Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
  • B01L3/02—Burettes; Pipettes
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
  • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
  • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures

Definitions

• addition step reactions typically proceed by combining the partially-
• building blocks are often added in a molar excess to the partially synthesized compound present so
• thermodynamically favorable building block addition proceeds substantially to completion.
• a pharmaceutical lead-compound selection particular in the field of pharmaceutical lead-compound selection.
• compound for a drug is a compound which exhibits a particular biologic activity of pharmaceutical
• the pharmaceutical chemist can use combinatorial protocols to generate in the laboratory compounds
• split and mix split and recombine
• Kit Lam Lam et al. 1991
• Richard Houghten Haoughten et al.
• the split and mix method was developed on resin beads and those typically accommodate
• Another option is to apply a macroscopic modular support, introduced by M.H. Geysen
• phase particles into a one-dimensional string referred to as necklace coding phase particles into a one-dimensional string referred to as necklace coding.
• reaction vessels are conventional and
• temperatures may range from -100 to +200 ° C and reactions may take minutes or sometimes days
• reaction vessel is a threaded Teflon tube enclosed on
• reaction vessel arrays are sealed with various sealing means.
• reaction vessels can be tailored to withstand any rigorous reaction conditions (i.e. high or low
• Solid-phase combinatorial synthesis typically proceeds according to the following steps. In a first
• reaction vessels are charged with one or more solid-phase supports, and the first of the
• a sufficient quantity of a solution containing the building block moiety selected for addition is accurately added to the reaction vessels so that the building block moiety is present in a molar excess to the intermediate compound.
• the reaction is triggered and promoted by activating reagents and other reagents and solvents, which are also added to the reaction vessel.
• the reaction vessel is then incubated at a controlled temperature for a time, typically between
• reaction vessel can be intermittently agitated or stirred.
• reaction vessel containing the solid-phase support with attached intermediate compound is
• the final compound is present in the reaction vessel attached to the solid-phase support.
• the final compounds can be utilized either directly attached to their synthetic supports, or alternatively, can be cleaved from their supports. In the latter case, the linker moiety attaching the compound to the solid-phase support is cleaved, and the library compound is extracted.
• a necklace may be a string, wire, rod, or device inserted through aligned holes in each object set.
• a necklace may be a string, wire, rod, or device inserted through aligned holes in each object set.
• applicants have found that Lanterns packed into a tube provided handling advantages when compared to a string of Lanterns, particularly as a result of the Directed Sort Apparatus described in this disclosure.
• This invention relates to a sorting apparatus and method for directed sort combinatorial chemical synthesis; more particularly it relates to a directed flexible, sorting apparatus and method for combinatorial chemical synthesis using a directed split and recombine process.
• the process utilizes one algorithm that is universal in directing and sorting a library of any size.
• this invention provides a method sorting solid supports for combinatorial chemical synthesis comprising delivering one or more supports which are organized in a one dimensional linear array in one or more reaction vessels, to an isolation and transfer chamber, transferring one or more support from each of said reaction vessels to one or more subsequent reaction vessels, in a patterned distribution; wherein the patterned distribution of supports in each subsequent transfer is identical and the position of each support in a reaction vessel codes for its previous synthesis history.
• this invention provides a directed sort apparatus a directed sort apparatus for performing combinatorial solid phase synthesis of compounds comprising two or more first
• reaction vessels for holding one or more object sets organized in a first ordered pattern; an isolation and transfer chamber for directed redistribution of object sets from each of said reaction vessels to one or more subsequent reaction vessels for receiving object sets from the isolation and transfer chamber; and repeating steps for each building block added.
• the invention provides a directed sort apparatus for performing combinatorial solid phase synthesis of compounds comprising performing a reaction in each of one or more first reaction vessels for holding one or more object sets organized in a one dimensional linear array, and delivering to an isolated and transfer chamber for directed redistribution of object sets from each of said reaction vessels to one or more subsequent reaction vessels for receiving object sets from the isolation and transfer chamber; and repeating the steps for each building block added.
• the invention provides a directed sort apparatus wherein all members of an object set at a given point in time are reacted with the same chemical building blocks throughout synthesis.
• Directed sort combinatorial synthesis of this invention is a method for split and mix chemical synthesis.
