Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.ClCCl.[C:6]1([C:12]2[CH:16]=[CH:15][O:14][C:13]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[Br:1][C:15]1[O:14][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:16]=1
Reactant: BrBr
Reactant: CCOC(=O)c1occc1-c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1oc(Br)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Bromine (1.29 ml) was added to a dichloromethane (40 ml) solution of ethyl 3-phenyl-2-furancarboxylate (3.60 g) at 0° C. and stirred overnight at 25° C. The reaction solution was diluted with chloroform and washed with saturated aqueous sodium hydrogencarbonate solution, 20% aqueous sodium thiosulphate solution, and saturated brine. The organic layer was dried over MgSO4, and the solvent was evaporated under reduced pressure, thereby giving 3.50 g of ethyl 5-bromo-3-phenyl-2-furancarboxylate.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11].[Br:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[CH:24][C:21]=1[CH2:22]Br>CC(C)=O>[Br:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[CH:24][C:21]=1[CH2:22][O:18][C:16]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([OH:7])[CH:17]=1
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: COc1cc(Br)c(CBr)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCc2cc(OC)c(OC)cc2Br)cc1O
Temperature: 80 °C

Procedure:
Potassium carbonate (1.12 g) was added to a solution of methyl 2,4-dihydroxybenzoate (454 mg) and 2-bromo-4,5-dimethoxybenzyl bromide (1.0 g) in dry acetone (80 ml). The reaction mixture was heated to reflux at 80° C. for 4 hours. The solvents were removed under vacuum and the residue was re-dissolved in DCM and washed with water (3×). The organic layer was passed through a hydrophobic frit and concentrated under vacuum. The crude residue was purified by chromatography on silica gel, eluting with petrol and increasing amounts of ethyl acetate.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[C:3]=1[N+:10]([O-])=O.C(N(CC)CC)C.[NH:20]1[CH2:25][CH2:24][C:23]2([C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][C:26]2=[O:34])[CH2:22][CH2:21]1>CO.[Pd]>[NH2:10][C:3]1[C:2]([N:20]2[CH2:25][CH2:24][C:23]3([C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][C:26]3=[O:34])[CH2:22][CH2:21]2)=[N:7][CH:6]=[N:5][C:4]=1[NH:8][CH3:9]
Reactant: CNc1ncnc(Cl)c1[N+](=O)[O-]
Reactant: O=C1Nc2ccccc2C12CCNCC2
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CNc1ncnc(N2CCC3(CC2)C(=O)Nc2ccccc23)c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 6-chloro-N-methyl-5-nitropyrimidin-4-amine (1.0 g, 5.3 mmol) in methanol (20 mL) was added triethylamine (2.0 mL, 14.3 mmol) and spiro[indoline-3,4′-piperidin]-2-one (1072.5 mg, 5.3 mmol). The mixture was stirred at ambient temperature for 2 h and then 10 wt % Pd on C (wet) was added. The resulting mixture was stirred under hydrogen for 18 hours, diluted with methanol, and was filtered through Celite. The filtrate was concentrated, and the resulting solid was triturated with a solution of 50% aqueous methanol. The methanol was removed in vacuo and the mixture was filtered and dried under reduced pressure. The resulting compound was submitted to next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 7.86 (s, 1H), 7.45 (d, 1H), 7.20 (td, 1H), 6.98 (t, 1H), 6.87 (d, 1H), 6.30 (q, 1H), 4.15 (s, 2H), 3.45 (dd, 2H), 3.26-3.18 (m, 2H), 2.86 (d, 3H), 1.97-1.88 (m, 2H), 1.82 (dd, 2H). MS (EI) for C14H20N6O: 325.6 (MH+).
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][C:7]([Cl:19])=[CH:6][CH:5]=2.C[Sn](C)(C)[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCOCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[Cl:19][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[C:10]2[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: C[Sn](C)(C)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CCCc1c(Br)[nH]c2ccc(Cl)cc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CCCc1c(-c2ccc([N+](=O)[O-])cc2)[nH]c2ccc(Cl)cc12
Temperature: 50 °C
Yield: 31 %

