Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[NH2:11][CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1.CN1CCOCC1.[CH3:30][N:31]([CH3:49])[C:32]1([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[CH:43]=2)[CH2:37][CH2:36][C:35](=[CH:38][C:39](O)=[O:40])[CH2:34][CH2:33]1.C1(N=C=NC2CCCCC2)CCCCC1.[OH-].[Na+]>CN(C)C=O.O>[CH3:49][N:31]([CH3:30])[C:32]1([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[CH:43]=2)[CH2:37][CH2:36][C:35](=[CH:38][C:39]([NH:11][CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)=[O:40])[CH2:34][CH2:33]1
Reactant: CN(C)C1(c2cccc(F)c2)CCC(=CC(=O)O)CC1
Reactant: NCCc1c[nH]c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: CN(C)C1(c2cccc(F)c2)CCC(=CC(=O)NCCc2c[nH]c3ccccc23)CC1
Temperature: 0 °C
Reaction time: 96 h
Yield: 62 %

Procedure:
1-Hydroxybenzotriazole (1.08 g, 8.0 mmol), tryptamine (640 mg, 4.0 mmol) and N-methylmorpholine (0.888 ml, 8.0 mmol) were added to a solution of [4-dimethylamino-4-(3-fluoro-phenyl)-cyclohexylidene]acetic acid (1.55 g, 4.0 mmol) in dry dimethylformamide (15 ml) under argon. The solution was cooled to 0° C., dicyclohexylcarbodiimide (1.64 g, 8.0 mmol) was added and the mixture was stirred at RT for 4 d. Working up of the mixture was carried out by separating off the urea which had precipitated out and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). Still further urea thereby precipitated out and was separated off. The aqueous phase was diluted with water (300 ml), 5 M sodium hydroxide solution (7 ml, 35 mmol) was added and the mixture was stored at 5° C. for 16 h. The crude product thereby precipitated out as a beige-coloured solid (1.3 g). After chromatography on silica gel (60 g) with EA/methanol (6:1), the product was obtained in a yield of 62% (1.03 g) with an m.p. of 172-176° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=2)[CH2:4][C@H:3]1[O:18][CH3:19].[Cl:20][C:21]1[N:22]=[C:23]([C:28](O)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:20][C:21]1[N:22]=[C:23]([C:28]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=3)[CH2:4][C@H:3]2[O:18][CH3:19])=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ccnc(C(=O)OC)c3)C[C@H]2OC)nc1Cl

Procedure:
The same operation as in Example (1g) was performed using methyl cis(±)-4-(4-amino-3-methoxypiperidin-1-yl)pyridine-2-carboxylate obtained in Example (160c) (21.2 mg, 0.08 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (14 mg, 0.08 mmol), WSC hydrochloride (45.98 mg, 0.24 mmol) and HOBt (10.81 mg, 0.08 mmol), to obtain 13.8 mg of the title compound as a white solid.
Reaction SMILES: CS(O[CH2:6][CH:7]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:8][CH2:9][CH2:10][CH3:11])(=O)=O.[C-:19]#[N:20].[Na+].O>CN(C)C=O>[CH:13]1([CH2:12][CH:7]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:6][C:19]#[N:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCCCC(COS(C)(=O)=O)CC1CCCCC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(CC#N)CC1CCCCC1
Temperature: 80 °C

Procedure:
2-(Cyclohexylmethyl)hexyl methanesulfonate (2.0 g) in a few ml of dimethylformamide (DMF) was added to a cooled stirred suspension of anhydrous sodium cyanide (0.53 g) in 5 ml of dry DMF. The mixture was heated overnight at 80° C., poured into water (100 ml) and the product extracted with ether. The combined extracts were washed with water, dried (MgSO4) and evaporated to give 3-(cyclohexylmethyl)heptanenitrile, used directly in the next step.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:59])[C:10]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]([P:47]([O:54]C(C)(C)C)([O:49]C(C)(C)C)=[O:48])([F:46])[F:45])=[CH:40][CH:39]=1)([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([P:25]([O:32]C(C)(C)C)([O:27]C(C)(C)C)=[O:26])([F:24])[F:23])=[CH:18][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([NH:8][C:9](=[O:59])[C:10]([CH2:37][C:38]1[CH:39]=[CH:40][C:41]([C:44]([F:46])([F:45])[P:47]([OH:54])([OH:49])=[O:48])=[CH:42][CH:43]=1)([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[P:25]([OH:32])([OH:27])=[O:26])=[CH:18][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(Cc1ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)(Cc1ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)C(=O)NCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(Cc1ccc(C(F)(F)P(=O)(O)O)cc1)(Cc1ccc(C(F)(F)P(=O)(O)O)cc1)C(=O)NCc1ccccc1
Yield: 116.7 %

