1(s),24.1(s),20.2(s).

[0212] Example 115: rac-(3aR,5R,7R,7aR)-5-(4-methoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(4-methoxyphenyl)-2,4,7-trimethyloct-6-enal (500 mg, 1.82 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (230 mg, 2.73 mmol), KCO (200 mg, 1.46 mmol) in toluene (50 mL) gave the title product (120 mg, 21% yield) as a pale yellow oil. GC / MS(EI):m / z(%):303(20)[M + ],302(39),288(5),245(13),216(42),195(10),180(19),148(100),126(20),98(15). 1H NMR(300MHz,CDCl3)δ7.18(d,J=8.7Hz,2H),6.81(d,J=8.7Hz,2H),3.74(s,3H),2.74(s,3H),2.33(d,J=12.7Hz,1H),2 .24-2.04(m,2H),1.94(dd,J=17.2,6.4Hz,1H),1.39-1.20(m,3H),1.15(dd,J=8.3,4.0Hz,9H),0.97(d,J=6.4Hz,3H). 13 C NMR(75MHz,CDCl3)δ157.3(q),138.8(q),126.7(t),113.9(t),78.9,78.1(t),55.2(t),5 4.0(s),48.7(s),46.1(d),39.4,36.9(d),34.6(s),33.1(t),26.6(s),24.8(s),20.1(s).

[0213] Example 116: rac-4-Methoxy-3-((3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile Following the general procedure described in Example 81b: reaction of 4-methoxy-3-(2,4,7-trimethyl-1-oxooct-6-en-4-yl)benzonitrile (350 mg, 1.07 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (130 mg, 1.60 mmol), KCO (120 mg, 0.85 mmol) in toluene (50 mL) gave the title product (100 mg, 28% yield) as a pale yellow oil. GC / MS(EI):m / z(%):328(72)[M + ],282(28),241(26),226(67),160(39),126(100),100(41),87(47). 1 H NMR(300MHz,CDCl3)δ7.58-7.42(m,2H),6.90(d,J=8.4Hz,1H),3.86(s,3H),2.84-2.58(m,3H),2.35-2.16( m,1H),2.05-1.82(m,4H),1.57(t,J=12.7Hz,1H),1.49-1.28(m,5H),1.27-1.18(m,3H),1.12-0.94(m,6H). 13 C NMR(75MHz,CDCl3)δ161.0(q),139.6(q),132.1(t),130.2(t),119.6(q),112.1(t),103.8(q),79.3(q),77.3 (t),55.5(s),53.4(t),48.9(s),43.7(d),39.0(q),34.3(d),32.9(t),26.9(s),24.9(s),23.1(s),20.2(s).

[0214] Example 117: rac-(3aR,5R,7S,7aR)-5-(3,5-difluorophenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(3,5-difluorophenyl)-2,4,7-trimethyloct-6-enal (550 mg, 0.69 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (90 mg, 1.04 mmol), KCO (80 mg, 0.55 mmol) in toluene (50 mL) gave the title product (90 mg, 40% yield) as a pale yellow oil. GC / MS(EI):m / z(%):309(56)[M + ],294(8),207(18),193(18),179(18),141(20),126(100),113(18),100(46),87(56). 1 H NMR(300MHz,CDCl3)δ6.88(d,J=7.7Hz,2H),6.63(tt,J=8.7,2.2Hz,1H),2.92-2.58(m,3H),2.40-2.19(m,1H),2 .12-1.86(m,2H),1.85-1.63(m,2H),1.55-1.39(m,2H),1.34-1.25(m,6H),1.18-1.12(m,3H),1.08-1.00(m,3H). 13C NMR(75MHz,CDCl3)δ164.8(q),164.6(q),161.5(q),161.4(q),155.6(q),108.5(t),108.2(t),101.7(t),101.3(t),101.0(t ),79.3(q),77.5(t),53.8(t),49.0(s),45.9(d),39.1(q),36.9(d),33.2(t),27.1(s),27.0(s),26.5(s),25.0(s),20.2(s).

[0215] Example 118: rac-2-chloro-5-((3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile Following the general procedure described in Example 81b: reaction of 2-chloro-5-(2,4,7-trimethyl-1-oxooct-6-en-4-yl)benzonitrile (400 mg, 1.32 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (170 mg, 1.98 mmol), KCO (150 mg, 1.05 mmol) in toluene (50 mL) gave the title product (80 mg, 18% yield) as a pale yellow oil. GC / MS(EI):m / z(%):332(23)[M + ], 286(9), 244(5), 230(8), 164(13), 150(11), 126(100), 113(16), 100(46), 87(55). or GC / MS(EI): m / z(%): 331(16) [M + ],274(19),195(20),177(34),150(15),126(88),98(300),68(100). 1 H NMR(300MHz,CDCl3)δ7.65(s,1H),7.59-7.50(m,1H),7.47-7.39(m,1H),2.88-2.57(m,3H),2.28(t,J= 11.7Hz,1H),2.10-1.69(m,4H),1.54-1.38(m,2H),1.32(s,3H),1.26(s,3H),1.12(s,3H),1.03(s,3H). 13C NMR(75MHz,CDCl3)δ150.9(q),134.2(q),131.2(t),130.9(t),129.8(t),116.3(q),113.1(q),79.2(q), 77.3(t),53.6(t),48.9(s),45.7(d),38.7(q),36.8(d),33.1(t),26.9(s),26.4(s),24.9(s),20.1(s).

[0216] Example 119: rac-3-chloro-5-((3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile Following the general procedure described in Example 81b: reaction of 3-chloro-5-(2,4,7-trimethyl-1-oxooct-6-en-4-yl)benzonitrile (200 mg, 0.66 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (82 mg, 0.99 mmol), KCO (73 mg, 0.53 mmol) in toluene (50 mL) gave the title product (36 mg, 16% yield) as a pale yellow oil. GC / MS(EI):m / z(%):334(16)[M + ],332(48)[M + ],286(24),244(20),230(33),126(100),100(49),98(36),87(66),70(22). 1 H NMR(300MHz,CDCl3)δ7.56(d,J=7.9Hz,2H),7.48(s,1H),2.88-2.63(m,3H),2.41-2.23(m,1H),2.13-1.92( m,2H),1.86-1.72(m,2H),1.55-1.41(m,2H),1.34(s,3H),1.28(s,3H),1.15(s,3H),1.05(d,J=6.1Hz,3H). 13C NMR(75MHz,CDCl3)δ154.7(q),135.3(q),130.6(t),129.4(t),127.5(t),117.9(q),113.9(q),79.3(q), 77.3(t),53.6(t),49.0(s),45.7(d),39.1(q),36.8(d),33.1(s),26.9(s),26.4(s),25.0(s),20.1(s).

[0217] Example 120: rac-(3aR,5R,7S,7aR)-5-(3,4-difluorophenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(3,4-difluorophenyl)-2,4,7-trimethyloct-6-enal (854 mg, 2.13 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (267 mg, 3.20 mmol), KCO (236 mg, 1.71 mmol) in toluene (50 mL) gave the title product (189 mg, 29% yield) as a yellow oil. GC / MS(EI):m / z(%):309(40)[M + ],294(5),207(14),193(10),179(8),141(28),126(100),113(15),100(45),87(54). 1 H NMR(300MHz,CDCl3)δ7.22-7.13(m,1H),7.12-7.05(m,2H),2.88-2.63(m,3H),2.37-2.22(m,1H),2.12-1. 86(m,2H),1.84-1.69(m,2H),1.57-1.39(m,2H),1.34-1.25(m,6H),1.19-1.11(m,3H),1.08-1.01(m,3H). 13C NMR(75MHz,CDCl3)δ151.8(q),150.0(q),148.5(q),121.1(t),121.0(t),121.0(t),120.9(t),116.9(t),116.7(t),114.6(t) ,114.4(t),79.3(q),77.5(t),53.8(t),49.0(s),46.2(d),38.5(q),37.1(d),33.2(t),27.0(s),26.7(s),25.0(s),20.2(s).

[0218] Example 121: rac-2-methyl-5-((3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile Following the general procedure described in Example 81b: reaction of 2-methyl-5-(2,4,7-trimethyl-1-oxooct-6-en-4-yl)benzonitrile (300 mg, 1.06 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (133 mg, 1.59 mmol), KCO (117 mg, 0.85 mmol) in toluene (50 mL) gave the title product (135 mg, 41% yield) as a pale yellow oil. GC / MS(EI):m / z(%):312(73)[M + ],266(33),207(34),157(27),144(32),126(100),100(45),98(33),87(55),70(19). 1 H NMR(300MHz,CDCl3)δ7.60(s,1H),7.52(d,J=8.1Hz,1H),7.27(d,J=8.3Hz,1H),2.90-2.64(m,3H),2.51(s,3H),2.31(t,J=10.7Hz, 1H),2.14-1.89(m,2H),1.88-1.70(m,2H),1.58-1.40(m,2H),1.31(d,J=15.1Hz,6H),1.16(d,J=8.5Hz,3H),1.05(d,J=5.9Hz,3H). 13C NMR(75MHz,CDCl3)δ149.6(q),139.3(q),130.2(t),129.8(t),129.2(t),118.5(q),112.6(q),79.2(q),77.4(t),53.7 (t),49.4(q),48.9(s),45.9(d),38.4(q),36.8(d),33.1(t),27.0(s),26.9(s),26.4(s),24.9(s),20.1(s),19.8(s).

[0219] Example 122: rac-methyl 4-methyl-3-((3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzoate Following the general procedure described in Example 81b: reaction of methyl (E)-4-methyl-3-(2,4,7-trimethyl-1-oxoocta-2,6-dien-4-yl)benzoate (1.40 g, 2.40 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (0.30 g, 3.61 mmol), KCO (0.27 g, 1.92 mmol) in toluene (50 mL) gave the title product (0.25 g, 30% yield) as a pale yellow oil. GC / MS(EI):m / z(%):345(68)[M + ],267(47),225(29),190(30),126(100),100(47),98(32),87(68),70(17). 1 H NMR(300MHz,CDCl3)δ8.02(s,1H),7.70(d,J=7.8Hz,1H),7.13(d,J=7.9Hz,1H),3.82(s,3H),2.81-2.58(m,3H),2.54(s,3H),2 .31-2.16(m,1H),2.10-1.85(m,4H),1.64-1.44(m,2H),1.39(s,3H),1.21(s,3H),1.09(d,J=5.6Hz,3H),0.99(d,J=5.8Hz,3H). 13C NMR(75MHz,CDCl3)δ167.2(q),148.3(q),141.6(q),133.3(t),127.5(t),127.0(t),126.7(t),79.2(q),76.9(t),53.6 (t),51.8(s),48.7(s),45.0(d),39.6(q),35.6(d),33.1(t),26.8(s),26.7(s),24.8(s),24.3(s),23.7(s),20.1(s).

[0220] Example 123: rac-(3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyl-5-(2-(methylthio)phenyl)octahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,4,7-trimethyl-4-(2-(methylthio)phenyl)oct-6-enal (792 mg, 0.76 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (96 mg, 1.15 mmol), KCO (84 mg, 0.61 mmol) in toluene (50 mL) gave the title product (80 mg, 33% yield) as a pale yellow oil. GC / MS(EI):m / z(%):319(46)[M + ],304(9),273(13),217(8),180(11),149(35),126(100),113(16),100(36),87(56). 1 H NMR(300MHz,CDCl3)δ7.47-7.32(m,2H),7.24-7.10(m,2H),2.92-2.71(m,3H),2.50(s,3H),2.36-2.24(m,2H) ,2.08-1.91(m,4H),1.90-1.77(m,1H),1.56(s,3H),1.27(s,3H),1.17(d,J=4.9Hz,3H),1.03(d,J=5.9Hz,3H). 13C NMR(75MHz,CDCl3)δ148.7(q),137.1(q),130.4(t),126.8(t),126.1(t),125.7(t),79.6(q),76.5(t),54.0 (t),48.9(s),44.4(d),40.4(q),34.7(d),33.5(t),27.0(s),27.0(s),25.0(s),24.3(s),20.3(s),18.8(s).

[0221] Example 124: rac-(3aR,5R,7S,7aR)-5-(2,5-difluorophenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(2,5-difluorophenyl)-2,4,7-trimethyloct-6-enal (614 mg, 0.88 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (110 mg, 1.31 mmol), KCO (97 mg, 0.70 mmol) in toluene (50 mL) gave the title product (108 mg, 38% yield) as a pale yellow oil. GC / MS(EI):m / z(%):309(25)[M + ],294(4),263(8),207(11),153(10),141(23),126(100),113(16),100(46),87(64). 1 H NMR(300MHz,CDCl3)δ7.14-6.78(m,3H),2.88-2.61(m,3H),2.41-2.22(m,1H),2.15-1.79(m, 4H),1.69-1.46(m,2H),1.41(s,3H),1.30-1.23(m,3H),1.19-1.10(m,3H),1.08-0.99(m,3H). 13C NMR(75MHz,CDCl3)δ160.3(q),159.3(q),157.1(q),117.8(t),117.6(t),1 17.4(t),117.3(t),113.9(t),113.8(t),113.6(t),113.6(t),113.5(t),7 9.4(q),77.4(t),53.5(t),49.0(s),44.3(d),44.2(d),38.6(d),38.5(q), 35.1(d),35.0(d),33.1(t),27.0(s),25.0(s),24.0(s),23.9(s),20.2(s).

[0222] Example 125: rac-(3aR,5R,7S,7aR)-5-(2,3-dimethylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(2,3-dimethylphenyl)-2,4,7-trimethyloct-6-enal (420 mg, 1.54 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (193 mg, 2.31 mmol), KCO (193 mg, 2.31 mmol) in toluene (50 mL) gave the title product (89 mg, 19% yield) as a pale yellow oil. GC / MS(EI):m / z(%):301(100)[M + ],180(22),171(28),146(37),126(93),100(48),98(34),87(69),70(17). 1 H NMR(300MHz,CDCl3)δ7.33-7.27(m,1H),7.11-7.06(m,2H),2.89-2.65(m,3H),2.46-2.40(m,3H),2.29(s,3H),2.21-2.10(m, 1H),2.08-1.89(m,4H),1.78-1.66(m,1H),1.63-1.54(m,1H),1.51(s,3H),1.33-1.27(m,3H),1.16(s,3H),1.08-1.03(m,3H). 13C NMR(75MHz,CDCl3)δ148.0(q),138.9(q),134.9(q),128.3(t),125.4(t),123.3(t),79.5(q),77.1(t),54.0 (t),48.9(s),45.9(d),39.5(q),36.5(d),33.4(t),27.0(s),25.3(s),25.0(s),21.6(s),20.4(s),19.3(s).

[0223] Example 126: rac-(3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyl-5-(2,4,5-trimethylphenyl)octahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,4,7-trimethyl-4-(2,4,5-trimethylphenyl)oct-6-enal (458 mg, 1.47 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (184 mg, 2.21 mmol), KCO (163 mg, 1.18 mmol) in toluene (50 mL) gave the title product (180 mg, 39% yield) as a pale yellow oil. GC / MS(EI):m / z(%):315(53)[M + ],199(9),180(24),160(15),149(36),133(23),126(100),113(16),100(41),87(59). 1 H NMR(300MHz,CDCl3)δ7.15(s,1H),6.95(s,1H),2.91-2.65(m,3H),2.51(s,3H),2.38-2.29(m,1H),2.23(d,J=13.2Hz,6H),2.15 -2.05(m,1H),2.03-1.82(m,3H),1.72-1.48(m,2H),1.45(s,3H),1.28(s,3H),1.20(s,1H),1.15(s,2H),1.06(d,J=6.0Hz,3H). 13C NMR(75MHz,CDCl3)δ145.7(q),135.0(t),134.2(q),133.7(q),133.1(q),126.9(t),79.5(q),77.3(t),54.0(t), 49.0(s),45.6(d),39.3(q),36.0(d),33.3(t),27.0(s),25.1(s),24.8(s),23.2(s),20.4(s),19.6(s),18.9(s).

[0224] Example 127: rac-(3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyl-5-(4-(methylthio)phenyl)octahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,4,7-trimethyl-4-(4-(methylthio)phenyl)oct-6-enal (350 mg, 1.21 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (151 mg, 1.81 mmol), KCO (133 mg, 0.96 mmol) in toluene (50 mL) gave the title product (68 mg, 18% yield) as a yellow oil. GC / MS(EI):m / z(%):319(99)[M + ],195(32),180(76),165(34),164(42),137(29),126(100),100(38),98(33),87(54). 1 H NMR(300MHz,CDCl3)δ7.32(d,J=8.5Hz,2H),7.22(d,J=8.5Hz,2H),2.88-2.63(m,3H),2.46(s,3H),2.39-2.23(m,1H),2.12-1.87( m,2H),1.86-1.72(m,2H),1.60-1.46(m,1H),1.42(d,J=12.3Hz,1H),1.33(s,3H),1.26(s,3H),1.13(s,3H),1.03(d,J=6.1Hz,3H). 13C NMR(75MHz,CDCl3)δ148.4(q),135.6(q),126.9(t),125.7(t),79.4(q),77.6(t),53.9(t),4 8.9(s),46.1(d),38.3(q),37.0(d),33.1(t),27.0(s),26.5(s),25.0(s),20.2(s),16.1(s).

[0225] Example 128: rac-4-Methoxy-3-((3aR,5R,7R,7aR)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile Following the general procedure described in Example 81b: reaction of 4-methoxy-3-(2,4,7-trimethyl-1-oxooct-6-en-4-yl)benzonitrile (351 mg, 1.07 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (134 mg, 1.60 mmol), KCO (118 mg, 0.85 mmol) in toluene (50 mL) gave the title product (84 mg, 24% yield) as a pale yellow oil. GC / MS(EI):m / z(%):328(100)[M + ],282(33),241(37),226(87),160(45),126(98),100(38),87(80). 1 H NMR(300MHz,CDCl3)δ7.59-7.35(m,2H),6.91(d,J=8.1Hz,1H),3.87(s,3H),2.70(s ,4H),2.47-2.29(m,1H),2.20-2.05(m,1H),1.85-1.62(m,2H),1.34-0.95(m,14H). 13 C NMR(75MHz,CDCl3)δ161.7(q),135.4(q),132.9(t),132.1(t),119.5(q),112.4(t),104.1(q),78.9(q),78.1 (t),55.4(s),54.7(t),48.7(s),46.5(d),40.9(q),35.6(d),33.4(t),29.5(s),26.6(s),24.7(s),20.2(s).

[0226] Example 129: rac-(3aR,5R,7S,7aR)-5-(3-fluoro-5-(trifluoromethyl)phenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(3-fluoro-5-(trifluoromethyl)phenyl)-2,4,7-trimethyloct-6-enal (400 mg, 1.21 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (152 mg, 1.82 mmol), KCO (134 mg, 0.97 mmol) in toluene (50 mL) gave the title product (140 mg, 32% yield) as a pale yellow oil. GC / MS(EI):m / z(%):359(52)[M + ],313(25),271(17),257(39),243(23),177(17),126(100),100(46),98(36),87(58). 1 H NMR(300MHz,CDCl3)δ7.44(s,1H),7.30(d,J=10.5Hz,1H),7.18(d,J=8.0Hz,1H),2.92-2.66(m,3H),2.45-2.27(m,1H), 2.18-1.93(m,2H),1.91-1.77(m,2H),1.61-1.42(m,2H),1.38(s,3H),1.29(s,3H),1.17(s,3H),1.08(d,J=6.0Hz,3H). 13 C NMR(75MHz,CDCl3)δ164.2(q),160.9(q),155.4(q),155.3(q),132.5(q),132.4(q),132. 1(q),132.0(q),125.3(q),125.3(q),121.7(q),121.7(q),117.8(t),117.7(t),117.7(t) ,116.2(t),115.9(t),110.6(t),110.5(t),110.2(t),110.1(t),79.3(q),77.4(t),53.7 (t),48.9(s),45.7(d),39.1(q),36.9(d),33.1(t),26.9(s),26.5(s),24.9(s),20.1(s).