Procedure:
A mixture of 200 mg (0.58.10−3 mol) of ethyl 2-bromo-5-chloro-1H-indole-3-butanoate, 498 mg (1.74.10−3 mol) of trimethyl(4-nitrophenyl)tin, 140 mg (0.46.10−3 mol) of triphenylarsine, 108 mg (0.12.10−3 mol) of tris(dibenzylideneacetone)dipalladium and 12 ml of dioxane is prepared and this reaction medium is heated at 50° C. for 6 days, with stirring. After cooling, 12 ml of water are added and the mixture is then extracted with ethyl ether. The organic phase is subsequently washed with water and then dried and concentrated under reduced pressure. The residue is purified by chromatography on silica gel using a petroleum ether/ethyl acetate mixture (85/15; v/v) as the eluent. The fractions containing the expected compound are purified again by reversed phase chromatography on C18-grafted silica using an acetonitrile/water mixture (7/3; v/v) as the eluent to give 70 mg of the expected compound in the form of a yellow paste (yield=31%).
Reaction SMILES: O[CH2:2][C:3]([O:5]C)=[O:4].ClC([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C(Cl)=O>C1COCC1.O>[C:12]1([CH2:2][C:3]([OH:5])=[O:4])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)CO
Reactant: O=C(Cl)C(Cl)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1ccccc1
Yield: 166.9 %

Procedure:
A mixture of methyl 2-hydroxyacetate (0.2 mol) in THF (100 ml) was stirred on an ice bath. 2-Chloro-2-phenylacetyl chloride (0.132 mol) was added dropwise. The mixture was stirred overnight, poured out in water and then stirred for 20 minutes. The mixture was extracted with DEPE. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 30 g of benzeneacetic acid, α-chloro-, 2-methoxy-2-oxoethyl ester (intermediate 43).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[N:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:19][N:18]=1.CC(O)CC.C1C2C(=CC=CC=2)C=NN=1>CCCCCC>[Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([NH:11][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:19][N:18]=2)=[CH:9][N:10]=1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Reactant: Nc1cnc(Oc2ccccc2Br)nc1
Agent: c1ccc2cnncc2c1
Solvent: CCC(C)O
Solvent: CCCCCC
Product: Brc1ccccc1Oc1ncc(Nc2nnc(-c3ccccc3)c3ccccc23)cn1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
2-(2-Bromophenoxy)pyrimidin-5-amine (3.01 g, 11.3 mmol), 1-chloro-4-phenylphthalazine (2.72 g, 11.3 mmol), and butan-2-ol (56.6 ml, 11.3 mmol) were placed in a sealed tube. The reaction vessel was sealed and mixture heated to 120° C. After 1.5 h, LCMS showed mainly product as [M+H]+=470 and a small amount of bromo starting material. 200 mg of phthalazine was added. After another 3.5 h, the reaction was cooled to RT. Hexane was added to allow a yellow solids to precipitate. The yellow solids were filtered and recrystallized with DCM and hexanes. The resulting dark brown solids were dried under vacuum overnight, affording the product, N-(2-(2-bromophenoxy)pyrimidin-5-yl)-4-phenylphthalazin-1-amine.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:21])[CH:19]=[CH2:20])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:4][CH2:3]1.[C:22]1([CH2:28][CH:29]=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:29]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:21])[CH:19]=[CH2:20])=[CH:13][CH:12]=2)(=[O:9])=[O:10])[CH2:4][CH2:3]1)[CH2:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=CCc1ccccc1
Reactant: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCC(N)CC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCC(NCCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 3.7 %

