Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:8])[C:5](=O)[C:3](=[O:4])[C:2]=1[OH:7].[CH3:9][C:10]([C:13]1[O:14][C:15]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:16][C:17](=[CH:19]C2C(Cl)(Cl)C(=O)C=2Cl)[CH:18]=1)([CH3:12])[CH3:11]>OS(C(F)(F)F)(=O)=O>[CH3:12][C:10]([C:13]1[O:14][C:15]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:16][C:17](=[CH:19][C:5]2[C:3](=[O:4])[C:2](=[O:7])[C:1]=2[OH:8])[CH:18]=1)([CH3:9])[CH3:11]
Reactant: CC(C)(C)C1=CC(=CC2=C(Cl)C(=O)C2(Cl)Cl)C=C(C(C)(C)C)O1
Reactant: O=c1c(O)c(O)c1=O
Agent: O=S(=O)(O)C(F)(F)F
Product: CC(C)(C)C1=CC(=Cc2c(O)c(=O)c2=O)C=C(C(C)(C)C)O1
Reaction time: 5 h
Yield: 87 %

Procedure:
This Example illustrates the preparation, by a reaction analogous to D→E shown in FIG. 1, of the squaric acid derivative of Formula II in which Q1 is a 2,6-bis(1,1-dimethylethyl)-4-pyrylidene grouping and R1 is a hydrogen atom. 3-[2,6-Bis(1,1-dimethylethyl)-(4H-pyran-4-ylidene)-methyl]-2,4,4-tri-chlorocyclobut-2-en-1-one (100 mg, 0.27 mmole, prepared in Example 47 above), was dissolved in triflic acid (1 mL) and the resultant solution heated at 60° C. for 1 hour, 80° C. for a further 2 hours, and finally at 105° C. for 5 hours. The hot mixture was then poured over ice, and the resultant mixture stirred to give a solid precipitate. The mixture was extracted several times with dichloromethane, and the extracts were combined, washed with brine, dried over sodium sulfate and evaporated to dryness. The residue was redissolved in dichloromethane and applied to two preparative silica gel chromatography plates. Elution with 8% methanol in dichloromethane resulted in the development of many minor bands, with a major yellow band streaking from the origin. The major yellow band was extracted with methanol, the resultant solution evaporated to dryness, the residue dissolved in dichloromethane, and the solution filtered and evaporated to dryness. Pumping under high vacuum gave a yellow-brown solid (70 mg, 87% yield). The structure of the product was confirmed by proton NMR spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([OH:23])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.Br.Br[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)=O.C1CCN2C(=NCCC2)CC1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:20]2[C:21](=[O:23])[O:22][CH2:26][C:27]=2[C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)c(Cl)c1
Reactant: O=C(CBr)c1ccncc1
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1OCC(c2ccncc2)=C1c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11.7 %

Procedure:
To a stirred solution of 2-(3-chloro-4-(quinolin-2-ylmethoxy)phenyl)acetic acid (6.0 g, 0.01 mol) in acetonitrile (50 mL) were added TEA (2.58 mL, 0.02 mol) and 2-bromo-1-(pyridin-4-yl)ethanone hydrobromide (6.16 g, 0.02 mol) at RT under an inert atmosphere. The reaction mixture was stirred for 30 minutes, cooled to 0° C., and then DBU (5.5 mL, 0.03 mol) was added. The reaction was stirred for an additional 15 minutes and then quenched with HCl (1 N) and extracted with DCM (2×300 mL). The combined organic layers were washed with water, dried over Na2SO4, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 3-(3-chloro-4-(quinolin-2-ylmethoxy)phenyl)-4-(pyridin-4-yl)furan-2(5H)-one (500 mg) as a solid. 1H NMR (500 MHz, d6-DMSO): δ 8.64 (d, J=7.8 Hz, 2H), 8.50-8.44 (m, 1H), 8.04-7.98 (m, 2H), 7.8 (t, J=7.2 Hz, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.64 (t, J=7.2 Hz, 1H), 7.50 (s, 1H), 7.38-7.32 (m, 3H), 7.26-7.22 (m, 1H), 5.55 (s, 2H), 5.38 (s, 2H). MS: M+H: m/z=429.1. HPLC: 90%, (Condition-I).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]([CH2:21][CH:22]2[CH2:24][CH2:23]2)[CH2:19][NH2:20])=[CH:14][N:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:15]1[CH:16]=[N:17][C:12]([CH3:11])=[N:13][CH:14]=1)[CH2:21][CH:22]1[CH2:24][CH2:23]1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: Cc1ncc(C(CN)CC2CC2)cn1
Product: Cc1ncc(C(CNC(=O)c2ccccc2Cl)CC2CC2)cn1