[0227] Example 130: rac-(3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyl-5-(2-methyl-5-(trifluoromethyl)phenyl)octahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,4,7-trimethyl-4-(2-methyl-5-(trifluoromethyl)phenyl)oct-6-enal (300 mg, 0.92 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (115 mg, 1.38 mmol), KCO (102 mg, 0.74 mmol) in toluene (50 mL) gave the title product (114 mg, 35% yield) as a yellow oil. GC / MS(EI):m / z(%):355(66)[M + ],309(17),253(25),187(33),173(25),126(100),100(45),98(32),87(53). 1 H NMR(300MHz,CDCl3)δ7.63(s,1H),7.39(d,J=7.8Hz,1H),7.29(s,1H),2.91-2.68(m,3H),2.63(s,3H),2.44-2.27(m,1H) ,2.20-2.09(m,1H),2.06-1.94(m,3H),1.71-1.53(m,2H),1.49(s,3H),1.32(s,3H),1.21(s,3H),1.09(d,J=6.0Hz,3H). 13 C NMR(75MHz,CDCl3)δ149.0(q),140.3(q),133.7(t),128.3(q),127.9(q),126.4(q),122.9(t),122.8(t),122.4(t),122.3(t),118.2(t ),79.4(q),77.0(t),53.8(t),48.9(s),45.1(d),39.9(q),35.7(d),33.3(t),27.0(s),26.9(s),25.0(s),24.5(s),23.7(s),20.3(s).

[0228] Example 131: rac-(3aR,5R,7S,7aR)-5-(2-ethoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(2-ethoxyphenyl)-2,4,7-trimethyloct-6-enal (600 mg, 1.66 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (208 mg, 2.50 mmol), KCO (184 mg, 1.33 mmol) in toluene (50 mL) gave the title product (201 mg, 38% yield) as a pale yellow oil. GC / MS(EI):m / z(%):317(94)[M + ],271(15),195(16),180(33),149(45),135(35),126(100),100(41),98(29),87(52). 1 H NMR(300MHz,CDCl3)δ7.31(d,J=7.8Hz,1H),7.23-7.13(m,1H),6.95-6.83(m,2H),4.15-3.97(m,2H),2.89-2.63(m,3H),2. 44-2.24(m,1H),2.15(t,J=10.3Hz,1H),2.02-1.73(m,5H),1.51-1.43(m,6H),1.26(s,3H),1.14(s,3H),1.05-0.99(m,3H). 13 C NMR(75MHz,CDCl3)δ157.4(q),137.8(q),127.2(t),126.2(t),120.3(t),112.2(t),79.5(q),77.3(t),63.2 (d),53.9(t),48.9(s),43.9(d),38.8(q),34.2(d),33.2(t),26.9(s),25.0(s),23.9(s),20.3(s),15.1(s).

[0229] Example 132: rac-(3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyl-5-(5-methylthiophen-2-yl)octahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,4,7-trimethyl-4-(5-methylthiophen-2-yl)oct-6-enal (854 mg, 1.55 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (194 mg, 2.33 mmol), KCO (171 mg, 1.24 mmol) in toluene (50 mL) gave the title product (142 mg, 31% yield) as a pale yellow oil. GC / MS(EI):m / z(%):293(23)[M + ],195(35),180(100),149(13),138(14),137(15),126(15),100(8),98(13),87(18). 1 H NMR(300MHz,CDCl3)δ6.64(d,J=3.4Hz,1H),6.60-6.52(m,1H),2.86-2.63(m,3H),2.44(s,3H),2.35-2.20(m,1H),2.14-2.03(m, 1H),1.79-1.71(m,2H),1.68-1.60(m,2H),1.54-1.46(m,1H),1.41(s,3H),1.29-1.25(m,3H),1.14(s,3H),1.01(d,J=6.3Hz,3H). 13 C NMR(75MHz,CDCl3)δ155.3(q),136.9(q),124.4(t),120.8(t),79.4(q),77.7(t),54.0(t),4 9.0(s),48.1(d),39.0(d),38.5(q),33.3(t),27.3(s),27.0(s),25.0(s),20.1(s),15.3(s).

[0230] Example 133: rac-(3aR,5R,7R,7aR)-1,3,3,5,7-pentamethyl-5-(2-(methylthio)phenyl)octahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,4,7-trimethyl-4-(2-(methylthio)phenyl)oct-6-enal (792 mg, 0.76 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (96 mg, 1.15 mmol), KCO (84 mg, 0.61 mmol) in toluene (50 mL) gave the title product (90 mg, 37% yield) as a pale yellow oil. GC / MS(EI):m / z(%):319(56)[M + ],304(9),273(13),217(10),180(8),161(14),149(36),126(80),113(22),87(100). 1 H NMR(300MHz,CDCl3)δ7.34-7.22(m,2H),7.18-7.04(m,2H),3.25-3.07(m,1H),2.81-2.57(m,3H),2. 49(s,3H),2.21-2.07(m,1H),1.94-1.73(m,2H),1.48(s,3H),1.33-1.10(m,9H),1.05-0.98(m,3H). 13 C NMR(75MHz,CDCl3)δ144.3(q),136.9(q),130.1(t),128.6(t),126.7(t),125.5(t),79.2(q),78.3(t), 54.4(t),48.8(s),47.7(d),42.2(q),36.6(d),33.5(t),29.4(s),26.9(s),24.8(s),20.2(s),18.7(s).

[0231] Example 134: rac-2-chloro-5-((3aR,5R,7R,7aR)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile Following the general procedure described in Example 81b: reaction of 2-chloro-5-(2,4,7-trimethyl-1-oxooct-6-en-4-yl)benzonitrile (400 mg, 1.32 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (165 mg, 1.98 mmol), KCO (146 mg, 1.05 mmol) in toluene (50 mL) gave the title product (94 mg, 21% yield) as a pale yellow oil. GC / MS(EI):m / z(%):332(25)[M + ],286(7),230(8),164(14),126(96),113(32),100(41),98(51),87(100),70(20). 1 H NMR(300MHz,CDCl3)δ7.58(s,1H),7.52-7.40(m,2H),2.78(s,3H),2.16(dd,J=20.7,11.4Hz,2H),1.7 5(t,J=11.2Hz,1H),1.66-1.56(m,1H),1.49-1.36(m,1H),1.31-1.12(m,11H),1.02(d,J=6.4Hz,3H). 13 C NMR(75MHz,CDCl3)δ147.2(q),134.2(q),131.8(t),131.7(t),130.3(t),116.3(q),113.6(q),78.8(q), 77.7(t),54.2(t),48.7(s),45.5(d),40.2(q),36.7(d),34.2(s),33.3(t),26.7(s),24.8(s),20.0(s).

[0232] Example 135: rac-3-methyl-4-((3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile Following the general procedure described in Example 81b: reaction of 3-methyl-4-(2,4,7-trimethyl-1-oxooct-6-en-4-yl)benzonitrile (1.26 g, 0.67 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (0.08 g, 0.100 mmol), KCO (0.07 g, 0.53 mmol) in toluene (50 mL) gave the title product (0.045 g, 21% yield) as a colorless oil. GC / MS(EI):m / z(%):312(43)[M + ],297(6),266(7),210(10),182(11),144(30),126(100),100(53),98(40),87(71),70(19). 1 H NMR(300MHz,CDCl3)δ7.56(d,J=7.8Hz,1H),7.28(s,1H),7.09(d,J=7.8Hz,1H),2.91-2.61(m,3H),2.38(s,3H),2.33-2.17( m,1H),2.06-1.79(m,3H),1.69(t,J=12.8Hz,1H),1.60-1.40(m,3H),1.28-1.21(m,3H),1.16(s,3H),1.04(d,J=6.2Hz,3H). 13 C NMR(75MHz,CDCl3)δ153.8(q),137.6(q),136.5(t),129.8(t),126.5(t),119.0(q),110.1(q),79.4(q),77.3 (t),53.7(t),48.9(s),45.0(d),40.4(q),35.7(d),33.3(t),27.0(s),25.0(s),24.4(s),23.7(s),20.3(s).

[0233] Example 136: rac-4-methyl-2-((3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile Following the general procedure described in Example 81b: reaction of 4-methyl-2-(2,4,7-trimethyl-1-oxooct-6-en-4-yl)benzonitrile (271 mg, 0.96 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (120 mg, 1.43 mmol), KCO (106 mg, 0.77 mmol) in toluene (40 mL) gave the title product (145 mg, 49% yield) as a pale yellow oil. GC / MS(EI):m / z(%):312(38)[M + ],297(6),281(7),266(28),249(5),207(45),126(100),100(34),87(55),70(12). 1 H NMR(300MHz,CDCl3)δ7.56(d,J=7.8Hz,1H),7.28(s,1H),7.09(d,J=7.8Hz,1H),2.91-2.61(m,3H),2.38(s,3H),2.33-2.17( m,1H),2.06-1.79(m,3H),1.69(t,J=12.8Hz,1H),1.60-1.40(m,3H),1.28-1.21(m,3H),1.16(s,3H),1.04(d,J=6.2Hz,3H). 13 C NMR(75MHz,CDCl3)δ153.3(q),143.6(q),136.0(t),127.2(t),127.1(t),120.6(q),107.6(q),79.5(q),76.6(t), 53.8(t),48.9(s),44.9(d),39.5(q),35.5(d),33.4(t),27.0(s),26.9(s),24.9(s),24.6(s),22.2(s),20.0(s).

[0234] Example 137: rac-(3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyl-5-(5-methylthiophen-3-yl)octahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,4,7-trimethyl-4-(5-methylthiophen-3-yl)oct-6-enal (758 mg, 1.29 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (162 mg, 1.94 mmol), KCO (143 mg, 1.03 mmol) in toluene (40 mL) gave the title product (83 mg, 22% yield) as a colorless oil. GC / MS(EI):m / z(%):293(44)[M + ],180(27),149(27),139(44),126(100),100(29),98(51),87(80). 1 H NMR(300MHz,CDCl3)δ6.72(t,J=10.0Hz,2H),2.88-2.61(m,3H),2.46(s,3H),2.35-2.19(m,1H),2.07(t,J=10.3Hz, 1H),1.99-1.82(m,1H),1.78-1.63(m,2H),1.61-1.34(m,4H),1.34-1.21(m,7H),1.15(s,3H),1.01(d,J=6.3Hz,3H). 13 C NMR(75MHz,CDCl3)δ153.1(q),139.8(q),124.3(t),115.4(t),79.4(q),77.8(t),53.7(t),4 9.0(s),46.5(d),37.6(q),37.3(d),33.1(t),27.0(s),26.0(s),25.0(s),20.2(s),15.5(s).

[0235] Example 138: rac-(3aR,5R,7S,7aR)-5-(furan-3-yl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(furan-3-yl)-2,4,7-trimethyloct-6-enal (558 mg, 1.19 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (149 mg, 1.79 mmol), KCO (132 mg, 0.95 mmol) in toluene (40 mL) gave the title product (100 mg, 32% yield) as a colorless oil. GC / MS(EI):m / z(%):263(46)[M + ],248(8),180(18),149(10),126(100),109(21),100(41),98(35),87(60). 1 H NMR(300MHz,CDCl3)δ7.37(t,J=1.6Hz,1H),7.22(s,1H),6.36(s,1H),2.90-2.70(m,3H),2.33-2.18(m,1H),2.08(t,J=10 .3Hz,1H),1.91(s,1H),1.72-1.60(m,2H),1.54-1.36(m,2H),1.28(d,J=10.8Hz,6H),1.13(s,3H),1.00(d,J=6.3Hz,3H). 13 C NMR(75MHz,CDCl3)δ143.0(t),136.9(t),136.7(q),108.6(t),79.4(q),77.9(t),53.6( t),49.0(s),46.5(d),37.4(d),34.1(q),33.0(t),27.0(s),25.6(s),25.0(s),20.1(s).

[0236] Example 139: rac-(3aR,5R,7S,7aR)-5-(4-(tert-butyl)phenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(4-(tert-butyl)phenyl)-2,4,7-trimethyloct-6-enal (658 mg, 1.97 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (247 mg, 2.96 mmol), KCO (218 mg, 1.58 mmol) in toluene (40 mL) gave the title product (267 mg, 41% yield) as a colorless oil. GC / MS(EI):m / z(%):329(37)[M + ],180(27),159(19),126(100),100(36),98(24),87(39),57(43). 1 H NMR(300MHz,CDCl3)δ7.40-7.29(m,4H),2.87-2.65(m,3H),2.40-2.24(m,1H),2.13-1.91(m,2H),1.82(t,J=11.2Hz, 2H),1.65-1.52(m,1H),1.51-1.42(m,1H),1.36(s,3H),1.32(s,9H),1.28(s,3H),1.13(s,3H),1.04(d,J=6.0Hz,3H). 13 C NMR(75MHz,CDCl3)δ148.6(q),148.2(q),125.1(t),124.7(t),79.4(q),77.7(t),53.9(t),49.0(s),4 6.2(d),38.2(q),37.1(d),34.3(q),33.2(t),31.4(s),27.1(s),27.0(s),26.6(s),25.0(s),20.3(s).

[0237] Example 140: rac-(3aS,5R,7S,7aS)-5-(4-fluorophenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(4-fluorophenyl)-2,4,7-trimethyloct-6-enal (323 mg, 1.23 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (154 mg, 1.85 mmol), KCO (136 mg, 0.98 mmol) in toluene (50 mL) gave the title product (44 mg, 12% yield) as a pale yellow oil. GC / MS(EI):m / z(%):291(34)[M + ],276(4),189(4),163(4),147(5),126(100),113(29),98(66),87(13). 1 H NMR(300MHz,CDCl3)δ7.32-7.22(m,2H),6.99(t,J=8.7Hz,2H),2.86-2.68(m,3H),2.44(t,J=6.6Hz,1 H),2.25-2.12(m,1H),2.05-1.94(m,1H),1.85-1.59(m,4H),1.30-1.23(m,9H),0.85(d,J=6.7Hz,3H). 13 C NMR(75MHz,CDCl3)δ162.6(q),159.3(q),145.7(q),145.6(q),127.2(t),127.1(t),115.1(t),114.9(t),80. 4(q),75.0(t),48.6(t),46.5(s),42.6(d),36.9(q),34.8(s),33.8(d),30.0(s),29.3(t),23.5(s),21.2(s).

[0238] Example 141: rac-(3aR,5R,7S,7aR)-5-(4-fluorophenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(4-fluorophenyl)-2,4,7-trimethyloct-6-enal (323 mg, 1.23 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (154 mg, 1.85 mmol), KCO (136 mg, 0.98 mmol) in toluene (50 mL) gave the title product rac-(3aR,5R,7S,7aR)-5-(4-fluorophenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole (164 mg, 46% yield) as a pale yellow oil. GC / MS(EI):m / z(%):291(50)[M + ],276(5),189(8),161(8),149(10),126(100),109(30),100(41),87(42). 1 H NMR(300MHz,CDCl3)δ7.40-7.28(m,2H),6.99(t,J=8.7Hz,2H),2.89-2.60(m,3H),2.40-2.21(m,1H),2.14-1.87(m,2H),1.85-1.6 9(m,2H),1.52(t,J=12.9Hz,1H),1.39(d,J=10.2Hz,1H),1.35-1.30(m,3H),1.29-1.22(m,3H),1.13(s,3H),1.02(d,J=6.1Hz,3H). 13 C NMR(75MHz,CDCl3)δ162.6(q),159.4(q),146.9(q),126.7(t),126.6(t),115.0(t),114.7(t),79.4(q), 77.6(t),53.9(t),48.9(s),46.3(d),38.3(q),37.2(d),33.1(t),26.9(s),26.7(s),24.9(s),20.2(s).

[0239] In the same reaction, additional isomers were also obtained: rac-(3aS,5R,7S,7aS)-5-(4-fluorophenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole (48 mg, 12% yield) and rac-(3aS,5R,7R,7aS)-5-(4-fluorophenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole (79 mg, 20% yield) as pale yellow oils. rac-(3aS,5R,7S,7aS)-5-(4-fluorophenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole: GC / MS(EI):m / z(%):291(33)[M + ],276(4),126(100),113(30),98(73),87(14). rac-(3aS,5R,7R,7aS)-5-(4-fluorophenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole: GC / MS(EI):m / z(%):291(67)[M + ],276(5),189(10),161(9),149(11),126(100),109(35),100(39),98(40),87(71).

[0240] Example 142: rac-(3aR,5R,7S,7aR)-5-(4-fluorophenyl)-1-isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(4-fluorophenyl)-2,4,7-trimethyloct-6-enal (619 mg, 1.27 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a) with N-isopropylhydroxylamine (144 mg, 1.91 mmol) in xylene (40 mL) gave the title product (114 mg, 28% yield) as a pale yellow oil. GC / MS(EI):m / z(%):319(30)[M + ],304(100),262(2),208(3),189(11),175(8),154(78),126(30),109(33),84(9). 1H NMR(300MHz,CDCl3)δ7.32(q,J=8.9,5.3Hz,2H),6.96(t,J=8.7Hz,2H),3.26-3.09(m,1H),2.49-2.18(m,2H),2.06- 1.85(m,1H),1.83-1.68(m,2H),1.57-1.33(m,2H),1.29(d,J=7.3Hz,6H),1.22(d,J=6.7Hz,3H),1.08-0.95(m,9H). 13 C NMR(75MHz,CDCl3)δ162.5(q),159.3(q),147.1(q),147.0(q),126.6(t),126.5(t),114.9(t),114.7(t),77.9(q),68.8(t) ,54.9(t),53.0(t),46.5(d),38.1(q),37.0(d),33.5(t),27.1(s),26.9(s),26.7(s),24.2(s),22.5(s),20.3(s),13.6(s).

[0241] Example 143: rac-(3aR,5R,7S,7aR)-5-(3-fluorophenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(3-fluorophenyl)-2,4,7-trimethyloct-6-enal (377 mg, 1.44 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (180 mg, 2.16 mmol), KCO (159 mg, 1.15 mmol) in xylene (40 mL) gave the title product (184 mg, 44% yield) as a pale yellow oil. GC / MS(EI):m / z(%):291(49)[M + ],276(5),189(13),161(15),147(7),126(100),109(26),100(31),87(51). 1H NMR(300MHz,CDCl3)δ7.20(q,J=14.4,7.4Hz,1H),7.09(d,J=8.0Hz,1H),7.00( d,J=11.3Hz,1H),6.80(td,J=8.2,1.6Hz,1H),2.85-2.55(m,3H),2.32-2.16(m, 1H),2.06-1.82(m,2H),1.79-1.64(m,2H),1.46(t,J=12.9Hz,1H),1.35(d,J=1 2.3Hz,1H),1.26(s,3H),1.23-1.16(m,3H),1.06(s,3H),0.96(d,J=6.1Hz,3H). 13 C NMR(75MHz,CDCl3)δ164.5(q),161.2(q),154.0(q),154.0(q),129.6(t),129.5(t),120.7(t),120.6(t),112.7(t),112.5(t),112 .4(t),112.1(t),79.2(q),77.5(t),53.7(t),48.8(s),45.9(d),38.6(q),36.8(d),33.0(t),26.9(s),26.5(s),24.9(s),20.1(s).

[0242] Example 144: rac-(3aR,5R,7S,7aR)-5-(2,4-difluorophenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(2,4-difluorophenyl)-2,4,7-trimethyloct-6-enal (401 mg, 0.14 mmol), N-methylhydroxylamine hydrochloride (18 mg, 0.22 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), KCO (16 mg, 0.11 mmol) in toluene (50 mL) gave the title product (26 mg, 60% yield) as a pale yellow oil. GC / MS(EI):m / z(%):309(38)[M + ],294(5),207(12),141(33),126(100),113(14),100(43),98(36),87(51).

