Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[S:2]([N:12]1[C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:21]([C@@H:24]4[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25]4)=[N:22][N:23]=3)[C:15]=2[CH:14]=[CH:13]1)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:30][CH2:31][CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:30][CH2:31][CH2:32][CH2:33][S:34]([NH:29][C@H:26]1[CH2:27][CH2:28][C@@H:24]([C:21]2[N:20]3[C:15]4[CH:14]=[CH:13][N:12]([S:2]([C:5]5[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=5)(=[O:4])=[O:3])[C:16]=4[N:17]=[CH:18][C:19]3=[N:23][N:22]=2)[CH2:25]1)(=[O:36])=[O:35]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@H](N)C4)n23)cc1
Reactant: O=S(=O)(Cl)CCCCl
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@H](NS(=O)(=O)CCCCl)C4)n23)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
To a suspension of (1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine hydrochloride (0.05 g, 0.11 mmol, prepared using E from Preparation #B.1 and HCl) and TEA (0.03 mL, 0.21 mmol) in DCM (5 mL) at about 0° C. was added 3-chloropropane-1-sulfonyl chloride (0.02 g, 0.11 mmol) dropwise. The reaction mixture was stirred at about 0° C. for about 1.5 h. The reaction mixture was diluted with 5% aqueous citric acid (10 mL), and the layers were separated. The organic layer was washed with saturated aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give 3-chloro-N-((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)propane-1-sulfonamide (0.052 g, 91%) as a brown residue: LC/MS (Table 1, Method a) Rt=2.18 min; MS m/z: 537 (M+H)+.
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3][CH3:4].[CH:6](=O)[CH:7]([CH3:9])[CH3:8]>O>[CH2:3]([C:2](=[CH:6][CH:7]([CH3:9])[CH3:8])[CH:1]=[O:5])[CH3:4]
Reactant: CC(C)C=O
Reactant: CCCC=O
Solvent: O
Product: CCC(C=O)=CC(C)C

Procedure:
Accordingly, it has been discovered that if water is added to the n-butyraldehyde feed to the distillation column in an amount effective to hydrolyze the isobutyraldehyde oligomers to the monomeric form during distillation, they can be stripped from the n-butyraldehyde, thereby reducing the amount of isobutyraldehyde which reacts to form 2-ethyl-4-methyl-pentenal during aldol condensation and subsequent hydrogenation of the 2-ethyl-4-methyl-pentenal to 2-ethyl-4-methyl pentanol during the hydrogenation stage. By this method the content of 2-ethyl-4-methyl-pentanol in the final product can be substantially reduced; typically from a range of from about 0.2 to about 0.4 wt. % without the water addition to less than 0.2 wt. %, preferably to within a range of from about 0.08 to about 0.1 wt. % with the water addition, based on 2-ethylhexanol. The degree of improvement will vary with the amount of water added, with increasing amounts of water tending to give increasing reductions in the amount of 2-ethyl-4-methyl-pentanol in the 2-ethylhexanol.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:12])[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:19][C:20]1[CH:32]=[CH:31][C:23]([O:24][CH:25]([CH3:30])[CH:26]=[CH:27][CH2:28][OH:29])=[CH:22][CH:21]=1>CS(C)=O>[F:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([O:19][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH:25]([CH3:30])[CH:26]=[CH:27][CH2:28][OH:29])=[CH:31][CH:32]=1)[CH:11]=[N:10]2
Reactant: Fc1ccc2nc(Cl)cnc2c1
Reactant: CC(C=CCO)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C=CCO)Oc1ccc(Oc2cnc3cc(F)ccc3n2)cc1
Temperature: 110 °C
Yield: 44.1 %

Procedure:
A mixture of 1.28 g (7 mmol) of 2-chloro-6fluoroquinoxaline, 1.16 g (8.4 mmol) of anhydrous, powdered potassium carbonate, 1.55 g (8 mmol) of 4-(4-hydroxyphenoxy)-2-penten-1-ol and 20 ml of DMSO was warmed, under nitrogen, at 110° C. for a period of 2 hours. The mixture was cooled to room temperature, poured into dilute, aqueous HCl and extracted with two portions of ether. The combined organic layers were washed twice with 1 percent aqueous NaOH and with water, dried over MgSO4 and evaporated to dryness. The residue was purified by preparative scale HPLC, eluting with 3:1 hexane:acetone. After removal of solvent the resulting tan crystals were recrystallized from methylcyclohexane to give 1.05 g of crystals which were further purified by recrystallization from toluene to leave nearly colorless crystals, m.p. 109-111° C. (Compound F)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27](O)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>C(#N)C>[CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=3)=[O:15])[C@H:11]([C:27]([N:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Solvent: CC#N
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.8 %

