Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[CH:8]=[C:7]2[CH2:12][NH:13][CH3:14].CNCC1C2C=CC=CC=2N2CCCC=12.[NH2:30][C:31]1[N:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39]([OH:41])=O)=[CH:33][CH:32]=1.Cl.O=C1NC2N=CC(/C=C/C(O)=O)=CC=2CC1>>[NH2:30][C:31]1[N:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39]([N:13]([CH2:12][C:7]2[C:6]3[C:10](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=3)[N:9]([CH3:11])[CH:8]=2)[CH3:14])=[O:41])=[CH:33][CH:32]=1
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Reactant: CNCc1cn(C)c2c(F)cccc12
Agent: CNCc1c2n(c3ccccc13)CCC2
Agent: Cl
Agent: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Product: CN(Cc1cn(C)c2c(F)cccc12)C(=O)/C=C/c1ccc(N)nc1
Yield: 28.4 %

Procedure:
According to the procedure of Example 24, except substituting 7-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole (0.2 g, 1.04 mmole) for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene, and substituting (E)-3-(6-aminopyridin-3-yl)acrylic acid (0.17 g, 1.04 mmole) for the (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride salt, the title compound (0.1 g, 27%) was prepared as an off-white powder: MS (ES) m/e 339 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:10]=1.Br[C:38]1[CH:39]=[C:40]([CH:44]([N:49]2[CH2:54][CH2:53][S:52](=[O:56])(=[O:55])[CH2:51][CH2:50]2)[CH2:45][C:46]([OH:48])=[O:47])[CH:41]=[CH:42][CH:43]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+].Cl>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].C(#N)C.C1COCC1>[O:56]=[S:52]1(=[O:55])[CH2:51][CH2:50][N:49]([CH:44]([C:40]2[CH:41]=[CH:42][CH:43]=[C:38]([C:15]3[CH:16]=[C:17]4[C:9]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[O:2][CH3:1])=[CH:10][N:11]([S:27]([C:30]5[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=5)(=[O:28])=[O:29])[C:12]4=[N:13][CH:14]=3)[CH:39]=2)[CH2:45][C:46]([OH:48])=[O:47])[CH2:54][CH2:53]1
Reactant: O=C(O)CC(c1cccc(Br)c1)N1CCS(=O)(=O)CC1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cccc(C(CC(=O)O)N4CCS(=O)(=O)CC4)c3)cc12
Yield: 53.5 %

Procedure:
To a mixture of 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (504 mg, 1 mmol) and 3-(3-bromo-phenyl)-3-(1,1-dioxothiomorpholin-4-yl)-propionic acid (362 mg, 1.0 mmol) in a 20 mL microwave reaction flask was added THF (3 mL), acetonitrile (3 mL) and sodium carbonate (3 mL, 1 N aqueous solution, 3 mmol). The mixture was purged with nitrogen for 1 minute. Dichloro[1,1′-bis(diphenylphoshino)ferrocene]palladium(II) dichloromethane adduct (82 mg, 0.1 mol) was added and the purging continued for another minute. The flask was sealed and irradiated in a microwave reactor to 135° C. for 20 minutes. Saturated sodium chloride (10 mL) was added and the pH was adjusted to 5 using hydrochloric acid (1 N). The resulting mixture was extracted with ethyl acetate (10 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel using a gradient of methanol in dichloromethane to afford 3-(1,1-dioxothiomorpholin-4-yl)-3-{3-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-propionic acid as a yellow solid (353 mg, 53% yield). MS: m/z 660 (M+H+).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:4]([CH:9]=O)=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:13][C:14]([S@@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>S([O-])([O-])(=O)=O.[Cu+2].C(Cl)Cl>[CH3:13][C:14]([S@@:17](/[N:19]=[CH:9]/[C:4]1[C:3]([C:2]([F:12])([F:11])[F:1])=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=Cc1ncccc1C(F)(F)F
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C/c1ncccc1C(F)(F)F
Reaction time: 1.5 h

Procedure:
To a solution of 3-(trifluoromethyl)picolinaldehyde (Frontier Scientific, 9.80 g, 56.0 mmol) and DCM (50 mL) was added (S)-2-methylpropane-2-sulfinamide (AK Scientific, 10.3 g, 85.0 mmol) and copper(II) sulfate (35.3 g, 221 mmol). After 1.5 h at rt, the reaction was filtered through a pad of Celite® brand filter agent and rinsed with DCM. The filtrate was concentrated in vacuo to give a dark green oil. The oil thus obtained was loaded onto a silica gel column and eluted with 30% EtOAc in hexanes to give (S,E)-2-methyl-N-((3-(trifluoro-methyl)pyridin-2-yl)methylene)propane-2-sulfinamide, as a golden oil. 1H NMR (δ ppm, CDCl3, 300 MHz): 9.02 (d, J=4.3 Hz, 1H), 8.70 (d, J=1.3 Hz, 1H), 8.38 (d, J=7.7 Hz, 1H), 7.79 (dd, J=7.9 & 4.8 Hz, 1H), 1.18 (s, 9H). MS (ESI pos. ion) m/z: 279.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[CH:21]=1)=[O:4].II.[I:24]([O-])(=O)=O.[K+].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[I:24][C:21]1[N:9]2[CH:10]=[C:11]([S:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:13][C:8]2=[N:7][C:6]=1[NH:5][C:3]([O:2][CH3:1])=[O:4]
Reactant: [O-][I+2]([O-])[O-]
Reactant: COC(=O)Nc1cn2cc(Sc3ccccc3)ccc2n1
Agent: II
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2ccc(Sc3ccccc3)cn2c1I
Temperature: 0 °C