[0243] Example 145: rac-1,3,3,5,7-pentamethyl-5-(4-methylpyridin-3-yl)octahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,4,7-trimethyl-4-(4-methylpyridin-3-yl)oct-6-enal (654 mg, 0.71 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (88 mg, 1.06 mmol), KCO (78 mg, 0.57 mmol) in toluene (50 mL) gave the title product (115 mg, 53% yield) as a pale yellow oil. GC / MS (isomer 1) (EI): m / z (%): 288 (52) [M + ], 271 (32), 242 (13), 228 (24), 134 (100), 126 (21), 98 (22). And GC / MS (isomer 2) (EI): m / z (%): 288 (51) [M + ],271(31),242(36),228(5),134(100),126(58),98(28). 1 H NMR(300MHz,CDCl3)δ8.60-8.36(m,1H),8.33-8.15(m,1H),7.06-6.89(m,1H),2.76(d,J=20.5Hz,2H),2.56-2.41(m,3 H),2.40-2.20(m,1H),2.20-1.89(m,2H),1.86-1.58(m,2H),1.57-1.35(m,3H),1.33-1.06(m,9H),1.04-0.93(m,3H). 13 C NMR(75MHz,CDCl3)δ149.2(t),147.2(t),147.1(t),146.8(t),145.4(q),145.1(q),143.3 (q),139.0(q),127.9(t),127.7(t),79.4(q),78.9(q),78.1(t),77.0(t),54.2(t),53.5(t ),48.8(s),48.6(s),46.9(d),44.9(d),40.8(q),38.9(q),36.7(d),35.7(d),33.2(t),33. 0(t),30.4(s),26.9(s),24.9(s),24.7(s),24.4(s),23.3(s),23.2(s),20.2(s),19.9(s).

[0244] Example 146: rac-2-(1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile Following the general procedure described in Example 81b: reaction of 2-(2,4,7-trimethyl-1-oxooct-6-en-4-yl)benzonitrile (389 mg, 1.44 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (181 mg, 2.17 mmol), KCO (160 mg, 1.16 mmol) in toluene (50 mL) gave the title product (229 mg, 53% yield) as a pale yellow oil. GC / MS (isomer 1) (EI): m / z (%): 298 (29) [M + ], 283(3), 252(21), 126(50), 113(19), 98(36), 87(100), 70(18). and GC / MS (isomer 2) (EI): m / z(%): 298(14) [M + ], 297(62), 252(40), 213(100), 198(71), 158(50), 144(44), 126(64), 98(49), 68(52). and GC / MS (isomer 3) (EI): m / z(%): 298(6) [M + ],297(24),252(16),240(19),196(33),144(28),126(100),98(30),68(43). 1 H NMR(300MHz,CDCl3)δ7.74-7.65(m,1H),7.58-7.40(m,2H),7.36-7.27(m,1H),2.98-2.75(m,3H),2.72-2.52(m,1H),2.43-2.20(m,1H),2.17( d,J=8.5Hz,2H),2.02-1.92(m,1H),1.78(s,1H),1.57(s,1H),1.49-1. 39(m,2H),1.36-1.24(m,3H),1.20-1.14(m,4H),1.06(d,J=6.2Hz,3H). 13C NMR(75MHz,CDCl3)δ153.3(q),149.8(q),136.3(t),135.8(t),132.8(t),132.7(t),128.3(t),126. 5(t),126.4(t),126.1(t),120.1(q),119.9(q),110.5(q),110.1(q),79.3(q),78.9(q),77.5(t),7 6.4(t),54.3(t),53.6(t),48.8(q),48.6(q),45.9,44.7,41.1(q),39.5(q),36.3(d),35.4(d),33. 4(s),33.2(s),31.2(s),30.8(s),26.7(s),26.5(s),24.7(s),24.5(s),24.4(s),19.8(s),19.7(s).

[0245] Example 147: rac-5-(3-methoxypyridin-2-yl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(6-methoxypyridin-2-yl)-2,4,7-trimethyloct-6-enal (485 mg, 0.92 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (115 mg, 1.37 mmol), KCO (101 mg, 0.73 mmol) in toluene (50 mL) gave the title product (234 mg, 84% yield) as a pale yellow oil. GC / MS (isomer 1) (EI): m / z (%): 304 (30) [M + ], 258 (20), 244 (17), 150 (100), 123 (14), 98 (11). and GC / MS (isomer 2) (EI): m / z (%): 304 (4) [M + ], 303(8), 258(100), 242(52), 218(60), 150(78), 123(28), 98(21). and GC / MS (isomer 3) (EI): m / z(%): 304(4) [M + ],258(10),247(16),231(18),150(52),123(13),97(100).And GC / MS(isomer 4)(EI):m / z(%):304(20)[M +],258(21),217(42),202(62),150(100),123(20),98(21). 1 H NMR(300MHz,CDCl3)δ7.46(q,J=8.0Hz,1H),6.82(t,J=6.8Hz,1H),6.49(dd,J=16.6 ,8.2Hz,1H),3.87(d,J=11.3Hz,3H),2.86-2.71(m,3H),2.68-2.52(m,1H),2.32(d,J =19.4Hz,1H),2.14-2.01(m,1H),2.00-1.78(m,2H),1.72(d,J=12.9Hz,1H),1.61(d, J=19.4Hz,1H),1.30(d,J=30.5Hz,4H),1.19(d,J=6.8Hz,3H),1.12(t,J=9.5Hz,5H). 13 C NMR(75MHz,CDCl3)δ166.9(q),164.0(q),163.2(q),163.0(q),138.9(t),138.8(t),112.6(t), 111.3(t),107.5(t),107.4(t),79.4(q),79.1(q),77.7(t),77.3(t),54.6(t),53.9(t),53.1(s ),52.9(s),48.9(s),48.8(s),45.4(d),45.1(d),42.6(q),41.4(q),35.8(d),35.7(d),33.5(t) ,33.1(t),32.6(s),32.5(s),27.0(s),26.7(s),25.0(s),24.9(s),21.9(s),20.2(s),20.1(s).

[0246] Example 148: rac-(3aR,7aR)-1,3,3-trimethyl-6-phenyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 7-methyl-3-phenyloct-6-enal (500 mg, 2.31 mmol), N-methylhydroxylamine hydrochloride (290 mg, 3.47 mmol), KCO (256 mg, 1.85 mmol) in toluene (50 mL) gave the title product (423 mg, 75% yield) as a yellow oil. GC / MS(EI):m / z(%):245(81)[M +],230(19),199(18),162(100),143(20),104(22),91(36). 1 H NMR(300MHz,CDCl3)δ7.35-7.27(m,2H),7.25-7.16(m,3H),2.76-2.53(m,4H),2.38(td,J=10. 9,3.4Hz,1H),2.10-1.76(m,4H),1.65-1.39(m,3H),1.39-1.30(m,3H),1.18(d,J=6.8Hz,3H). 13 C NMR(75MHz,CDCl3)δ145.7(q),128.5(t),126.9(t),126.4(t),79.6(q),71.8(t),5 7.3(t),44.6(q),42.5(t),36.1(d),33.9(d),28.0(s),27.0(s),25.2(s),24.8(d).

[0247] Example 149: rac-(3aR,5R,7S,7aR)-1-isopropyl-3,3,7-trimethyl-5-phenyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,7-dimethyl-4-phenyloct-6-enal (258 mg, 0.92 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a) with N-isopropylhydroxylamine (207 mg, 2.76 mmol) in xylene (80 mL) gave the title product (153 mg, 58% yield) as a pale yellow oil. GC / MS(EI):m / z(%):287(31)[M + ],272(100),230(5),157(12),154(43),126(21),115(18),91(27). 1 H NMR(300MHz,CDCl3)δ7.48-6.99(m,5H),3.35-3.08(m,1H),2.69(d,J=12.0Hz,1H),2.51(t,J=9.7Hz,1H),2.13(t ,J=10.7Hz,1H),1.86(d,J=12.6Hz,3H),1.43(t,J=12.3Hz,1H),1.35-1.19(m,7H),1.07(dd,J=24.9,7.3Hz,9H). 13 C NMR(75MHz,CDCl3)δ146.0(q),128.5(t),126.9(t),126.3(t),78.0(q),68.4(t),57.7(t),5 4.9(t),44.0(t),42.5(d),37.4(t),32.9(s),27.3(s),24.4(s),22.7(s),20.2(s),13.7(s).

[0248] Example 150: rac-(3aR,5R,7S,7aR)-1,3,3,7-tetramethyl-5-phenyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,7-dimethyl-4-phenyloct-6-enal (301 mg, 1.07 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (134 mg, 1.61 mmol), KCO (118 mg, 0.86 mmol) in toluene (50 mL) gave the title product (105 mg, 38% yield) as a pale yellow oil. GC / MS(EI):m / z(%):259(13)[M + ],258(32),201(23),172(24),126(100),104(84),91(31),68(13). 1 H NMR(300MHz,CDCl3)δ7.35-7.27(m,2H),7.22(dd,J=7.6,3.6Hz,3H),2.85(s,3H),2.73-2.60(m,1H),2.16 (dt,J=12.2,6.4Hz,2H),2.00-1.71(m,3H),1.52-1.33(m,2H),1.25(d,J=12.2Hz,3H),1.21-0.96(m,6H). 13 C NMR(75MHz,CDCl3)δ145.8(q),128.5(t),126.8(t),126.3(t),79.3(q),77.0(t),5 8.5(t),48.9(s),44.0(t),42.2(d),37.0(t),32.9(d),27.0(s),25.1(s),20.0(s).

[0249] Example 151: rac-(3aR,5R,7S,7aR)-1,3,3,7-tetramethyl-5-(o-tolyl)octahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,7-dimethyl-4-(o-tolyl)oct-6-enal (289 mg, 1.18 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (148 mg, 1.77 mmol), KCO (131 mg, 0.95 mmol) in toluene (50 mL) gave the title product (114 mg, 35% yield) as a pale yellow oil. GC / MS(EI):m / z(%):273(7)[M + ],272(16),215(11),186(29),126(78),118(100),105(22),98(24),91(16). 1 H NMR(300MHz,CDCl3)δ7.33-6.97(m,4H),2.95-2.79(m,3H),2.36(s,3H),2.16(dd,J=19.9,5.6Hz, 2H),1.80(d,J=13.2Hz,3H),1.44(dd,J=13.5,10.3Hz,2H),1.33-1.21(m,4H),1.19-1.01(m,6H). 13 C NMR(75MHz,CDCl3)δ143.6(q),135.2(q),130.5(t),126.2(t),126.0(t),125.3(t),79.3(q),77.2 (t),58.7(t),48.9(s),41.4(d),39.3(t),37.1(t),31.9(d),27.0(s),25.1(s),20.0(s),19.5(s).

[0250] Example 152: rac-(3aR,5R,7S,7aR)-5-(4-(tert-butyl)phenyl)-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(4-(tert-butyl)phenyl)-2,7-dimethyloct-6-enal (558 mg, 1.79 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (224 mg, 2.69 mmol), KCO (198 mg, 1.43 mmol) in xylene (40 mL) gave the title product (224 mg, 40% yield) as a pale yellow oil. GC / MS(EI):m / z(%):315(38)[M + ],300(11),145(18),126(100),100(57),98(27),87(45),57(43). 1 H NMR(300MHz,CDCl3)δ7.33(d,J=8.1Hz,2H),7.17(d,J=8.1Hz,2H),2.91-2.73(m,3H),2.68(d,J=13.3Hz,1H),2.22- 2.07(m,2H),1.95-1.74(m,3H),1.51-1.35(m,2H),1.33-1.25(m,12H),1.18(d,J=7.1Hz,3H),1.04(d,J=6.3Hz,3H). 13 C NMR(75MHz,CDCl3)δ149.1(q),142.8(q),126.5(t),125.4(t),79.4(q),77.1(t),58.6(t),49.0( s),43.5(t),42.2(d),37.0(t),34.4(q),33.1(d),31.4(s),27.1(s),27.0(s),25.2(s),20.1(s).

[0251] Example 153: rac-(3aR,5R,7S,7aR)-5-(4-(tert-butyl)phenyl)-1-isopropyl-3,3,7-trimethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(4-(tert-butyl)phenyl)-2,7-dimethyloct-6-enal (558 mg, 1.79 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a) with N-isopropylhydroxylamine (202 mg, 2.69 mmol) in xylene (40 mL) gave the title product (203 mg, 33% yield) as a pale yellow oil. GC / MS(EI):m / z(%):343(30)[M + ],328(100),213(5),154(65),145(15),128(21),126(20),115(16),57(26). 1 H NMR(300MHz,CDCl3)δ7.33(d,J=8.2Hz,2H),7.17(d,J=8.2Hz,2H),3.28-3.20(m,1H),2.77-2.60(m,1H),2.51(t,J=9.9Hz, 1H),2.21-2.06(m,1H),1.92-1.69(m,3H),1.48-1.36(m,1H),1.33-1.24(m,16H),1.15-1.07(m,6H),1.01(d,J=7.8Hz,3H). 13 C NMR(75MHz,CDCl3)δ149.1(q),142.9(q),126.5(t),125.3(t),77.9(q),68.4(t),57.8(t),54.9(t),43.5( t),42.5(d),37.4(t),34.4(q),33.0(d),31.4(s),27.3(s),27.0(s),24.4(s),22.7(s),20.2(s),13.7(s).

[0252] Example 154: rac-3-((3aR,5R,7S,7aR)-1-isopropyl-3,3,7-trimethyloctahydrobenzo[c]isoxazol-5-yl)-4-methoxybenzonitrile Following the general procedure described in Example 81b: reaction of 3-(2,7-dimethyl-1-oxooct-6-en-4-yl)-4-methoxybenzonitrile (528 mg, 1.57 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a) with N-isopropylhydroxylamine (177 mg, 2.36 mmol) in xylene (40 mL) gave the title product (233 mg, 43% yield) as a pale yellow oil. GC / MS(EI):m / z(%):342(25)[M + ],327(100),212(12),154(54),146(24),128(21),126(27),116(19),84(9). 1 H NMR(300MHz,CDCl3)δ7.55-7.39(m,2H),6.87(d,J=8.3Hz,1H),3.85(s,3H),3.24-3.06(m,2H),2.47(t,J=9.9Hz,1H),2.19-2.01 (m,1H),1.88-1.67(m,3H),1.41-1.30(m,1H),1.28-1.19(m,6H),1.15(t,J=6.7Hz,1H),1.10-1.04(m,6H),0.99(d,J=6.3Hz,3H). 13 C NMR(75MHz,CDCl3)δ160.2(q),135.5(q),131.9(t),130.5(t),119.5(q),110.8(t),103.8(q),77.9(q),68.4(t), 57.5(t),55.7(s),54.9(t),40.7(d),37.3(t),35.9(t),30.9(d),27.2(s),27.0(s),24.4(s),22.6(s),20.1(s).

[0253] Example 155: rac-(3aR,5R,7S,7aR)-1-ethyl-5-(2-methoxyphenyl)-3,3,7-trimethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: 4-(2-methoxyphenyl)-2,7-dimethyloct-6-enal (558 mg, 1.82 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-ethylhydroxylamine (167 mg, 2.73 mmol) in xylene (40 mL) was reacted to give the title product (189 mg, 34% yield) as a pale yellow oil. GC / MS(EI):m / z(%):303(36)[M + ],288(24),187(7),140(100),121(28),114(44),112(36),101(39),91(26). 1 H NMR(300MHz,CDCl3)δ7.23-7.12(m,2H),6.97-6.80(m,2H),3.82(s,3H),3.26-3.09(m,1H),3.07-2.93(m,1H),2.91-2.68(m ,1H),2.33(t,J=10.1Hz,1H),2.18-2.04(m,1H),1.92-1.74(m,3H),1.51-1.34(m,2H),1.30-1.19(m,6H),1.18-0.95(m,6H). 13 C NMR(75MHz,CDCl3)δ156.7(q),133.9(q),127.0(t),126.5(t),120.5(t),110.4(t),79.3(q),74.8(t), 57.9(t),56.5(d),55.3(s),40.8(d),37.6(t),36.2(t),31.3(d),26.6(s),24.9(s),20.0(s),13.8(s).

[0254] Example 156: rac-(3aR,5R,7S,7aR)-5-(2-ethylphenyl)-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(2-ethylphenyl)-2,7-dimethyloct-6-enal (658 mg, 1.91 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (239 mg, 2.86 mmol), KCO (211 mg, 1.53 mmol) in xylene (40 mL) gave the title product (213 mg, 39% yield) as a pale yellow oil. GC / MS(EI):m / z(%):287(38)[M + ],272(11),185(6),171(10),143(9),126(100),117(19),100(65),87(41). 1 H NMR(300MHz,CDCl3)δ7.25-7.11(m,4H),3.01-2.83(m,3H),2.70(q,J=7.4Hz,3H), 2.27-2.07(m,2H),1.75(M,3H),1.57-1.37(m,2H),1.33-1.15(m,9H),1.05(M,3H). 13 C NMR(75MHz,CDCl3)δ143.2(q),141.3(q),128.9(t),126.3(t),126.2(t),125.9(t),79.4(q),77.3(t), 58.8(t),49.0(s),42.2(d),38.7(t),37.2(t),32.9(d),27.1(s),26.0(d),25.2(s),20.1(s),16.1(s).

[0255] Example 157: rac-(3aR,5R,7S,7aR)-5-(2-ethylphenyl)-1-isopropyl-3,3,7-trimethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(2-ethylphenyl)-2,7-dimethyloct-6-enal (528 mg, 1.53 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a) with N-isopropylhydroxylamine (173 mg, 2.30 mmol) in xylene (40 mL) gave the title product (165 mg, 34% yield) as a pale yellow oil. GC / MS(EI):m / z(%):315(34)[M+ ],300(100),258(3),185(8),171(6),154(60),128(28),115(24),91(11). 1 H NMR(300MHz,CDCl3)δ7.25-7.11(m,4H),3.31-3.14(m,1H),3.04-2.89(m,1H),2.69(q,J=7.5Hz,2H),2.54(t,J=9.9Hz,1H),2 .21-2.07(m,1H),1.84-1.70(m,3H),1.45(q,J=24.8,12.6Hz,1H),1.32-1.19(m,10H),1.15-1.07(m,6H),1.06-1.00(m,3H). 13 C NMR(75MHz,CDCl3)δ143.4(q),141.4(q),128.9(t),126.2(t),126.2(t),125.9(t),78.0(q),68.6(t),58.0 (t),55.0(t),42.6(d),38.7(t),37.6(t),32.8(d),27.3(s),26.0(d),24.5(s),22.7(s),20.3(s),16.0(s).

[0256] Example 158: rac-(3aR,5R,7S,7aR)-5-(2,5-dimethylphenyl)-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(2,5-dimethylphenyl)-2,7-dimethyloct-6-enal (400 mg, 1.55 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (194 mg, 2.32 mmol), KCO (0.171 mg, 1.238 mmol) in toluene (50 mL) gave the title product (125 mg, 28% yield) as a yellow oil. GC / MS(EI):m / z(%):287(100)[M + ],272(20),171(17),157(15),126(75),119(20),100(50),98(27),87(52). 1H NMR(300MHz,CDCl3)δ7.09-7.02(m,2H),6.97-6.90(m,1H),3.01-2.62(m,4H),2.33(d,J=2.3Hz,6H),2.2 7-2.03(m,2H),1.93-1.72(m,3H),1.55-1.32(m,2H),1.31-1.26(m,3H),1.17(s,3H),1.12-1.02(m,3H). 13 C NMR(75MHz,CDCl3)δ143.4(q),135.5(q),132.0(q),130.4(t),126.7(t),126.0(t),79.3(q),77.2(t), 58.7(t),48.9(s),41.4(d),39.2(t),37.2(t),32.0(d),27.0(s),25.2(s),21.2(s),20.0(s),19.0(s).