Procedure:
A solution of methyl 3-(benzylamino)-2,2-di{4-[(di-tert-butoxyphosphoryl)(difluoro)methyl]benzyl}-3-oxopropanoate (15 mg) in 2 mL of CH2Cl2 and 1.5 mL of TFA was stirred for 2 h and then concentrated. The residue was dissolved in 3 mL of water and washed with 3×2 mL of ether and the aqueous solution was lyopholized to give 13 mg of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].I[CH:24]([CH3:26])[CH3:25]>CN(C)C=O>[F:16][C:2]([F:1])([F:15])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[N:7]([CH:24]([CH3:26])[CH3:25])[CH:6]=1)=[O:4]
Reactant: CC(C)I
Reactant: O=C(c1c[nH]c2cc(F)ccc12)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(C(=O)C(F)(F)F)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.3 %

Procedure:
A solution of 2,2,2-trifluoro-1-(6-fluoro-1H-indol-3-yl)-ethanone (1.63 g, 7.05 mmol) in N,N-dimethylformamide (15 mL) at 25° C. was treated with potassium carbonate (2.44 g, 17.63 mmol). The resulting mixture was stirred at 25° C. for 15 min. At this time, the reaction was treated with 2-iodopropane (1.06 mL, 10.58 mmol). The reaction was heated at 65° C. for 18 h. At this time, the reaction was cooled to 25° C. and was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic layer was washed with a 1N aqueous hydrochloric acid solution (1×25 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 2/1 hexanes/ethyl acetate) afforded 2,2,2-trifluoro-1-(6-fluoro-1-isopropyl-1H-indol-3-yl)-ethanone (1.74 g, 90%) as a yellow solid: mp 67-69° C.; EI-HRMS m/e calcd for C13H11F4NO (M+) 273.0776, found 273.0780.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:33][CH2:32][C:27]4([O:31][CH2:30][CH2:29][O:28]4)[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(=O)([O-])O.[Na+]>O1CCOCC1.ClCCl>[O:31]1[C:27]2([CH2:32][CH2:33][N:24]([C:21]3[CH:20]=[CH:19][C:18]([N:11]4[C:12]5[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=5)[NH:8][CH2:9][CH2:10]4)=[CH:23][CH:22]=3)[CH2:25][CH2:26]2)[O:28][CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCC4(CC3)OCCO4)cc2)c2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: c1ccc2c(c1)NCCN2c1ccc(N2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 28 h
Yield: 99.9 %