Procedure:
11.7 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid [prepared as described in step (b) above] were dissolved in 100 ml of anhydrous acetonitrile. 4.9 g of N,N'-carbonyldiimidazole were then added to the solution, which was then stirred for 30 minutes at room temperature. At the end of this time, 3.5 g of N-methylpiperazine were added to the reaction solution, and it was then stirred at room temperature for 30 minutes, and then at 40° C. for 30 minutes. The reaction solution was then condensed to 30 ml by evaporation under reduced pressure, and the residue was diluted with 300 ml of ethyl acetate. The resulting solution was washed once with 100 ml of a saturated aqueous solution of sodium hydrogencarbonate three times with 100 ml of water and once with 100 ml of a saturated aqueous solution of sodium chloride. The ethyl acetate layer was condensed by evaporation under reduced pressure, to obtain 1.36 g of a crystalline residue. Recrystallization of this crystalline residue from 100 ml of ethanol gave 13.0 g of the title compound as colorless needles, melting at 140°-141° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[S:20](Cl)(=[O:22])=[O:21]>CN(C1C=CN=CC=1)C>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[S:20]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)(=[O:22])=[O:21]
Reactant: Nc1cccc2cccnc12
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cccc2cccnc12)c1c(F)cccc1F
Yield: 44.6 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoquinoline (100 mg, 0.70 mmol), 2,6-difluorobenzenesulfonyl chloride (170 mg, 0.83 mmol) and DMAP (cat.) gave the title compound (100 mg, 45%) after purification by column chromatography with DCM as the eluent followed by trituration from EtOAc/n-hexane.
Reaction SMILES: [CH3:1][C:2]1O[CH:7]=[CH:6][C:4](=[O:5])[C:3]=1[OH:9].[NH2:10][CH3:11]>>[CH3:1][C:2]1[N:10]([CH3:11])[CH:7]=[CH:6][C:4](=[O:5])[C:3]=1[OH:9]
Reactant: Cc1occc(=O)c1O
Reactant: CN
Product: Cc1c(O)c(=O)ccn1C
Temperature: 25 °C

Procedure:
Deferiprone was synthesized as described previously. (Gale et al, Res Comun Chem Pathol Pharmacol Vol. 73, No. 3, September 1991) An aqueous suspension of 3-hydroxy-2-methyl-pyrone, maltol, (Aldrich Chemical Co., Milwaukee, Wis., 50 gm, 396 nmol) and NH2CH3 (Aldrich Chemical Co., Milwaukee, Wis., 3 eq, 92 ml, 1.18 mol, 12.88 M) in distilled, degassed H2O was heated under reflux for 12 hours. The solution was allowed to cool to room temperature. The excess methyl amine was removed under reduced pressure and the brown mixture was carefully concentrated to a volume of approximately 200 ml. Reagent grade acetone (50 ml) was added to this brown suspension and the solid recovered by filtration. The solid was washed with 1200 ml of acetone and briefly allowed to dry. To this crude solid was added 2 g of Norite and 2 g of Celite 545 (fisher Scientific, Pittsburgh, Pa.) and the crude solid was dissolved in a minimal amount of hot water. The Celite/Norite matrix was removed from the solution by filtration. The pure crystalline compound was recovered by filtration to give 29.8 g (54%) of the title compound. All recovery and transfer procedures were performed with a porcelain spatula rather than stainless steel equipment due to the potent iron chelating property of 1,2-dimethyl-3-hydroxypyrid-4-one. Analytically pure 1,2-dimethyl-3-hydroxypyrid-4-one was obtained by a single recrystallization from H2O. Other alkyl-substituted pyridones can be prepared by similar measures.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][CH:16]([NH2:20])[C:17]([OH:19])=[O:18].C(=O)(O)[O-].[Na+]>C(O)C.O>[CH3:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH:20][CH:16]([CH3:15])[C:17]([OH:19])=[O:18])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: CC(N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(NC(C)C(=O)O)c([N+](=O)[O-])c1