Procedure:
From 2-chlorobenzoic acid and 2-(2-methyl-pyrimidin-5-yl)-3-cyclopropyl-propylamine. LCMS (MH+): m/z=330.1, tR (minutes, Method F)=2.32
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8](O)[CH3:9])[CH:5]=[CH:4][N:3]=1.C(N(S(F)(F)[F:17])CC)C>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([F:17])[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: CC(O)c1ccnc(Cl)n1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(F)c1ccnc(Cl)n1
Reaction time: 3 h
Yield: 49.2 %

Procedure:
To a solution of 1-(2-chloropyrimidin-4-yl)ethanol (150 mg, 0.950 mmol) in dichloromethane (3 mL) at 0° C. was added diethylaminosulfur trifluoride (183 mg, 1.14 mmol) dropwise and stirred for 3 hr. The solution was diluted with dichloromethane, washed with saturated aqueous NaHCO3, dried with MgSO4, and concentrated to dryness. Purification on silica gel by flash chromatography (0-50% EtOAc/hexanes) afforded 2-chloro-4-(1-fluoroethyl)pyrimidine (75 mg, 0.467 mmol, 49% yield) as a yellow oil. MS ESI: [M+H]+ m/z 161.0. 1H NMR (500 MHz, CDCl3) δ 8.67 (d, J=4.2, 1H), 7.46 (d, J=4.2, 1H), 5.58 (dq, J=6.7, 48, 1H), 1.74-1.57 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH3:9])[CH:5]=[C:4]([Cl:11])[N:3]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]([NH:15][CH:12]2[CH2:14][CH2:13]2)[CH3:9])[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: CC(=O)c1cc(Cl)nc(Cl)c1
Reactant: NC1CC1
Product: CC(NC1CC1)c1cc(Cl)nc(Cl)c1

Procedure:
1-(2,6-Dichloropyridin-4-yl)ethanone and cyclopropylamine were treated in the similar manner to Reference Example 6(6) to give N-[1-(2,6-dichloropyridin-4-yl)ethyl]-cyclopropylamine [Ex(297-1)] as a pale yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][C:6]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[C:38]([F:47])[CH:37]=1.C(N(CC)CC)C>O1CCCC1>[C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([NH:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[C:38]([F:47])[CH:37]=2)=[O:13])=[CH:7][C:6]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Reactant: COCCOc1cc(OCC(=O)O)ccc1C(C)(C)C
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCOc1cc(OCC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)ccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
To a tetrahydrofuran (THF) (3 ml) solution of [4-tert-butyl-3-(2-methoxyethoxy)phenoxy]acetic acid (100 mg, 0.35 mmol) was added 1,1′-carbonyl-diimidazole (63 mg, 0.39 mmol) and the mixture was stirred for 1 hour at ambient temperature. To the mixture was added N-[4-(aminomethyl)-2-fluorophenyl]methanesulfonamide hydrochloride (99 mg, 0.39 mmol) and triethyl amine (150 ul, 1.1 mmol) and the mixture was stirred for 1 hour at ambient temperature. After filtration to separate solvent and the resulting percipitate, the solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with ethyl acetate/hexane=1/1 to furnish 78 mg (46% yield) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:8]CC)(=[O:7])[C:2](OCC)=O.[O-]CC.[K+].[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1C)([O-:17])=[O:16]>CCOCC>[CH3:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([N+:15]([O-:17])=[O:16])[C:19]=1[CH2:2][C:1]([OH:8])=[O:7]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cccc([N+](=O)[O-])c1C
Agent: CC[O-]
Agent: [K+]
Solvent: CCOCC
Product: Cc1cccc([N+](=O)[O-])c1CC(=O)O
Yield: 45 %