Procedure:
To a solution of N-[4-(4-amino-piperidine-1-sulfonyl)-phenyl]-acrylamide (0.2 g, 3.1 mmol) and phenylacetaldehyde (0.06 ml, 0.52 mmol) in DCE (15 ml) was added triethylamine (0.066 ml, 0.47 mmol) in one portion. The resulting mixture was then stirred at room temperature under a nitrogen atmosphere for 30 minutes, after which time sodium triacetoxy borohydride (0.1 g, 0.47 mmol) was added portion wise. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for a further 2 hours before being concentrated under vacuum. The resulting residue was purified by Prep HPLC to afford the title compound (8 mg, 7% yield) as an off-white powder.
Reaction SMILES: [Br:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C@@H:15]([NH:23][S@](C(C)(C)C)=O)[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl>ClCCl.CO>[Br:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C@@H:15]([NH2:23])[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)[S@](=O)N[C@@H](Cc1ccccn1)c1ccccc1-c1noc2cc(Br)ccc12
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: N[C@@H](Cc1ccccn1)c1ccccc1-c1noc2cc(Br)ccc12
Yield: 89.8 %

Procedure:
To a solution of (S)—N-((1S)-1-(2-(6-bromobenzo[d]isoxazol-3-yl)phenyl)-2-(pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (Compound 14a) (1.76 g) dissolved in dichloromethane (10 mL) was added 2N hydrochloric acid (10 mL) and the mixture left to stand at room temperature. The resulting mixture was taken up in methanol and loaded onto a 20 g SCX column and eluted with neat methanol, followed by ammonia-methanol and the fractions containing product were evaporated to give the title product (1.25 g) as a clear yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:8]1[C:9]([N:14]2[CH2:17][CH:16]([C:18]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:20]=4[N:19]=3)[CH2:15]2)=[N:10][CH:11]=[CH:12][N:13]=1.CN1C(=O)CCC1.[O:35]1[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]1>CCOC(C)=O>[CH3:27][C:25]1[CH:24]=[CH:23][C:21]2[NH:22][C:18]([CH:16]3[CH2:17][N:14]([C:9]4[C:8]([O:41][CH:38]5[CH2:39][CH2:40][O:35][CH2:36][CH2:37]5)=[N:13][CH:12]=[CH:11][N:10]=4)[CH2:15]3)=[N:19][C:20]=2[CH:26]=1
Reactant: Cc1ccc2[nH]c(C3CN(c4nccnc4Cl)C3)nc2c1
Reactant: OC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1ccc2[nH]c(C3CN(c4nccnc4OC4CCOCC4)C3)nc2c1
Temperature: 100 °C
Yield: 49.4 %

Procedure:
To a mixture of cesium carbonate (0.223 g, 0.684 mmol) and 2-(1-(3-chloropyrazin-2-yl)azetidin-3-yl)-5-methyl-1H-benzo[d]imidazole (0.103 g, 0.344 mmol) was added NMP (1 mL) and tetrahydro-2H-pyran-4-ol (0.20 mL, 2.1 mmol). The reaction mixture was heated to 100° C. for 1 h, heated to 130° C. for 2 h, and heated to 150° C. for 21 h. The reaction was diluted with EtOAc, and the organic phase was washed with saturated NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (60% to 100% EtOAc in hexanes) gave 5-methyl-2-(1-(3-(tetrahydro-2H-pyran-4-yloxy)pyrazin-2-yl)azetidin-3-yl)-1H-benzo[d]imidazole (0.061 g, 0.17 mmol, 49% yield) as a pale yellow foam. [M+1] 366. IC50 (uM) 0.2388.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[I:18]N1C(=O)CCC1=O.O>C(O)(=O)C>[I:18][C:11]1[CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:16])([F:17])[F:1])[CH:4]=2)[CH:14]=[CH:13][C:12]=1[OH:15]
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ccc(-c2cccc(C(F)(F)F)c2)cc1
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc(-c2cccc(C(F)(F)F)c2)cc1I
Temperature: 25 °C
Yield: 39.2 %