• One compound per support or many compounds per support may be used to produce large amounts of each compound with great efficiency, simplicity, and speed.
• the solid supports can be delivered either for reaction in flow through tubes or for handling in microplates.
• the sort apparatus follows an algorithm that is universal in directing the sorting of any library regardless of size.
• a single support can be sorted at a time or multiple supports, "object sets", can be used to increase the scale/yield of each compound synthesized.
• the problem of lost chemical history due to mixing of individual supports after each combinatorial step is addressed by preserving the order of supports, e.g., as they are placed into the reaction vessels.
• the algorithm can be used to sort any object, including vessels for solution phase synthesis or even for sorting the control of valves for directing the addition of reagents to certain reaction vessels.
• Use of the single universal algorithm only requires the chemist to enter a library design (i.e. a number of steps and the number of building blocks in each step).
• a computer following the algorithm can then design the synthesis and the synthesis batch size. All building blocks can be validated allowing for increased quality control.
• Combinatorial chemistry synthesis protocols prescribe the stepwise, sequential addition of building blocks to intermediate partially-synthesized intermediate compounds in order to synthesize a final compound. These protocols are, generally, divided into liquid-phase protocols and solid-phase protocols. In liquid-phase protocols, final compounds are synthesized in solution. In solid-phase synthesis, final compounds are synthesized attached to solid-phase supports that permit the use of
• a preferred solid-phase support for the present invention includes
• synphase lanterns which may optionally be functionalized in order to covalently attach intermediate
• the directed sort combinatorial synthesis method provides a low cost alternative to radio tagging.
• the method combines the efficiency of the split mix approach with the simplicity of recording the
• this invention comprises other combination and sub-combinations of the
• Directed sort combinatorial synthesis can be accomplished
• an array of reaction vessels e.g. a 3-D array, e.g., ( Figure 8) is separated from the
• array can be constructed where, physically, the reaction vessels are not in an array, but are linked
• the receiving vessels fixed, the receiving vessels can be indexed and the delivery vessels remain fixed,
• isolation and transfer chamber can be replaced with valves or other
• support transport means such as the electromotive transport of supports in a microfluidic system.
• reaction vessels can be used instead, within which the reactions are carried out, such as
• Building block refers to any molecule that can be covalently attached to other molecules to
• the strategy consists of the systematic and repetitive covalent connection of structurally different
• Linker refers to a molecule or group of molecules covalently attached to the solid support on
• Linkers have different molecular structures
• Solid support refers to a material or group of materials having a rigid or semi-rigid surface, appropriate size, shape, and porosity, and high chemical resistance. Examples of solid supports are
• polyethyleneglycol copolymer silica gel, alumina gel, plastic, polyamides, polyimides,
• Resin refers to a solid support material which has been grafted with a linker for attachment of the
• first building block examples of preferred resins are IRORI MicroKans , Wang resin (a).
• polystyrene-based resin with a 2-methoxy4-alkoxybenzyl alcohol linker are preferred resins.
• reaction vessel refers to the vessel in which reactions take place. In some cases it may act as a
• the reaction vessel is capable of resisting the solvents and reaction
• object set refers to one or more solid support, resin, or in the case of liquid phase synthesis a reaction vessel that shares the same chemical history. Members of an object set move
• An object set may be only one
• vessels or resin cans can be used.
• FIG. la TEFLON tube as reaction vessel, dispensing vessel and receiving vessel
• FIG. lb TEFLON tube as reaction vessel, dispensing vessel and receiving vessel
• FIG. 2 illustrates sorting algorithm
• FIG. 2 A further illustrates the algorithm of figure 2; each necklace represents a different reaction
• each letter represents the addition of a building block.
• FIG. 3a Depicts the details of a dispensor which can be used to transfer object sets such as lanterns
• FIG. 3b Depicts arrangements using a plurality of dispensers in a conversion manifold for
• distributing object sets one-by-one from a set of delivery tubes to a set of receiving tubes using a
• FIG. 3 c Depicts arrangements using a plurality of dispensers in a conversion manifold for
• distributing object sets one-by-one from a set of delivery tubes to a set of receiving tubes using a
• FIG. 3d Depicts arrangements using a plurality of dispensers in a conversion manifold for
• distributing object sets one-by-one from a set of delivery tubes to a set of receiving tubes using a
• FIG . 4 illustrate a 12 channel solid support reshuffler
• FIG . 5 Traceless synthesis of benzimidazoles
• FIG. 6 Analytical gradient HPLC profile of crude benzimidazole
• FIG. 7a Depicts the circular 2-D linear arrangement of delivery tubes, conversion manifold, and receiving tubes used for the simple sorting of object sets between synthesis steps.