Procedure:
Diethyl oxalate (30 mL) in 20 mL dry ether was added with stirring to 19 g potassium ethoxide suspended in 50 mL of dry ether. The mixture was cooled in an ice bath and 20 mL of 3-nitro-o-xylene in 20 mL of dry ether was slowly added. The thick dark red mixture was heated to reflux for 0.5 hr, concentrated to a dark red solid, and treated with 10% sodium hydroxide until almost all of the solid dissolved. The dark red mixture was treated with 30% hydrogen peroxide until the red color changed to yellow. The mixture was treated alternately with 10% sodium hydroxide and 30% hydrogen peroxide until the dark red color was no longer present. The solid was filtered and the filtrate acidified with 6 N hydrochloric acid. The resulting precipitate was collected by vacuum filtration, washed with water, and dried under vacuum to give 9.8 g (45% yield) of 2-methyl-6-nitrophenylacetic acid as an off-white solid. The solid was hydrogenated in methanol over 10% palladium on carbon to give 9.04 g of 4-methyl-2-oxindole as a white solid.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:17])=[CH:9]1)=O)(C)(C)C.[CH:18]([O-:20])=O.[NH4+]>CO.[Pd]>[O:20]([C:14]1[CH:15]=[C:16]2[C:11]([CH2:10][CH2:17][CH2:9][NH:8]2)=[CH:12][CH:13]=1)[C:18]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C[O-]
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2ccccc12
Agent: [Pd]
Agent: [NH4+]
Solvent: CO
Product: c1ccc(Oc2ccc3c(c2)NCCC3)cc1
Temperature: 60 °C