Procedure:
0.27 g of 4-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester is placed in 3 ml of a 4N solution of hydrochloric acid in dioxane. The mixture is stirred at ambient temperature for 28 h. The reaction mixture is diluted with dichloromethane and then a saturated aqueous sodium hydrogencarbonate solution is added. The aqueous phase is extracted three times with dichloromethane. The organic phases are combined, dried over sodium sulphate and concentrated under vacuum. 0.21 g of 1-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]-1,2,3,4-tetrahydroquinoxaline is obtained.
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)#[N:15]>CN(C1C=CN=CC=1)C>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:20]([C:19]1[CH:23]=[CH:24][C:16]([C:14]#[N:15])=[CH:17][CH:18]=1)=[O:21])[CH2:3][CH2:4][CH3:5]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CCCC[n+]1c(C)sc(C)c1C
Agent: CN(C)c1ccncc1
Agent: [I-]
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 4-cyanobenzoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.93 (t, 3 H) 1.32-1.45 (m, 2 H) 1.60-1.68 (m, 2 H) 2.19 (s, 3 H) 2.23 (s, 3 H) 4.06-4.12 (m, 2 H) 6.67 (s, 1 H) 7.90 (d, 2 H) 8.10 (d, 2 H); MS (ESI) m/z 313 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][N:13]([CH2:17][CH2:18][C:19]4([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:23][CH2:22][NH:21][CH2:20]4)[CH2:14]3)[CH2:10]2)=[O:8])=[C:5]([CH3:30])[N:4]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][N:32]=2)[N:3]=1.[CH:41]1([C:46](Cl)=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42]1.C(OC(=O)C)(=O)C.FC1(F)CC(C(O)=O)C1.CCN=C=NCCCN(C)C>>[CH:41]1([C:46]([N:21]2[CH2:22][CH2:23][C:19]([CH2:18][CH2:17][N:13]3[CH2:14][CH:15]4[CH2:16][N:9]([C:7]([C:6]5[C:2]([CH3:1])=[N:3][N:4]([C:31]6[CH:36]=[CH:35][C:34]([C:37]([F:39])([F:40])[F:38])=[CH:33][N:32]=6)[C:5]=5[CH3:30])=[O:8])[CH2:10][CH:11]4[CH2:12]3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20]2)=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: O=C(Cl)C1CCCC1
Reactant: Cc1nn(-c2ccc(C(F)(F)F)cn2)c(C)c1C(=O)N1CC2CN(CCC3(c4ccccc4)CCNC3)CC2C1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)C1CC(F)(F)C1
Solvent: CC(=O)OC(C)=O
Product: Cc1nn(-c2ccc(C(F)(F)F)cn2)c(C)c1C(=O)N1CC2CN(CCC3(c4ccccc4)CCN(C(=O)C4CCCC4)C3)CC2C1

Procedure:
The following were prepared analogously from [3,5-dimethyl-1-(5-trifluoromethyl-pyridin-2-yl)-1H-pyrazol-4-yl]-{5-[2-(3-phenyl-pyrrolidin-3-yl)-ethyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-methanone using the acylating agent in parenthesis in place of cyclopentylcarbonyl chloride in the final step: III-10 (acetic anhydride) and III-12 (3,3-difluorocyclobutane-carboxylic acid using the EDCI coupling procedure in step 6 of example 6).
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=O)=[C:7]([CH2:19][CH3:20])[CH:6]=1.Cl.NN=CC1C=CC(NC(=O)CCC(O)=O)=CC=1.[NH2:39][CH:40]([CH:47]=[CH2:48])[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]>>[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([NH:39][CH:40]([CH:47]=[CH2:48])[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:17])=[C:7]([CH2:19][CH3:20])[CH:6]=1
Reactant: C=CC(N)CC(=O)OCC
Reactant: CCc1cc(C=NN)ccc1NC(=O)CCC(=O)O
Agent: Cl
Agent: NN=Cc1ccc(NC(=O)CCC(=O)O)cc1
Product: C=CC(CC(=O)OCC)NC(=O)CCC(=O)Nc1ccc(C=NN)cc1CC

Procedure:
The title compound was prepared in the manner of Example 1 substituting 4-[[4-(aminoiminomethyl)-2-ethylphenyl]amino]-4-oxobutanoic acid hydrochloride for 4-[[4-(aminoiminomethyl)phenyl]amino]-4-oxobutanoic acid hydrochloride and using ethyl 3-amino-4-pentenoate. The product was purified by reverse phase HPLC using the conditions of Example 1 to afford the title compound. The product was verified by 13C NMR (CD3OD) δ 12.8, 13.1, 23.7, 30.5, 31.3, 38.9, 48.4, 60.4, 114.5, 124.6, 125.2, 125.6, 128.1, 136.8, 138.0, 140.9, 166.8, 171.0, 171.1, 172.5; Chemical Ionization Mass Spectrometry (MH+)=389.
Reaction SMILES: [Na:1].CC1(C)O[C@H]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][S:17]([C:19]3[NH:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[N:20]=3)=[O:18])[C:11]=2[CH3:28])CO1.[O:30]1[C:34]2([CH2:38][CH2:37][CH2:36][CH:35]2CO)[O:33][CH2:32][CH2:31]1>>[Na:1].[O:30]1[C:34]2([CH2:38][CH2:37][CH2:36][CH:35]2[CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][S:17]([C:19]3[NH:20][C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)=[O:18])[C:11]=2[CH3:28])[O:33][CH2:32][CH2:31]1
Reactant: OCC1CCCC12OCCO2
Reactant: Cc1c(OC[C@@H]2COC(C)(C)O2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Agent: [Na]
Product: Cc1c(OCC2CCCC23OCCO3)ccnc1CS(=O)c1nc2ccccc2[nH]1