[0257] Example 159: rac-(3aR,5R,7S,7aR)-5-(3-chloro-2-methylphenyl)-1-isopropyl-3,3,7-trimethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(3-chloro-2-methylphenyl)-2,7-dimethyloct-6-enal (300 mg, 1.08 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a) with N-isopropylhydroxylamine (121 mg, 1.61 mmol) in toluene (50 mL) gave the title product (90 mg, 25% yield) as a pale yellow oil. GC / MS(EI):m / z(%):337(9)[M + ],335(28)[M + ],322(33),320(100),154(67),141(21),139(21),126(20),115(17). 1H NMR(300MHz,CDCl3)δ7.22(d,J=7.5Hz,1H),7.17-7.05(m,2H),3.29-3.14(m,1H),3.06-2.89(m,1H),2.52(t,J=9.9Hz,1H),2.42- 2.32(m,3H),2.22-2.06(m,1H),1.91-1.68(m,3H),1.50-1.33(m,1H),1.32-1.23(m,7H),1.14-1.07(m,6H),1.02(d,J=6.3Hz,3H). 13 C NMR(75MHz,CDCl3)δ145.8(q),135.2(q),133.5(q),127.1(t),126.7(t),123.9(t),77.9(q),68.5(t),57.8 (t),54.9(t),41.8(d),40.2(s),37.5(t),31.9(d),27.3(s),24.5(s),22.7(s),20.2(s),15.7(s),13.7(s).

[0258] Example 160: rac-(3aR,5R,7S,7aR)-5-(2,4-dimethylphenyl)-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(2,4-dimethylphenyl)-2,7-dimethyloct-6-enal (400 mg, 1.55 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (194 mg, 2.32 mmol), KCO (171 mg, 1.24 mmol) in toluene (50 mL) gave the title product (170 mg, 38% yield) as a yellow oil. GC / MS(EI):m / z(%):287(100)[M + ],288(21),171(20),126(74),119(21),100(46),98(25),87(47). 1H NMR(300MHz,CDCl3)δ7.18-7.10(m,1H),7.06-6.96(m,2H),2.99-2.64(m,4H),2.39-2.26(m,6H),2.2 6-2.07(m,2H),1.93-1.72(m,3H),1.54-1.37(m,2H),1.29(s,3H),1.19(s,3H),1.05(d,J=6.3Hz,3H). 13 C NMR(75MHz,CDCl3)δ140.6(q),135.3(q),135.0(q),131.2(t),126.8(t),125.2(t),79.3(q),77.2(t), 58.7(t),48.9(s),41.5(d),38.9(t),37.1(t),32.0(s),27.0(s),25.1(s),20.8(s),19.9(s),19.3(s).

[0259] Example 161: rac-4-methyl-3-((3aR,5R,7S,7aR)-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile Following the general procedure described in Example 81b: reaction of 3-(2,7-dimethyl-1-oxooct-6-en-4-yl)-4-methylbenzonitrile (492 mg, 1.08 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (135 mg, 1.62 mmol), KCO (119 mg, 0.86 mmol) in toluene (50 mL) gave the title product (115 mg, 36% yield) as a pale yellow oil. GC / MS(EI):m / z(%):298(50)[M + ],283(24),252(10),196(10),182(10),142(10),126(100),113(18),100(79),87(63). 1 H NMR(300MHz,CDCl3)δ7.54(s,1H),7.47-7.39(m,1H),7.29(s,1H),3.05-2.64(m,4H),2.45(s,3H),2.30- 2.03(m,2H),1.92-1.76(m,3H),1.57-1.38(m,2H),1.34-1.28(m,3H),1.23(s,3H),1.08(d,J=6.2Hz,3H). 13 C NMR(75MHz,CDCl3)δ145.2(q),141.3(q),131.3(t),129.7(t),129.5(t),119.4(q),110.2(q),79.4(q), 77.3(t),58.6(t),49.1(s),41.3(d),39.3(t),37.2(t),31.8(d),27.1(s),25.2(s),20.1(s),20.0(s).

[0260] Example 162: rac-(3aR,5R,7S,7aR)-5-(5-chloro-2-methylphenyl)-1-isopropyl-3,3,7-trimethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(5-chloro-2-methylphenyl)-2,7-dimethyloct-6-enal (600 mg, 2.15 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a) with N-isopropylhydroxylamine (242 mg, 3.23 mmol) in xylene (50 mL) gave the title product (211 mg, 29% yield) as a pale yellow oil. GC / MS(EI):m / z(%):337(9)[M + ],335(27)[M + ],322(33),320(100),154(68),141(19),139(21),126(18),115(15). 1 H NMR(300MHz,CDCl3)δ7.16(s,1H),7.02(s,2H),3.26-3.11(m,1H),2.85(t,1H),2.56-2.42(m,1H),2.26(s,3H),2. 18-1.95(m,2H),1.85-1.62(m,3H),1.44-1.28(m,1H),1.26-1.19(m,6H),1.12-1.04(m,6H),0.99(d,J=6.3Hz,3H). 13C NMR(75MHz,CDCl3)δ145.7(q),133.6(q),131.7(q),131.6(t),125.8(t),125.5(t),77.8(q),68.3(t),57.7 (t),54.8(t),41.5(d),39.4(t),37.4(t),31.6(d),27.2(s),24.4(s),22.5(s),20.0(s),18.8(s),13.6(s).

[0261] Example 163: rac-(3aR,5R,7S,7aR)-5-(5-fluoro-2-methylphenyl)-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(5-fluoro-2-methylphenyl)-2,7-dimethyloct-6-enal (300 mg, 1.14 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (143 mg, 1.72 mmol), KCO (126 mg, 0.92 mmol) in toluene (50 mL) gave the title product (102 mg, 31% yield) as a yellow oil. GC / MS(EI):m / z(%):291(100)[M + ],276(33),175(17),136(23),126(83),100(62),98(32),87(55). 1 H NMR(300MHz,CDCl3)δ7.11-7.01(m,1H),6.94-6.85(m,1H),6.81-6.70(m,1H),2.97-2.57(m,4H),2.28(s,3H) ),2.22-1.99(m,2H),1.89-1.68(m,3H),1.46-1.29(m,2H),1.24(s,3H),1.16(s,3H),1.02(d,J=6.3Hz,3H). 13C NMR(75MHz,CDCl3)δ163.2(q),160.0(q),145.8(q),145.7(q),131.6(t),131.5(t),130.6(t),112.7(t),112.4(t),112.4(t) ,112.1(t),79.3(q),77.1(t),58.6(t),48.9(s),41.2(d),39.5(t),37.1(t),31.8(d),27.1(s),25.1(s),19.9(s),18.7(s).

[0262] Example 164: rac-(3aR,5R,7S,7aR)-5-(4-fluoro-2-methylphenyl)-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(4-fluoro-2-methylphenyl)-2,7-dimethyloct-6-enal (300 mg, 1.14 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (143 mg, 1.72 mmol), KCO (126 mg, 0.92 mmol) in toluene (50 mL) gave the title product (115 mg, 35% yield) as a yellow oil. GC / MS(EI):m / z(%):291(100)[M + ],276(27),136(28),126(83),123(28),100(57),98(31),87(52),70(15). 1 H NMR(300MHz,CDCl3)δ7.19-7.10(m,1H),6.88-6.77(m,2H),2.93-2.59(m,4H),2.31(s,3H),2.23-2. 03(m,2H),1.88-1.67(m,3H),1.50-1.30(m,2H),1.28-1.19(m,3H),1.15(s,3H),1.05-0.97(m,3H). 13C NMR(75MHz,CDCl3)δ162.4(q),159.2(q),139.3(q),139.3(q),137.5(q),137.4(q),126.8(t),126.6(t),117.0(t),116.7(t),112 .8(t),112.5(t),79.3(q),79.1(t),58.7(t),48.9(s),41.6(t),38.8(t),37.1(t),32.1(d),27.0(s),25.1(s),19.9(s),19.5(s).

[0263] Example 165: rac-(3aR,5R,7S,7aR)-5-(4-chloro-2-methylphenyl)-1-isopropyl-3,3,7-trimethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(4-chloro-2-methylphenyl)-2,7-dimethyloct-6-enal (700 mg, 2.51 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a) with N-isopropylhydroxylamine (283 mg, 3.77 mmol) in xylene (50 mL) gave the title product (288 mg, 34% yield) as a pale yellow oil. GC / MS(EI):m / z(%):337(10)[M + ],335(30)[M + ],322(33),320(100),154(73),141(22),139(31),126(19),115(16). 1 H NMR(300MHz,CDCl3)δ7.17-7.05(m,3H),3.27-3.12(m,1H),2.86(t,J=12.0,7.8,3.3Hz,1H),2.50(t,J=9.9Hz,1H),2.31(s ,3H),2.18-2.04(m,2H),1.84-1.63(m,3H),1.44-1.31(m,1H),1.28-1.20(m,6H),1.12-1.04(m,6H),1.00(d,J=6.4Hz,3H). 13C NMR(75MHz,CDCl3)δ142.3(q),137.2(q),131.2(q),130.1(t),126.7(t),126.1(t),77.9(q),68.4(t),57.8 (t),54.9(t),41.7(d),38.9(t),37.4(t),31.8(d),27.2(s),24.4(s),22.6(s),20.1(s),19.3(s),13.6(s).

[0264] Example 166: rac-(3aR,5R,7S,7aR)-1-isopropyl-5-(2-methoxyphenyl)-3,3,7-trimethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(2-methoxyphenyl)-2,7-dimethyloct-6-enal (525 mg, 2.02 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a) with N-isopropylhydroxylamine (227 mg, 3.02 mmol) in xylene (40 mL) gave the title product (280 mg, 44% yield) as a colorless oil. GC / MS(EI):m / z(%):317(35)[M + ],302(100),187(16),154(89),141(14),128(33),126(46),121(49),112(18),91(41). 1 H NMR(300MHz,CDCl3)δ7.24-7.12(m,2H),6.92(t,J=7.4Hz,1H),6.85(d,J=8.2Hz,1H),3.87-3.74(m,3H),3.30-3.11(m,2 H),2.51(t,J=9.8Hz,1H),2.19-2.09(m,1H),1.93-1.74(m,3H),1.62-1.32(m,2H),1.31-1.21(m,6H),1.16-0.95(m,9H). 13C NMR(75MHz,CDCl3)δ156.7(q),133.9(q),126.9(t),126.5(t),120.5(t),110.4(t),78.0(q),68.5(t),57.5 (t),55.2(s),54.7(t),41.1(d),37.2(t),36.0(t),31.2(d),27.2(s),24.3(s),22.4(s),20.1(s),13.6(s).

[0265] Example 167: rac-(3aR,5R,7S,7aR)-5-(2-methoxyphenyl)-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(2-methoxyphenyl)-2,7-dimethyloct-6-enal (300 mg, 1.15 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (144 mg, 1.73 mmol), KCO (127 mg, 0.92 mmol) in toluene (50 mL) gave the title product (155 mg, 47% yield) as a pale yellow oil. GC / MS(EI):m / z(%):289(65)[M + ],274(16),243(6),187(11),126(100),121(38),100(58),91(38),87(55),70(13). 1 H NMR(300MHz,CDCl3)δ7.18(t,J=8.0Hz,2H),7.01-6.78(m,2H),3.82(s,3H),3.27-3.06(m,1H), 2.91-2.55(m,3H),2.23-2.07(m,2H),1.95-1.71(m,3H),1.53-1.28(m,2H),1.27-0.95(m,9H). 13 C NMR(75MHz,CDCl3)δ156.7(q),133.8(q),127.0(t),126.5(t),120.5(t),110.4(t),79.4(q),77.2 (t),58.6(t),55.3(s),48.9(s),40.7(d),37.0(t),36.2(t),31.3(d),27.0(s),25.1(s),20.0(s).

[0266] Example 168: rac-(3aR,5R,7S,7aR)-1-isopropyl-3,3,7-trimethyl-5-(o-tolyl)octahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,7-dimethyl-4-(o-tolyl)oct-6-enal (258 mg, 1.06 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a) with N-isopropylhydroxylamine (238 mg, 3.17 mmol) in xylene (80 mL) gave the title product (208 mg, 66% yield) as a pale yellow oil. GC / MS(EI):m / z(%):301(63)[M + ],286(100),244(4),171(17),154(71),126(38),115(30),105(37),91(13). 1 H NMR(300MHz,CDCl3)δ7.28-7.05(m,4H),3.23(dd,J=13.0,6.5Hz,1H),3.03-2.83(m,1H),2.54(t,J=9.9Hz,1H),2.35(s,3H),2.23-2.0 4(m,2H),1.78(d,J=12.4Hz,3H),1.43(dd,J=24.5,12.3Hz,1H),1.26(dd,J=13.5,6.7Hz,7H),1.10(t,J=7.5Hz,5H),1.07-0.96(m,3H). 13 C NMR(75MHz,CDCl3)δ143.9(q),135.3(q),130.5(t),126.3(t),126.0(t),125.4(t),78.1(q),68.5(t),57.9 (t),54.9(t),41.8(d),39.3(t),37.5(t),31.9(d),27.3(s),24.5(s),22.6(s),20.2(s),19.5(s),13.6(s).

[0267] Example 169: rac-(3aR,7S,7aR)-5,5-diethyl-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4,4-diethyl-2,7-dimethyloct-6-enal (500 mg, 2.38 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (298 mg, 3.57 mmol), KCO (263 mg, 1.90 mmol) in toluene (50 mL) gave the title product (236 mg, 42% yield) as a colorless oil. GC / MS(EI):m / z(%):239(44)[M + ],224(36),210(20),193(14),137(17),126(100),100(50),55(16). 1 H NMR(300MHz,CDCl3)δ2.77-2.52(m,3H),1.97(ddd,J=31.6,17.0,6.8Hz,2H),1.76-1.63(m,1H),1.34 (ddd,J=13.5,10.2,7.7Hz,4H),1.14(dd,J=26.2,20.4Hz,7H),0.98-0.81(m,5H),0.80-0.59(m,7H). 13 C NMR(75MHz,CDCl3)δ79.2(q),78.1(t),53.1(t),48.8(s),43.9(d),36.5(q),33 .4(d),32.9(d),32.4(t),26.9(s),25.4(d),24.8(s),20.2(s),7.6(s),7.5(s).

[0268] Example 170: rac-(3aR,5R,7aR)-5-ethyl-1-isopropyl-3,3-dimethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-ethyl-7-methyloct-6-enal (1.00 g, 4.22 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-isopropylhydroxylamine hydrochloride (0.71 g, 6.33 mmol), KCO (0.47 g, 3.38 mmol) in toluene (50 mL) gave the title product (0.47 g, 50% yield) as a pale yellow oil. GC / MS(EI):m / z(%):225(18)[M+ ],210(100),151(7),114(21),95(29),81(11),67(8). 1 H NMR(300MHz,CDCl3)δ3.06-2.80(m,1H),2.48(dd,J=10.8,3.5Hz,1H),1.96-1.85(m,1H),1. 82-1.73(m,1H),1.70-1.62(m,1H),1.55-1.15(m,8H),1.13-0.99(m,9H),0.93-0.75(m,5H). 13 C NMR(75MHz,CDCl3)δ78.5(q),66.4(t),57.8(t),57.2(t),39.0(t),31.3(d) ,31.2(d),30.9(d),29.5(d),26.9(s),24.6(s),20.6(s),19.3(s),11.7(s).

[0269] Example 171: rac-(3aR,7aS)-1,3,3,4,5,7-hexamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,4,5,7-tetramethyloct-6-enal (235 mg, 1.08 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (136 mg, 1.62 mmol), KCO (120 mg, 0.87 mmol) in toluene (50 mL) gave the title product (77 mg, 34% yield) as a colorless oil. GC / MS(EI):m / z(%):211(63)[M + ],196(91),165(10),140(100),123(19),109(25),100(80),84(29),69(16),55(33). 1 H NMR(300MHz,CDCl3)δ2.71-2.57(m,3H),2.50-2.39(m,1H),1.91-1.73(m,2H),1.70-1.55(m,2H),1.39-1.25(m,8H),0.99-0.85(m,9H). 13C NMR(75MHz, CDCl3)δ81.1(q),74.7(t),57.2(t),46.2(s),37.4(d),34.8(t),32.8(t),30.6(s),29.4(t),23.7(s),20.6(s),19.9(s),19.2(s).

[0270] Example 172: rac-(3aR,7aR)-1,3,3,4,5,7-hexamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,4,5,7-tetramethyloct-6-enal (235 mg, 1.08 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (136 mg, 1.62 mmol), KCO (120 mg, 0.87 mmol) in toluene (50 mL) gave the title product (77 mg, 34% yield) as a colorless oil. GC / MS(EI):m / z(%):211(55)[M + ],196(61),165(14),140(55),123(19),109(28),100(100),87(24),69(16),55(25). 1 H NMR(300MHz,CDCl3)δ2.85-2.51(m,3H),2.17-1.98(m,1H),1.78-1.56(m,3H) ,1.49-1.39(m,1H),1.36-1.23(m,3H),1.21-1.07(m,5H),1.02-0.88(m,9H). 13 C NMR(75MHz, CDCl3) δ79.8(q),77.8(t),63.3(t),49.0(s),44.2(d),39.0(t),38.7(t),36.6(t),29.1(s),24.7(s),20.1(s),19.1(s),16.2(s).

[0271] Example 173: rac-(3aR,5R,7aR)-1-ethyl-3,3-dimethyl-5-propyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 7-methyl-4-propyloct-6-enal (700 mg, 3.84 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-ethylhydroxylamine hydrochloride (562 mg, 5.76 mmol), KCO (425 mg, 3.07 mmol) in toluene (50 mL) gave the title product (310 mg, 36% yield) as a colorless oil. GC / MS(EI):m / z(%):225(50)[M + ],210(100),165(25),123(12),109(36),100(87),95(24),81(17),74(17),67(15). 1 H NMR(300MHz,CDCl3)δ2.91(dd,J=12.7,7.1Hz,1H),2.65(dq,J=13.7,6.9Hz,1H),2.37-2.19(m,1H), 1.83(t,J=10.2Hz,3H),1.69(d,J=12.3Hz,1H),1.41-1.12(m,12H),1.06(s,3H),0.98-0.70(m,5H). 13 C NMR(75MHz,CDCl3)δ79.2(q),69.9(t),57.2(t),53.1(d),39.2(d),37.2(t ),31.6(d),31.1(d),29.3(d),27.6(s),25.2(s),20.3,14.4(s),13.1(s).

[0272] Example 174: rac-(3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyl-5-propyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,4,7-trimethyl-4-propyloct-6-enal (842 mg, 3.12 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (391 mg, 4.68 mmol), KCO (345 mg, 2.50 mmol) in toluene (50 mL) gave the title product (246 mg, 33% yield) as a colorless oil. GC / MS(EI):m / z(%):239(42)[M+ ],224(50),193(15),137(18),126(100),109(14),100(64),81(13),69(18),55(23). 1 H NMR(300MHz,CDCl3)δ2.81-2.54(m,3H),2.20-1.85(m,2H),1.82-1.63(m,1H),1.42-1.13(m,9H),1.05(d,J=13.8Hz,3H),1.01-0.79(m,11H). 13 C NMR(75MHz,CDCl3)δ79.4(q),78.2(t),53.8(t),48.9(t),48.6(d),46.7(d),36. 5(d),34.5(q),32.9(t),26.9(s),24.9(s),23.6(s),20.2(s),16.8(d),15.1(s).

[0273] Example 175: rac-(3aR,5R,7aR)-1,3,3-trimethyl-5-propyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 7-methyl-4-propyloct-6-enal (859 mg, 4.50 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (564 mg, 6.76 mmol), KCO (498 mg, 3.60 mmol) in toluene (50 mL) gave the title product (200 mg, 21% yield) as a colorless oil. GC / MS(EI):m / z(%):211(23)[M + ],210(100),196(33),165(48),153(85),126(61),109(33),96(41),82(66),67(34),55(26). 1 H NMR(300MHz,CDCl3)δ2.62(s,3H),2.11(td,J=10.9,3.1Hz,1H),1.78(dd,J=15.9,7. 2Hz,3H),1.66(d,J=12.3Hz,1H),1.38-1.13(m,9H),1.05(s,3H),0.95-0.73(m,5H). 13C NMR (75MHz, CDCl3) δ79.4(q),72.0(t),57.6(s),44.8(s),39.1(d),37.1(t),31.5(d),30.9(d),28.5(d),27.9(s),25.2(s),20.3(d),14.4(s).

