Algorithm: CE-DB (cross entropy-dynamic binning)

Input:$K_{\text{CE}},\rho ,{\beta }_{max,}$ and κmin

1: $\gamma \leftarrow \{v_1,\cdots ,v_M\}$, where vj is a vector of 1s with length βmax

2: i ← −1

3: repeat

4:  i ← i + 1

5:  while running core sdwSSA with $K=K_{\text{CE}}$do

6:   mark the $\lceil \rho K_{\text{CE}}\rceil$ trajectories evolving farthest in the direction of E

7:   record min(πj) and max(πj)

8:  endwhile

9:  ${\mathcal{E}}_i\leftarrow$ at most $\lceil \rho K_{\text{CE}}\rceil$ states closest to E reached by the marked trajectories (one per trajectory)

10:  $c_j^r\leftarrow \text{min}\left({\pi }_j\right)+\frac{\text{max}\left({\pi }_j\right)-\text{min}\left({\pi }_j\right)}{{\beta }_{max}}\times r,r\in \{1,\cdots ,({\beta }_{max}-1)\}$

11:  while running core sdwSSA with $K=K_{\text{CE}}$do

12:   record the number of firings among βmax bins for each reaction

13:   store information of trajectories that reach ${\mathcal{E}}_i$

14:  endwhile

15:  forj = 1 → Mdo

16:   merge bins until every bin contains greater than κmin reaction firings

17:   update $\{c_j^1,\cdots ,c_j^{{\beta }_j-1}\}$ according to the result from step 16

18:  endfor

19:  $\gamma \leftarrow$ result of Eq. 14 evaluated using ${\mathcal{E}}_i$ and trajectories from step 13

20: until${\mathcal{E}}_i\subseteq \mathcal{E}$

21: return$\widehat{{\gamma }^{*}}=\gamma$ and c