Procedure:
A suspension of 2-(methoxycarbonylamino)-6-(phenylthio) imidazo [1,2-a] pyridine (600 mg., 2 mmoles), iodine (420 mg., 3.2 mmoles) and potassium iodate (180 mg., 0.8 mmole) in 60% aqueous acetic acid (50 ml.) containing 2 ml. of concentrated sulfuric acid is stirred at room temperature for 48 hours. The solution is diluted with ice water and the pH adjusted to 8 with aqueous sodium bicarbonate. The reaction mixture is extracted with dichloromethane and the dried extracts are evaporated in vacuo to yield 3-iodo-2-(methoxycarbonylamino)-6-(phenylthio) imidazo [1,2-a] pyridine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.N[C:10]1[S:11][CH:12]=[CH:13][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[CH:3]=1
Reactant: Nc1nccs1
Reactant: Cc1ccnc(N)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: Cc1ccnc(Nc2nccs2)c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
A suspension of 4-methyl-2-aminopyridine (5.10 g, 40.0 mmol), 2-aminothiazole (4.81 g, 48 mmol, 1.2 eq), sodium carbonate (5.94 g, 56.0 mmol, 1.4 eq) and XANTPHOS (0.278 g, 0.48 mmol, 0.012 eq) in THF (100 mL, bubbled with argon for 5 minutes) was bubbled again with argon for 5 additional minutes. Tris(dibenzylideneacetone)dipalladium (0) (0.146 g, 0.16 mmol, 0.004 eq) was then added to the suspension which was heated at 130° C. for 2 days. Additional quantities of XANTPHOS (0.278 g) and tris(dibenzylideneacetone)dipalladium (0) (0.146 g) were added again and the reaction was heated at 130° C. for 4 more days. The mixture was cooled down to RT and filtered. The resulting solid was suspended in water and stirred for 1 hour. After filtration, the resulting solid was dried under vacuum overnight. The THF filtrate was evaporated and the residue was combined to the previously isolated solid. This was precipitated from MeOH to give the title compound (5.14 g, 67%) as a solid. The mother liquor was evaporated and the residue purified by silica gel chromatography (50% ethyl acetate/dichloromethane to 100% ethyl acetate) and afforded the title material (0.825 g, 11%) as a solid, 1H NMR (400 MHz, CDCl3) δ (ppm): 2.36 (3H, s), 6.71 (1H, s), 6.75 (1H, br d, J=5.1 Hz), 6.84 (1H, d, J=3.5 Hz), 7.43 (1H, d, J=3.5 Hz), 8.24 (1H, d, J=5.3 Hz). LC/MS (M+H)+: 192. HPLC ret. time (Condition A): 1.285 min.
Reaction SMILES: [OH:1][CH:2]([CH2:9][CH:10]([OH:13])[CH:11]=[CH2:12])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:14]12(CS(O)(=O)=O)C(C)(C)C(C[CH2:20]1)C[C:15]2=O>ClCCl.COC(OC)(C)C>[CH:11]([CH:10]1[O:13][C:14]([CH3:20])([CH3:15])[O:1][CH:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:9]1)=[CH2:12]
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: C=CC(O)CC(O)CC(=O)OCC
Solvent: COC(C)(C)OC
Solvent: ClCCl
Product: C=CC1CC(CC(=O)OCC)OC(C)(C)O1
Reaction time: 8 h