Procedure:
A mixture of 810 g of 4-chloro-3,5-dinitrotoluene, 384 g of dl-alpha-alanine, and 840 g of sodium bicarbonate was stirred and refluxed in 8 l of 95% ethanol for 18 hours. The mixture was diluted with water, filtered, and the ethanol was distilled off under reduced pressure. 1 l of water was added during the distillation in order to maintain the solids in solution. The aqueous solution was cooled by the addition of 2 kg of ice and acidified with concentrated hydrochloric acid (Congo Red) whilst stirring. The initially formed sticky precipitate crystallized on continued stirring to a dark-yellow solid which was filtered off, washed with water, and air-dried to give 2-(4-methyl-2,6-dinitroanilino)propionic acid (1 A), m.p.: 158°-161° C.
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27]C)=[O:26])=[CH:20][C:19]=3[F:29])=[C:14]([F:30])[CH:13]=2)[C:9]([CH3:31])=[N:8][C:7]=1[CH3:32])(=[O:5])[NH2:4].Cl>C(O)(C)(C)C>[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][C:19]=3[F:29])=[C:14]([F:30])[CH:13]=2)[C:9]([CH3:31])=[N:8][C:7]=1[CH3:32])(=[O:5])[NH2:4]
Reactant: COC(=O)Cc1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2F)c(F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: Cc1nc(C)c(-c2ccc(-c3ccc(CC(=O)O)cc3F)c(F)c2)nc1C(N)=O
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
Powdered potassium hydroxide (96 mg, 1.71 mmol) was added in one portion to methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,2′-difluorobiphenyl-4-yl)acetate (Intermediate 6-1; 234 mg, 0.57 mmol) in tert-butanol (10 mL) at 45° C. The resulting solution was stirred at 45° C. for 30 minutes, 2M HCl (2 mL) was added and the mixture was evaporated to remove the organic solvent. The suspension was collected by filtration, washed with water (5 mL) and dried under vacuum to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,2′-difluorobiphenyl-4-yl)acetic acid (132 mg, 58.5%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:7][C:6](=[O:8])[CH:5]([CH2:9][C:10](=O)[CH3:11])[C:4](=O)[CH2:3]1.C([O-])(=O)C.[NH4+:19].O>C(O)(=O)C>[CH3:11][C:10]1[NH:19][C:4]2[CH2:3][C:2]([CH3:14])([CH3:1])[CH2:7][C:6](=[O:8])[C:5]=2[CH:9]=1
Reactant: [NH4+]
Reactant: CC(=O)CC1C(=O)CC(C)(C)CC1=O
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc2c([nH]1)CC(C)(C)CC2=O
Temperature: 65 °C

Procedure:
The crude tri-ketone from Example 37 was dissolved in 300 mL of acetic acid to which ammonium acetate (55 g, 0.714 mmol) was added. The reaction mixture was heated at 65° C. until all starting material had disappeared (2-3 h), cooled to RT, added to H2O, and washed with EtOAc. The organic layer was washed with saturated NaHCO3 (×3), brine (×1) and dried over MgSO4. Solvent was removed in vacuo and the oily residue was passed through a plug of silica. The appropriate fractions were collected and solvent was removed. The resulting solid was washed with EtOAc and hexanes (if too much hexanes is added the material crashing back out of solution after the addition of EtOAc will be gummy. To remedy this simply add a little EtOAc). The solid was filtered and washed with hexanes. More solid can be recovered by removing the solvent and repeating this procedure. LCMS m/z M+H=178.1. Approximately 5 g of a tan solid was collected and identified as 2,6,6-trimethyltetrahydroindol-4-one.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[S:21][CH:22]=[CH:23][N:24]=3)=[CH:16][C:15]=2[CH:25]2[CH2:30][C:29]([CH3:32])([CH3:31])[CH2:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.ClCCl.[OH-].[Na+]>O.C(OCC)(=O)C>[CH3:31][C:29]1([CH3:32])[CH2:28][C:27]([CH3:33])([CH3:34])[CH2:26][CH:25]([C:15]2[CH:16]=[C:17]([C:20]3[S:21][CH:22]=[CH:23][N:24]=3)[CH:18]=[CH:19][C:14]=2[N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:30]1
Reactant: CC1(C)CC(c2cc(-c3nccs3)ccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CC(c2cc(-c3nccs3)ccc2N2CCNCC2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 101.4 %

