Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([CH3:21])=[C:10]1[C:22](OCC)=[O:23].[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]=[C:38](Cl)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[O:45][CH3:46]>>[CH3:20][C:13]1[NH:12][C:11]2[CH:21]=[C:38]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[O:45][CH3:46])[N:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[O:30][CH3:29])[C:22](=[O:23])[C:10]=2[CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:28])([F:1])[F:27])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: COc1ccccc1N=C(Cl)c1ccccc1OC
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Product: CCOC(=O)C1=C(C)Nc2cc(-c3ccccc3OC)n(-c3ccccc3OC)c(=O)c2C1c1ccccc1C(F)(F)F

Procedure:
This product is obtained using the procedure of Example 1 from diethyl 1,4-dihydro-4-(2-trifluoromethylphenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate and N-(2-methoxyphenyl)-2-methoxy-benzimidoyl chloride (1.2 g, 4.1%).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]2[CH:9]=[C:10]3[N:14]([C:7]=2[CH:6]=[CH:5][N:4]=1)[CH2:13][CH2:12][CH:11]3O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[C:43]([O:50][CH3:51])(=[O:49])[CH2:44][C:45]([O:47][CH3:48])=[O:46]>C1COCC1>[CH3:1][S:2][C:3]1[C:8]2[CH:9]=[C:10]3[N:14]([C:7]=2[CH:6]=[CH:5][N:4]=1)[CH2:13][CH2:12][CH:11]3[CH:44]([C:43]([O:50][CH3:51])=[O:49])[C:45]([O:47][CH3:48])=[O:46]
Reactant: CSc1nccc2c1cc1n2CCC1O
Reactant: COC(=O)CC(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC)C1CCn2c1cc1c(SC)nccc12

Procedure:
To a suspension of 1-(methylthio)-7,8-dihydro-6H-pyrido[3,4-b]pyrrolizin-8-ol (0.54 g, 2.1 mmol) in THF (10 mL) at −78° C. were added 1M NaHMDS in THF (2.35 mL, 2.4 mmol) and diphenyl chlorophosphate (0.53 mL, 2.6 mmol). After a period of 30 min. dimethyl malonate (0.73 mL, 6.4 mmol) and 1M NaHMDS in THF (6.8 mL, 6.8 mmol) were added. The reaction mixture was brought to 0° C. and then to room temperature. The mixture was then partitioned between ETOAc and NH4Cl. The organic phase was dried over MgSO4, filtered and evaporated. The title compound was purified by flash chromatography.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH2:8]([O:11][N:12]=[C:13]([C:17]1[N:18]=[C:19]([NH2:22])[S:20][CH:21]=1)[C:14]([OH:16])=[O:15])[C:9]#[CH:10].C(OC(C)C)(C)C>C(O)=O>[CH2:8]([O:11][N:12]=[C:13]([C:17]1[N:18]=[C:19]([NH:22][CH:1]=[O:3])[S:20][CH:21]=1)[C:14]([OH:16])=[O:15])[C:9]#[CH:10]
Reactant: CC(=O)OC(C)=O
Reactant: C#CCON=C(C(=O)O)c1csc(N)n1
Solvent: O=CO
Solvent: CC(C)OC(C)C
Product: C#CCON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Formic acid (107 g.) was added to acetic anhydride (239 g.) under ice-cooling, and the mixture was stirred for 1 hour at 50° C. and then cooled to 20° C. To the mixture was added 2-(2-propynyloxyimino)-2-(2-aminothiazol-4-yl)acetic acid (syn isomer) (135 g.), and the mixture was stirred for 3 hours at ambient temperature. To the mixture was added diisopropyl ether (400 ml.) and then the precipitated crystals were collected by filtration, washed with diisopropyl ether and then dried to give 2-(2-propynyloxyimino)-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (118.4 g.).
