Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]2[N:11]([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[F:22])[C:12](=[O:14])[NH:13][C:9]=2[C:8]2[O:7][CH:6]=[CH:5][C:4]=2[C:3]=1[F:23].[CH2:24]([O:31][CH2:32][CH:33]1[CH2:35][CH:34]1[S:36](Cl)(=[O:38])=[O:37])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(OCC)(=O)C>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCCCCC>[CH2:24]([O:31][CH2:32][CH:33]1[CH2:35][CH:34]1[S:36]([IH:21][C:18]1[CH:19]=[CH:20][C:15]([N:11]2[C:10]3[C:2]([F:1])=[C:3]([F:23])[C:4]4[CH:5]=[CH:6][O:7][C:8]=4[C:9]=3[NH:13][C:12]2=[O:14])=[C:16]([F:22])[CH:17]=1)(=[O:37])=[O:38])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=c1[nH]c2c3occc3c(F)c(F)c2n1-c1ccc(I)cc1F
Reactant: O=S(=O)(Cl)C1CC1COCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: O=c1[nH]c2c3occc3c(F)c(F)c2n1-c1ccc([IH]S(=O)(=O)C2CC2COCc2ccccc2)cc1F
Temperature: 30 °C
Reaction time: 12 h
Yield: 59 %

Procedure:
TEA (0.0941 g, 0.930 mmol) was added to a solution of 4,5-difluoro-3-(2-fluoro-4-iodophenyl)-1H-1-benzofuro[6,7-d]imidazol-2(3H)-one (I-32a: 0.2 g, 0.4651 mmol) in dry DCM (5 mL) at 0° C. This was followed by the addition of 2-benzyloxymethyl-cyclopropanesulfonyl chloride (0.181 g, 0.6976 mmol) and catalytic amount of DMAP (0.010 g). The reaction mass was stirred for 12 hours at 20-40° C. The reaction was monitored by TLC (30% ethyl acetate in hexane). The reaction mass was diluted with DCM (50 mL) and partitioned between water and DCM. The organic layer was washed with water, brine solution and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (15% ethyl acetate in hexane) afforded 0.180 g of the product (60% yield). 1H NMR (CDCl3, 300 MHz): δ 7.71 (d, 1H), 7.59-7.65 (m, 2H), 7.24-7.28 (m, 3H), 7.12-7.18 (m, 3H), 6.98 (d, 1H), 4.48 (s, 2H), 3.56 (dd, 1H), 3.38-3.48 (m, 1H), 3.25-3.35 (m, 1H), 2.28-2.38 (m, 1H), 1.56-1.58 (m, 1H), 1.38-1.48 (m, 1H). LCMS: 98.72%, m/z=654.9 (M+1)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.N1C=CC=CC=1>O1CCOCC1>[N+:16]([C:3]1[CH:4]=[C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:6]=[CH:7][C:2]=1[N:28]1[CH2:29][CH2:30][N:25]([C:20]2[N:19]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:26][CH2:27]1)([O-:18])=[O:17]
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: CC1CC(=O)NN=C1c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC1CC(=O)NN=C1c1ccc(N2CCN(c3ncccn3)CC2)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
3.0 g (11.2 mmol) of 6-(4-chloro-3-nitro-phenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone, 3.7 g (22.4 mmol) of 1-(2-pyrimidyl)-piperazine and 0.9 g (11.2 mmol) of pyridine are boiled under reflux in 50 ml of dioxane. A further 1.9 g (11.6 mmol) of 1-(2-pyrimidyl)-piperazine is added after 6 hours and the reaction mixture is boiled for a further 4 hours. When the reaction mixture has cooled, it is poured out on 300 ml of ice water and the precipitated solid is suction filtered, washed with a small quantity of diethyl ether and recrystallized from 40 ml of 2-methoxyethanol. 3.1 g (70%) of orange red crystals, m.p. 232° to 233° C., are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.NC1C=CN(C[CH2:49][CH2:50][CH2:51][OH:52])N=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:49][CH2:50][CH2:51][OH:52])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reactant: Nc1ccn(CCCCO)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCCCO)n2)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 12.3 %