[0274] Example 176: rac-(3aR,5R,7S,7aR)-1-isopropyl-3,3,5,7-tetramethyl-5-propyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,4,7-trimethyl-4-propyloct-6-enal (748 mg, 2.77 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-isopropylhydroxylamine (312 mg, 4.16 mmol), KCO (383 mg, 2.77 mmol) in toluene (50 mL) gave the title product (216 mg, 29% yield) as a colorless oil. GC / MS(EI):m / z(%):267(15)[M + ],252(100),210(5),154(48),137(10),128(18),95(13),81(10),69(14),55(20). 1 H NMR(300MHz,CDCl3)δ3.26-3.05(m,1H),2.35-2.22(m,1H),2.20-2.07(m,1H),1.83-1.54(m,2H),1.35-1.25(m,4H),1.24 (d,J=7.2Hz,5H),1.19(dd,J=11.9,2.8Hz,3H),1.04(d,J=6.2Hz,3H),1.01(s,3H),0.96-0.90(m,7H),0.89-0.85(m,3H). 13 C NMR(75MHz,CDCl3)δ78.1(q),69.5(t),54.8(t),52.7(t),48.6(d),47.0(d),36.4(d),34. 4(q),33.0(t),27.1(s),24.2(s),23.6(s),22.5(s),20.4(s),16.8(d),15.1(s),13.6(s).

[0275] Example 177: rac-(3aR,5R,7S,7aR)-1,5,7-triethyl-3,3-dimethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,4-diethyl-7-methyloct-6-enal (2.01 g, 2.04 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-ethylhydroxylamine (0.19 g, 3.06 mmol), KCO (0.23 g, 1.63 mmol) in toluene (50 mL) gave the title product (0.39 g, 78% yield) as a colorless oil. GC / MS(EI):m / z(%):239(24)[M + ],224(100),179(6),140(24),128(18),112(11),74(14). 1 H NMR(300MHz,CDCl3)δ2.93-2.53(m,2H),2.21(t,J=10.0Hz,1H),2.02-1.74(m,2H),1.74-1.35 (m,4H),1.34-1.19(m,4H),1.15(dd,J=7.9,5.6Hz,5H),1.08-0.94(m,4H),0.91-0.72(m,7H). 13 C NMR(75MHz,CDCl3)δ79.3(q),73.7(t),57.9(t),56.7(d),43.9(t),39.1(t),36. 5(d),31.2(d),29.5(d),26.4(s),26.2(d),24.6(s),13.9(s),11.7(s),10.7(s).

[0276] Example 178: rac-(3aR,5R,7S,7aR)-1-ethyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,4,7-trimethyloct-6-enal (400 mg, 2.38 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-ethylhydroxylamine hydrochloride (348 mg, 3.57 mmol), KCO (263 mg, 1.90 mmol) in toluene (50 mL) gave the title product (123 mg, 24% yield) as a pale yellow oil. GC / MS(EI):m / z(%):211(23)[M +],196(100),151(10),140(16),114(27),109(11),95(14). 1 H NMR(300MHz,CDCl3)δ3.08-2.53(m,2H),2.14(t,J=10.1Hz,1H),1.90(t,J=10.8Hz,1H),1.72-1.44( m,4H),1.19(dd,J=9.1,4.8Hz,6H),1.05(d,J=16.4Hz,3H),0.95(t,J=8.4Hz,6H),0.88-0.63(m,2H). 13 C NMR (75MHz, CDCl3) δ79.2(q),74.9(t),57.8(t),56.5(d),43.4(d),37.2(t),33.8(d),32.6(t),26.7(s),24.9(s),21.9(s),20.2(s),13.8(s).

[0277] Example 179: rac-(3aR,5R,7aR)-5-butyl-1-isopropyl-3,3-dimethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-butyl-7-methyloct-6-enal (700 mg, 3.57 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-isopropylhydroxylamine hydrochloride (597 mg, 5.35 mmol), KCO (394 mg, 2.85 mmol) in toluene (50 mL) gave the title product (42 mg, 5% yield) as a brown oil. GC / MS(EI):m / z(%):253(15)[M + ],238(100),196(3),123(8),114(16),95(8),81(9),67(7),55(6). 1 H NMR(300MHz,CDCl3)δ3.07-2.79(m,1H),2.51(td,J=10.8,3.2Hz,1H),1.84(ddd,J=25.2,15.4,7.9H z,3H),1.67(d,J=14.1Hz,1H),1.26(dd,J=25.5,6.2Hz,11H),1.13-0.98(m,9H),0.93-0.75(m,5H). 13C NMR(75MHz,CDCl3)δ78.6(q),66.4(t),57.7(t),57.1(t),37.3(t),36.6(d),31.7(d) ,31.3(d),31.1(d),29.4(d),26.9(s),24.6(s),23.0(d),20.5(s),19.1(s),14.1(s).

[0278] Example 180: rac-(3aR,5R,7aR)-5-butyl-1-ethyl-3,3-dimethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-butyl-7-methyloct-6-enal (812 mg, 4.14 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-ethylhydroxylamine hydrochloride (605 mg, 6.20 mmol), KCO (457 mg, 3.31 mmol) in toluene (50 mL) gave the title product (519 mg, 52% yield) as a colorless oil. GC / MS(EI):m / z(%):239(44)[M + ],224(100),179(17),140(8),123(20),109(21),100(82),81(20),67(16). 1 H NMR(300MHz,CDCl3)δ2.90(dd,J=12.7,7.1Hz,1H),2.64(dd,J=12.7,6.8Hz,1H),2.35-2.19(m,1H),1.90-1. 75(m,3H),1.68(d,J=12.5Hz,1H),1.39-1.19(m,12H),1.16(t,J=7.1Hz,3H),1.05(s,3H),0.91-0.81(m,4H). 13 C NMR(75MHz,CDCl3)δ79.1(q),69.9(t),57.2(t),53.1(d),37.5(t),36.6(d),31. 6(d),31.1(d),29.5(d),29.3(d),27.5(s),25.2(s),23.0(d),14.1(s),13.1(s).

[0279] Example 181: 1,3,3-trimethyl-6-((R)-4-methylcyclohex-3-en-1-yl)octahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 7-methyl-3-((R)-4-methylcyclohex-3-en-1-yl)oct-6-enal (700 mg, 2.99 mmol), N-methylhydroxylamine hydrochloride (374 mg, 4.48 mmol), KCO (330 mg, 2.39 mmol) in toluene (50 mL) gave the title product (648 mg, 82% yield) as a pale yellow oil. GC / MS(EI):m / z(%):263(100)[M + ],248(23),217(19),166(32),121(22),112(22),95(40),81(28),67(30),55(20). 1 H NMR(300MHz,CDCl3)δ5.29(s,1H),2.59(s,3H),2.11(d,J=9.2Hz,2H),1.99-1.61(m,8H),1.56(s,3H),1.41-1.11(m,7H),1.09-0.86(m,5H). 13 C NMR(75MHz,CDCl3)δ133.9(q),120.6(t),79.3(q),71.9(t),57.8(t),44.5(s),40.4(t),38.6(t),38.5(t),32.2(d ),32.0(d),30.8(t),30.7(d),29.3(d),29.2(d),29.1(d),27.9(s),26.9(d),26.6(d),25.1(s),24.4(d),23.4(s).

[0280] Example 182: rac-(3aR,5R,7aR)-1,3,3-trimethyl-5-pentyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-(3-methylbut-2-en-1-yl)nonane al (412 mg, 1.74 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (218 mg, 2.61 mmol), K2CO3 (193 mg, 1.39 mmol) in toluene (50 mL) gave the title product (295 mg, 70% yield) as a colorless oil. GC / MS(EI):m / z(%):239(31)[M+ ],224(27),193(13),137(9),123(15),109(28),86(100),67(22),55(28). 1 H NMR(300MHz,CDCl3)δ2.57(s,3H),2.07(td,J=11.0,3.2Hz,1H),1.74(dd,J=15.6,7. 6Hz,3H),1.63(d,J=12.5Hz,1H),1.31-1.09(m,13H),1.01(s,3H),0.91-0.67(m,5H). 13 C NMR(75MHz,CDCl3)δ79.4(q),71.9(t),57.5(t),44.6(s),37.3(t),36.7(d),32. 1(d),31.4(d),30.8(d),28.4(d),27.8(s),26.9(d),25.1(s),22.6(d),14.1(s).

[0281] Example 183: rac-(3aR,5R,7S,7aR)-5,7-diethyl-1-isopropyl-3,3-dimethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,4-diethyl-7-methyloct-6-enal (1000 mg, 5.09 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-isopropylhydroxylamine hydrochloride (852 mg, 7.64 mmol), KCO (563 mg, 4.07 mmol) in toluene (50 mL) gave the title product (125 mg, 10% yield) as a pale yellow oil. GC / MS(EI):m / z(%):253(20)[M + ],238(100),196(28),179(5),154(12),123(13),109(8),95(10),81(8),69(9),55(11). 1H NMR(300MHz,CDCl3)δ3.09(dt,J=13.0,6.5Hz,1H),2.42(t,J=9.8Hz,1H),1.99-1.85(m,1H),1.78(d,J=13.2Hz,1H),1.60(d d,J=37.5,28.7Hz,3H),1.34-1.13(m,10H),1.04(dd,J=12.8,6.4Hz,6H),0.92-0.73(m,7H),0.61(dd,J=24.6,11.6Hz,1H). 13 C NMR(75MHz,CDCl3)δ77.9(q),66.7(t),57.9(t),55.0(t),43.6(t),39.1(t),36.6(d) ,31.3(d),29.6(d),27.1(s),25.9(d),24.3(s),22.7(s),13.9(s),11.8(s),10.4(s).

[0282] Example 184: rac-(3aR,5R,7S,7aR)-1-isopropyl-3,3,7-trimethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,7-dimethyl-4-(3-methylbut-2-en-1-yl)oct-6-enal (853 mg, 3.64 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-isopropylhydroxylamine hydrochloride (610 mg, 5.47 mmol), KCO (403 mg, 2.92 mmol) in toluene (50 mL) gave the title product (250 mg, 25% yield) as a pale yellow oil. GC / MS(EI):m / z(%):279(23)[M + ],264(100),222(4),154(6),128(4),107(4),95(7),69(13),55(5). 1H NMR(300MHz,CDCl3)δ5.08(t,J=7.3Hz,1H),3.19-2.99(m,1H),2.28(t,J=9.9Hz,1H),1.86(dd,J=17.2,5.5Hz,3H),1.69-1.46(m,9H) ),1.38(dd,J=7.2,3.6Hz,1H),1.24-1.10(m,6H),1.00(dd,J=10.3,3.9Hz,6H),0.90(d,J=6.4Hz,3H),0.73(dd,J=25.1,12.8Hz,2H). 13 C NMR(75MHz,CDCl3)δ132.2(q),122.8(t),77.8(q),68.7(t),57.4(t),54.7(t),41.3(d),38.3(t ),36.9(t),35.1(d),31.4(d),27.2(s),25.8(s),24.3(s),22.6(s),20.2(s),17.8(s),13.6(s).

[0283] Example 185: rac-(3aR,5R,7S,7aR)-1-ethyl-3,3,7-trimethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,7-dimethyl-4-(3-methylbut-2-en-1-yl)oct-6-enal (2.00 g, 8.99 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-ethylhydroxylamine (0.82 g, 13.49 mmol), KCO (0.99 g, 7.20 mmol) in toluene (50 mL) gave the title product (0.91 g, 38% yield) as a pale yellow oil. GC / MS(EI):m / z(%):265(42)[M + ],250(100),222(3),194(6),140(18),114(18),95(10),81(8),69(22). 1H NMR(300MHz,CDCl3)δ5.11(t,J=7.3Hz,1H),3.03-2.55(m,2H),2.14(t,J=10.1Hz,1H),1.97-1.79(m,3H),1. 66(d,J=8.6Hz,5H),1.56(s,3H),1.50-1.25(m,2H),1.24-1.09(m,6H),1.08-0.87(m,6H),0.85-0.59(m,2H). 13 C NMR(75MHz,CDCl3)δ132.3(q),122.8(t),79.2(q),75.1(t),57.6(t),56.4(d),41.1(d),38 .4(t),37.2(t),35.1(d),31.5(d),26.6(s),25.8(s),24.8(s),20.2(s),17.8(s),13.8(s).

[0284] Example 186: rac-(3aR,5R,7S,7aR)-1-ethyl-3,3,5,7-tetramethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,4,7-trimethyl-4-(3-methylbut-2-en-1-yl)oct-6-enal (2.00 g, 7.95 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-ethylhydroxylamine hydrochloride (1.16 g, 11.93 mmol), KCO (0.88 g, 6.36 mmol) in toluene (50 mL) gave the title product (1.03 g, 46% yield) as a pale yellow oil. GC / MS(EI):m / z(%):279(55)[M + ],264(80),210(7),149(11),140(100),114(42),69(35),55(20). 1 H NMR(300MHz,CDCl3)δ5.19(t,J=7.6Hz,1H),3.08-2.60(m,2H),2.18-2.00(m,2H),1.91(d,J=7.5Hz,2H), 1.72(s,4H),1.58(s,3H),1.48-1.26(m,3H),1.26-1.14(m,6H),1.12-0.99(m,4H),0.91(d,J=4.3Hz,6H). 13C NMR(75MHz,CDCl3)δ133.5(q),120.4(t),79.3(q),75.7(t),56.4(d),53.0(t),46.2(d),43.6(d ),36.2(d),35.8(q),33.4(t),26.6(s),26.2(s),24.7(s),24.0(s),20.3(s),18.0(s),13.9(s).

[0285] From the same reaction, an additional diastereomer was isolated: rac-(3aR,5R,7R,7aR)-1-ethyl-3,3,5,7-tetramethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole (320 mg, 14% yield) as a yellow oil. GC / MS(EI):m / z(%):279(63)[M + ],264(90),140(100),114(47),95(19),83(21),69(41),55(27).

[0286] Example 187: rac-(3aR,5R,7aR)-5-butyl-1,3,3-trimethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-butyl-7-methyloct-6-enal (821 mg, 4.18 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (524 mg, 6.27 mmol), KCO (462 mg, 3.35 mmol) in toluene (50 mL) gave the title product (675 mg, 72% yield) as a colorless oil. GC / MS(EI):m / z(%):225(39)[M + ],210(29),179(21),123(24),109(26),95(27),86(100),67(21),55(26). 1 H NMR(300MHz,CDCl3)δ2.65(s,3H),2.12(dd,J=10.9,3.1Hz,1H),1.95-1.77(m,3H) ,1.70(d,J=12.2Hz,1H),1.31(d,J=21.1Hz,11H),1.09(s,3H),0.98-0.75(m,5H). 13 C NMR(75MHz,CDCl3)δ79.5(q),72.1(t),57.7(t),44.8(s),37.4(t),36.6(d) ,31.6(d),31.0(d),29.5(d),28.6(d),28.0(s),25.3(s),23.0(d),14.2(s).

[0287] Example 188: rac-(3aR,5R,7aR)-1-isopropyl-3,3-dimethyl-5-propyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 7-methyl-4-propyloct-6-enal (1.50 g, 8.23 ​​mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-isopropylhydroxylamine (4.00 g, 53.30 mmol), KCO (0.91 g, 6.58 mmol) in toluene (50 mL) gave the title product (1.02 g, 52% yield) as a colorless oil. GC / MS(EI):m / z(%):239(25)[M + ],224(100),182(4),165(7),114(31),109(35),95(21),81(20),67(20),55(18). 1 H NMR(300MHz,CDCl3)δ2.89(dt,J=12.8,6.4Hz,1H),2.46(td,J=10.8,3.3Hz,1H ),1.93-1.53(m,4H),1.40-1.10(m,9H),1.09-0.94(m,9H),0.93-0.67(m,5H). 13 C NMR(75MHz,CDCl3)δ78.5(q),66.3(t),57.7(t),57.0(t),39.1(d),36.9(t) ,31.6(d),31.2(d),26.8(s),24.5(s),20.5(s),20.2(d),19.1(s),14.3(s).

[0288] Example 189: 1-Ethyl-3,3,5,7-tetramethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,4,7-trimethyl-4-(3-methylbut-2-en-1-yl)oct-6-enal (2.00 g, 7.95 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-ethylhydroxylamine hydrochloride (1.16 g, 11.93 mmol), KCO (0.88 g, 6.36 mmol) in toluene (50 mL) gave the title product (1.03 g, 46% yield) as a pale yellow oil. GC / MS(EI):m / z(%):279(55)[M + ],264(80),210(7),149(11),140(100),114(42),69(35),55(20).And GC / MS(EI):m / z(%):279(50)[M + ],264(80),208(15),152(21),140(100),114(45),69(41),55(22). 1 H NMR(300MHz,CDCl3)δ5.09(dt,J=24.7,7.2Hz,1H),3.00-2.52(m,2H),2.07(d,J=14.8Hz,2H),1.83(t,J=9 .7Hz,2H),1.75-1.61(m,4H),1.52(s,3H),1.40(d,J=12.9Hz,1H),1.33-1.09(m,7H),1.07-0.76(m,11H). 13 C NMR(75MHz,CDCl3)δ133.3(q),133.1(q),120.4(t),120.2(t),79.1(q),75.6(t),56.4(d),56.3(d),52.9(t),46.9(d),46.1(d),43.5(d),3 6.1(d),35.7(d),35.6(d),35.3(q),33.3(t),33.2(t),29.2(s),26.5 (s),26.0(s),24.5(s),23.8(s),20.2(s),18.0(s),17.9(s),13.7(s).

[0289] Example 190: 5-Ethyl-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4-ethyl-2,4,7-trimethyloct-6-enal (584 mg, 2.439 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (306 mg, 3.66 mmol), KCO (270 mg, 1.951 mmol) in toluene (50 mL) gave the title product (342 mg, 62% yield) as a colorless oil. GC / MS(EI):m / z(%):225(26)[M + ],210(38),196(7),179(12),137(9),126(100),109(20),100(68),55(28). 1 H NMR(300MHz,CDCl3)δ2.86-2.46(m,3H),2.16-1.82(m,2H),1.69(d,J=7.1Hz,1H),1.49-1.13(m,7H),1.10-0.64(m,14H). 13 C NMR(75MHz,CDCl3)δ79.2(q),79.1(q),78.2(t),78.0(t),53.8(t),53.5(t),48.9(s),46.5(d),46.2(d),38.0(d),35.9(d) ,35.2(d),34.4(q),34.2(q),32.8(t),32.5(t),29.5(d),28.5(s),26.9(s),24.9(s),24.8(s),23.0(s),20.2(s),7.9(s).

[0290] Example 191: 1,3,3,6-Tetramethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 3,7-dimethyloct-6-enal (3.125 g, 20.26 mmol), N-methylhydroxylamine hydrochloride (2.54 g, 30.40 mmol), KCO (2.24 g, 16.21 mmol) in cyclohexane (80 mL) gave the title product (1.99 g, 54% yield) as a colorless oil. GC / MS(EI):m / z(%):183(71)[M +],168(54),137(94),126(9),109(15),100(100),95(43),81(44). 1 H NMR(300MHz,CDCl3)δ2.58(s,3H),2.14(td,J=10.9,3.5Hz,1H),1.81-1.55(m,4H ),1.49-1.28(m,1H),1.27-1.10(m,4H),1.05(d,J=9.8Hz,3H),0.99-0.81(m,5H). 13 C NMR(75MHz, CDCl3) δ79.4(q),71.7(t),57.4(t),44.5(s),37.3(d),34.4(d),30.9(t),28.0,25.2(s),24.5(d),21.9(s).

