Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Na+].[I-].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:34]([O:38][CH2:39][CH3:40])(=[O:37])[CH:35]=[CH2:36].CCN(CC)CC>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].CCOCC.CCCCCC>[CH3:40][CH2:39][O:38][C:34](/[CH:35]=[CH:36]/[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)=[O:37]
Reactant: C=CC(=O)OCC
Reactant: COc1ccc(Cl)cc1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1ccc(OC)cc1
Yield: 73.7 %

Procedure:
4-Chloroanisole (1430 mg, 10 mmoles, 1229 ml), NiBr2 (438 mg, 2 mmoles), NaI (1650 mg, 11 mmoles) and P(o-tol)3 (1216 mg, 4 mmoles) were combined according to Method B and treated with ethyl acrylate (1100 mg, 11 mmoles, 1.130 ml), Et3N (1111 mg, 11 mmoles, 1.530 ml), and Pd(dba)2 (29 mg, 0.05 mmoles). Isolation by radial chromatography as described in Example 2 (Si gel, 5:1 volume mixture of hexane and Et2O for the first fraction, 1:1 volume mixture of hexane and Et2O for the second) gave 1519 mg (74 mole % yield) of 4-methoxy ethyl cinnamate as a brown oil. The results of NMR (CDCl3) analysis were: δ1.35 (t, 3H,--COOCH2CH3), 3.84 (s, 3H, OCH3), 4.26 (q, 2H, COOCH2CH3), 6.33 (d, 1H, PhCH=CH--), 6.90 (d, 2H, aromatic), 7.49 (d, 2H, aromatic), 7.65 (d, 1H, PhCH=CH--R), indicating the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](Cl)=[O:13])[CH:6]=[CH:5]2.[NH:15]1[C:19]2[CH:20]=[CH:21][C:22]([NH2:24])=[CH:23][C:18]=2[N:17]=[CH:16]1>>[NH:15]1[C:19]2[CH:20]=[CH:21][C:22]([NH:24][C:12]([C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=4)[CH:8]=3)=[O:13])=[CH:23][C:18]=2[N:17]=[CH:16]1
Reactant: O=C(Cl)c1ccc2cc(Br)ccc2c1
Reactant: Nc1ccc2[nH]cnc2c1
Product: O=C(Nc1ccc2[nH]cnc2c1)c1ccc2cc(Br)ccc2c1

Procedure:
This material was prepared analogous to the procedure described for Example 1 (b). 6-Bromo-naphthalene-2-carbonyl chloride, Example 1(a), reacted with 1H-benzoimidazol-5-ylamine (TimTec) to give the title compound as an amorphous solid. MS (ESI, pos. ion.) m/z: 366 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[C:13]([F:29])=[CH:14][C:15]3[O:20][CH2:19][C:18](=[O:21])[NH:17][C:16]=3[C:22]=2[NH:23][C:24](=[O:28])[CH:25](Cl)[CH3:26])=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:12]2[C:22]3[NH:23][C:24](=[O:28])[CH:25]([CH3:26])[N:17]4[C:18](=[O:21])[CH2:19][O:20][C:15]([C:16]=34)=[CH:14][C:13]=2[F:29])=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9]
Reactant: CC(Cl)C(=O)Nc1c2c(cc(F)c1-c1nn(C)c(OC(F)F)c1Cl)OCC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1C(=O)Nc2c(-c3nn(C)c(OC(F)F)c3Cl)c(F)cc3c2N1C(=O)CO3
Temperature: 0 °C
Yield: 75.8 %