Reaction SMILES: [C:1]([CH:4]([C:12](=O)[CH3:13])[CH:5]([C:9](=O)[CH3:10])[C:6](=O)[CH3:7])(=O)[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][C:17]=1[CH2:25][OH:26].CC(O)=O.[NH2:31][NH2:32]>CCO>[CH2:23]([O:22][C:19]1[CH:20]=[CH:21][C:16]([N:15]2[C:1]([CH3:2])=[C:4]3[C:5]([C:9]([CH3:10])=[N:31][N:32]=[C:12]3[CH3:13])=[C:6]2[CH3:7])=[C:17]([CH2:25][OH:26])[CH:18]=1)[CH3:24]
Reactant: CC(=O)C(C(C)=O)C(C(C)=O)C(C)=O
Reactant: NN
Reactant: CCOc1ccc(N)c(CO)c1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOc1ccc(-n2c(C)c3c(C)nnc(C)c3c2C)c(CO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1,1,2,2-tetraacetylethane (600 mg, 3.0 mol) and (2-amino-5-ethoxy-phenyl)-methanol (496 mg, 3.0 mmol) was refluxed in EtOH (10 mL)/AcOH (1%) for 14 h. It was cooled to rt, and anhydrous hydrazine (200 μL, 6.3 mmol) was added. After stirring at rt for 1 h, the reaction mixture was poured into ice water (50 mL). The resulting precipitate was filtered, washed with diethyl ether (20 mL), and then dried under vacuum to afford [5-ethoxy-2-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-phenyl]-methanol as a pale yellow solid: 1H NMR (CDCl3, 500 MHz) δ 7.22 (s, 1H), 6.95 (m, 2H), 4.40 (s, 2H), 4.16 (q, 2H), 2.66 (s, 6H), 2.41 (s, 6H), 1.50 (t, 3H); MS (ESI) 326 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH:5]=[O:6])([CH3:4])[CH3:3].[Li][CH2:8][CH2:9][CH2:10][CH3:11]>C1COCC1.CCCCCC>[CH3:1][C:2]([CH3:4])([CH:5]([OH:6])[CH2:8][CH2:9][CH2:10][CH3:11])[CH3:3]
Reactant: CC(C)(C)C=O
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCC(O)C(C)(C)C
Temperature: -65 °C
Reaction time: 1 h

Procedure:
20 g (0.232 mol) of pivaldehyde dissolved in 600 mL of THF was added to a 2 L 3-neck round bottom flask equipped with a magnetic stir bar, thermometer and rubber stopper. The vessel was maintained under N2. The reaction mixture was cooled to −65° C. in a dry ice/acetone bath. 112 mL (0.279 mol) of a 2.5 M BuLi solution in hexane was slowly added in 5 mL portions with a 20 mL glass syringe, maintaining the temperature below −55° c. The reaction was stirred at −60° C. for one hour, then allowed to warm to −5° C. over one hour. The reaction was cooled again to −60° C. and slowly quenched with NH4Cl/H2O solution, maintaining the temperature below −50° C. 100 mL of water were added and the reaction was allowed to warm to room temperature. The THF was removed on a rotary evaporator with a bath temperature of 25° C. until an oil was observed. The product was extracted with ethyl ether, and the ether was dried and evaporated carefully to yield 31.0 g of 2,2-dimethyl-heptan-3-ol that was used directly in a subsequent oxidation reaction. 1H NMR (CDCl3, 500 MHz) δ (ppm): 3.2 (m, 1H), 1.2-1.7 (m, 3H), 0.93 (m, 3H), 0.89 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.[CH3:13][N:14]=[C:15]=[O:16].[CH3:17][C:18]([CH3:20])=O>>[Cl:12][C:8]1[C:9]([Cl:11])=[CH:10][C:4]2[N:3]=[C:2]3[NH:1][C:18]([CH3:20])([CH3:17])[N:14]([CH3:13])[C:15](=[O:16])[N:6]3[C:5]=2[CH:7]=1
Reactant: CN=C=O
Reactant: CC(C)=O
Reactant: Nc1nc2cc(Cl)c(Cl)cc2[nH]1
Product: CN1C(=O)n2c(nc3cc(Cl)c(Cl)cc32)NC1(C)C

Procedure:
Reaction of 2-amino-5,6-dichlorobenzimidazole with acetone and methyl isocyanate according to the procedure of Example 1, first paragraph, provided the title compound. In this case, a 10-N-methylcarbamoyl derivative was not isolated from the reaction mixture. The product was recrystallized from acetone to give a solid, mp 220° C. (dec.). The confirmatory elemental analysis is shown in Table III.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].Br[CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[I:36]>>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:29]=[CH:28][C:27]=3[I:36])[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: FC(F)(F)c1ccc(I)c(CBr)c1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I