• FIG. 7b Details of the device shown in Figure 7a.
• FIG. 8 3-D array in which each reaction vessel is separated from the nearest neighbor reaction vessels by valves.
• FIG. 9 Diagram of a 3 building block X 4 building block library ;
• FIG 10. Diagram of a 4 building block X 3 building block library
• FIG 11. Depicts a three step process with three building blocks in each step. Each string is a separate reaction vessel with nine supports in each.
• FIG 12 Depicts the three step process of figure 11. The relationship of the building blocks
• FIG. 13 Depicts the use of multiple short tubes in place of one long tube, forming a "virtual tube
• components of this invention can be applied to appropriate liquid-phase, combinatorial chemistry synthesis protocols, to other solid- or liquid-phase chemical protocols, or to any combination thereof.
• This invention can employ a general sorting protocol that (i) applies the same algorithm before any combinatorial step of the synthesis, and (ii) which is independent of the number of building blocks in individual steps, and (iii) which permits multiples of standard capacity (or length) dispensing and receiving tubes to be used to synthesize any size library.
• Lanterns can be organized in one-dimensional, or linear, array in each dispensing tube ( Figure 2).
• the first receiving tube is
• n x n t0t /BB x Lanterns, where n x is the
• n tot is the total number of compounds
• BB X is the number of building blocks in the x-
• reaction vessels, or a necklace can be used to transfer object sets from a reaction vessel to a
• This algorithm is applicable to the directed sort by any process, including the Directed Sort
• strung necklaces are depicted, each containing 12 Lanterns which are reacted with representative
• Figure 2a further depicts the relationship of the building blocks (e.g., letters) as the Lanterns move through the synthesis steps.
• the Lantems (object sets) of figure 11 are numbered to show the
• Figure 12 further depicts the
• the tubes provide convenient
• reaction vessels with the advantage of using a continuous flow method for washing resins beads
• Apparatus Directed Sort Apparatus can be used to sort Lanterns between each consecutive combinatorial step. Such apparatus can simply permit the Lanterns to be sorted one by one from one dispensing tube at a time and transferred to the each appropriate receiving tube (Figure 3).
• Figure 3a Depicts the details of a dispenser which can be used to transfer object sets such as lanterns one-by-one from a delivery tube to selected receiving tubes. A plurality of dispensers may be used in a
• a sorting device such as the Directed Sort Apparatus can handle a multiplicity of dispensing and receiving tubes concurrently (Figure 4).
• the receiving tubes can be used as reactors, and in turn become dispensing tubes for distribution before the next round of synthesis.
• the Lanterns from each receiving tube can be transferred into reaction vessels, so long as the order is maintained.
• the Lanterns can be transferred into cleavage or storage vessels, such as 96-well plates, one Lantem per well, using the Directed Sort Apparatus. Therefore, for purely practical reasons to conveniently accommodate the 96 well plate format, the apparatus can be built to accommodate twelve tube reactors at a time and
• Directed sort combinatorial synthesis can be accomplished through a directed sort of supports or reaction vessels where they are physically moved, or in yet another embodiment , through the directed sort of supports or reaction vessels in which they are not moved, but rather addition of reagents is directed, or a combination of both.
• One skilled in the art can envision numerous ways of controlling the delivery of reagents to locations (e.g. control of valves directing the addition of reagents to certain reaction vessels) described by the algorithm of this invention, rather than directly sorting the supports, to achieve the same directed synthesis.
• reaction vessels can be constructed where, physically, the reaction vessels are not in an array, but are linked by
• reaction vessels need only have a single pair of valves or ports
• Each reaction vessel has 6 valves
• valve a for flow-through of reagents in the x-axis, y-axis, and z-axis directions, valve a to valve c, valve b
• the 3-D array of reaction vessels is labeled x, y, and z, and each vertical layer of the 3-D array of
• reaction vessels is labeled 1, 2, and 3.