Procedure:
The same procedure as in the steps (14a) to (14e) of Example 14 was repeated using the 1,4-dioxaspiro[4.4]non-6-ylmethanol obtained in the step (80b) above to obtain the title compound (383 mg, the total yield of 5 steps: 14.6%) as a light yellow solid. Note that in the same process as in the step (14c), methanol was used as a solvent instead of ethanol.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.N1C=CC=CC=1.[NH2:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[OH:24]>C(O)=O>[OH:24][C:16]1[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=1[NH:14][CH:1]=[O:3]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: c1ccncc1
Product: O=CNc1cc([N+](=O)[O-])ccc1O
Reaction time: 18 h

Procedure:
To a stirred mixture of formic acid (20.7 g, 0.449 mol), acetic anhydride (32.0 g, 0.313 mol) and pyridine (37 g, 0.468 mol) is added at ambient temperature 2-amino-4-nitrophenol (24.0 g, 0.156 mol) in 15 mL of formic acid. Stirring is continued for 18 h. The solid formed is separated by suction filtration, washed with aqueous sodium bicarbonate, water, DCM and hexanes. After air drying for 18 h, N-(2-hydroxy-5-nitrophenyl)-formamide is obtained as a light green solid: (M−H)−=181.1.
Reaction SMILES: Br.Cl[C:3]1[C:4]([CH3:14])=[C:5]([CH3:13])[C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=1.[O-:15][CH2:16][CH3:17].[Na+]>C(O)C>[CH2:16]([O:15][C:3]1[C:4]([CH3:14])=[C:5]([CH3:13])[C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=1)[CH3:17]
Reactant: Cc1c(Cl)nn2c(N)nnc2c1C
Reactant: CC[O-]
Agent: Br
Agent: [Na+]
Solvent: CCO
Product: CCOc1nn2c(N)nnc2c(C)c1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 108.9 %

Procedure:
6-Chloro-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.006; 4 g) were dissolved in ethanol (120 ml), admixed under argon with sodium ethoxide (5.86 g) and stirred at 60° C. for 1 h. Then the mixture was dried and the residue was purified using a 40 g silica gel cartridge (0-20% dichloromethane-ethanol gradient in 40 min). The clean product fractions were combined and dried. 3.24 g of the title compound were obtained, which still contained residual amounts of dichloromethane. LC-MS rt: 0.53 min [M+H]+: 208.1 (met. b)
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[OH:9][C:10]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:11]=1[C:12]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=O.C([SiH](CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[OH:9][C:10]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:11]=1[CH2:12][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: Cc1cc(C)c(C(=O)CCC(=O)O)c(O)c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)c(CCCC(=O)O)c(O)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Trifluoromethanesulphonic acid (0.2 ml, 2.3 mM) in dichloromethane (0.5 ml) was added dropwise to a solution of the epsilon-lactone of 3-(2-hydroxy-4,6-dimethylbenzoyl)propionic acid, [m.p. 77° C.; prepared by the method described in Acta. Chem. Scand. 1972, 26, 2372, but starting from 3-(2-hydroxy-4,6-dimethylbenzoyl)propionic acid, itself prepared as described in Liebigs Ann. Chem. 1985, 560] in dichloromethane (1 ml) at 0° C. under argon, followed by a solution of triethylsilane (200 mg, 1.7 mM) in dichloromethane (0.5 ml). After 5 minutes, a further portion of trifluoromethanesulphonic acid (0.2 ml, 2.3 mM) in dichloromethane (0.5 ml) was added followed by triethylsilane (200 mg; 1.7 mM) in dichloromethane (0.5 ml). The reaction mixture was stirred for 2 hours at ambient temperature, then poured into saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The combined extracts were washed with brine, dried (Na2SO4), and the solvent was removed by evaporation. The residual oil was purified by flash chromatography, eluting with hexane/dichloromethane (1:1 v/v increasing in polarity to 1:3 v/v), giving the epsilon-lactone of 4-(2-hydroxy-4,6-dimethylphenyl)butyric acid (C) as a colourless oil; NMR: 2.10(2H,tt), 2.29(6H,s), 2.43(2H,t), 2.79(2H,t), 6.75(1H,s), 6.86(1H,s); I.R (thin film) 1720 cm-1.
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: N[C@H](CO)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
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: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:32])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:24]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.Cl[C:34]1[N:39]=[N:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:32])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:24]([CH:26]3[CH2:31][CH2:30][N:29]([C:34]4[N:39]=[N:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=4)[CH2:28][CH2:27]3)=[O:25])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Cl)nn1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCNCC2)C[C@H]1c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)nn3)CC2)C[C@H]1c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 74.2 %