Procedure:
4-Chloro-3-[7-fluoro-5-(2-chloropropionylamino)-2H-1,4-benzoxazine-3(4H)-on-6yl]-1-methyl-5-difluoromethoxy-1H-pyrazole (300 mg, 0.66 mmol) was dissolved in anhydrous dimethylformamide (10 ml) and solution stirred under ice-cooling. Sodium hydride (20 mg, 95%, 0.79 mmol) was added slowly in portions and solution stirred at room temperature for 2 hr. Solution was then added to ice-water and product extracted with ethyl acetate. Evaporation of the solvent afforded a residue which was purified by flash chromatography on silica gel in hexane-ethyl acetate (1:1) to furnish the title compound (209.2 mg, 0.50 mmol).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[C:13]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19])#[N:14]>CCCCCC.C1COCC1.C(OCC)C>[C:13]([C:15]1[CH:16]=[C:17]([CH:18]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[OH:19])[CH:20]=[CH:21][CH:22]=1)#[N:14]
Reactant: N#Cc1cccc(C=O)c1
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#Cc1cccc(C(O)c2cccnc2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
52.8 ml of 2.5 molar butyllithium solution (0.132 mol) in n-hexane are cooled to -78° C. under argon in a mixture of 66 ml of abs. THF and 66 ml of abs. diethyl ether. 17.38 g (0.11 mol) of 3-bromopyridine in 132 ml of abs. diethyl ether are added dropwise to this in the course of 90 min. and the mixture is subsequently stirred for 10 min. 14.5 g (0.11 mol) of 3-cyanobenzaldehyde in 275 ml of abs. diethyl ether and 44 ml of abs. THF are added dropwise to this solution. It is slowly allowed to come to room temperature and stirred overnight at room temperature. It is then stirred into 1100 ml of ice water, extracted twice using 550 ether each time and the combined organic phases are washed by shaking with satd. NaCl solution. After drying over Na2SO4, the organic phase is evaporated and the residue is dried in a high vacuum.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH2:37][O:38][CH3:39])[O:5][C:6]1[CH:7]=[C:8]([O:26][C:27]2[CH:28]=[N:29][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:31][CH:32]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21](OCC)=[O:22])[CH2:18][N:19]=1)=[CH:11]2.[BH4-].[Li+].O>O1CCCC1.CO>[CH3:1][O:2][CH2:3][CH:4]([CH2:37][O:38][CH3:39])[O:5][C:6]1[CH:7]=[C:8]([O:26][C:27]2[CH:28]=[N:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][CH2:21][OH:22])[CH2:18][N:19]=1)=[CH:11]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC(COC)COC)c3[nH]2)S1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CCO)S3)[nH]c12
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 51.5 %

Procedure:
Ethyl [2-(7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetate (220 mg) was dissolved in a mixture of tetrahydrofuran (2 mL) and methanol (1 mL). Lithium borohydride (41 mg) was added to the mixture at 0° C. and the mixture was stirred at room temperature for 6.5 h. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (methanol/ethyl acetate/hexane=0/40/60 to 15/85/0, volume ratio) to give an orange oil. The oil was crystallized from acetonitrile. The crystals were recrystallized from acetonitrile-diethyl ether to give the title compound (105 mg, 75%) as colorless crystals. MS 536 (MH+). mp 69-71° C.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([O:15][C:16]([NH:18][OH:19])=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[C:1]1([CH2:7][C:8]([O:19][NH:18][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NO
Product: CC(C)(C)OC(=O)NOC(=O)Cc1ccccc1

Procedure:
[(tert-Butoxy)carbonyl]amino 2-phenylacetate is prepared from phenylacetyl chloride and N-tert-butoxycarbonyl hydroxylamine according to Scheme 1 using literature conditions. (8.8 g, 100%), 1H NMR (500 MHz, DMSO-d6) δ ppm 10.66 (1H, br. s.), 7.24-7.38 (5H, m), 3.80 (2H, s), 1.38 (9H, s).
Reaction SMILES: C(O)(=O)C(O)=O.C1(C(C2C=CC=CC=2)=C2CCN(CCCOC3C=CC=CC=3)CC2)C=CC=CC=1.[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[OH:44])=[CH:39][CH:38]=1.[Cl:58][CH2:59][CH2:60][CH2:61][O:62][C:63]1[CH:68]=[CH:67][C:66]([C:69](=[O:71])[CH3:70])=[C:65]([O:72][CH3:73])[CH:64]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].Cl>C(O)CCC>[ClH:58].[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([C:51]2[CH:52]=[CH:53][C:54]([F:57])=[CH:55][CH:56]=2)([OH:44])[CH:45]2[CH2:46][CH2:47][N:48]([CH2:59][CH2:60][CH2:61][O:62][C:63]3[CH:68]=[CH:67][C:66]([C:69](=[O:71])[CH3:70])=[C:65]([O:72][CH3:73])[CH:64]=3)[CH2:49][CH2:50]2)=[CH:39][CH:38]=1
Reactant: COc1cc(OCCCCl)ccc1C(C)=O
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CCCCO
Product: COc1cc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)ccc1C(C)=O