Procedure:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (400 mg, 1.28 mmol) was treated with NaH (60% in oil, 128 mg, 3.2 mmol) and 2-(bromomethyl)-1-iodo-4-(trifluoromethyl)benzene (Example 70, 466 mg, 1.28 mmol) as described in Example 66 to afford (4S,5R)-5-[3,5-b is(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one as a white solid. LCMS=598.0 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 8.06 (d, J=8.2 Hz, 1 H), 7.93 (s, 1 H), 7.82 (s, 2 H), 7.61 (s, 1 H), 7.33 (dd, J=8.2, 1.4 Hz, 1 H), 5.79 (d, J=7.8 hz, 1 H), 4.91 (d, J=16 Hz, 1 H), 4.40 (d, J=16 Hz, 1 H), 4.16-4.06 (m, 1 H), 0.83 (d, J=6.4 Hz, 3 H).
Reaction SMILES: [CH3:1][Mg]I.[CH3:4][C:5]1[CH:10]=[C:9]([O:11]C)[C:8](C)=[CH:7][C:6]=1[CH:14]=[CH:15][C:16](OCC)=O.O.C[CH2:23][O:24][CH2:25][CH3:26]>>[CH3:4][C:5]1[CH:26]=[C:25]([O:24][CH3:23])[C:15]([CH3:16])=[CH:14][C:6]=1[CH:7]=[CH:8][C:9]([CH3:10])([OH:11])[CH3:1]
Reactant: C[Mg]I
Reactant: CCOC(=O)C=Cc1cc(C)c(OC)cc1C
Reactant: CCOCC
Solvent: O
Product: COc1cc(C)c(C=CC(C)(C)O)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 0.3M of methyl magnesium iodide in 100 ml of ether, stirred under a nitrogen atmosphere and in a cooling bath of -5° C., was added dropwise a solution of ethyl 3-(2,5-dimethyl-4-methoxyphenyl)-acrylate (23.4 g, 0.1M) in 50 ml of diethyl ether. This mixture was stirred for 3 hours at room temperature. Cold water (150 ml) was added, and the product was extracted into ether. The ethereal layer was washed with brine, dried (magnesium sulfate) and concentrated on rotary evaporator to give 21.4 g of 4-(2,5-dimethyl-4-methoxyphenyl)-2-methyl-3-buten-2-ol as yellow powder.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[N:4]1)[CH3:2].S(Cl)([Cl:12])=O>C(Cl)Cl>[ClH:12].[Cl:12][CH2:8][C:5]1[CH:6]=[CH:7][N:3]([CH2:1][CH3:2])[N:4]=1
Reactant: CCn1ccc(CO)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCn1ccc(CCl)n1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
To (1-ethyl-1H-pyrazol-3-yl)methanol (4.41 g, 34.96 mmol) in DCM (30 mL) at 0° C. was cautiously added thionyl chloride (15.26 mL, 209.7 mmol). The cold bath was removed and the reaction mixture was stirred at ambient temperature for 3 hours. The mixture was concentrated under reduced pressure to give the crude product (5.78 g) which was used directly in the next step.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]#[N:7])[CH:3]=[C:2]1[C:8]#[N:9].[H-].[Na+].[NH2:12]OP(=O)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C=O)C>[NH2:12][N:1]1[CH:5]=[C:4]([C:6]#[N:7])[CH:3]=[C:2]1[C:8]#[N:9]
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Reactant: N#Cc1c[nH]c(C#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C#N)n(N)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.7 %

Procedure:
To a solution of DMF (100 mL) was added 1H-pyrrole-2,4-dicarbonitrile (1.00 g, 8.54 mmol) followed by NaH, 60% dispersion in mineral oil (0.51 g, 12.8 mmol). The solution was stirred at rt for 15 min and then (aminooxy)(diphenyl)phosphine oxide (2.99 g, 12.8 mmol) was added, and the solution was heated to 80° C. for 2 h. Upon cooling to rt the solution was filtered washing with CH2Cl2. The solution was partially concentrated and a white precipitate formed which was filtered. The mother liquor was then evaporated under vacuum and subsequently purified by MPLC (Isco) 100% CH2Cl2 ramping to 9:1 v/v CH2Cl2-EtOAc. The resulting purified fractions were combined and concentrated in vacuo yielding 0.92 g of a white solid (6.98 mmol, yield 82%). 1H-NMR (DMSO-d6) 7.92 (d, J=1.8 Hz, 1H), 7.39 (d, J=1.9 Hz, 1H), 6.66 (s, 2H); MS [M+H]+=133.0; LCMS RT=0.96 min.