Procedure:
A well-stirred solution of Compound 7, where R1 is phenyl, R2A is benzyl, R3 is 3-methyl-indole-1-carboxylic acid tert-butyl ester and R4 is methyl, (0.1 g, 0.189 mmol) and ammonium formate (0.06 g 0.945 mmol) in 3 ml of MeOH in a capped vial was treated with 0.05 g of solid 10% palladium on charcoal. The mixture was heated at 60° C. for 1 h with stirring, filtered through celite bed and washed with MeOH. The crude product was further purified by filtration through a silica plug, washing with CH2Cl2/MeOH (20/1) to afford the 7-phenoxy-3,4-dihydro-2H-quinoline-4-spiro-5′-3′-(1H-indol-2-ylmethyl-1-carboxylic acid tert-butyl ester)-1′-methyl-imidazolidine-21, 4′-dione as a colorless oil in quantitative yields. 1H NMR (CDCl3) δ 8.13-8.02 (m, 2H); 7.76-7.64 (m, 2H); 7.35-6.90 (m, 9H); 6.63-6.60 (m, 1H); 6.17-6.12 (m, 2H); 4.81 (s, 2H); 4.18-3.91 (m, 2H); 3.77 (bs, 1H); 3.33-3.27 (m, 1H); 2.70 (s, 3H); 2.29-1.90 (m, 22H); 1.64 (s, 9H).
Reaction SMILES: [CH:1]1(/[CH:5]=[N:6]/[S@:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8])[CH2:4][CH2:3][CH2:2]1.[CH3:13][Mg]Br.CCOCC>O1CCCC1>[CH:1]1([C@H:5]([NH:6][S@:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8])[CH3:13])[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)[S@](=O)/N=C/C1CCC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@@H](N[S@@](=O)C(C)(C)C)C1CCC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Into a 10-L 4-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of (S)—N-[(1E)-cyclobutylmethylidene]-2-methylpropane-2-sulfinamide (200 g, 1.07 mol) in tetrahydrofuran (3000 mL). This was followed by the addition of methylmagnesium bromide in ether (1070 mL, 3.00 equiv) dropwise with stirring at −78° C. over 1 hr. The resulting solution was stirred for 1 h at −70° C., 1 h at −60° C., 1 h at −50° C. and 2 h at −40° C. The reaction was then quenched by the addition of 10 L of saturated aqueous NH4Cl solution. The resulting solution was extracted with 2×3 L of ether. The organic layers were combined, washed with 2×3 L of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was diluted with 250 mL of n-hexane. The resulting solid was collected and washed with 2×100 mL of cold n-hexane to afford (S)—N-[(1R)-1-cyclobutylethyl]-2-methylpropane-2-sulfinamide.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@H:18]3[CH2:20][O:19]3)=[CH:12][CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]>C(NCC)C.C1COCC1>[CH2:1]([C:5]1[N:6]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)=[CH:23][CH:22]=2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@H:18]([OH:19])[CH2:20][N:6]([CH2:7][CH3:8])[CH2:5][CH3:1])=[CH:12][CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-c2ccc(OC[C@H]3CO3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: CCNCC
Solvent: C1CCOC1
Product: CCCCc1nc(-c2ccc(OC[C@H](O)CN(CC)CC)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A solution of 2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-((R)-1-oxiranylmethoxy)-phenyl]-1H-imidazole (100 mg, 2.1 mmol, from intermediate A2) in 1 mL of diethylamine and 2 mL of THF was stirred at 76° C. for 1 h in a microwave reactor. Upon completion (determined by LC/MS), the reaction was evaporated in vacuo and purified by silica gel flash column chromatography using a gradient of EtOAc to 96% EtOAc/(2M NH3/MeOH) as an eluent to afford (R)-1-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-3-diethylamino-propan-2-ol.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[C:6](/OS(C(F)(F)F)(=O)=O)=[CH:7]/[C:8]([O:10][CH2:11][CH3:12])=[O:9].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:29]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)#[N:30]>O1CCOCC1>[C:29]([C:31]1[CH:36]=[C:35](/[C:6](/[C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:7]\[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:34]=[CH:33][CH:32]=1)#[N:30]
Reactant: CCOC(=O)/C=C(\OS(=O)(=O)C(F)(F)F)c1ccco1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)/C=C(\c1cccc(C#N)c1)c1ccco1
Reaction time: 8 h
Yield: 23.5 %

Procedure:
To a solution of ethyl (Z)-3-(2-furyl)-3-{[(trifluoromethyl)sulfonyl]-oxy}-2-propenoate (500 mg, 1.59 mmol) in 7 ml anhydrous dioxane was added potassium phosphate (506 mg, 2.4 mmol), 3-cyanophenyl boronic acid (234 mg, 1.59 mmol), and tetrakis (triphenylphosphine)palladium(0) (46 mg, 0.04 mmol). Reaction mixture was heated to reflux and stirred overnight. Mixture was filtered through a pad of Celite, diluted with 50 ml ethyl acetate, washed with 2×50 ml water, 2×50 ml saturated brine solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was chromatographed on silica gel using a gradient from 5% EtOAc in hexane to 10% EtOAc in hexane as the eluent to give ethyl (E) 3-(3-cyanophenyl)-3-(2-furyl)-2-propenoate (100 mg, 24%) as a clear yellow oil after drying. H1NMR (CDCl3) 1.1-1.14 (t, 3H); 4.016-4.035 (m, 2H); 5.293 (s, H); 7.45-7.549 (m, 3H); 7.669 (m, H). ES-MS (M+H+): 268.05
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[C:19]([CH3:20])=[CH:18][C:12]2[CH:13]([CH3:17])[C:14](=[O:16])[O:15][C:11]=2[CH:10]=1)C1C=CC=CC=1.[H][H]>O1CCOCC1.[Pd]>[NH2:8][C:9]1[C:19]([CH3:20])=[CH:18][C:12]2[CH:13]([CH3:17])[C:14](=[O:16])[O:15][C:11]=2[CH:10]=1
Reactant: [H][H]
Reactant: Cc1cc2c(cc1N(Cc1ccccc1)Cc1ccccc1)OC(=O)C2C
Agent: [Pd]
Solvent: C1COCCO1
Product: Cc1cc2c(cc1N)OC(=O)C2C