• opening valves b and d wifl permit reagents to flow
• valves a and c will permit reagents to
• reaction vessels in layer z ii) add BB4 and carry out reaction 2 entering through open valve f and exiting (with recycling if desired) through open valve e of all reaction vessels in layer x, through add BB5 and carry out reaction 2 entering through open valve f and exiting (with recycling if desired) through open valve e of all reaction vessels in layer y, and add BB6 and carry out reaction 2 entering through open valve f and exiting (with recycling if desired) through open valve e of all reaction vessels in layer z; iii) add BB7 and carry out reaction 3 entering through open valve b and exiting (with recycling if desired) through open valve d of all reaction vessels in vertical layer 1, add BB8 and carry out reaction 3 entering through open valve b and exiting (with recycling if desired) through open valve d of all reaction vessels in vertical layer 2, and add BB9 and carry out reaction 3 entering through open valve b and exiting (with recycling if desired) through open valve d of all reaction vessels in vertical layer 3.
• a -28 UNF thread is cut on both ends of Teflon tube (Cole-Palmer, Vemon Hill, IL; OD 8 mm, ID 5.6 mm). The length of the tube is cut to allow 5.3 mm for each Lantern plus 2 times 5 mm for both threads.
• the tube is filled with Lanterns and enclosed from both sides using two female Luer fittings with -28 UNF thread (Figure la).
• Figure la depicts the use of a teflon tube as a reaction vessel which can be capped at both ends after object sets have been loaded in.
• the diameter of the tube constrains the object sets to remain in an ordered, linear array, preventing mixing.
• Reagents can be flowed into or through the tube, and in the case of lanterns, the hollow aligned cores of each permit insertion of a necklace for manipulating the object sets, or of a necklace containing or serving as a catalyst, etc.
• Figure lb Depicts the basic concept of the lantern, depicting its hollow core, various types of reaction or delivery and receiving vessels including a simple tube, tubes contained in a microplate, or a syringe, and the ability to deliver object sets into, or remove object sets from such a tube using a necklace.
• the ability to add or remove reagents is depicted, as is the ability to use caped or minimally occluded tubes sufficient only to retain the object sets unless pressure is applied.
• L-Series Lantem (5 x 5 mm in size) with a loading of 15 mmol
• D-Series Lantem (5 x 12.5 mm in size) with 35 mmol.
• L-Series Lanterns are used though the described concept is applicable to either series of Lanterns, since the diameter of both Lanterns is identical such that they can fit into the same tube and each has a hole in the center convenient for mnning a wire through and "stringing" the Lantems.
• the tube reactor filled with Lantems is attached using 1/8 Teflon tube to two Teflon distribution valves used for operating the Domino Blocks.
• Four ports of the solvent selection valve are connected using a 1/8 Teflon tube to four reservoirs with solvents.
• the common port was connected to the tube reactor.
• the second end of the tube reactor is connected to the tube reactor selection valve.
• the common port of this valve is connected to the evacuated waste container.
• the appropriate solvent is chosen by the solvent selection valve.
• the flow through the tube reactor is adjusted by the tube reactor selection valve.
• the typical volume of washing solvent is 200 mL per tube reactor of 50 Lantems.
• the delivery and receiving chambers are offset so that a support in the delivery chamber could not directly pass through into the receiving chamber.
• the support isolation and transfer chamber separates the delivery and receiving chambers in such a way that only one, or the desired number of supports, could pass from the delivery chamber into the isolation and transfer chamber, and then these supports are either transferred within this chamber or the isolation and transfer chamber itself is re-positioned to allow the supports to be transferred to the receiving chamber.
• the isolation and transfer chamber is incorporated into a push-rod, as shown in Figure 3.
• the pushrod configuration is a simple method to shuttle one or a specified number of supports (regulated by the dimensions of the isolation and transfer chamber) from the delivery chamber(s) to the receiving chamber(s) in any desired series of steps. Reliable transfer without jamming or failure to transfer is important for directed sort to be used for library synthesis where the identification of each synthesized compound is based on knowing the position of each support throughout the synthesis process rather then based on the analytical interrogation of some tag. This shuttle mechanism provides this reliability.