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of [α,α-bis(p-fluorophenyl)]-4-piperidinemethanol, 2.4 g (0.01 mole) of 1-[4-(3-chloropropoxy)-2-methoxyphenyl]ethanone, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol gave a gum as residue. The gum was purified by column chromatography on 80 g of Florisil® and the fractions eluted with 20% acetone in benzene were combined and concentrated under reduced pressure to give a solid as residue. The solid was converted to the hydrochloride and this solid was recrystallized from 2-propanol-isopropyl ether to yield 2.2 g (40%) of white power, m.p. 196°-197° C.
Reaction SMILES: [Li+].CCC[CH2-].[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:7]=1.CN(C)CCN(C)C.[I:28]I>C(OCC)C.O>[I:28][C:9]1[CH:10]=[CH:11][N:6]=[CH:7][C:8]=1[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)Nc1cccnc1
Reactant: II
Agent: CN(C)CCN(C)C
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cnccc1I
Temperature: -20 °C
Reaction time: 2.5 h
Yield: 61.3 %

Procedure:
N-Butyllithium (1.6M hexane solution 400 mL, 0.64 mol) was added to a solution of tert-butyl N-(3-pyridyl)carbamate (51.8 g, 0.27 mol) and tetramethylethylenediamine (96.6 mL, 0.64 ml) in diethyl ether (1.5 L) at −78° C., followed by stirring at −20° C. for 2.5 hr. After cooling to −78° C. again, a solution of iodine (94.8 g, 0.37 mol) in diethyl ether (200 mL) was added and stirred for one day while raising a temperature to room temperature. Water was added, extracted with diethyl ether, and the organic layer was washed with hypo-water and brine, dried over anhydrous magnesium sulfate and evaporated. The resulting crystals were washed with hexane, to give the title compound (53.0 g) as white crystals.
Reaction SMILES: [CH:1]([CH:3]([NH:8][C:9](=[O:26])[C@H:10]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:4][CH2:5][CH2:6][CH3:7])=O.Cl.[NH2:28][CH2:29][CH2:30][SH:31].C(N(CC)CC)C.S(=O)(=O)(O)O>CO>[S:31]1[CH2:30][CH2:29][NH:28][CH:1]1[CH:3]([NH:8][C:9](=[O:26])[C@H:10]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCC(C=O)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Reactant: NCCS
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCC(NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C1NCCS1
Yield: 103.2 %

Procedure:
In 20 ml of methanol was dissolved 1.0 g of N-benzyloxycarbonyl-L-leucine-(1-formyl)pentylamide obtained in the same manner as in Example 4-(b), and 400 mg of 2-aminoethanethiol hydrochloride, 0.4 ml of triethylamine, and a catalytic amount of concentrated sulfuric acid were added thereto. The mixture was allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under redueed pressure. The residue was purified by medium-pressure column chromatography on silica gel to obtain 1.2 g of the titled compound as a colorless crystal.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Si:9]([CH3:19])([CH3:18])/[CH:10]=[CH:11]/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C1(C#C)C=CC=CC=1.C[SiH](C)C1C=CC=CC=1COC1CCCCO1.C#CCCCCCC>CCCCCC.C(OCC)(=O)C>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Si:9]([CH3:18])([CH3:19])/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCCCCC/C=C/[Si](C)(C)c1ccccc1CO
Agent: C#CCCCCCC
Agent: C[SiH](C)c1ccccc1COC1CCCCO1
Solvent: CCCCCC
Solvent: C#Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[Si](C)(/C=C/c1ccccc1)c1ccccc1CO
Yield: 84 %