Procedure:
4 g of 6-dibenzylamino-3,5-dimethylbenzofuran-2(3H)-one are dissolved in 40 ml of dioxane and reduction is carried out at room temperature, under normal pressure, with hydrogen and with 0.4 g of palladium-on-carbon. The mixture is then filtered, and the filtrate is concentrated to dryness by evaporation and recrystallised from methanol. In this manner 6-amino-3,5-dimethylbenzofuran-2(3H)-one having a melting point of 123°-124° C. is obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[C:7]([F:15])[CH:6]=1)(=[O:3])[CH3:2].[NH2:16][C:17]1[CH:18]=[CH:19][C:20]2[CH2:24][O:23][B:22]([OH:25])[C:21]=2[CH:26]=1.C(N(CC)CC)C.Cl>CN(C)C=O>[F:15][C:7]1[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=[CH:9][C:8]=1[S:11](=[O:13])(=[O:12])[NH:16][C:17]1[CH:18]=[CH:19][C:20]2[CH2:24][O:23][B:22]([OH:25])[C:21]=2[CH:26]=1
Reactant: Nc1ccc2c(c1)B(O)OC2
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)c(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(F)c1
Yield: 73.8 %

Procedure:
A solution of 4-acetamido-2-fluorobenzene-1-sulfonyl chloride (1.47 g, 5.84 mmol) and 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (0.870 g, 5.84 mmol), triethylamine (8.2 mL, 58.4 mmol), and N,N-dimethylformamide (30 mL) was stirred for one hour at room temperature. The solution was then made to pH 5 using 6 N hydrochloric acid. The solution was then extracted using ethyl acetate and water. The organic layer was washed five times with water, and then washed with brine. The organic layer was dried over sodium sulfate and filtered. The solvent was removed under reduced pressure to give N-(3-fluoro-4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetamide (1.57 g, 74% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 2.04 (s, 3H), 4.85 (s, 2H), 7.17 (dd, J=2.1 Hz, J=8.2 Hz, 1H), 7.24 (d, J=8.2 Hz, 1H), 7.30 (dd, J=1.8 Hz, J=8.7 Hz, 1H), 7.45 (d, J=1.7 Hz, 1H), 7.65-7.70 (m, 2H), 9.19 (s, 1H), 10.41 (s, 1H), 10.44 (s, 1H)
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31](O)[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH2:37]2)=[CH:24]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>>[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31]([O:9][C:8](=[O:10])[CH:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][CH:13]=2)[CH2:11][CH3:12])[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:45])[CH3:46])[CH2:37]2)=[CH:24]1)([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16]
Reactant: CCC(Oc1ccc(Br)cc1)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CCC(Oc1ccc(Br)cc1)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 96 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 0.94 g of (2RS)-2-(4-bromophenoxy)butyric acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.38 g of the title compound as a colorless foam.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[CH2:8]([O:15][C:16](Cl)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([O:15][C:16]([NH:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@H](CO)C(=O)O
Product: O=C(N[C@H](CO)C(=O)O)OCc1ccccc1