Procedure:
To a solution of 3′-(trifluoromethyl)biphenyl-4-ol (Preparation 1, 2.17 g, 9.11 mmol) in acetic acid (20 mL) at 0° C. was added N-iodosuccinimide (2.05 g, 9.11 mmol). The reaction was allowed to warm to room temperature and stirred for 48 hours before the addition of water (20 mL). The reaction mixture was extracted with dichloromethane (2×20 mL) and the combined extracts were washed with saturated aqueous sodium thiosulfate solution, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (2%-20% ethyl acetate in heptane gradient elution) to afford the title compound (1.30 g, 39%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[O:3]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[N:25]=[C:26]=[O:27]>ClCCl>[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[NH:25][C:26]([NH:13][C:12]1[CH:14]=[CH:15][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)=[O:27]
Reactant: Cc1ccc(F)c(N=C=O)c1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Solvent: ClCCl
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
A 0° C. mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.5 g, 2.28 mmol) and 1-fluoro-2-isocyanato-4-methylbenzene (0.297 mL, 2.28 mmol) in dichloromethane (15 mL) was allowed to gradually warm to room temperature and stirred overnight. The resulting suspension was diluted with hexanes resulting in the formation of more precipitate, which was collected by filtration to provide 0.68 g of the desired product. MS (ESI(+)) m/e 370.7 (M+H)+.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[O:21][CH3:22])OC1C=CC=CC=1)#[N:2].Cl.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][NH2:32].C(N(CC)CC)C>C(O)(C)C>[CH3:22][O:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=1[NH:12][C:4]1[N:3]=[C:1]([NH2:2])[N:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[F:24])[N:32]=1
Reactant: NNc1ccccc1F
Reactant: COc1ccc(N=C(NC#N)Oc2ccccc2)c(OC)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: COc1ccc(Nc2nc(N)n(-c3ccccc3F)n2)c(OC)c1
Temperature: 100 °C
Yield: 89.3 %

Procedure:
A mixture of N-cyano-N′-(2,4-dimethoxyphenyl)-O-phenylisourea (0.10 g, 0.34 mmol), 2-fluoro-phenylhydrazine hydrochloride (0.08 g, 0.50 mmol) and triethylamine (0.01 mL, 0.68 mmol) in isopropanol (3 mL) was heated at 100° C. for 18 h and evaporated. Purification by flash chromatography (SiO2) eluted with 1:1 ethyl acetate:hexanes provided the title compound (0.10 g, 85% yield).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:19](Br)=[CH:18][C:17]([O:21][C:22](=[O:24])[CH3:23])=[CH:16][C:14]=3[N:15]=2)=[CH:7][C:6]=1[F:25])(=[O:3])[CH3:2].[CH2:26]([Sn](CCCC)(CCCC)C=C)[CH2:27]CC.CC1C=CC(C)=CC=1>C(OCC)C>[C:22]([O:21][C:17]1[CH:18]=[C:19]([CH:26]=[CH2:27])[C:13]2[O:12][C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][C:1](=[O:3])[CH3:2])=[C:6]([F:25])[CH:7]=3)=[N:15][C:14]=2[CH:16]=1)(=[O:24])[CH3:23]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(=O)Oc1cc(Br)c2oc(-c3ccc(OC(C)=O)c(F)c3)nc2c1
Solvent: Cc1ccc(C)cc1
Solvent: CCOCC
Product: C=Cc1cc(OC(C)=O)cc2nc(-c3ccc(OC(C)=O)c(F)c3)oc12
Temperature: 130 °C
Reaction time: 5 h
Yield: 56.9 %