Reaction SMILES: C1(C=[N:8][N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[C:10]2=[O:19])C=CC=CC=1.C1(C=NN2CCN(CCCCI)C2=O)C=CC=CC=1.[H][H].[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[O:52][C:51]([CH:53]=O)=[CH:50][CH:49]=2)=[CH:44][CH:43]=1>Cl.[Pd].CN(C)C=O>[ClH:41].[Cl:41][C:42]1[CH:43]=[CH:44][C:45]([C:48]2[O:52][C:51]([CH:53]=[N:8][N:9]3[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([CH3:17])[CH3:18])[C:10]3=[O:19])=[CH:50][CH:49]=2)=[CH:46][CH:47]=1
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2)o1
Reactant: [H][H]
Reactant: CN(C)CCN1CCN(N=Cc2ccccc2)C1=O
Agent: [Pd]
Agent: Cl
Agent: O=C1N(CCCCI)CCN1N=Cc1ccccc1
Solvent: CN(C)C=O
Product: CN(C)CCN1CCN(N=Cc2ccc(-c3ccc(Cl)cc3)o2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-phenylmethyleneamino-3-[2-(dimethylamino)ethyl]-2-imidazolidinone, prepared as described in Part II above (6.17 g, 0.023 mole) in 2N HCl (166 ml) is treated with 5% palladium on carbon (50% wet catalyst) (1.3 g). The reaction mixture is reduced on Parr apparatus under hydrogen. The hydrogen uptake stopped after 1/2 hour with 100% of theoretical uptake observed. The catalyst is removed and the filtrate concentrated under reduced pressure to leave a white residue. The residue is treated with a solution of 5-(4-chlorophenyl)-2-furancarboxaldehyde (prepared as described in U.S. Pat. No. 4,882,354 to Huang et al., assigned to Norwich Eaton Pharmaceuticals, Inc., issued Nov. 21, 1989, see Example 3, cols. 7, 8, hereby incorporated by reference herein) (4.81 g, 0.023 mole) in dry dimethylformamide (137 ml). The reaction is stirred at ambient temperature overnight. The reaction mixture is filtered and washed with anhydrous ether to give 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-[2-(dimethylamino) ethyl]-2-imidazolidinone hydrochloride.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.[C:12](OC(=O)C)(=[O:14])[CH3:13].[Cl-].[Na+]>C1(C)C=CC=CC=1>[CH3:8][C:6]1([CH3:9])[CH2:7][CH:2]([NH:1][C:12](=[O:14])[CH3:13])[CH2:3][C:4]([CH3:11])([CH3:10])[NH:5]1
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)CC(N)CC(C)(C)N1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)NC1CC(C)(C)NC(C)(C)C1
Reaction time: 0.5 h
Yield: 874.6 %

Procedure:
A solution of 100.0 grams (64 mmol) of 4-amino-2,2,6,6-tetramethylpiperidine in 150 ml of toluene and a solution of 65.4 grams (64 mmol) of acetic anhydride in 175 ml of toluene are simultaneously added over a 45-minute period to a flask containing 150 ml of toluene. The reaction temperature is maintained at 25°-35° C. by using an ice water bath. The reaction mixture is stirred for 30 minutes after the addition is complete. Solids are separated by filtration, washed with ether and dissolved in 500 ml of water. This aqueous solution is added to a solution of 28 grams of sodium hydroxide in 100 ml of water. A crude solid is isolated by filtration and the filtrate is saturated with solid sodium chloride to precipitate more of the product. The solids are combined, dried and dissolved in warm isopropanol. The alcohol solution is filtered to remove salts, and the filtrate is concentrated to give an oil. The oil is crystallized from heptane to afford 111.0 grams (87% yield) of the title compound as a white solid melting at 100°-102° C.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14](=O)[CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:12]=2)[CH:7]=[CH:6]1.C1(C)C=CC=CC=1.Cl>[Zn].[Hg]Cl.O>[CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:12]=2)[CH:7]=[CH:6]1