Procedure:
A mixture of 4-[2-(3,3,5,5-tetramethylcyclohexyl)-4-thiazol-2-ylphenyl]piperazine-1-carboxylic acid t-butyl ester (113 mg, 0.234 mmol) produced in Example (99b), trifluoroacetic acid (0.3 mL, 3.89 mmol) and dichloromethane (2 mL) was stirred for 1 hour and 50 minutes at room temperature. The reaction mixture was cooled in an ice water bath, and then 5N aqueous solution of sodium hydroxide was added thereto to make the mixture basic. Next, ethyl acetate and water were added and extraction was performed with ethyl acetate. The separated organic layer was washed with water and brine and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure to give 91 mg of a crude product of the title compound as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:23]([O:25]CC)=[CH2:24])CCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([C:23](=[O:25])[CH3:24])=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)c1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 600 mg of the compound [1-1], 75 mg of dichlorobis(triphenylphosphine)palladium (II), 743 μL of tributyl (1-ethoxyvinyl)tin, and 3 mL of 1,4-dioxane, was stirred overnight at 100° C. After standing to cool, the insolubles were filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=8/2) to obtain 367 mg of tert-butyl[(1S)-1-(4-acetylphenyl)ethyl]carbamate [1-2] (hereinafter, referred to as the compound [1-2]) as a colorless solid.
Reaction SMILES: [OH:1][CH:2]([CH2:10][OH:11])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[C:12]([C:14]1[CH:19]=[CH:18][N:17]=[N:16][C:15]=1[Cl:20])#[N:13]>O1CCOCC1.Cl.C(O)(C)C>[ClH:20].[ClH:20].[C:12]([C:14]1[CH:19]=[CH:18][N:17]=[N:16][C:15]=1[N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:10][OH:11])[CH2:5][CH2:6]1)#[N:13]
Reactant: OCC(O)CN1CCNCC1
Reactant: N#Cc1ccnnc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: N#Cc1ccnnc1N1CCN(CC(O)CO)CC1

Procedure:
Grams 6.9 of 1-(2,3-dihydroxypropyl)piperazine and 3.0 g of 4-cyano-3-chloropyridazine in 60 ml dioxane were refluxed for 2 hours. The reaction mixture was settled, the supernatant liquor evaporated to dryness and the residue, which formed, was dissolved in 10 ml concentrated hydrochloric acid and diluted with 10 volumes of isopropanol. A precipitate was obtained formed by a gummy oil, which solidified afterwards giving 5.9 g of 3-[4-(4-cyanopyridazin-3-yl)piperazin-1yl]propane-1,2-diol dihydrochloride which melted at 128°-130° C.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([O:14][CH2:15][CH3:16])[C:11]([CH3:18])([CH3:17])[C:10]=2[CH:19]=1)(=[O:4])=[O:3].C(OC(=O)C)(=[O:22])C.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([O:14][C:15](=[O:22])[CH3:16])[C:11]([CH3:18])([CH3:17])[C:10]=2[CH:19]=1)(=[O:3])=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC1Oc2ccc(OS(C)(=O)=O)cc2C1(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)OC1Oc2ccc(OS(C)(=O)=O)cc2C1(C)C
Reaction time: 2 h

Procedure:
2-ethoxy-2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate (7 parts) was treated with a mixture of acetic anhydride (20 parts) and sulphuric acid (0.6 parts) and left at 50° C. for two hours. The solution was then poured into an excess of ice and sodium bicarbonate. An oil precipitated which solidified and was filtered off and recrystallised from 90, aqueous ethanol to give 2-acetoxy-2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate (6.6 parts) melting point 83°-85° C.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:6][CH:5]=[C:4]([CH2:25][OH:26])[N:3]=1.C([O-])(=O)C.[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:51]([O-:55])(=[O:54])[CH:52]=[CH2:53].[K+]>CN(C=O)C.O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.[Pd](Cl)Cl>[OH:26][CH2:25][C:4]1[N:3]=[C:2]([CH:53]=[CH:52][C:51]([OH:55])=[O:54])[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:6][CH:5]=1
Reactant: C=CC(=O)[O-]
Reactant: COc1ccc(CCCCCCCCOc2ccc(CO)nc2Br)cc1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CCCCCCCCOc2ccc(CO)nc2C=CC(=O)O)cc1
Temperature: 120 °C