Procedure:
To a solution of [(3S,4R)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester (186 mg, 0.40 mmol) in DMF (2 mL) was added 6-chloro-3-pyridazinecarbonitrile (67 mg, 0.48 mmol) and N,N-diisopropyl ethyl amine (208, 1.21 mmol). The resulting dark brown solution was stirred for 3 h at 80° C. After cooling to ambient temperature the reaction mixture was diluted with ethyl acetate (15 mL) and washed with aqueous sodium carbonate (1M, 15 mL), water (15 mL) and brine (15 mL). The aqueous layers were extracted with ethyl acetate (15 mL) and the combined organic layers dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=50:50 to 0:100) afforded the title compound (167 mg, 73%) as a white foam. MS m/e: 563.3 [M]+.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][CH:16]([CH2:19]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].O>O1CCCC1>[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][C:16](=[CH2:19])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.1 %

Procedure:
2.24 g (0.02 mole) of potassium t-butoxide were added to a solution of 3.55 g (0.01 mole) of 1-t-butoxycarbonyl-3-(p-toluenesulfonyloxymethyl)pyrrolidine [prepared as described in Step (3) above] dissolved in 50 ml of tetrahydrofuran. The mixture was then stirred at room temperature for 3 hours, after which it was poured into water and then extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried and concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through silica gel eluted with a 5:95 by volume mixture of ethyl acetate and toluene, to give 0.79 g of 1-t-butoxycarbonyl-3-methylenepyrrolidine as a pale yellow liquid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:28][C:29]([F:39])([F:38])[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH2:37]>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:23])([CH3:24])[C@:12]([C:15]2[CH:20]=[C:19]([NH:37][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[O:30][C:29]([F:28])([F:38])[F:39])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Br)ccc2F)N=C1NC(=O)OC(C)(C)C
Reactant: Nc1ccccc1OC(F)(F)F
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3ccccc3OC(F)(F)F)ccc2F)N=C1N

Procedure:
The coupling of [(S)-4-(5-bromo-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate E8) and o-(trifluoromethoxy)phenylamine according to procedure A followed by deprotection yielded the title compound as a white solid. MS (ESI): m/z=439.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2([C:13]([O:15][CH2:16]C)=[O:14])[CH2:11][CH2:10][CH2:9][CH:8]2[OH:12])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2([C:13]([O:15][CH3:16])=[O:14])[CH2:11][CH2:10][CH2:9][CH:8]2[O:12][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(Cc2ccc(C)cc2)CCCC1O
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1(Cc2ccc(C)cc2)CCCC1OC(=O)c1ccccc1

Procedure:
5.24 grams of 2-p-methylbenzyl-2-ethoxycarbonyl-cyclopentanol obtained in Example 18 were diluted with 60 ml of methylene chloride. At room temperature and with magnetic stirring, 2.44 ml of pyridine was slowly added, then 3.55 ml of benzoyl chloride was dropwise added. Upon the completion of the addition, the reaction was continued under reflux condition for 12 hours. Then the procedure as described in Example 23 was followed, to give 7.41 g of yellow liquid. MS: m/e 367(M++1), 366(M+), 293(M+—CO2CH2CH3), 261(M+—C6H5CO2), 216, 198, 170, 155, 105, 91, 77.