Procedure:
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 200 mg, 0.61 mmol) was dissolved in methylene chloride (3 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (305 μL, 0.61 mmol) was added and the reaction stirred at 25° C. for 20 min. The solution was chilled to 0° C. and 2,6-lutidine (145 μL, 1.22 mmol) was added. The reaction continued to stir at 0° C. for 20 min. The 4-(3-amino-pyrazol-1-yl)-butan-1-ol (93 mg, 0.61 mmol) was added, the ice bath was removed and the reaction continued to stir at 25° C. for 45 min. The reaction was diluted with methylene chloride (10 mL), washed with water (2×4 mL), saturated aqueous brine solution (1×4 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Purification by reverse phase preparative HPLC (Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 30% acetonitrile/water to 100% acetonitrile/water; 30 mL/min flow rate for 15 min run) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(4-hydroxy-butyl)-1H-pyrazol-3-yl]-propionamide (35 mg, 12%) as a white foam: ESI-LRMS m/e calcd for C22H30ClN3O4S [M+] 467.2, found 468.0 [M+H+], 450.1 [M−H2O+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.06-1.23 (m, 2H, CH2), 1.45-1.99 (m, 12H, 6×CH2), 2.17-2.30 (m, 1H, CH), 2.71 (brs, 1H, OH), 3.26 (s, 3H, SO2CH3), 3.60 (t, J=7.8 Hz, 1H, CH), 3.69 (t, J=6.2 Hz, 2H, OCH2), 4.09 (t, J=6.6 Hz, 2H, NCH2), 6.70 (s, 1H, Ar), 7.30 (s, 1H, Ar), 7.49 (d, Jo=8.3 Hz, 1H, Ar), 7.62 (s, 1H, Ar), 8.10 (d, Jo=8.6 Hz, 1H, Ar), 8.47 (brs, 1H, NH).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25](O)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:28][C@@H:29]1[CH2:34][CH2:33][C@@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C@@H:31]([F:43])[CH2:30]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:28][C@H:29]4[CH2:34][CH2:33][C@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:40])[CH3:41])[C@H:31]([F:43])[CH2:30]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:2][CH2:3]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](N)C[C@@H]1F
Product: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)[C@H](F)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.g1) and tert-butyl [(1R*,2S*,4R*)-4-amino-2-fluorocyclohexyl]carbamate (example C55) the title compound is obtained as pale yellow foam.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:19](CC)CC)C.C(OC(Cl)=O)C(C)C.N>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH2:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)CCNC(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.05 h

Procedure:
111.7 g of benzyloxycarbonyl-β-alanine were dissolved in 1 liter of dimethylformamide, cooled to -20° C, treated with 70 ml of triethylamine and 67 ml of chloroformic acid isobutyl ester and stirred at -20° C for 3 minutes. Dry ammonia gas was led into this mixture until the pH rose to 11, care being taken that the temperature did not exceed -10° C. The mixture was stirred for a further 30 minutes at room temperature, filtered and the filtrate concentrated in vacuo. The residue was recrystallised from water. Yield: 91 g; melting point 162°-165° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:36][CH3:37])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:34])[C:22]4[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:8][C:7]=2[CH:35]=1.[H][H]>C(O)C.[C].[Pd]>[CH3:37][O:36][C:4]1[C:3]([O:2][CH3:1])=[CH:35][C:7]2[CH2:8][CH:9]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:34])[C:22]4[CH:23]=[C:24]([O:32][CH3:33])[C:25]([O:30][CH3:31])=[C:26]([O:28][CH3:29])[CH:27]=4)[CH2:17][CH2:16]3)=[O:14])[CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)N1CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)CC1)=C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1cc2c(cc1OC)CC(C(=O)N1CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)CC1)CCC2