Procedure:
To a solution of 2-bromo-6-hydroxymethyl-[8(4-methoxyphenyl)octyloxy]pyridine (5.00 g, 11.8 mmol) in DMF (22.8 ml) and water (1.2 ml) were added potassium acetate (2.91 g, 29.7 mmol), tetra-n-butylammonium iodide (4.37 g, 11.8 mmol); triphenylphosphine (0.245 g, 0.94 mmol), palladium chloride (83 mg, 0.47 mmol) and potassium acrylate (3.91 g, 35.4 mmol). The mixture was placed under nitrogen and stirred and heated at 120° C. for 3.3 h. Some potassium acrylate remained undissolved. The mixture was cooled, solids filtered and washed with ethyl acetate (2×60 ml). The filtrate was washed with water (250 ml) and with 5% sodium chloride solution (2×125 ml). The organic layer was dried and evaporated. The pure product was obtained by flash column chromatography (silica, 20% ether in dichloromethane) (3.52 g, 72%). mp 112°-114° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([O:14][CH2:15][CH3:16])[C:11]([OH:13])=O.Cl.Cl.[CH2:19]([O:26][C:27](=[O:39])[NH:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][NH2:38])=[CH:33][CH:32]=1)=[NH:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.CCN(CC)CC>[CH2:19]([O:26][C:27](=[O:39])[NH:28][C:29]([C:31]1[CH:32]=[CH:33][C:34]([CH2:37][NH:38][C:11](=[O:13])[CH:10]([C:3]2[C:4]([F:9])=[CH:5][C:6]([OH:8])=[CH:7][C:2]=2[F:1])[O:14][CH2:15][CH3:16])=[CH:35][CH:36]=1)=[NH:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(CN)cc1
Reactant: CCOC(C(=O)O)c1c(F)cc(O)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(C(=O)NCc1ccc(C(=N)NC(=O)OCc2ccccc2)cc1)c1c(F)cc(O)cc1F
Temperature: 25 °C
Yield: 67.6 %

Procedure:
(RS)-(2,6-Difluoro-4-hydroxy-phenyl)-ethoxy-acetic acid (2.3 g) was dissolved in DMF (75 ml) and [(4-aminomethyl-phenyl)-imino-methyl]-carbamic acid benzyl ester dihydrochloride [Prepared according to Ch. Lila, Ph. Gloanec, L. Cadet, Y. Hervé, J. Fournier, F. Leborgne, T. J. Verbeuren, G. De Nanteuil, Synthetic Communications 1998, 28, 23, 4419–4429] (3.18 g) and HOBt (2.15 g) were successively added. The slurry was cooled in an ice bath and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (3.05 g) was added. Et3N (8.0 ml) was slowly added. The resulting mixture was left to stir over night warming up to rt. After removing the solvent precipitation from CH2Cl2/MeOH 19:1 yielded the product. Drying over night on the high vacuum afforded 3.0 g (60 g) of pure (RS)-[(4-{[2-(2,6-difluoro-4-hydroxy-phenyl)-2-ethoxy-acetylamino]-methyl}-phenyl)-imino-methyl]-carbamic acid benzyl ester. White solid. MS 498.3 ([M+H]+).
Reaction SMILES: C([S:4][CH2:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:9]=[C:8]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:27])=[CH:21][CH:20]=2)[N:7]=1)(=N)N.Br[CH:36]1[CH2:40][CH2:39][NH:38][C:37]1=[O:41].[OH-].[Na+].CO>CN(C=O)C.O>[CH3:18][C@H:13]1[CH2:14][O:15][CH2:16][CH2:17][N:12]1[C:10]1[CH:11]=[C:6]([CH2:5][S:4][CH:36]2[CH2:40][CH2:39][NH:38][C:37]2=[O:41])[N:7]=[C:8]([C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:27])=[CH:23][CH:24]=2)[N:9]=1
Reactant: O=C1NCCC1Br
Reactant: C[C@H]1COCCN1c1cc(CSC(=N)N)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: C[C@H]1COCCN1c1cc(CSC2CCNC2=O)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
1-[4-[4-(Carbamimidoylsulfanylmethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-phenyl-urea (125 mg) was dissolved in DMF (3 mL). The solution was then treated with 3-bromo-pyrrolidin-2-one (48 mg) followed by sodium hydroxide (42 mg) in water (1 mL), heated to 40° C. and left to stir for 24 h. The reaction was diluted in a little methanol and loaded onto a SCX-2 column (20 g), which was washed with methanol and the desired product eluted with 7N ammonia in methanol to give the desired material which was used without further characterisation.