Procedure:
Dichlorobis(tri-o-tolyphosphine)palladium (II) (46 mg, 0.06 mmol) was added into a mixture 4-[5-(acetyloxy)-7-bromo-1,3-benzoxazol-2-yl]-2-fluorophenyl acetate (0.8 g, 1.98 mmol), tributyl(vinyl)tin (0.9 g, 2.8 mmol) and p-xylene (9 mL). The reaction mixture was stirred at 130° C. for 5 h, cooled to room temperature, diluted with ethyl ether (10 mL) and treated with activated carbon. The mixture was filtered through MgSO4 and concentrated. Purification by flash chromatography (hexanes/EtOAc 5/1) gave a white solid (0.4 g, 56% yield, m.p. 154–156° C.); MS m/e 356 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[C:15]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:14][C:11]([CH2:12]O)=[CH:10][C:9]=1[S:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[BrH:26]>O>[CH2:1]([C:8]1[C:15]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:14][C:11]([CH2:12][Br:26])=[CH:10][C:9]=1[S:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1cc(CO)cc(S(N)(=O)=O)c1Cc1ccccc1
Reactant: Br
Solvent: O
Solvent: CC(=O)O
Product: CSc1cc(CBr)cc(S(N)(=O)=O)c1Cc1ccccc1

Procedure:
4-Benzyl-3-methylthio-5-sulfamylbenzyl alcohol (10 g; prepared as described in Example 1) is while stirring added in portions to acetic acid saturated with dry hydrogen bromide (50 ml), and the mixture is stirred for 24 hours. The resulting solution is diluted with water (100 ml) and cooled to precipitate crude 4-benzyl-3-methylthio-5-sulfamylbenzyl bromide. After recrystallization from methanol it is obtained with a melting point of 149°-150° C.
Reaction SMILES: [NH2:1][C@H:2]([CH2:13][O:14][CH3:15])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[CH3:17][C:16]([NH:1][C@@H:2]([C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])[CH2:13][O:14][CH3:15])=[O:18]
Reactant: CC(=O)OC(C)=O
Reactant: COC[C@@H](N)C(=O)NCc1ccccc1
Product: COC[C@@H](NC(C)=O)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The (R)-2-amino-N-benzyl-3-methoxypropionamide solution prepared above was cooled to <5° C. and acetic anhydride (10 ml, 0.106 mol) added at <15° C. The reaction mixture is warmed to room temperature over 30 minutes and aged for a further 30 minutes. The mixture is then washed with water (44 ml), 8% sodium bicarbonate (44 ml) and water (44 ml). The methylene chloride was exchanged for ethyl acetate by distillation and the solution distilled to a volume of 115 ml. The product was crystallized by cooling the solution to 0-5° C. and the pure Lacosamide isolated by filtration (18.7 g, 69.8%) HPLC purity 99.98%, Chiral purity 99.8% ee.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:6]([C:9]1[CH:10]=[C:11]([N:15]=[C:16]=[O:17])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7]>C1COCC1>[N+:6]([C:9]1[CH:10]=[C:11]([NH:15][C:16]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:17])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7]
Reactant: C1CCNC1
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: O=C(Nc1cccc([N+](=O)[O-])c1)N1CCCC1