Procedure:
The same operation as in the preparation of the compound 1a except that phenylacetylene (0.20 g, 2.0 mmol) was used instead of 0.55 g and 2.2 mmol of dimethyl[2-(2-tetrahydro-2H-pyranoxymethyl)phenylsilane (R2 and R3 in (5): methyl group) and 1-octyne, thereby obtaining (E)-(2-(hydroxymethyl)phenyl) dimethyl(2-phenylethenyl)silane (0.45 g, yield of 84%) as a colorless oil, Rf: 0.20 (hexane-ethyl acetate=10:1). 1H NMR (400 MHz, CDCl3) δ 7.62 (dd, J=7.4, 1.3 Hz, 1H), 7.51-7.41 (m, 4H), 7.37-7.27 (m, 4H), 6.97 (d, J=19.2 Hz, 1H), 6.67 (d, J=19.2 Hz, 1H), 4.79 (s, 2H), 0.52 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 146.5, 145.2, 138.0, 136.4, 135.3, 130.0, 128.6, 128.3, 127.9, 127.8, 127.1, 126.5, 65.4, −1.2; Anal. Calcd for C17H20Osi; C, 76.07; H, 7.51. Found: C, 75.73; H, 7.55.
Reaction SMILES: C[Al](C)C.[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:12][C:13]1[C:14]2[C:40]([CH3:46])([C:41](OCC)=[O:42])[C:39](=[O:47])[NH:38][C:15]=2[N:16]=[C:17]([C:19]2[C:27]3[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=3)[N:21]([CH2:29][CH2:30][C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])[N:20]=2)[N:18]=1.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>CCOC(C)=O.C1(C)C=CC=CC=1>[NH2:12][C:13]1[C:14]2[C:40]([CH3:46])([C:41]([NH:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:42])[C:39](=[O:47])[NH:38][C:15]=2[N:16]=[C:17]([C:19]2[C:27]3[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=3)[N:21]([CH2:29][CH2:30][C:31]([F:36])([F:37])[C:32]([F:35])([F:33])[F:34])[N:20]=2)[N:18]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C1(C)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4cc(Cl)ccc34)nc(N)c21
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC1(C(=O)Nc2ccccc2)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4cc(Cl)ccc34)nc(N)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trimethylaluminum (2.0 M in toluene, 1.2 mL, 2.4 mmol) was added to a toluene (8 mL) solution of aniline (248 mg, 2.66 mmol). After stirring at room temperature for 2 hours, solid ethyl 4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylate, as described in Example 157, (250 mg, 0.469 mmol) was added. The reaction solution was stirred at 50° C. for 30 minutes and then at room temperature overnight. Sodium potassium tartrate (0.5M aqueous, 25 mL) and EtOAc (25 mL) were added and the mixture stirred vigorously for 30 minutes. The phases were separated and the organic phase was washed with water (2×) and brine. The organic phase was then dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated product. Chiral separation using SFC on a Chiralpak AD-H column provided both enantiomers of the title compound. 1H NMR (400 MHz, CH3CN-d3): δ 9.19 (s, 1H); 8.55 (d, J=8.69 Hz, 1H); 7.64 (s, 1H); 7.55 (d, J=8.01 Hz, 2H); 7.32 (t, J=7.77 Hz, 2H); 7.20-7.10 (m, 2H); 6.45 (s, 2H); 4.72 (t, J=7.10 Hz, 2H); 2.85-2.69 (m, 2H); 1.79 (s, 3H). m/z=580.2 (M+H).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:14])([F:13])[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[CH:11]=[O:12]>CO>[F:13][C:4]([F:3])([F:14])[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[CH2:11][OH:12]
Reactant: O=Cc1cnccc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cnccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of sodium borohydride (324 mg, 8.6 mmol) in methanol (20 mL) was added a solution of 4-(trifluoromethyl)pyridine-3-carbaldehyde (1.0 g, 5.7 mmol) in methanol (10 mL) at 0° C. The mixture was stirred for 1.5 hours at room temperature. The solvent was evaporated, water was added, and the mixture was extracted 3 times with ethyl acetate. The combined organic phases were washed with brine and dried over sodium sulfate. After evaporation of the solvent, [4-(trifluoromethyl)pyridin-3-yl)methanol was obtained as an oil (980 mg, 97% yield) and used in the next step without further purification.
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]>[Pd].N1C=CC=CC=1>[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
Agent: [Pd]
Solvent: c1ccncc1
Product: COC[C@@H](NC(C)=O)C(=O)NCc1ccccc1