Reactant: Cc1cccc(C)c1Cn1ccc2ccc(C(=O)CCC(=O)O)cc21
Agent: Cl
Agent: Cl[Hg]
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(C)c1Cn1ccc2ccc(CCCC(=O)O)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To an aqueous solution (2 mL) of zinc powder (1.2 g) was added mercury chloride (124 mg) at room temperature, and then the reaction mixture was stirred at room temperature for 30 minutes. To the reaction mixture were added the compound [59] obtained in Example 59 (73 mg), toluene (1 mL), water (1 mL) and concentrated hydrochloric acid (1 mL) at room temperature, and then the reaction mixture was heated at reflux for 4 hours. After cooling to room temperature, the reaction mixture was quenched with water, and extracted with chloroform. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (35 mg) as a yellow solid.
Reaction SMILES: [NH2:1][C@H:2]([C:12]([O:14][CH3:15])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].N1C=CC=CC=1.[C:22](Cl)(Cl)=[O:23].C1(C)C=CC=CC=1.[NH2:33][C:34]1[C:43]2[C:38](=[CH:39][C:40]([OH:44])=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1>ClCCl>[CH3:15][O:14][C:12](=[O:13])[C@@H:2]([NH:1][C:22]([NH:33][C:34]1[C:43]2[C:38](=[CH:39][C:40]([OH:44])=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1)=[O:23])[CH2:3][CH2:4][C:5]([O:6][C:7]([CH3:9])([CH3:10])[CH3:8])=[O:11]
Reactant: COC(=O)[C@@H](N)CCC(=O)OC(C)(C)C
Reactant: O=C(Cl)Cl
Reactant: Nc1cccc2cc(O)ccc12
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)Nc1cccc2cc(O)ccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To H-Glu(OtBu)-OCH3 (2.0 mmol, 0.50 g) in dichloromethane (25 mL) at 0° C. was added pyridine (8 mmol, 0.66 mL) then followed by dropwise addition of phosgene in toluene (3.0 mmol, 1.60 mL, 1.92 M). After stirring at 0° C. for 2 hours, 1-amino-6-naphthol (2.0 mmol, 0.32 g) was added in dichloromethane. After stirring at room temperature for 12 hours, the reaction mixture was evaporated to dryness and purified on silica gel (1:19, methanol/dichloromethane) to provide product as a light brown solid (0.71 g, 88%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4]N=1.[CH2:11]([O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH3:12].[C:25]([O-])([O-])=O.[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([C:25]2[CH:2]=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=[O:7])[CH:4]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH3:12]
Reactant: CCOc1cc(B(O)O)ccc1OC
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOc1cc(-c2cccc(C(=O)O)c2)ccc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.3 %

Procedure:
6-Bromonicotinic acid (2.02 g, 10.0 mmol) was dissolved in DME (80 mL) under nitrogen. Pd(PPh3)4 (0.58 g, 0.5 mmol) was added, and the resulting mixture was stirred at ambient temperature for 15 minutes. 3-ethoxy-4-methoxyphenylboronic acid (2.4 g, 12.2 mmol) and 2N Na2CO3 (40 mL, 80 mmol) were added, and the resulting mixture was heated to reflux with stirring for 24 hours. The mixture was poured into 300 mL of water and extracted with ethyl acetate (3×200 mL), and the product precipitated upon standing, providing 2.05 g of the product in 76% yield: 1H NMR (CDCl3) δ 1.53 (t, J=7.0 Hz, 3H), 3.96 (s, 3H), 4.22 (q, J=7.0 Hz, 2H), 7.00 (d, J=8.6 Hz, 1H), 7.53-7.58 (m, 2H), 7.91-8.02 (m, 2H), 8.12 (dd, J=6.9 Hz, J=1.5 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:18][CH2:19][NH2:20])[CH:5]=[C:6]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[C:7]=1[Cl:8].CCN(C(C)C)C(C)C.[C:30](O)(=[O:33])[CH2:31][CH3:32].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CCOCC.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:18][CH2:19][NH:20][C:30](=[O:33])[CH2:31][CH3:32])[CH:5]=[C:6]([CH2:9][O:10][Si:11]([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:12])[CH3:13])[C:7]=1[Cl:8]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(CCN)cc(Cl)c1Cl