• a plurality of reaction vessels and sorters can be used to simultaneously yet individually transfer object sets from one set of reaction vessels to another.
• the plurality of sorters can be arranged as a 2-D or 3-D conversion manifold.
• one such arrangement utilizes a 2-D circular set of sorters as a conversion manifold and a circular and rotatable set of reaction or delivery vessels above a second circular set of reaction or receiving vessels.
• reaction vessels are used, they can be inserted.
• delivery vessels are different from the reaction vessels, a method, such as the use of a necklace (rod with a gripper/stop, simple wire, string, or post) can be used to transfer the column of object sets from each reaction vessel to a respective delivery vessel.
• a second apparatus is suitable for large library synthesis ( Figure 4).
• This "Directed Sort Apparatus” is designed to simultaneously move Lanterns from twelve (or any desired number) dispensing tubes (chambers) into twelve (or same desired number of) receiving tubes (chambers). Twelve dispensing tubes are attached to the upper part of the circular dispensing stainless steel manifold. The receiving tubes are connected in a linear fashion to the bottom of the conversion manifold.
• the conversion manifold which contains twelve (or the same desired number of) isolation and transfer chambers, is connected with the circular dispensing manifold by twelve tubes.
• the conversion manifold serves the function of converting the circular arrangement of dispensing tubes into a linear arrangement of receiving tubes.
• a spring-loaded moving circular part with twelve openings of a size of a Lantem moves a single Lantern from below each of the dispensing tubes to a position above each of the receiving conversion tubes. Once each Lantern reaches the top of the respective receiving conversion tube, it passes through the conversion manifold into the receiving tube.
• the circular array of isolation and transfer chambers is designed with one isolation and transfer chamber for each dispensing tube, and only rotates a half step, from below each respective delivery tube to above each respective receiving tube.
• each isolation and transfer chamber directs the sort of supports from one delivery tube to a specific receiving tube.
• the delivery tubes rotate above the conversion manifold, so that supports from each delivery tube can be delivered to all 12 receiving tubes according to any desired sort pattern.
• a stainless steel 2 g weight is placed on the top of Lantems in all dispensing tubes.
• the receiving tubes are connected to an evacuated reservoir via a solenoid valve to apply negative pressure or air flow to increase the reliability of lantern transfer through the curved tubes.
• the valve is opened for a fraction of second at the same time when the moving Lantern is positioned above the receiving tube. The negative pressure gradient /air flow assists in the movement of lanterns into the receiving tube.
• Figure 7a depicts the circular 2-D linear arrangement of delivery tubes, conversion manifold, and receiving tubes used for the simple sorting of object sets between synthesis steps.
• the delivery tubes rotate in a circular manner such that the tubes change position, while the conversion manifold and receiving tubes do not.
• the Conversion manifold instead rotates back and forth a portion (e.g. half) of a step (where a step is the distance between two delivery or receiving tubes), and consists of the number of chambers as there are delivery tubes, each capable of receiving a single object set in the first position, and when rotated, delivering said object set to a receiving tube.
• Figure 7b details the device shown in Figure 7a.
• the first step depicts the conversion manifold in its first position aligned with the delivery tubes.
• each delivery tube there is a weight which assures that the object sets enter the conversion manifold.
• the circular array of delivery tubes and conversion manifold is mated to a linear array of receiving tubes (arranged in the x direction) by flexible tubing, the connecting transport tubes, and there is vacuum at the bottom of each receiving tube.
• the object sets can be pushed out of each of their respective tubes into a reaction tube (flipped to maintain the orientation of top object set to top object set), or retrieved on a necklace and either reacted on the necklace or transferred from the necklace into a reaction vessel.
• a reaction tube flipped to maintain the orientation of top object set to top object set
• the receiving plate can be indexed one tube over in the y direction, or another set of empty tubes can be placed under the connecting transport tubes.
• a 96-well plate is placed below the conversion manifold for final distribution of Lanterns into wells after finishing the synthesis.
• This distribution from columns of object sets in tubes to single object sets in each well of a microplate would be frequently common for any number of reaction vessel configurations, whether circular or in another 2-D arrangement, and would be facilitated by a different configuration for the plurality of sorters (conversion manifold) used .