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(OC([NH:11][C@@H:12]([CH2:33][C:34](=[O:53])[NH:35]C(C1C=CC(OC)=CC=1)C1C=CC(OC)=CC=1)[C:13]([NH:15][C@H:16]([C@@H:20]([NH:22][C@H:23]([C:30]([OH:32])=[O:31])[CH2:24][C:25]1[N:26]=[CH:27][NH:28][CH:29]=1)[CH3:21])[C:17]([OH:19])=[O:18])=[O:14])=O)C1C=CC=CC=1.Br.C(OCC)(=O)C>C(O)(=O)C>[NH2:11][C@@H:12]([CH2:33][C:34](=[O:53])[NH2:35])[C:13]([NH:15][C@H:16]([C@@H:20]([NH:22][C@H:23]([C:30]([OH:32])=[O:31])[CH2:24][C:25]1[N:26]=[CH:27][NH:28][CH:29]=1)[CH3:21])[C:17]([OH:19])=[O:18])=[O:14]
Reactant: COc1ccc(C(NC(=O)C[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@@H](C(=O)O)[C@H](C)N[C@@H](Cc2c[nH]cn2)C(=O)O)c2ccc(OC)cc2)cc1
Agent: Br
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C[C@H](N[C@@H](Cc1c[nH]cn1)C(=O)O)[C@@H](NC(=O)[C@@H](N)CC(N)=O)C(=O)O
Temperature: 0 °C
Yield: 59 %

Procedure:
A solution of (2R,3S)-2-[[(2S)-2-benzyloxycarbonylamino-3-[N-[bis(4-methoxyphenyl)methyl]carbamoyl]propionyl]amino]-3-[[(1S)-1-carboxy-2-(4-imidazolyl)ethyl]amino]butyric acid (635 mg) and 30% hydrogen bromide in acetic acid (5 ml) was stirred for 2 hours at room temperature and the mixture was poured into a mixture of ice-water (20 ml) and ethyl acetate (20 ml). The aqueous phase was separated and subjected to a column of Dowex 50W x 8 (H+, 20 ml). The column was washed with water and the elution was carried out with 2.8% aqueous ammonia. The object fractions were collected and evaporated in vacuo. The residue was dissolved in water (50 ml) and lyophilized to give (2R,3S)-2-[[(2S)-2-amino-3-carbamoylpropionyl]amino]-3-[[(1S)-1-carboxy-2-(4-imidazolyl)ethyl]amino]butyric acid (190 mg) as a white powder.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([S:19](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:21])=[O:20])=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]1=[O:34].[NH2:35][C:36]1[S:40][N:39]=[CH:38][N:37]=1>CCOC(C)=O>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([S:19]([NH:35][C:36]3[S:40][N:39]=[CH:38][N:37]=3)(=[O:21])=[O:20])=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]1=[O:34]
Reactant: Nc1ncns1
Reactant: COC1CCCCC1n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Solvent: CCOC(C)=O
Product: CO[C@H]1CCCC[C@@H]1n1c(=O)ccc2cc(S(=O)(=O)Nc3ncns3)ccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 38.8 %