Procedure:
To a solution of 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)-4-(3,4,5-trimethoxybenzoyl)piperazine (1.0 g) obtained in Example 62 in ethanol (50 ml) is added 10% palladium-carbon (50 mg), followed by catalytic reduction in a stream of hydrogen. The reaction mixture is filtered off, and the filtrate is concentrated under reduced pressure. To the residue is added ether, and the mixture is stirred to obtain 1-(2,3-dimethoxy-5,6,7,8-tetrahydrobenzocyclohepten-6-ylcarbonyl)-4-(3,4,5-trimethoxy-benzoyl)piperazine as a colorless powder.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)[Cl:11]>>[C:1]([Cl:11])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: ClCCl
Product: O=C(Cl)c1ccccc1

Procedure:
Shaking once with 300 ml of methylene chloride completely removes small quanitites of benzoic acid formed by the hydrolysis of adhering benzoyl chloride. The hydrolysis solution is neutralized with sodium hydroxide and made up with water to 750 ml. The 1,3-dimethyl-1-oxophospholine is isolated from the neutral solution in the same way as in Example 1. Yield: 109 g of 1,3-dimethyl-1-oxophospholine (41.9% of the theoretical yield).
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([C:33]3[CH:50]=[CH:49][CH:48]=[CH:47][C:34]=3[CH2:35][N:36]3C(=O)C4C(=CC=CC=4)C3=O)[N:14]3[C:19]4[CH:20]=[CH:21][N:22](S(C5C=CC(C)=CC=5)(=O)=O)[C:18]=4[N:17]=[CH:16][C:15]=23)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].NN.[OH-].[Na+]>CCO.CCOC(C)=O>[NH2:36][CH2:35][C:34]1[CH:47]=[CH:48][CH:49]=[CH:50][C:33]=1[C:13]1[N:14]2[C:19]3[CH:20]=[CH:21][NH:22][C:18]=3[N:17]=[CH:16][C:15]2=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:2]([OH:1])([CH3:3])[CH3:4])=[CH:6][CH:7]=2)[N:12]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(-c4ccc(C(C)(C)O)cc4)nc(-c4ccccc4CN4C(=O)c5ccccc5C4=O)n23)cc1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(O)c1ccc(-c2nc(-c3ccccc3CN)n3c2cnc2[nH]ccc23)cc1
Temperature: 85 °C
Yield: 24.5 %

Procedure:
The 2-(2-(3-(4-(2-hydroxypropan-2-yl)phenyl)-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)benzyl)isoindoline-1,3-dione (0.154 g, 0.226 mmol) in EtOH (4 mL) was treated with hydrazine (0.147 mL, 4.68 mmol) then heated to about 85° C. for about 15 min. The mixture was diluted with EtOAc (20 mL). The insoluble material was removed by filtration and washed with EtOAc (5 mL). The filtrate was concentrated under reduced pressure then the material was dissolved in 1,4-dioxane (4 mL) and treated with aqueous NaOH (50 wt %, 0.260 g, 3.25 mmol). The mixture was heated in a microwave at about 120° C. for about 20 min. The mixture was concentrated under reduced pressure then dissolved in AcOH (1 mL) and DMF (3 mL). The material was purified by preparative reverse phase HPLC (Table 2, Method i). The fractions with desired material were collected and lyophilized. The material was purified using a 5 g Si-Carbonate column (Silicycle™) and eluting wiht MeOH. The material was treated with EtOAc (˜10 mL) then concentrated under reduced pressure. This was repeated several times until a yellow solid was obtained. The material was triturated with EtOAc (3 mL) and heptane (15 mL) and the solid was collected by filtration and dried to constant weight under vacuum at about 70° C. to give 2-(4-(1-(2-(aminomethyl)phenyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)phenyl)propan-2-ol (0.022 g, 25%): LC/MS (Table 2, Method a) Rt=1.62 min; MS m/z 398 (M+H)+. Syk IC50=B.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][NH:11][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]1=[O:20])[CH2:4][CH3:5])[CH3:2].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:9](=[O:20])[CH:10]2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:24][CH:23]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCN(CC)CCN1CCNC(c2ccccc2)C1=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCN(CC)CCN1CCN(Cc2ccc(Cl)cc2)C(c2ccccc2)C1=O

