Stoichiometry and atom economy are closely associated with any chemical transformation.

A highly atom economical chemical process is considered as a transformation where most of the atoms present in the reactant or re- agents (but not in all cases) are incorporated in the product. 5 The atom economy is measured as a ratio of product and all reactant and reagents (when used as reactants) used multiplied by 100, and reflects that lesser amounts of reactants used is directly proportional to higher atom economy. This calculation is widely accepted for multistep processes too. Usually in such a calculation, intermediates that are formed and consumed in the next step are omitted. There are certain assumptions made about all the com- ponents of the reaction as shown in Scheme 1.3. In this hypothetical synthesis, in order to calculate the atom economy for intermediate EE, reactants G and R are factored in, whereas the calculation of atom economy for product Y, all the reactants G, R, N, H, M, S are considered. For instance, a reactant is considered as any material that gets incorpor- ated into an intermediate, product or by-product during the synthesis e.g. certain component of protecting groups and reagents used in stoichiometric quantities (or more than that). Anything used in catalytic quantities is omitted from the calculation as they do not contribute to any of the inter- mediates or product(s). Solvents are also not considered as part of the atom economy calculation.

Understandably, Green Chemistry is seen as the‘right way’of doing chem- istry in any phase of the process development. The business impact of Green Chemistry cannot be realised if it does not provide greener alternatives that enable a rise in optimal output in any given transformation. There are many hazardous reagents used for extremely important transformations but these are associated with high environmental impacts.

One of the important areas of development in Green Chemistry is the selection of safer reagent(s), considering the nature of transformations. Reagent selection must arguably be guided by 12 Green Chemistry principles. Visiting these principles while designing the manufacturing processes could shed light on certain charac- teristics of reagents, allowing the selection of non-hazardous reagents. In fact, these principles do not only aid in finding safer reagent(s) but also help in reviewing the processes entirely. Chemists across both academia and industry mainly focus on achieving the highest yield in any given chemical transformation without considering anything that might add to the ineffi- ciency of the overall process. A quest arises for the consideration of other Green Chemistry components when it is perceived that the yield is not going to be great. More often, Green Chemistry is considered last due to various reasons. In general, raw material cost, ease, and timely availability of raw material or reagent drive the decision-making in route selection. There ap- pears to be opportunities to use the recommendations of reagent selection guidelines made available by various pharmaceutical industries in the lit- erature. The most recent one is a very comprehensive reagent selection guideline made available by GSK. 6 During discovery research, a specific re- agent is used that is not necessarily the ideal one and this provides the opportunity for chemists to use an alternative reagent for the same trans- formation during development followed by scale-up.

One has to make smart choices while opting for alternate reagents, considering certain guidelines otherwise it amounts only to unproductive time-consuming efforts. It be- comes more challenging when we deal with generics as the best possible set of reagents available in the market have already been tried by innovator companies and others; however, the newly discovered potential alternates would not have readily been available during the manufacturing of the branded medicine when there was no competition for that particular product. These new reagents need to be assessed for commercial- and manufacturing- scale viability before the entire product development and manufacturing strategies are finalized. Moreover, in order to use safer and greener alternative reagents, it is important to refer to the established reagent selection guideline Introduction to Hazardous Reagent Substitution in the Pharmaceutical Industry 5 toolbox and scientific rationale towards finalizing the set of reagents for any given transformation.

The reagent selection guidelines are made available by considering the impact on health due to exposure of the reagents or their by-products, safety, environmental impact, their projected carbon footprint, transformational output and, last but not the least their contribution, towards over all process‘greenness’.

Biocatalysts are broadly accepted as the best reagent alternates provided such processes do not employ large amounts of water or any other solvent, demanding reaction conditions, and organic solvents in the downstream processes.

Moreover, reagent selection in my opinion is an ever-evolving science that has potential to contribute to the wellbeing of human health, business and the environment.