[0291] Example 192: 1,3,3,5,7-pentamethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,4,7-trimethyl-4-(3-methylbut-2-en-1-yl)oct-6-enal (2.00 g, 5.84 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (0.73 g, 8.76 mmol), KCO (0.65 g, 4.67 mmol) in toluene (50 mL) gave the title product (1.04 g, 67% yield) as a pale yellow oil. GC / MS(EI):m / z(%):265(81)[M + ], 250(78), 194(8), 149(18), 138(19), 126(100), 100(57), 69(41), 55(20). and GC / MS(EI): m / z(%): 265(66) [M + ],250(79),194(27),153(27),138(31),126(100),100(63),69(52),55(28). 1H NMR(300MHz,CDCl3)δ5.10(d,J=25.1Hz,1H),2.90-2.44(m,3H),2.06(s,1H),1.88(t,J=10.2Hz,2H),1.66(s,4H),1.54(s,3H),1.48-0.62(m,17H). 13 C NMR(75MHz,CDCl3)δ133.4(q),133.1(q),120.4(t),120.2(t),79.2(q),79.1(q),78.1(t),77.9(t),53.7(t),48.8(s),46.8(d),46.1(d),4 3.5(d),36.1(d),35.7(q),35.6(d),35.5(d),35.3(q),32.8(t),29.2 (s),26.9(s),26.1(s),24.8(s),23.8(s),20.1(s),18.0(s),17.9(s).

[0292] Example 193: 1-Isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,4,7-trimethyloct-6-enal (2.83 g, 15.78 mmol), N-isopropylhydroxylamine hydrochloride (2.64 g, 23.67 mmol), K2CO3 (1.75 g, 12.62 mmol) in toluene (50 mL) gave the title product (1.63 g, 45% yield) as a colorless oil. GC / MS(EI):m / z(%):225(18)[M + ],210(100),168(19),151(7),128(9),109(10),95(19). 1 H NMR(300MHz,CDCl3)δ3.05(dd,J=13.0,6.5Hz,1H),2.22(t,J=9.9Hz,1H),1.94-1.76(m,1H),1.61-1.35( m,4H),1.16-1.07(m,6H),0.98-0.90(m,6H),0.83(dt,J=14.1,7.0Hz,6H),0.69(dd,J=24.9,12.7Hz,2H). 13C NMR(75MHz,CDCl3)δ77.5(q),68.4(t),57.4(t),54.6(t),43.5(d),36.8(t) ,33.5(d),32.3(t),27.1(s),24.2(s),22.5(s),21.7(s),20.1(s),13.5(s).

[0293] Example 194: rac-(3aR,5R,7S,7aR)-1-isopropyl-3,3,5,7-tetramethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,4,7-trimethyl-4-(3-methylbut-2-en-1-yl)oct-6-enal (2.02 g, 8.53 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a) with N-isopropylhydroxylamine hydrochloride (1.92 g, 25.6 mmol) in xylene (50 mL) gave the title product rac-(3aR,5R,7S,7aR)-1-isopropyl-3,3,5,7-tetramethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole (517 mg, 20% yield) as a pale yellow oil. GC / MS(EI):m / z(%):293(24)[M + ],278(100),154(38),128(13),107(13),95(9),83(8),69(23),55(11). 1 H NMR(300MHz,CDCl3)δ5.15(t,J=7.4Hz,1H),3.12(dt,J=12.9,6.5Hz,1H),2.24(t,J=10.1Hz,1H),2.16-2.01(m,1H) ),1.87(d,J=7.5Hz,2H),1.78-1.60(m,4H),1.55(s,3H),1.34-1.11(m,8H),1.05-0.94(m,7H),0.93-0.76(m,7H). 13C NMR(75MHz,CDCl3)δ133.4(q),120.4(t),77.8(q),69.4(t),54.8(t),52.8(t),46.5(d),43.6(d),36 .1(d),35.7(d),33.2(t),27.1(s),26.1(s),24.2(s),23.8(s),22.6(s),20.3(s),18.0(s),13.7(s).

[0294] From the same reaction, two additional isomers were isolated as pale yellow oils: rac-(3aS,5R,7S,7aS)-1-isopropyl-3,3,5,7-tetramethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole (412 mg, 6% yield) and rac-(3aS,5R,7R,7aS)-1-isopropyl-3,3,5,7-tetramethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole (412 mg, 15% yield). rac-(3aS,5R,7S,7aS)-1-isopropyl-3,3,5,7-tetramethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole: GC / MS(EI):m / z(%):293(21)[M + ],278(73),154(100),126(51),107(33),95(22),84(26),69(99),55(24). rac-(3aS,5R,7R,7aS)-1-isopropyl-3,3,5,7-tetramethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole: GC / MS(EI):m / z(%):293(20)[M + ],278(100),154(60),128(18),107(22),95(22),81(18),69(79),55(22).

[0295] Example 195: 1,3,3,7-tetramethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,7-dimethyl-4-(3-methylbut-2-en-1-yl)oct-6-enal (7.13 g, 28.8 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (3.61 g, 43.3 mmol), KCO (3.19 g, 23.08 mmol) in toluene (60 mL) gave the title product (5.75 g, 79% yield) as a colorless oil. GC / MS(EI):m / z(%):251(24)[M + ],236(19),193(29),180(23),149(40),126(100),108(42),93(58),69(38),55(18). 1 H NMR(300MHz,CDCl3)δ5.02(t,J=7.3Hz,1H),2.82-2.37(m,3H),1.99-1.74(m,4H), 1.59(s,5H),1.48(s,3H),1.42-1.19(m,2H),1.17-0.80(m,9H),0.79-0.54(m,2H). 13 C NMR(75MHz,CDCl3)δ132.1(q),122.6(t),79.0(q),77.3(t),58.2(t),48.7(s),40.9(d ),38.2(t),36.4(t),34.9(d),31.3(d),26.8(s),25.7(s),24.9(s),19.9(s),17.7(s).

[0296] Example 196: 1-Isopropyl-5,7-dimethylhexahydro-1H-spiro[benzo[c]isoxazole-3,1'-cyclopentane] Following the general procedure described in Example 81b: reaction of 6-cyclopentylidene-2,4-dimethylhexanal (215 mg, 1.11 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-isopropylhydroxylamine hydrochloride (185 mg, 1.66 mmol), KCO (122 mg, 0.89 mmol) in toluene (50 mL) gave the title product (93 mg, 33% yield) as a colorless oil. GC / MS(EI):m / z(%):251(34)[M + ],236(100),222(31),180(26),128(41),109(22),95(28),81(18),67(14),55(19). 1 H NMR(300MHz,CDCl3)δ3.13(dt,J=12.9,6.5Hz,1H),2.33-2.19(m,1H),2.17-2.03(m,1H),1.83(dd,J=11.9,7.8 Hz,1H),1.75-1.34(m,11H),1.27-1.14(m,3H),1.04(t,J=8.5Hz,3H),0.95(t,J=8.9Hz,6H),0.90-0.68(m,2H). 13 C NMR(75MHz,CDCl3)δ88.9(q),69.4(t),55.5(t),55.0(t),43.8(d),37.1(t),36.6(d) ,34.5(d),33.9(d),32.5(t),24.9(d),23.7(d),22.7(s),22.0(s),20.3(s),14.1(s).

[0297] Example 197: 1,3,3,5,7-Pentamethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,4,7-trimethyloct-6-enal (20.00 g, 102.00 mmol), N-methylhydroxylamine hydrochloride (12.78 g, 153.00 mmol), K2CO3 (11.28 g, 82.00 mmol) in toluene (300 ml) gave the title product (16.18 g, 80% yield) as a colorless oil. GC / MS (isomer 1) (EI): m / z (%): 197 (32) [M + ], 182 (100), 151 (17), 126 (22), 109 (18), 100 (47), 60 (19). and GC / MS (isomer 2) (EI): m / z (%): 197 (31) [M + ],182(100),151(20),126(20),109(18),100(44),60(19). 1H NMR(300MHz,CDCl3)δ2.91-2.50(m,3H),2.01(ddd,J=21.1,15.3,5.2Hz,3H),1.55(ddd,J= 18.9,17.9,9.5Hz,3H),1.40(dd,J=10.7,7.0Hz,1H),1.30-1.05(m,5H),1.04-0.64(m,8H). 13 C NMR(75MHz,CDCl3)δ79.2(q),79.1(q),77.9(t),77.2(t),58.4(t),51.9(t),48.9(s),43.2(d),40.1(d),36.6(t),33. 7(d),32.5(t),31.9(t),30.9(d),27.7(s),26.9(s),26.8(s),25.0(s),24.8(s),21.8(s),20.1(s),20.0(s),19.2(s).

[0298] Example 198: 5,7-Diethyl-1,3,3-trimethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 2,4-diethyl-7-methyloct-6-enal (412 mg, 1.99 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (250 mg, 2.99 mmol), KCO (220 mg, 1.60 mmol) in toluene (50 mL) gave the title product (0.30 mg, 66% yield) as a colorless oil. GC / MS(EI):m / z(%):225(25)[M + ], 210(100), 179(7), 126(23), 114(20), 98(11), 81(9). and GC / MS(EI): m / z(%): 225(17) [M + ],210(19),179(6),126(100),109(23),96(25). 1 H NMR(300MHz,CDCl3)δ2.84-2.53(m,3H),2.22-2.05(m,1H),2.03-1.43(m, 5H),1.41-1.23(m,4H),1.23-1.05(m,6H),0.99(s,1H),0.94-0.76(m,7H). 13 C NMR(75MHz,CDCl3)δ79.4(q),76.1(t),75.6(t),58.8(t),52.8(t),49.4(s),43.4(t),39.2(t),39.1(t),36.4(d),35.0(t),33. 4(d),31.3(d),29.5(d),28.7(d),26.8(s),26.7(s),26.0(d),25.4(d),25.0(s),24.8(s),12.7(s),11.8(s),11.0(s),10.5(s).

[0299] Example 199: 1,5,7-trimethylhexahydro-1H-spiro[benzo[c]isoxazole-3,1'-cyclopentane] Following the general procedure described in Example 81b: reaction of 6-cyclopentylidene-2,4-dimethylhexanal (604 mg, 3.11 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (389 mg, 4.66 mmol), KCO (344 mg, 2.49 mmol) in toluene (50 mL) gave the title product (303 mg, 44% yield) as a colorless oil. GC / MS(EI):m / z(%):223(40)[M + ], 181(28), 152(100), 139(23), 122(27), 95(39), 82(32), 67(23), 55(35). and GC / MS(EI): m / z(%): 223(32) [M + ],181(19),152(100),139(14),122(24),95(29),82(21),67(19),55(28). 1 H NMR(300MHz,CDCl3)δ2.84-2.52(m,3H),2.38-1.82(m,3H),1.78-1.41(m,11H),1.30-0.85(m,7H),0.84-0.58(m,1H). 13C NMR(75MHz,CDCl3)δ90.2(q),78.8(t),78.1(t),56.0(t),49.5(t),49.2(t),43.4(d),40.2(d),36.8(t),36.3(d),36.2(d) ,35.7(d),35.5(d),33.9(d),32.5(t),32.0(t),31.1(d),27.8(t),25.1(d),23.9(d),21.9(s),20.2(s),20.1(s),19.3(s).

[0300] Example 200: 1,3,3,5,7-Pentamethyloctahydrobenzo[c]isoxazole hydrochloride A flask was charged with 1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole (313 mg, 1.59 mmol) and acetone (40 mL), followed by the dropwise addition of 2.7 mL 1 M HCl at rt and stirring overnight to afford the title product (304 mg, 1.29 mmol, 81% yield) as a white solid. 1 H NMR(300MHz,CDCl3)δ14.92(s,1H),3.15-2.86(m,3H),2.83-2.59(m,1H),2.56-2.31(m,1H),2.27-1.90(m,1H),1.88-1.68(m,2 H),1.66-1.31(m,5H),1.20(d,J=3.1Hz,3H),1.15-1.07(m,3H),1.00(d,J=7.2Hz,1H),0.92(t,J=7.2Hz,2H),0.85-0.67(m,1H). 13C NMR(75MHz,CDCl3)δ88.9(q),87.7(q),87.5(q),78.4(t),77.8(t),73.2(t),72.8(t),54.7(t),5 1.1(t),48.8(t),44.7(s),42.8(d),42.3(d),40.0(d),39.3(s),33.0(d),32.9(d),32.8(t),31. 9(t),31.4(t),31.3(t),30.5(s),28.4(t),26.9(t),26.9(t),26.2(s),26.1(s),23.5(s),23.4( s),22.5(s),21.2(s),21.1(s),20.5(s),19.5(s),19.4(s),19.3(s),19.2(s),18.8(s),18.5(s).

[0301] Example 201: 1-Isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole hydrochloride A flask was charged with 1-isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole (185 mg, 0.81 mmol) and acetone (40 mL), followed by the dropwise addition of 1.4 mL of 1 M HCl at rt and stirring overnight to afford the title product (180 mg, 0.69 mmol, 85% yield) as a light brown solid. 1 H NMR(300MHz,CDCl3)δ14.36(s,1H),3.90-3.47(m,1H),2.92-2.35(m,3H),1.75-1.53(m,3H),1.46(d,J=6. 5Hz,3H),1.39(s,3H),1.19(d,J=6.5Hz,3H),1.12-1.00(m,6H),0.84(d,J=6.8Hz,3H),0.79-0.60(m,2H). 13 C NMR(75MHz,CDCl3)δ86.0(q),70.9(t),56.7(t),53.1(t),43.1(d),32.9(d) ,32.1(t),31.0(t),26.4(s),23.0(s),21.2(s),19.2(s),18.7(s),13.6(s).

[0302] Example 202: 6-Isopentyl-1,4,4,8-tetramethyloctahydro-2H-benzo[d][1,3]oxazine A flask was charged with 40 mg Pd / C (10%), 1,3,3,7-tetramethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole (325 mg, 1.25 mmol), and methanol (50 mL). The reaction mixture was stirred overnight at room temperature under hydrogen gas. The reaction mixture was filtered and washed with MTBE (50 mL). The filtrate was concentrated to give the crude product. Flash chromatography (hexane / MTBE = 4:1 to 1:1) afforded the title product (88 mg, 0.33 mmol, 26% yield) as a colorless oil. GC / MS(EI):m / z(%):267(8)[M + ],252(7),208(2),194(2),140(100),110(14),95(6),81(3),67(3). 1 H NMR(300MHz,CDCl3)δ4.65(d,J=10.8Hz,1H),4.22(d,J=10.8Hz,1H),2.49-2.22(m,4H),1.7 9-1.54(m,3H),1.52-1.36(m,2H),1.28-1.06(m,11H),0.97-0.79(m,9H),0.76-0.47(m,2H). 13 C NMR(75MHz,CDCl3)δ81.2(d),74.6(q),63.8(t),41.6(d),40.5(t),37.1(t),36.3(d),34. 9(d),34.0(d),33.9(t),32.8(s),29.1(s),28.4(t),22.8(s),22.7(s),18.6(s),18.6(s).

[0303] In the same reaction, an additional product was isolated: 2-(5-isopentyl-3-methyl-2-(methylamino)cyclohexyl)propan-2-ol (178 mg, 0.66 mmol, 52% yield) as a colorless oil. GC / MS(EI):m / z(%):255(12)[M + ],240(10),128(34),110(25),84(100),70(15),59(7).

[0304] Example 203: 6-Isopentyl-1,4,4,8-tetramethyloctahydro-2H-benzo[d][1,3]oxazin-2-one A mixture of 2-(5-isopentyl-3-methyl-2-(methylamino)cyclohexyl)propan-2-ol (556 mg, 2.18 mmol) and di(1H-imidazol-1-yl)methanone (459 mg, 2.83 mmol) in 1,2-dichloroethane (40 mL) was stirred at room temperature under Ar for 5 min. The mixture was heated to 80 °C under Ar overnight, and the reaction was monitored by GC and GC-MS. After cooling to room temperature, the reaction mixture was filtered, and the filter was washed with MTBE. The combined filtrates were concentrated in vacuo to give the crude product, which was purified by flash chromatography (PE:MTBE = 1:2) to afford 6-isopentyl-1,4,4,8-tetramethyloctahydro-2H-benzo[d][1,3]oxazin-2-one (485 mg, 75% yield) as a white solid. GC / MS(EI):m / z(%):281(13)[M + ],238(2),222(22),194(7),154(40),126(3),110(100),84(25),55(9). 1 H NMR(300MHz,CDCl3)δ2.98(s,3H),2.52(t,J=9.9Hz,1H),1.78-1.50(m,4H),1.48-1 .29(m,2H),1.24(s,3H),1.19-1.00(m,10H),0.83-0.73(m,7H),0.72-0.56(m,1H). 13 C NMR(75MHz,CDCl3)δ155.5(q),79.2(q),65.0(t),49.1(t),42.9(d),40.0(t),38.2(s),37. 1(t),36.1(d),34.3(d),33.4(d),28.1(t),27.2(s),22.5(s),22.4(s),22.3(s),20.4(s).

[0305] Example 204: rac-(3aR,5R,7S,7aR)-5-isopentyl-1-isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: 4-isopentyl-2,4,7-trimethyloct-6-enal (1.317 g, 4.47 mmol), N-isopropylhydroxylamine (0.504 g, 6.71 mmol) in xylene (50 mL) at reflux temperature gave the title product (438 mg, 31% yield) as a colorless oil. GC / MS(EI):m / z(%):295(12)[M + ],280(100),154(53),128(14),109(11),95(11),69(10),55(10). 1 H NMR(300MHz,CDCl3)δ3.31-3.00(m,1H),2.35-2.20(m,1H),2.18-2.05(m,1H),1.92-1.49(m,3H) ,1.47-1.35(m,1H),1.33-1.24(m,2H),1.23-1.09(m,9H),1.09-0.95(m,7H),0.94-0.78(m,12H). 13 C NMR(75MHz,CDCl3)δ78.1(q),69.5(d),54.8(d),52.7(d),47.1(t),43.7(t),36.4(t),34.2(q) ,33.0(d),32.6(t),28.9(d),27.1(s),26.2(s),24.2(s),23.6(s),22.8(d),22.4(s),20.4(s).

[0306] Example 205: rac-(3aR,5S,7aR)-1,3,3,5-tetramethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole Following the general procedure described in Example 81b: reaction of 4,7-dimethyl-4-(3-methylbut-2-en-1-yl)oct-6-enal (0.589 g, 2.145 mmol) (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride (0.269 g, 3.22 mmol), KCO (0.237 g, 1.716 mmol) in toluene (50 mL) gave the title product (165 mg, 28% yield) as a pale yellow oil. GC / MS(EI):m / z(%):251(55)[M +],236(100),180(18),166(23),139(21),124(56),86(69),69(26),55(17). 1 H NMR(300MHz,CDCl3)δ5.14(t,J=7.2Hz,1H),2.59(s,3H),2.15-1.92(m,2H),1.88(d,J=7.5Hz,2H) ,1.72-1.58(m,4H),1.54(s,3H),1.48-1.35(m,2H),1.32-1.08(m,6H),1.02(s,3H),0.83(s,3H). 13 C NMR(75MHz,CDCl3)δ133.4(q),120.3(d),79.4(q),72.4(d),52.7(d),44.7(q),43.6( t),35.9(t),35.4(t),27.81(s),26.11(s),25.02(s),24.9(t),22.97(s),17.93(s).

[0307] Example 206: 5-(2,5-dimethoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole The title compound was prepared following the general procedure described in Example 81b: reaction of 4-(2,5-dimethoxyphenyl)-2,4,7-trimethyloct-6-enal (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride, and K2CO3 in toluene gave the title product (a mixture of two diastereomers) as a pale yellow oil. GC / MS (isomer 1) (EI): m / z (%): 333 (55) [M + ],246(75),178(100),163(21),151(17),138(25),126(23),96(8). GC / MS (isomer 2) (EI): m / z (%): 333 (30) [M + ],246(36),178(100),163(25),151(19),138(15),126(45),96(20).