Procedure:
The second method describes the process, wherein D-serine is protected with benzyloxycarbonyl chloride to give N-Benzyloxycarbonyl-D-serine of Formula-IV. The compound of Formula-IV on alkylation with methyl iodide in the presence of silver oxide and solvent acetonitrile yields the compound (2R)-methyl 2-(benzyloxycarbonylamino)-3-methoxypropanoate of Formula-V, and which is purified by flash column chromatography using silica gel and methanol-chloroform eluent before the next stage. The compound of Formula-V is hydrolyzed to give (2R)-2-(benzyloxycarbonylamino)-3-methoxypropanoic acid of Formula-VI. The compound of Formula-VI is cooled to −78° C. in tetrahydrofuran and reacted with isobutyl chloroformate in presence of N-methylmorpholine followed by reaction with benzylamine to yield the compound (2R)-benzyl 1-(benzylamino)-3-methoxy-1-oxopropan-2-ylcarbamate of Formula-VII. The compound of Formula-VII on hydrogenation using palladium on carbon gives deprotected compound (2R)-2-amino-N-benzyl-3-methoxy-propanamide of Formula-VIII. The compound of Formula-VIII is acetylated using acetic anhydride in the presence of solvent pyridine to give crude Lacosamide of the Formula-I. The crude compound is purified by flash column chromatography to give pure Lacosamide.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]1[C:18]2[C:13](=[C:14]([O:21][CH3:22])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[C:11]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:10]=1>>[CH3:22][O:21][C:14]1[C:15]([O:19][CH3:20])=[CH:16][CH:17]=[C:18]2[C:13]=1[CH:12]=[C:11]([NH:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1)[N:10]=[C:9]2[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1OC
Product: COc1ccc2c(Oc3ccccc3)nc(Nc3cc(C)[nH]n3)cc2c1OC

Procedure:
Similar procedure as described in example 10 was used, starting from phenol and (1-chloro-5,6-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (5,6-dimethoxy-1-phenoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 367(MH+).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH:9]([C:11]([CH3:13])=O)=[CH2:10]>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[CH:10][CH:9]=[C:11]2[CH3:13]
Reactant: C=CC(C)=O
Reactant: Nc1ccccc1F
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: Cc1ccnc2c(F)cccc12
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 65 %

Procedure:
To a stirred solution of 2-fluoroaniline (1 g. 9.0 mmol.) in acetic acid (10 ml), activated silferc (1.4 g. ferric chloride 9.0 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred for 5 minutes and methyl vinyl ketone (MVK) (0.7 g, 9.9 mmol) was added slowly over a period of 15 minutes. The reaction mixture was heated to 70° C. and maintained between 70-75° C. for one hour. Anhydrous zinc chloride (1.2 g. 9.0 mmol) was added and the reaction was further refluxed for two hours. The reaction mixture was cooled, filtered, basified with 10% NaOH solution, extracted with ethyl acetate (3×20 ml), dried over Na2SO4 and evaporated to give the product; Yield 65%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][N:15]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16]2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][N:15]4[CH2:19][CH2:18][CH:17]([C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=5)[CH2:16]4)=[CH:6][CH:7]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CN1CCC(c2ccccc2)C1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN4CCC(c5ccccc5)C4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 5-(4-bromo-phenyl)-3-methyl-4-(3-phenyl-pyrrolidin-1-ylmethyl)-isoxazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[CH2:13]([N:15](CC)[CH2:16]C)C.CNC.O1CCCC1>C(#N)C>[CH3:13][N:15]([CH3:16])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: CNC
Solvent: CC#N
Solvent: C1CCOC1
Product: CN(C)CCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A pressure tube was charged with 1-(2-bromoethyl)-4-nitrobenzene (1 g, 4.35 mmol) in acetonitrile (5 mL). Triethylamine (2.4 mL) and dimethylamine, 2M in tetrahydrofuran (0.784 g, 17.39 mmol) were added, and the sealed tube was stirred at ambient temperature for 2 days. The reaction mixture was partitioned between dilute NaHCO3 solution and ethyl acetate, then extracted another two times with ethyl acetate. The product was then extracted into 2N HCl (2×25 mL). Following neutralization with 2N NaOH, the aqueous mixture was extracted with ethyl acetate (3×). The extracts were dried (Na2SO4), filtered and concentrated to give the title compound. MS (ESI(+)) m/e 194.9 (M+H)+.