The present invention provides a process of producing a trifluoromcthoxylated aryl or trifluoromothoxylated heteroaryl having the structure: ##STR00001##
wherein
A is an aryl or heteroaryl, each with or without substitution; and
R.sub.1 is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl).sub.2, —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl), comprising:
(a) reacting a compound having the structure: ##STR00002##
with a trifluoromethylating agent in the presence of a base in a first suitable solvent under conditions to produce a compound having the structure: ##STR00003##
and
(b) maintaining the compound produced in step (a) in a second suitable solvent under conditions sufficient to produce the trifluoromethoxylated aryl or trifluormethoxylated heteroaryl having the structure: ##STR00004##

The present invention provides a process of producing a trifluoromcthoxylated aryl or trifluoromothoxylated heteroaryl having the structure: ##STR00001##
wherein
A is an aryl or heteroaryl, each with or without substitution; and
R.sub.1 is —H, -(alkyl), -(alkenyl), -(alkynyl), -(aryl), -(heteroaryl), -(alkylaryl), -(alkylheteroaryl), —NH-(alkyl), —N(alkyl).sub.2, —NH-(alkenyl), —NH-(alkynyl) —NH-(aryl), —NH-(heteroaryl), —O-(alkyl), —O-(alkenyl), —O-(alkynyl), —O-(aryl), —O-(heteroaryl), —S-(alkyl), —S-(alkenyl), —S-(alkynyl), —S-(aryl), or —S-(heteroaryl), comprising:
(a) reacting a compound having the structure: ##STR00002##
with a trifluoromethylating agent in the presence of a base in a first suitable solvent under conditions to produce a compound having the structure: ##STR00003##
and
(b) maintaining the compound produced in step (a) in a second suitable solvent under conditions sufficient to produce the trifluoromethoxylated aryl or trifluormethoxylated heteroaryl having the structure: ##STR00004##

A method for producing a compound represented by formula (C) wherein R.sup.1 represents an amino group protected with a protecting group, the method comprising a step of subjecting a compound represented by formula (B) wherein R.sup.1 represents the same meaning as above, to intramolecular cyclization to convert the compound into the compound represented by formula (C). ##STR00001##

A method for producing a compound represented by formula (C) wherein R.sup.1 represents an amino group protected with a protecting group, the method comprising a step of subjecting a compound represented by formula (B) wherein R.sup.1 represents the same meaning as above, to intramolecular cyclization to convert the compound into the compound represented by formula (C). ##STR00001##

A method for producing a compound represented by formula (C) wherein R.sup.1 represents an amino group protected with a protecting group, the method comprising a step of subjecting a compound represented by formula (B) wherein R.sup.1 represents the same meaning as above, to intramolecular cyclization to convert the compound into the compound represented by formula (C). ##STR00001##

A method for producing a compound represented by formula (C) wherein R.sup.1 represents an amino group protected with a protecting group, the method comprising a step of subjecting a compound represented by formula (B) wherein R.sup.1 represents the same meaning as above, to intramolecular cyclization to convert the compound into the compound represented by formula (C).

##STR00001##

A method for producing a compound represented by formula (C) wherein R.sup.1 represents an amino group protected with a protecting group, the method comprising a step of subjecting a compound represented by formula (B) wherein R.sup.1 represents the same meaning as above, to intramolecular cyclization to convert the compound into the compound represented by formula (C).

##STR00001##

A method for producing a compound represented by formula (C) wherein R.sup.1 represents an amino group protected with a protecting group, the method comprising a step of subjecting a compound represented by formula (B) wherein R.sup.1 represents the same meaning as above, to intramolecular cyclization to convert the compound into the compound represented by formula (C).

##STR00001##

Bis(2-haloacetamido)-compounds for use as linkers to chemically cross-linking multiple thiol groups, and particularly, although not exclusively, the thiol groups of cysteine amino acids in peptide chains are described, along with their use as linking agents and resultant products which comprise antibodies, half-antibodies and antibody fragments having thiol groups bonded to said linkers (e.g. antibody-protein conjugates and antibody-drug conjugates), and methods of making said conjugates and products. (Formula I)

##STR00001##

Bis(2-haloacetamido)-compounds for use as linkers to chemically cross-linking multiple thiol groups, and particularly, although not exclusively, the thiol groups of cysteine amino acids in peptide chains are described, along with their use as linking agents and resultant products which comprise antibodies, half-antibodies and antibody fragments having thiol groups bonded to said linkers (e.g. antibody-protein conjugates and antibody-drug conjugates), and methods of making said conjugates and products. (Formula I)

##STR00001##