[0308] Example 207: rac-(3aR,5R,7S,7aR)-1,3,3,5,7-pentamethyl-5-(m-tolyl)octahydrobenzo[c]isoxazole The title compound was prepared following the general procedure described in Example 81b: reaction of 2,4,7-trimethyl-4-(m-tolyl)oct-6-enal (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride, and K2CO3 in toluene gave the title product as a pale yellow oil. GC / MS(EI):m / z(%):287(1)[M + ],195(35),180(44),184(20),157(12),132(100),126(35),117(22),105(20),91(23).

[0309] Example 208: rac-(3aR,5R,7S,7aR)-1-isopropyl-5-(6-methoxypyridin-2-yl)-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole The title compound was prepared according to the general procedure described in Example 81b: reaction of 4-(6-methoxypyridin-2-yl)-2,4,7-trimethyloct-6-enal (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a) and N-isopropylhydroxylamine in toluene gave the title product as a pale yellow oil. GC / MS(EI):m / z(%):332(16)[M + ],317(28),259(29),231(52),150(89),125(100),110(82),84(20).

[0310] Example 209: 5-(2,4-dimethoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole The title compound was prepared following the general procedure described in Example 81b: reaction of 4-(2,4-dimethoxyphenyl)-2,4,7-trimethyloct-6-enal (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride, and K2CO3 in toluene gave the title product (a mixture of two diastereomers) as a pale yellow oil. GC / MS (isomer 1) (EI): m / z (%): 333 (52) [M + ],246(50),178(100),163(53),151(27),138(55),126(15),108(42). GC / MS (isomer 2) (EI): m / z (%): 333 (2) [M + ], 195(90), 180(100), 178(60), 163(40), 151(23), 138(19), 126(12).

[0311] Example 210: 2-Methyl-3-(1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile The title compound was prepared following the general procedure described in Example 81b: reaction of 2-methyl-3-(2,4,7-trimethyl-1-oxooct-6-en-4-yl)benzonitrile (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride, and K2CO3 in toluene gave the title product (a mixture of two diastereomers) as a pale yellow oil. GC / MS (isomer 1) (EI): m / z (%): 312 (56) [M + ],210(20),144(32),126(100),113(32),98(55),87(95),68(27). GC / MS (isomer 2) (EI): m / z (%): 312 (52) [M + ],210(14),144(25),126(100),113(18),98(35),87(56),68(25).

[0312] Example 211: rac-(3aR,5R,7S,7aR)-5-(3,5-dimethoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole The title compound was prepared following the general procedure described in Example 81b: reaction of 4-(3,5-dimethoxyphenyl)-2,4,7-trimethyloct-6-enal (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride, and K2CO3 in toluene gave the title product as a pale yellow oil. GC / MS(EI):m / z(%):333(42)[M + ],246(100),231(32),204(44),178(83),165(15),139(22),126(28).

[0313] Example 212: 1,3,3,5,7-pentamethyl-5-(pyridin-3-yl)octahydrobenzo[c]isoxazole The title compound was prepared following the general procedure described in Example 81b: reaction of 2,4,7-trimethyl-4-(pyridin-3-yl)oct-6-enal (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride, and K2CO3 in toluene gave the title product (mixture of three diastereomers) as a pale yellow oil. GC / MS (isomer 1) (EI): m / z (%): 274 (55) [M + ],257(45),228(14),120(100),98(37),87(14),70(12). GC / MS (isomer 2) (EI): m / z (%): 274 (15) [M + ],273(69),228(12),120(100),98(18),91(12),68(22). GC / MS (isomer 3) (EI): m / z (%): 274 (5) [M + ],273(30),228(12),187(65),149(32),120(100),98(20).

[0314] Example 213: rac-(3aR,5R,7S,7aR)-5-(4-fluoro-2-methoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole The title compound was prepared following the general procedure described in Example 81b: reaction of 4-(4-fluoro-2-methoxyphenyl)-2,4,7-trimethyloct-6-enal (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride, and K2CO3 in toluene gave the title product (mixture of three diastereomers) as a white solid. GC / MS(EI):m / z(%):321(70)[M + ],219(14),180(18),153(32),139(30),126(100),100(40),87(45).

[0315] Example 214: rac-(3aR,5R,7S,7aR)-5-(2,6-dimethylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole The title compound was prepared following the general procedure described in Example 81b: reaction of 4-(2,6-dimethylphenyl)-2,4,7-trimethyloct-6-enal (obtained from the corresponding α,β-unsaturated aldehyde using the general procedure described in Example 81a), N-methylhydroxylamine hydrochloride, and K2CO3 in toluene gave the title product as a yellow oil. GC / MS(EI):m / z(%):301(1)[M + ],300(10),214(18),195(49),180(28),146(100),126(36),96(15).

[0316] Example 4: Assay for TRPM8 modulators A HEK293 cell line stably expressing hTRPM8 was generated according to Klein et al. (Chem. Senses 36:649-658, 2011), and receptor activation was monitored by calcium imaging in a Flexstation. For Ca imaging assays of TRPM8 channel activation, cells were seeded at a density of 12,000 cells per well in Dulbecco's Modified Eagle's Medium (DMEM) containing 9% fetal bovine serum in black, clear-bottom 96-well plates coated with 0.001% polyethyleneimine (molecular weight = 60,000, Acros Organics) on day 0. On day 2, agonists were assessed via calcium imaging using Fluo-4. Briefly, growth medium was discarded, and cells were incubated in 50 μL loading buffer containing 2.7 μM Fluo-4 AM (Invitrogen) and 2.5 μM probenecid (Sigma-Aldrich) in DMEM (without serum) for 1 h at 37°C in the dark. After incubation, plates were washed five times with 100 μL assay buffer (in mM: 130 NaCl, 5 KCl, 10 HEPES, 2 CaCl, and 10 glucose, pH 7.4) and further incubated at room temperature for 30 min in the dark. Cells were then washed five times with 100 μL assay buffer, and calcium influx to serial dilutions of compounds of the present invention was measured on a Flexstation 3 (Molecular Devices). Receptor activation was initiated following the addition of 20 μL of a 10x concentrated ligand stock solution (also prepared in assay buffer). Fluorescence was continuously monitored for 15 seconds prior to and 105 seconds after ligand addition (120 seconds total). Maximal receptor activation was determined relative to the solvent control and relative to 31.6 μM menthol. Data from the serial dilutions were processed with the KNIME workflow to fit a sigmoidal dose-response curve to estimate EC50 values.

[0317] TRPM8 agonists exhibiting EC50 values ​​below 35 μM are presented in Table 1 below. Table 1:

Table 1-1

[0318]

Table 1-2

[0319]

Table 1-3

[0320]

Table 1-4

[0321]

Table 1-5

[0322]

Table 1-6

[0323]

Table 1-7

[0324]

Table 1-8

[0325]

Table 1-9

[0326]

Table 1-10

[0327] Example 5: Sensory studies in aqueous solutions The compounds as listed in Table 2 below were dissolved in propylene glycol at a concentration of 1 wt-%. Appropriate aliquots of these solutions were then dispensed into deionized water containing 0.5 wt-% Poloxamer 407 (a hydrophilic non-ionic surfactant, e.g., commercially available from Sigma-Aldrich) and 0.25 wt-% Cremaphor® RH40 (obtained from BASF) as solubilizers to obtain the desired final concentration of each compound of 40 ppm (parts per million).

[0328] A group of trained panelists evaluated aqueous solutions containing the test compounds by rapidly holding 20 mL of the solution in their mouths (for 60 seconds) and then expectorating it, without rinsing their mouths between evaluations. Panelists rated and recorded cooling performance and other sensory and organoleptic attributes at different time points over a 2-hour period. Cooling performance was assessed on a scale of 0 to 10, with 0 being no effect and 10 being extremely freezing. The ratings were averaged across all panelists, and cooling intensity was considered as "None" (on a scale of 0), "Low" (on a scale above 0, up to 1), "Medium" (on a scale above 1, up to 4), "Strong" (on a scale above 4, up to 8), and "E" (on a scale above 8). These are presented in Table 2. None of the tested compounds exhibited any statistically significant bitterness or negative organoleptic characteristics. All samples tested produced a cooling sensation that began during ingestion (almost immediately upon contact with mucous membrane) and continued until exhalation.

[0329] Table 2: [Table 2-1]

[0330] [Table 2-2]

[0331] Example 6: Sensory study on model toothpaste The compounds listed in Table 3 were dissolved in propylene glycol at a concentration of 1 wt-%. Appropriate aliquots of these solutions were then dispensed into model unflavored dentifrices to give the desired final concentration of test compound of 100 ppm (parts per million), the recipe for which is given below (each ingredient was obtained from the supplier indicated in parentheses).

[0332] [Table 3]

[0333] A group of trained panelists evaluated dentifrices containing a compound of formula (I) by brushing their teeth with 1 g of the dentifrice for 60 seconds using a toothbrush, then spitting it out, without rinsing their mouths between evaluations. The panelists rated and recorded cooling performance and other sensory and organoleptic attributes at different time points over a 2-hour period. Cooling performance was assessed on a scale of 0 to 10, with 0 being no effect and 10 being extremely freezing. The ratings were averaged across all panelists, and cooling intensity was considered as "None" (scale of 0), "Low" (scale above 0, up to 1), "Moderate" (scale above 1, up to 4), "Strong" (scale above 4, up to 8), and "Extreme" (scale above 8). These are summarized in Table 3 below. None of the tested compounds exhibited any statistically significant bitterness or negative organoleptic characteristics. All samples tested produced a cooling sensation that began during the swallow (almost immediately upon contact with the mucous membrane) and continued until exhalation.

[0334] Table 3: [Table 4]

Claims

1. A method (excluding therapeutic methods) for activating transient receptor potential channel melastatin member 8 (TRPM8), comprising activating said receptor with a compound of formula (Ia): 【Chemical 1】 During the ceremony X is CH; R 3 is hydrogen, C 1 ~C 6 Alkyl, C substituted with one or two OH groups 1 ~C 7 Alkyl, C 3 ~C 7 Cycloalkyl, C substituted with one or two OH groups 3 ~C 7 Cycloalkyl, C 5 ~C 7 Cycloalkenyl, 1, 2, or 3 C 1 ~C 3 Alkyl-substituted C 5 ~C 7 cycloalkenyl, and phenyl; R 1 is selected from: C 1 ~C 6 Alkyl, C substituted with one or two OH groups 1 ~C 7 Alkyl, C 3 ~C 7 alkenyl, Phenyl (optionally halogen, C≡N, NO 2 , C 1 ~C 6 Alkyl, C containing up to 5 halogen atoms 1 ~C 6 Alkyl, C 1 ~C 6 Alkyloxy, C containing up to 5 halogen atoms 1 ~C 6 Alkyloxy, C 3 ~C 7 Cycloalkyl, -C(O)OR 10 (where R 10 is hydrogen and C 1 ~C 3 alkyl), and -SR 11 (where R 11 is hydrogen and C 1 ~C 3 alkyl), Naphthyl (optionally halogen, C≡N, NO 2 , C 1 ~C 6 Alkyl, C containing up to 5 halogen atoms 1 ~C 6 Alkyl, C 1 ~C 6 Alkyloxy, C containing up to 5 halogen atoms 1 ~C 6 Alkyloxy, C 3 ~C 7 Cycloalkyl, -C(O)OR 10 (where R 10 is hydrogen and C 1 ~C 3 alkyl), and -SR 11 (where R 11 is hydrogen and C 1 ~C 3 alkyl), and C 5 ~C 10 monocyclic or bicyclic aryl of the formula (wherein one or two C atoms are replaced by heteroatoms independently selected from sulfur, nitrogen and oxygen, and optionally halogen, C≡N, NO 2 , C 1 ~C 6 Alkyl, C containing up to 5 halogen atoms 1 ~C 6 Alkyl, C 1 ~C 6 Alkyloxy, C containing up to 5 halogen atoms 1 ~C 6 Alkyloxy, C 3 ~C 7 Cycloalkyl, -C(O)OR 10 (where R 10 is hydrogen and C 1 ~C 3 alkyl), and -SR 11 (where R 11 is hydrogen and C 1 ~C 3 alkyl); R 2 is selected from hydrogen and methyl; R 4 , R 5 , and R 7 are independently hydrogen and C 1 ~C 6 selected from alkyl; R 6 is hydrogen, C 1 ~C 6 Alkyl, and C 3 ~C 7 selected from cycloalkyl; R 8 and R 9 are independently hydrogen, and C 1 ~C 6 alkyl; or R 8 and R 9 together with the C atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl ring; A compound represented by 1,3,3,6-tetramethyloctahydrobenzo[c]isoxazole, 1,3,3-trimethyl-6-(4-methylcyclohex-3-en-1-yl)octahydrobenzo[c]isoxazole, 6-Isopentyl-1,4,4,8-tetramethyloctahydro-2H-benzo[d][1,3]oxazin-2-one, 6-isopentyl-1,4,4,8-tetramethyloctahydro-2H-benzo[d][1,3]oxazine, rac-(3aR,7aR)-1,3,3-trimethyl-6-phenyloctahydrobenzo[c]isoxazole, rac-(3aR,7S,7aR)-5,5-diethyl-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole, A compound selected from the group consisting of: The method comprises bringing the compound into contact with

2. The compound has the formula R 3 But hydrogen, C 1 ~C 6 Alkyl, C substituted with one or two OH groups 1 ~C 7 Alkyl, C 3 ~C 7 Cycloalkyl, C substituted with one or two OH groups 3 ~C 7 Cycloalkyl, C 5 ~C 7 Cycloalkenyl, 1, 2, or 3 C 1 ~C 3 Alkyl-substituted C 5 ~C 7 2. The method of claim 1, wherein the compound is a compound of formula (Ia), or a salt or solvate thereof, selected from cycloalkenyl, and phenyl.

3. The compounds are 4-methyl-3-(1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile; 4-methoxy-3-(1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile; 1-ethyl-5-(2-methoxyphenyl)-3,3,7-trimethyloctahydrobenzo[c]isoxazole; 5-(2-methoxyphenyl)-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole; 5-(3,5-difluorophenyl)- 1,3,3,5,7-Pentamethyloctahydrobenzo[c]isoxazole;1,3,3,5,7-Pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;1,3,3,5,7-Pentamethyl-5-(o-tolyl)octahydrobenzo[c]isoxazole;5-(5-chloro-2-methylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;3-(1-Isopropyl-3,3,7-trimethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile 5-(2,5-dimethylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;3-(1-ethyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazol-5-yl)-4-methylbenzonitrile;5-(5-fluoro-2-methylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;1-Isopropyl-5-(2-methoxyphenyl)-3,3,7-trimethyloctahydrobenzo[c]isoxazole 3-chloro-5-(1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;3-(1-isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;5-(3,4-difluorophenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;3-(1-isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazol-5-yl)-4-methylbenzonitrile;5-(2-Methoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;2-Methyl-5-(1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;Methyl 4-methyl-3-(1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzoate;1-Isopropyl-3,3,5,7-tetramethyl-5-(o-tolyl)octahydrobenzo[c]isoxazole;5-(3-Fluorophenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;1,3,3,5,7-Pentamethyl-5-phenyloctahydrobenzo[c]isoxazole; 1-Isopropyl-3,3,7-trimethyl-5-phenyloctahydrobenzo[c]isoxazole;5-(4-chloro-2-methylphenyl)-1-isopropyl-3,3,7-trimethyloctahydrobenzo[c]isoxazole;5-(2,4-dimethylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;5-(4-fluoro-2-methylphenyl)-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole ]isoxazole;5-(2,5-difluorophenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;1-Ethyl-3,3,5,7-tetramethyl-5-phenyloctahydrobenzo[c]isoxazole;1,3,3,5,7-pentamethyl-5-(p-tolyl)octahydrobenzo[c]isoxazole;1-Isopropyl-3,3,5,7-tetramethyl-5-phenyloctahydrobenzo[c]isoxazole 1,3,3,7-Tetramethyl-5-phenyloctahydrobenzo[c]isoxazole;1-Isopropyl-5-(2-methoxyphenyl)-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole;5-(2-Fluorophenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;4-(1,3,3,5,7-Pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;3-Methyl-4-(1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;5-(2,4-difluorophenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;5-(2,5-dimethoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;5-(2,3-dimethylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;1,3,3,5,7-pentamethyl-5-(2,4, 5-(3-Chloro-2-methylphenyl)octahydrobenzo[c]isoxazole;1,3,3,5,7-Pentamethyl-5-(4-(methylthio)phenyl)octahydrobenzo[c]isoxazole;2-(1,3,3,5,7-Pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;5-(3-Methoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;5-(3-Chloro-2-methylphenyl)-1-isopropyl-3,3,7-trimethyloctahydrobenzo[c]isoxazole Oxazole;1,3,3,5,7-Pentamethyl-5-(naphthalen-2-yl)octahydrobenzo[c]isoxazole;5-(2,4-Dimethylphenyl)-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole;4-Methyl-3-(1,3,3,7-tetramethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;1,3,3,7-Tetramethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole;5-(2-Ethylphenyl)-1,3,3,5, 7-Pentamethyloctahydrobenzo[c]isoxazole;1,3,3,5,7-Pentamethyl-5-(m-tolyl)octahydrobenzo[c]isoxazole;1,3,3,5,7-Pentamethyl-5-(5-methylthiophen-3-yl)octahydrobenzo[c]isoxazole;1-Ethyl-3,3,7-trimethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole;5-(2-Ethylphenyl)-1-isopropyl-3,3,7-trimethyloctahydrobenzo[c]isoxazole;1,3,3,5,7-Pentamethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole;5-(2,6-dimethylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;5-(benzo[d][1,3]dioxol-5-yl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;1-Isopropyl-5-(6-methoxypyridin-2-yl)-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole;5-(5 -Chloro-2-methylphenyl)-1-isopropyl-3,3,7-trimethyloctahydrobenzo[c]isoxazole;5-Butyl-1,3,3-trimethyloctahydrobenzo[c]isoxazole;5-(2,4-Dimethoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;1-Isopropyl-3,3,7-trimethyl-5-(o-tolyl)octahydrobenzo[c]isoxazole;1-Isopropyl-3,3,7-trimethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole;1-Isopropyl-3,3,7-trimethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole Hydrobenzo[c]isoxazole;5-(5-fluoro-2-methylphenyl)-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole;5-(3,5-dimethylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;1-Isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole;1,3,3-Trimethyl-6-(4-methylcyclohex-3-en-1-yl)octahydrobenzo[c]isoxazole;5-(3-fluoro-5-(trifluorophenyl)-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole 1-Isopropyl-3,3-dimethyl-5-propyloctahydrobenzo[c]isoxazole;1,3,3-Trimethyl-5-pentyloctahydrobenzo[c]isoxazole;1-Ethyl-3,3,5,7-tetramethyl-5-(o-tolyl)octahydrobenzo[c]isoxazole;5-(3,5-Dimethylphenyl)-1-isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole;5-(2,5-Dimethylphenyl)-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole;5,7-Diethyl-1-isopropyl-3,3-dimethyloctahydrobenzo[c]isoxazole;1,3,3,5,7-Pentamethyl-5-(2-methyl-5-(trifluoromethyl)phenyl)octahydrobenzo[c]isoxazole;1-Ethyl-3,3-dimethyl-5-propyloctahydrobenzo[c]isoxazole;1,3,3,5,7-Pentamethyl-5-propyloctahydrobenzo[c ]isoxazole;1,3,3-Trimethyl-5-propyloctahydrobenzo[c]isoxazole;2-Methyl-3-(1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;1,3,3,7-Tetramethyl-5-(o-tolyl)octahydrobenzo[c]isoxazole;5-Butyl-1-ethyl-3,3-dimethyloctahydrobenzo[c]isoxazole;5-(4-Fluorophenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole 5-(2-Ethoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;5-(3-chloro-2-methylphenyl)-1,3,3,5 ,7-Pentamethyloctahydrobenzo[c]isoxazole;5-(6-methoxypyridin-2-yl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;1,3,3,5,7-pentamethyl-5-(5-methylthiophen-2-yl)octahydrobenzo[c]isoxazole;1,3,3,5,7-pentamethyl-5-(4-methylpyridin-3-yl)octahydrobenzo[c]isoxazole;1-Ethyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole;5-(2-Ethylphenyl)-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole;5-Butyl-1-isopropyl-3,3-dimethyloctahydrobenzo[c]isoxazole;1-Ethyl-3,3,5,7-tetramethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole;5-(4-Fluoro-2-methylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;1-Isopropyl-5,7-dimethylhexahydro-1H-spiro[benzyl]isoxazole 1,5,7-Triethyl-3,3-dimethyloctahydrobenzo[c]isoxazole;1-Isopropyl-3,3,5,7-tetramethyl-5-propyloctahydrobenzo[c]isoxazole;6-Isopentyl-1,4,4,8-tetramethyloctahydro-2H-benzo[d][1,3]oxazine;5-(3,5-Dimethoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;5,7-Diethyl-1,3,3-trimethylocta Hydrobenzo[c]isoxazole;1-Isopropyl-5-(4-methoxyphenyl)-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole;5-(3-Isopropylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;1,3,3-Trimethyl-6-phenyloctahydrobenzo[c]isoxazole;5-Ethyl-1-isopropyl-3,3-dimethyloctahydrobenzo[c]isoxazole;1,3,3,5,7-Pentamethyl-5-(2-(methylthio)phenyl)octahydrobenzo[c]isoxazole )Octahydrobenzo[c]isoxazole;1,5,7-trimethylhexahydro-1H-spiro[benzo[c]isoxazole-3,1'-cyclopentane];5-ethyl-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;5-(4-methoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;1,3,3,4,5,7-hexamethyloctahydrobenzo[c]isoxazole;1,3,3,5,7-Pentamethyl-5-(pyridin-3-yl)octahydrobenzo[c]isoxazole;1,3,3,5,7-Pentamethyloctahydrobenzo[c]isoxazole hydrochloride;5-(4-Fluoro-2-methoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;5-(4-Fluorophenyl)-1-isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole;4-Methyl-2-(1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;1,3,3,5- Tetramethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole;6-Isopentyl-1,4,4,8-tetramethyloctahydro-2H-benzo[d][1,3]oxazin-2-one;1-Isopropyl-3,3,5,7-tetramethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole;5-Isopentyl-1-isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole;2-Chloro-5-(1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzyl; 5-(4-(tert-butyl)phenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole; 5-(4-(tert-butyl)phenyl)-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole; 5-(4-(tert-butyl)phenyl)-1-isopropyl-3,3,7-trimethyloctahydrobenzo[c]isoxazole; and 1,3,3,6-tetramethyloctahydrobenzo[c]isoxazole, or a salt or solvate thereof.