Procedure:
80 g. of 1-(diethylamino ethyl)-2-keto-3-phenyl piperazine containing the above mentioned isomer are boiled under reflux with 54 g. of p-chloro benzylchloride, 101 g. of triethylamine, and 300 cc. of toluene for 5 hours. The precipitated triethyl ammonium chloride is removed from the reaction solution by extraction with water while still warm. The separated toluene layer is freed of the solvent, the residue is dissolved in benzene, and insoluble matter is filtered off.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1>C(O)(=O)C.[Pt]=O>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1
Reactant: O=C(O)Cc1ccncc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: O=C(O)CC1CCNCC1
Reaction time: 18 h

Procedure:
4-pyridine acetic acid (10 g) and platinum oxide (1.0 g) are combined in acetic acid (100 ml) and the mixture shaken under hydrogen at 50 psi for about 18 hours. The mixture is filtered and the solution evaporated in vacuo and toluene azeotroped from the residue to give 2-(piperidin-4-yl)acetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11]O)[CH:10]=1)[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]2.[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[C:29]([CH3:30])=[N:28][NH:27][C:24]2=[N:25][CH:26]=1)=[O:20]>>[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[C:29]([CH3:30])=[N:28][N:27]([CH2:11][C:9]3[CH:10]=[C:2]([Br:1])[CH:3]=[C:4]4[C:8]=3[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]4)[C:24]2=[N:25][CH:26]=1)=[O:20]
Reactant: COC(=O)c1cnc2[nH]nc(C)c2c1
Reactant: CC(C)Cn1ncc2cc(Br)cc(CO)c21
Product: COC(=O)c1cnc2c(c1)c(C)nn2Cc1cc(Br)cc2cnn(CC(C)C)c12
Yield: 50 %

Procedure:
Compound 38 was prepared following general method 3A, using compound 18 as a starting material and 3-Methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid methyl ester as the heterocycle. Yield: 50%.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[CH:4][C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].O.[OH-].[Li+].S(OC)(O[CH3:21])(=O)=O>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[C:3]([O:13][CH3:21])=[CH:4][C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1cc(Br)c(O)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)c(OC)cc1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 129.1 %

Procedure:
A solution of methyl 5-bromo-2-chloro-4-hydroxybenzoate (Preparation 51, 2.5 g, 9.42 mmol) and lithium hydroxide monohydrate (395 mg, 9.42 mmol) in THF (10 mL) was stirred at room temperature for 10 minutes. Dimethyl sulphate (0.45 mL, 4.71 mmol) was added dropwise and left to stir at room temperature for 45 minutes before heating to 75° C. for 3 hours. Additional dimethyl sulphate (0.45 mL, 4.71 mmol) was added dropwise and the reaction stirred at 75° C. for 16 hours. The reaction was cooled to room temperature, diluted with EtOAc (20 mL), washed with brine (30 mL), dried over magnesium sulphate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting from 5-10% EtOAc in heptanes to afford the title compound as a white solid (1.70 g, 65%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]([OH:43])[CH:34]=[C:35]([S:37]([CH:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:43][C:33]2[CH:34]=[C:35]([S:37]([CH:40]([CH3:41])[CH3:42])(=[O:39])=[O:38])[CH:36]=[C:31]([Br:30])[CH:32]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Reactant: CC(C)S(=O)(=O)c1cc(O)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(S(=O)(=O)C(C)C)c2)c1CCC(=O)OCC
Yield: 69.4 %

Procedure:
A similar procedure as described in Example 40, step 6 was used, starting from 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (632 mg, 1.34 mmol), 3-bromo-5-(propane-2-sulfonyl)-phenol (340 mg, 1.22 mmol), and potassium carbonate (337 mg, 2.44 mmol) to afford 4-[3-{6-[3-bromo-5-(propane-2-sulfonyl)-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (567 mg, 70%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C32H45BrO8S (M+Na)+ 691.1911, found 691.1908.