• a 50-rnL syringe is loaded with 50 Lanterns, Lanterns are neutralized with 50% piperidine in DMF, and washed 5 times with DMF.
• Fmoc-4-methoxy-4 -(ga ma- carboxyprophyloxy)benzhydrylamine (5mmol, 2.69 g) and HOBt.H 2 0 (5mmol, 0.765 g) are dissolved in 15 mL NMP, and DIG (5 mmol, 0.782 mL) is added. The solution is added to the syringe with Lanterns and kept on a tumbler overnight (16 h).
• Lanterns are washed 5 times with DMF, THF, and DCM, and dried by a stream of nitrogen.
• a half mL of 50 % piperidine/DMF solution is added to one Lantern in a 2.5 mL syringe and kept on a tumbler for 10 min.
• the Lantem was washed 5 times with DMF and all washes are collected, diluted, and the absorbance is measured at 302 nm against DMF. Fmoc release indicates a linker substitution of 37 umol/Lantern.
• a 20-mL syringe is was loaded with ten Lanterns (acylated with linker as described above) and 50 % piperidine/DMF solution is added. After 10 min the Lantems are washed 5 times with DMF, 3 times with dry DMSO, 5 mL of 1 M solution of o- fluoronitrobenzene and DIE A (0.17 mL) in DMSO is added to the syringe. The syringe is left shaking in an incubator at 75 C overnight (16 h). Lanterns are washed 5 x with DMSO, DMF, DCM, and dried by nitrogen. One ring from a Lantem is cut, the product cleaved by TFA for 1 h, and analyzed by analytical gradient HPLC at 280 nm.
• a 20-mL syringe with ten Lanterns from step 1 is charged with 5 mL of 2 M solution of tin(II) chloride dihydrate in NMP, bubbled with argon for 15 min. The syringe is left on a tumbler overnight, washed 3 times NMP, DMF, DMF/water, DMF, THF, DCM, dried by nitrogen. One ring from a Lantern is cut, the product is cleaved by TFA for 1 h, and analyzed by analytical gradient HPLC at 220 nm.
• a 20-mL syringe with ten Lanterns from step 2 is charged with 5 mL of 1 M isothiocyanate solution in NMP.
• the syringe is left on a tumbler overnight, washed 3 times DMF, THF, and DCM, dried by nitrogen.
• One ring from a Lantern is cut, the product cleaved by TFA for 1 h, and analyzed by analytical gradient HPLC at 280 nm.
• a 20-mL syringe with ten Lanterns from step 3 is charged with 5 mL of 1 M DIC solution in DMF.
• the syringe is left on a tumbler overnight, washed 3 times DMF, THF, and DCM, dried by nitrogen.
• One ring from a Lantern is cut, the product cleaved by TFA for 1 h, and analyzed by analytical gradient HPLC at 280 nm.
• a 20-mL syringe with ten Lanterns from step 4 is charged with 5 mL of 1 M isocyanate solution in DMF.
• the syringe is left on a tumbler overnight, washed 3 times DMF, THF, and DCM, dried by nitrogen.
• One ring from a Lantem is cut, the product was cleaved by TFA for 1 h, and analyzed by analytical gradient HPLC at 280 nm.
• each set of short tubes forms a "virtual tube" when aligned head-to-tail as shown to the left of the vertical line.
• To the right of the vertical line is a comparison of the first two steps of the synthesis of a 3 x 3 x 3 library using short tubes (on the left) containing three object sets each and comprising "virtual tube” sets, versus on the right a long tube containing nine object sets each.
• the building blocks are indicated as BB1, BB2, BB3 for the first reaction and BB4, BB5, BB6 for the second reaction.
• the object sets are numbered so that their location within tubes and between sorts can be followed.
• Each 3 tube set when ordered head-to-tail represents a "Virtual Tube” containing 9 object sets, as can be seen by comparing the numbers for BBl short tubes to the long tube corresponding to BBl to the right (see dotted arrow).
• Three 3-tube sorts are then carried out, in preparation for which one tube of each reaction set BB reaction of tubes is combined (as shown) with one of each of the other reaction set tubes to form the 3-tube delivery tube set.
• the "virtual tube” head-to-tail layout dictates how these tubes are recombined before the sorts.

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