4. A method (excluding therapeutic methods) of inducing a cooling sensation in a human or animal, comprising contacting said human or animal with a compound as defined in any one of claims 1 to 3, or a salt or solvate thereof.

5. A method (excluding therapeutic methods) for exerting a cooling effect on the skin or mucous membranes, comprising contacting the skin or mucous membranes with a product comprising a compound as defined in any one of claims 1 to 3.

6. A consumer product comprising one or more compounds as defined in any one of claims 1 to 3.

7. A pharmaceutical composition comprising one or more compounds as defined in any one of claims 1 to 3.

8. A composition for providing a cooling sensation, the composition comprising a compound represented by formula (Ia) 【Chemistry 2】 During the ceremony X is CH; R 3 is hydrogen, C 1 ~C 6 Alkyl, C substituted with one or two OH groups 1 ~C 7 Alkyl, C 3 ~C 7 Cycloalkyl, C substituted with one or two OH groups 3 ~C 7 Cycloalkyl, C 5 ~C 7 Cycloalkenyl, 1, 2, or 3 C 1 ~C 3 Alkyl-substituted C 5 ~C 7 cycloalkenyl, and phenyl; R 1 is selected from: C 1 ~C 6 Alkyl, C substituted with one or two OH groups 1 ~C 7 Alkyl, C 3 ~C 7 alkenyl, Phenyl (optionally halogen, C≡N, NO 2 , C 1 ~C 6 Alkyl, C containing up to 5 halogen atoms 1 ~C 6 Alkyl, C 1 ~C 6 Alkyloxy, C containing up to 5 halogen atoms 1 ~C 6 Alkyloxy, C 3 ~C 7 Cycloalkyl, -C(O)OR 10 (where R 10 is hydrogen and C 1 ~C 3 alkyl), and -SR 11 (where R 11 is hydrogen and C 1 ~C 3 alkyl), Naphthyl (optionally halogen, C≡N, NO 2 , C 1 ~C 6 Alkyl, C containing up to 5 halogen atoms 1 ~C 6 Alkyl, C 1 ~C 6 Alkyloxy, C containing up to 5 halogen atoms 1 ~C 6 Alkyloxy, C 3 ~C 7 Cycloalkyl, -C(O)OR 10 (where R 10 is hydrogen and C 1 ~C 3 alkyl), and -SR 11 (where R 11 is hydrogen and C 1 ~C 3 alkyl), and C 5 ~C 10 monocyclic or bicyclic aryl, wherein one or two C atoms are independently replaced by a heteroatom selected from sulfur, nitrogen, and oxygen, and optionally, halogen, C≡N, NO 2 , C 1 ~C 6 Alkyl, C containing up to 5 halogen atoms 1 ~C 6 Alkyl, C 1 ~C 6 Alkyloxy, C containing up to 5 halogen atoms 1 ~C 6 Alkyloxy, C 3 ~C 7 Cycloalkyl, -C(O)OR 10 (where R 10 is hydrogen and C 1 ~C 3 alkyl), and -SR 11 (where R 11 is hydrogen and C 1 ~C 3 alkyl); R 2 is selected from hydrogen and methyl; R 4 , R 5 , and R 7 are independently hydrogen and C 1 ~C 6 selected from alkyl; R 6 is hydrogen, C 1 ~C 6 Alkyl, and C 3 ~C 7 selected from cycloalkyl; R 8 and R 9 are independently hydrogen, and C 1 ~C 6 alkyl; or R 8 and R 9 together with the C atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl ring; A compound represented by 1,3,3,6-tetramethyloctahydrobenzo[c]isoxazole, 1,3,3-trimethyl-6-(4-methylcyclohex-3-en-1-yl)octahydrobenzo[c]isoxazole, 6-Isopentyl-1,4,4,8-tetramethyloctahydro-2H-benzo[d][1,3]oxazin-2-one, 6-isopentyl-1,4,4,8-tetramethyloctahydro-2H-benzo[d][1,3]oxazine, rac-(3aR,7aR)-1,3,3-trimethyl-6-phenyloctahydrobenzo[c]isoxazole, rac-(3aR,7S,7aR)-5,5-diethyl-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole, The composition comprising a compound selected from the group consisting of:

9. Formula (Ia) 【Chemistry 3】 During the ceremony X is CH; R 3 is hydrogen, C 1 ~C 6 Alkyl, C substituted with one or two OH groups 1 ~C 7 Alkyl, C 3 ~C 7 Cycloalkyl, C substituted with one or two OH groups 3 ~C 7 Cycloalkyl, C 5 ~C 7 Cycloalkenyl, 1, 2, or 3 C 1 ~C 3 Alkyl-substituted C 5 ~C 7 cycloalkenyl, and phenyl; R 1 is selected from: C 1 ~C 6 Alkyl, C substituted with one or two OH groups 1 ~C 7 Alkyl, C 3 ~C 7 alkenyl, Phenyl (optionally halogen, C≡N, NO 2 , C 1 ~C 6 Alkyl, C containing up to 5 halogen atoms 1 ~C 6 Alkyl, C 1 ~C 6 Alkyloxy, C containing up to 5 halogen atoms 1 ~C 6 Alkyloxy, C 3 ~C 7 Cycloalkyl, -C(O)OR 10 (where R 10 is hydrogen and C 1 ~C 3 alkyl), and -SR 11 (where R 11 is hydrogen and C 1 ~C 3 alkyl), Naphthyl (optionally halogen, C≡N, NO 2 , C 1 ~C 6 Alkyl, C containing up to 5 halogen atoms 1 ~C 6 Alkyl, C 1 ~C 6 Alkyloxy, C containing up to 5 halogen atoms 1 ~C 6 Alkyloxy, C 3 ~C 7 Cycloalkyl, -C(O)OR 10 (where R 10 is hydrogen and C 1 ~C 3 alkyl), and -SR 11 (where R 11 is hydrogen and C 1 ~C 3 alkyl), and C 5 ~C 10 monocyclic or bicyclic aryl of the formula (wherein one or two C atoms are replaced by heteroatoms independently selected from sulfur, nitrogen and oxygen, and optionally halogen, C≡N, NO 2 , C 1 ~C 6 Alkyl, C containing up to 5 halogen atoms 1 ~C 6 Alkyl, C 1 ~C 6 Alkyloxy, C containing up to 5 halogen atoms 1 ~C 6 Alkyloxy, C 3 ~C 7 Cycloalkyl, -C(O)OR 10 (where R 10 is hydrogen and C 1 ~C 3 alkyl), and -SR 11 (where R 11 is hydrogen and C 1 ~C 3 alkyl); R 2 is selected from hydrogen and methyl; R 4 , R 5 , and R 7 are independently hydrogen and C 1 ~C 6 selected from alkyl; R 6 is hydrogen, C 1 ~C 6 Alkyl, and C 3 ~C 7 selected from cycloalkyl; R 8 and R 9 are independently hydrogen, and C 1 ~C 6 alkyl; or R 8 and R 9 together with the C atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl ring; A compound represented by 1,3,3-trimethyl-6-(4-methylcyclohex-3-en-1-yl)octahydrobenzo[c]isoxazole, 6-Isopentyl-1,4,4,8-tetramethyloctahydro-2H-benzo[d][1,3]oxazin-2-one, 6-isopentyl-1,4,4,8-tetramethyloctahydro-2H-benzo[d][1,3]oxazine, rac-(3aR,7aR)-1,3,3-trimethyl-6-phenyloctahydrobenzo[c]isoxazole, rac-(3aR,7S,7aR)-5,5-diethyl-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole, or a salt or solvate thereof.

10. 4-Methyl-3-(1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;4-Methoxy-3-(1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;1-Ethyl-5-(2-methoxyphenyl)-3,3,7-trimethyloctahydrobenzo[c]isoxazole;5-(2-Methoxyphenyl)-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole;5-(3,5-Difluorophenyl)- 1,3,3,5,7-Pentamethyloctahydrobenzo[c]isoxazole;1,3,3,5,7-Pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;1,3,3,5,7-Pentamethyl-5-(o-tolyl)octahydrobenzo[c]isoxazole;5-(5-chloro-2-methylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;3-(1-Isopropyl-3,3,7-trimethyloctahydrobenzo[c]isoxazol-5-yl)- 4-Methoxybenzonitrile;5-(2,5-dimethylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;3-(1-ethyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazol-5-yl)-4-methylbenzonitrile;5-(5-fluoro-2-methylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;Isopropyl-5-(2-methoxyphenyl)-3,3,7-trimethyloctahydrobenzo[c]isoxazole Chloro-5-(1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;3-(1-Isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;5-(3,4-Difluorophenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;3-(1-Isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazol-5-yl)-4-methylbenzonitrile;5-(2-Methoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;2-Methyl-5-(1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;Methyl 4-methyl-3-(1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzoate;1-Isopropyl-3,3,5,7-tetramethyl-5-(o-tolyl)octahydrobenzo[c]isoxazole;5-(3-Fluorophenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;1,3,3,5,7-Pentamethyl-5-phenyloctahydrobenzo[c]isoxazole; 1-Isopropyl-3,3,7-trimethyl-5-phenyloctahydrobenzo[c]isoxazole;5-(4-chloro-2-methylphenyl)-1-isopropyl-3,3,7-trimethyloctahydrobenzo[c]isoxazole;5-(2,4-dimethylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;5-(4-fluoro-2-methylphenyl)-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole ]isoxazole;5-(2,5-difluorophenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;1-Ethyl-3,3,5,7-tetramethyl-5-phenyloctahydrobenzo[c]isoxazole;1,3,3,5,7-pentamethyl-5-(p-tolyl)octahydrobenzo[c]isoxazole;1-Isopropyl-3,3,5,7-tetramethyl-5-phenyloctahydrobenzo[c]isoxazole 1,3,3,7-Tetramethyl-5-phenyloctahydrobenzo[c]isoxazole;1-Isopropyl-5-(2-methoxyphenyl)-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole;5-(2-Fluorophenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;4-(1,3,3,5,7-Pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;3-Methyl-4-(1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;5-(2,4-difluorophenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;5-(2,5-dimethoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;5-(2,3-dimethylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;1,3,3,5,7-pentamethyl-5-(2,4, 5-(3-Chloro-2-methylphenyl)octahydrobenzo[c]isoxazole;1,3,3,5,7-Pentamethyl-5-(4-(methylthio)phenyl)octahydrobenzo[c]isoxazole;2-(1,3,3,5,7-Pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;5-(3-Methoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;5-(3-Chloro-2-methylphenyl)-1-isopropyl-3,3,7-trimethyloctahydrobenzo[c]isoxazole Oxazole;1,3,3,5,7-Pentamethyl-5-(naphthalen-2-yl)octahydrobenzo[c]isoxazole;5-(2,4-Dimethylphenyl)-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole;4-Methyl-3-(1,3,3,7-tetramethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;1,3,3,7-Tetramethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole;5-(2-Ethylphenyl)-1,3,3,5, 7-Pentamethyloctahydrobenzo[c]isoxazole;1,3,3,5,7-Pentamethyl-5-(m-tolyl)octahydrobenzo[c]isoxazole;1,3,3,5,7-Pentamethyl-5-(5-methylthiophen-3-yl)octahydrobenzo[c]isoxazole;1-Ethyl-3,3,7-trimethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole;5-(2-Ethylphenyl)-1-isopropyl-3,3,7-trimethyloctahydrobenzo[c]isoxazole;1,3,3,5,7-Pentamethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole;5-(2,6-dimethylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;5-(benzo[d][1,3]dioxol-5-yl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;1-Isopropyl-5-(6-methoxypyridin-2-yl)-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole;5-(5 -Chloro-2-methylphenyl)-1-isopropyl-3,3,7-trimethyloctahydrobenzo[c]isoxazole;5-Butyl-1,3,3-trimethyloctahydrobenzo[c]isoxazole;5-(2,4-Dimethoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;1-Isopropyl-3,3,7-trimethyl-5-(o-tolyl)octahydrobenzo[c]isoxazole;1-Isopropyl-3,3,7-trimethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole;1-Isopropyl-3,3,7-trimethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole Hydrobenzo[c]isoxazole;5-(5-fluoro-2-methylphenyl)-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole;5-(3,5-dimethylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;1-Isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole;1,3,3-Trimethyl-6-(4-methylcyclohex-3-en-1-yl)octahydrobenzo[c]isoxazole;5-(3-fluoro-5-(trifluorophenyl)-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole 1-Isopropyl-3,3-dimethyl-5-propyloctahydrobenzo[c]isoxazole;1,3,3-Trimethyl-5-pentyloctahydrobenzo[c]isoxazole;1-Ethyl-3,3,5,7-tetramethyl-5-(o-tolyl)octahydrobenzo[c]isoxazole;5-(3,5-Dimethylphenyl)-1-isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole;5-(2,5-Dimethylphenyl)-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole;5,7-Diethyl-1-isopropyl-3,3-dimethyloctahydrobenzo[c]isoxazole;1,3,3,5,7-Pentamethyl-5-(2-methyl-5-(trifluoromethyl)phenyl)octahydrobenzo[c]isoxazole;1-Ethyl-3,3-dimethyl-5-propyloctahydrobenzo[c]isoxazole;1,3,3,5,7-Pentamethyl-5-propyloctahydrobenzo[c ]isoxazole;1,3,3-Trimethyl-5-propyloctahydrobenzo[c]isoxazole;2-Methyl-3-(1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;1,3,3,7-Tetramethyl-5-(o-tolyl)octahydrobenzo[c]isoxazole;5-Butyl-1-ethyl-3,3-dimethyloctahydrobenzo[c]isoxazole;5-(4-Fluorophenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole 5-(2-Ethoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;5-(3-chloro-2-methylphenyl)-1,3,3,5 ,7-Pentamethyloctahydrobenzo[c]isoxazole;5-(6-methoxypyridin-2-yl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;1,3,3,5,7-pentamethyl-5-(5-methylthiophen-2-yl)octahydrobenzo[c]isoxazole;1,3,3,5,7-pentamethyl-5-(4-methylpyridin-3-yl)octahydrobenzo[c]isoxazole;1-Ethyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole;5-(2-Ethylphenyl)-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole;5-Butyl-1-isopropyl-3,3-dimethyloctahydrobenzo[c]isoxazole;1-Ethyl-3,3,5,7-tetramethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole;5-(4-Fluoro-2-methylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;1-Isopropyl-5,7-dimethylhexahydro-1H-spiro[benzyl]isoxazole 1,5,7-Triethyl-3,3-dimethyloctahydrobenzo[c]isoxazole;1-Isopropyl-3,3,5,7-tetramethyl-5-propyloctahydrobenzo[c]isoxazole;6-Isopentyl-1,4,4,8-tetramethyloctahydro-2H-benzo[d][1,3]oxazine;5-(3,5-Dimethoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;5,7-Diethyl-1,3,3-trimethylocta Hydrobenzo[c]isoxazole;1-Isopropyl-5-(4-methoxyphenyl)-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole;5-(3-Isopropylphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;1,3,3-Trimethyl-6-phenyloctahydrobenzo[c]isoxazole;5-Ethyl-1-isopropyl-3,3-dimethyloctahydrobenzo[c]isoxazole;1,3,3,5,7-Pentamethyl-5-(2-(methylthio)phenyl)octahydrobenzo[c]isoxazole )Octahydrobenzo[c]isoxazole;1,5,7-trimethylhexahydro-1H-spiro[benzo[c]isoxazole-3,1'-cyclopentane];5-ethyl-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;5-(4-methoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;1,3,3,4,5,7-hexamethyloctahydrobenzo[c]isoxazole;1,3,3,5,7-Pentamethyl-5-(pyridin-3-yl)octahydrobenzo[c]isoxazole;1,3,3,5,7-Pentamethyloctahydrobenzo[c]isoxazole hydrochloride;5-(4-Fluoro-2-methoxyphenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole;5-(4-Fluorophenyl)-1-isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole;4-Methyl-2-(1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;1,3,3,5-Tetramethyloctahydrobenzo[c]isoxazole 6-Isopentyl-1,4,4,8-tetramethyloctahydro-2H-benzo[d][1,3]oxazin-2-one;Isopropyl-3,3,5,7-tetramethyl-5-(3-methylbut-2-en-1-yl)octahydrobenzo[c]isoxazole;5-Isopentyl-1-isopropyl-3,3,5,7-tetramethyloctahydrobenzo[c]isoxazole;2-Chloro-5-(1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazol-5-yl)benzonitrile;5-(; 10. The compound of claim 9, which is selected from the group consisting of 4-(tert-butyl)phenyl)-1,3,3,5,7-pentamethyloctahydrobenzo[c]isoxazole; 5-(4-(tert-butyl)phenyl)-1,3,3,7-tetramethyloctahydrobenzo[c]isoxazole; and 5-(4-(tert-butyl)phenyl)-1-isopropyl-3,3,7-trimethyloctahydrobenzo[c]isoxazole, or a salt or solvate thereof.

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