Procedure:
Pyrrolidine (1.5 mL, 18.3 mmol) was added to a stirred solution of 3-nitrophenyl isocyanate (1.5 g, 9.14 mmol) in anhydrous THF (60 mL) and the mixture stirred at reflux for 1 hour. The solvent was evaporated in vacuo. The crude product was then purified by column chromatography (Flashmaster, 40-63 mesh silica gel, 50% isohexane-EtOAc) to provide the title compound as an off white solid (1.85 g, 86%); LC-MS, Rt=2.80 min (MeOH-FA), m/z 236 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][C:13](=[O:15])[CH2:12][C:11](=O)[CH2:10]1.Cl.[NH2:18][CH2:19][C:20]#[C:21][CH3:22].O1CCCC1>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:10][C:11]2[N:18]=[CH:19][CH:20]=[C:21]([CH3:22])[C:12]=2[C:13](=[O:15])[CH2:14]1
Reactant: COc1ccccc1C1CC(=O)CC(=O)C1
Reactant: CC#CCN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1C1CC(=O)c2c(C)ccnc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
To a mixture of 5-(2-methoxyphenyl)-1,3-cyclohexanedione (1.0 g), 1-amino-2-butyne hydrochloride (0.5 g), molecular sieves 4A (2 g) and tetrahydrofuran (20 ml) was added triethylamine (0.48 g). The mixture was stirred at room temperature for 1 hour, refluxed for 12 hours and cooled, and insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and the residue was stirred for 4 hours at 220° C. and cooled, to which was added ethyl acetate and sodium hydrogen carbonate solution. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane) to give oil of 7-(2-methoxyphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:26])[CH2:15][CH:16]([CH2:22][CH2:23][O:24][CH3:25])[C:17]([O:19]CC)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:28]1[S:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1.[OH-].[Na+].Cl>C(O)CCC.CO>[S:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=[C:28]1[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14](=[O:26])[CH2:15][CH:16]([CH2:22][CH2:23][O:24][CH3:25])[C:17]([OH:19])=[O:18])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CCOC)CC(=O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: Clc1nc2ccccc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: CO
Product: COCCC(CC(=O)c1ccc(-c2ccc(Nc3nc4ccccc4s3)cc2)cc1)C(=O)O
Temperature: 90 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
To a solution of ethyl 4-(4′-amino-1,1′-biphenyl-4-yl)-2-(2-methoxyethyl)-4-oxobutanoate (75 mg, 0.21 mmol) in butanol (4 mL), 2-chloro-benzothiazole (43 mg, 0.25 mmol) was added and the reaction mixture was heated at 90° C. overnight. The solvent was removed by rotary evaporation, the residue was redissolved in DMF (1 mL), a solution of 1 N aqueous NaOH (0.63 mL, 0.63 mmol) was added, and the mixture was stirred at rt overnight. A solution of 1 N aqueous HCl (0.3 mL, 0.3 mmol) and methanol (5 mL) were added to the reaction mixture, and the crude product was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford 4-[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]-2-(2-methoxyethyl)-4-oxobutanoic acid as a white solid (30 mg, 31%). 1H NMR (300 MHz, DMSO-d6) δ 8.05 (d, 2 H), 7.95 (d, 2 H), 7.70 (m, 5 H), 7.60 (d, 1 H), 7.30 (t, 1 H), 7.15 (t, 2 H), 3.35 (m, 2 H), 3.25 (s, 3 H), 3.20 (m, 2 H), 2.90 (m, 1 H), 1.95–1.75 (m, 2 H); LC-MS ret. time 3.29 min (method 2), m/z 461.15 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)(O)[O-].[Na+].[CH3:23][C:24](CC(C)C)=O.O.ClCC(Cl)=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:11]2[O:12][CH2:24][CH2:23][N:13]([CH2:14][CH2:15][CH2:16][CH3:17])[C:10]=2[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=1
Reactant: CC(=O)CC(C)C
Reactant: CCCCNc1cc(C(=O)OC)cc(Br)c1O
Agent: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCN1CCOc2c(Br)cc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cold, stirred solution of Methyl 3-bromo-5-(butylamino)-4-hydroxybenzoate (440 mg) and sodium bicarbonate (280 mg) in 1:1 isobutyl methyl ketone/water (10 mL) was added chloroacetyl chloride (226 mg). The mixture was stirred for 1 h, warmed to room temperature, and heated at reflux for 14 h. The mixture was cooled to room temperature, diluted with chloroform, and the layer separated. The organic layer was washed with water, and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure to give a white solid: 1H NMR (300 MHz, CDCl3) δ 7.94, 7.62, 4.76, 3.98, 3.93, 1.65, 1.43, 0.97, which was used in the next step without further purification or characterization.