Procedure:
A 10-mL RBF was charged with (±)-perfluorophenyl 1-(2-methoxycyclohexyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (65 mg, 0.129 mmol), 5-amino-1,2,4-thiadiazole (19.6 mg, 0.194 mmol) then purged with nitrogen for 10 min. Tetrahydrofuran (323 μL) and dimethyl sulfoxide (990 μL) were sequentially introduced via syringe and the resultant solution cooled to 0° C. A solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.0 M, (871 μL, 0.871 mmol) was added dropwise via syringe to the stirred reaction mixture over 3 min. After 15 min, 1.0 N HCl (5 mL) was introduced and the resultant reaction mixture was allowed to warm to ambient temperature. The mixture was diluted with and EtOAc (10 mL) and the layers were separated, and the aqueous layer was further extracted with EtOAc (3×10 mL). The combined organic layers were then washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure. The residue was dissolved in DMSO (2 mL), filtered through a 0.2 micron filter, and purified by reverse-phase HPLC (Waters XBridge Prep Shield RP18 10 μm OBD 19×100 mm) gradient, 20 to 75% MeCN in water (containing 0.1% trifluoroacetic acid as an additive), flow rate 40 mL/min to afford 1-((1S,2S)-2-methoxycyclohexyl)-2-oxo-N-1,2,4-thiadiazol-5-yl-1,2-dihydro-6-quinolinesulfonamide (21 mg, 0.050 mmol, 38.7% yield, mixture of enantiomers) as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.44 (s, 1 H) 8.20 (s, 1 H) 8.04 (d, J=9.54 Hz, 1H) 7.90-7.96 (m, 1 H) 7.84-7.90 (m, 1 H) 6.61 (d, J=9.47 Hz, 1 H) 4.41 (br. s., 2 H) 3.03 (s, 3 H) 2.90 (br. s., 1 H) 2.22 (d, J=11.48 Hz, 1 H) 1.61-1.85 (m, 3 H) 1.38-1.57 (m, 1 H) 1.07-1.37 (m, 2 H). m/z (ESI) 421.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.[OH-].[Ba+2].[OH-].C(O)C>Cl>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8](=[O:10])[CH:9]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)c1cccc(O)c1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1ccccc1)c1cccc(O)c1
Yield: 93.6 %

Procedure:
To a 250 ml round bottom flask equipped with a magnetic stirrer and reflux condensor, was charged 2.7 g (0.02 moles) of 3'-hydroxyacetophenone, 2.1 g (0.02 moles) of benzaldehyde, 2.0 g (0.011 moles) of barium hydroxide, monohydrate, and 20 ml of absolute ethanol. The reaction was refluxed for a total of 2.5 hours, after which it became thick and difficult to stir. Upon cooling, the resulting solid was dissolved in 100 mls of 1N aqueous hydrochloric acid, and another solid was observed to precipitate from solution. The solid was collected by vacuum filtration, and washed with 100 mls of water, then 100 mls of hexane and dried in vacuo at 40° C. for 24 hours. 4.2 g (93% yield) of 3'-hydroxychalcone was isolated as a tan solid. MP=143°-147° C.
Reaction SMILES: [I:1][C:2]1[C:3]([C:7]([OH:9])=O)=[N:4][NH:5][CH:6]=1.Cl.Cl.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[CH:18][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][C:16]=1[NH:21][C:7]([C:3]1[C:2]([I:1])=[CH:6][NH:5][N:4]=1)=[O:9]
Reactant: O=C(O)c1n[nH]cc1I
Reactant: COc1ccc(N)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(N)c(NC(=O)c2n[nH]cc2I)c1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A suspension of 4-iodo-1H-pyrazole-3-carboxylic acid Compound 1a(500 mg, 2.101 mmol), 4-methoxy-benzene-1,2-diamine dihydrochloride (443 mg, 2.101 mmol), HATU (799 mg, 2.101 mmol), and diisopropyl ethylamine (815 mg, 6.303 mmol) in 15 ml DMF was stirred at 50° C. for 16 hrs. After cooled to rt, the mixture was diluted with 150 ml EtOAc, washed with water (7 times) and brine, then dried with Na2SO4. Evaporation give 4-iodo-1H-pyrazole-3-carboxylic acid (2-amino-5-methoxy-phenyl)-amide Compound 1b (615 mg, 81.7%) as a yellowish powder. NMR (DMSO): δ 3.70 (s, 3H), 6.20 (m, 1H), 6.46 (s, H), 7.12 (d, J=8.0 Hz, 1H), 8.10 (s, 1H). MS m/z 358 (MH+).