Reactant: CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCC(=O)NCCc1cc(Cl)c(Cl)c(CO[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a DMF (0.2 M) solution of 2-[3,4-dichloro-5-({[(1,1-dimethylethyl)(dimethyl)-silyl]oxy}methyl)phenyl]ethanamine (1 eq.) from the previous step, Hunig's base (3 eq.) and propionic acid (1.1 eq.) was added portionwise O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.2 eq.). The resulting reaction solution was stirred at RT for 48 h. The now reddish solution was diluted with ether and washed sequentially with 1 N aq. NaOH, water and brine. The organic extract was then dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford a brown oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 7:3 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][C:6]=1[C:7]([O:9]C)=O.[NH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1.O>C1(C)C=CC=CC=1>[CH:13]1[C:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][C:6]([C:7]([NH:23][CH2:24][CH:25]2[NH:26][CH2:27][CH2:28][CH2:29][CH2:30]2)=[O:9])=[C:5]([O:4][CH2:3][C:2]([F:1])([F:22])[F:21])[CH:14]=1
Reactant: NCC1CCCCN1
Reactant: COC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(NCC1CCCCN1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Temperature: 25 °C
Yield: 87.1 %

Procedure:
A mixture of methyl 2,5-bis(2,2,2-trifluoroethoxy)benzoate (1.5 g), 2-(aminomethyl)piperidine (0.62 g) in toluene (3 ml) was stirred at reflux for 10 hours. After cooling to room temperature, water (10 ml) was added and two layers solution were separated. The aqueous layer was extracted with toluene (2×10 ml) and the combined organic layers were washed with water (3×10 ml). The organic layer was concentrated under reduced pressure to give Flecainide free base as a white solid (1.63 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[OH-].[K+].Cl[CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[O:12][CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C(C)Cl
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C(C)Oc1cc([N+](=O)[O-])c(F)cc1Cl
Reaction time: 0.5 h

Procedure:
At 22° C., 100 g (0.522 mol) of 2-chloro-4-fluoro-5-nitrophenol were added with stirring to a solution of 34.5 g (0.522 mol) of 85% strength potassium hydroxide in 500 ml of methanol, and the mixture was stirred for another 30 min. At 40° C., the reaction mixture was then concentrated under reduced pressure. The residue was dried at 50° C. in a vacuum cabinet overnight. The pulverulent residue was then, at 40° C., dissolved with stirring in 1 l of dimethylformamide (DMF), 70.7 g (0.574 mol) of methyl 2-chloropropionate were added dropwise at 50° C. over a period of 30 min and the mixture was stirred at 80° C. for another 2 h. The solvent was removed under reduced pressure, the residue was introduced into 700 ml of water and undissolved components were filtered off. The aqueous phase was extracted three times with in each case 300 ml of methyl tert-butyl ether. The combined organic extracts were washed with about 500 ml of saturated sodium chloride solution and dried over magnesium sulfate. Concentration gave 106 g (73.1% of theory) of the title compound as a colorless resin.