Procedure:
The crude β,δ-dihydroxy-6-heptenoic acid, ethyl ester from the previous step was dissolved in a mixture of 30 mL of dichloromethane and 10 mL of 2,2-dimethoxypropane. Camphorsulfonic acid (0.05 g) was added, and the mixture was stirred overnight. Concentration of the reaction mixture and flash chromatography of the residue yielded 1.1 g of 6-ethenyl-2,2-dimethyl-l,3-dioxane-4-acetic acid, ethyl ester.
Reaction SMILES: [Si]([O:8]/[N:9]=[C:10]1\[NH:11][C@@H:12]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[Br:29])[CH2:13][C:14]2[N:15]=[C:16]([NH2:21])[N:17]=[C:18]([CH3:20])[C:19]\1=2)(C(C)(C)C)(C)C.C(O)(C(F)(F)F)=O.O>O1CCOCC1>[NH2:21][C:16]1[N:17]=[C:18]([CH3:20])[C:19]2=[C:14]([CH2:13][C@H:12]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[Br:29])[NH:11]/[C:10]/2=[N:9]\[OH:8])[N:15]=1
Reactant: Cc1nc(N)nc2c1/C(=N/O[Si](C)(C)C(C)(C)C)N[C@@H](c1ccc(F)cc1Br)C2
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: Cc1nc(N)nc2c1/C(=N/O)N[C@@H](c1ccc(F)cc1Br)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
To a solution of (R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-tert-butyldimethylsilyloxime (85b, 384 mg, 0.8 mmol) in dioxane (2 mL) was added 1:9 TFA-H2O and the reaction mixture stirred at room temperature for 2 h. The resulting solid was filtered and washed with dioxane, then dried to afford (R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one oxime (85c, 206 mg, 70%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.56 (s, 3H) 2.83 (dd, J=15.92, 4.55 Hz, 1H) 3.17 (dd, J=16.04, 5.94 Hz, 1H) 4.90 (q, J=4.97 Hz, 1H) 7.20 (d, J=1.52 Hz, 1H) 7.21-7.23 (m, 1H) 7.57 (ddd, J=8.34, 1.64, 1.39 Hz, 1H) 9.82 (s, 1H). MS (ES) [M+H] calculated for C14H14BrFN5O, 366.03; found 366.20.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:18])[C:12]([CH2:19][OH:20])=[C:11]2[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1.C(N(CC)CC)C>ClCCl.CS(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:18])[C:12]([CH:19]=[O:20])=[C:11]2[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1
Reactant: Cc1nc2ccc(Cl)cc2c(-c2ccc(F)cc2)c1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2ccc(Cl)cc2c(-c2ccc(F)cc2)c1C=O
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of oxalyl chloride (8.85 mL, 1.1 equivalents) in 150 mL of dry dichloromethane at -78° C. under nitrogen, was added dropwise a solution of dimethylsulfoxide (14.2 mL, 2.2 equivalents) in 125 mL of dichloromethane. After complete addition, the mixture was stirred for five minutes at -78° C. and then a solution of 6-chloro-4-(4-fluorophenyl)-2-methyl-3-quinolinemethanol (27.8 ) in 100 mL of dichloromethane and 50 mL of dimethylsulfoxide was added dropwise. This solution was stirred at -78° C. for one hour, after which triethylamine (64.1 mL, 5.0 equivalents) was added. The cooling bath was removed and 400 mL of saturated ammonium chloride solution was added to the reaction mixture.
Reaction SMILES: [C:1]([N:4]1[CH:10]([CH3:11])[CH2:9][C:8]2[CH:12]=[C:13]([Cl:17])[C:14]([Cl:16])=[CH:15][C:7]=2[C:6]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[C:20]([Cl:27])[CH:19]=2)=[N:5]1)(=[O:3])[CH3:2].O.NN>CO.ClCCl.[Ni]>[C:1]([N:4]1[CH:10]([CH3:11])[CH2:9][C:8]2[CH:12]=[C:13]([Cl:17])[C:14]([Cl:16])=[CH:15][C:7]=2[C:6]([C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([Cl:27])[CH:19]=2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1N=C(c2ccc([N+](=O)[O-])c(Cl)c2)c2cc(Cl)c(Cl)cc2CC1C
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1N=C(c2ccc(N)c(Cl)c2)c2cc(Cl)c(Cl)cc2CC1C
Reaction time: 0.75 h
Yield: 70.6 %

Procedure:
4.26 g (10 mmoles) of (±)-3-acetyl-4,5-dihydro-7,8-dichloro-1-(3-chloro-4-nitrophenyl)-4-methyl-3H-2,3-benzodiazepine are dissolved in a mixture of 40 cm3 of methanol and 40 cm3 of dichloromethane, then 3.0 g of wet Raney nickel catalyst and, under vigorous stirring, 1.7 cm3 (35 mmoles) of 98% hydrazine hydrate are added. The reaction mixture is stirred for further 45 minutes, the catalyst is filtered, washed with dichloromethane, the filtrate is evaporated, and the residue is rubbed with 50 cm3 of water to obtain solid matter. The crude product is recrystallized from acetonitrile. Thus, 2.80 g (71%) of the title compound are obtained in the form of butter coloured solids melting at 127–129° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]3[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccccc3)c2c1Cl
Product: Cc1sc2nc(-n3ccnc3)nc(NCc3ccccc3)c2c1Cl

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2,5-dichloro-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5-chloro-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH:3]1[C:15]([NH2:17])=O.B.CSC.CO>C1COCC1>[NH2:17][CH2:15][CH:3]1[CH:2]([OH:1])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4]1
Reactant: NC(=O)C1CN(Cc2ccccc2)CCC1O
Agent: B
Solvent: CO
Solvent: C1CCOC1
Solvent: CSC
Product: NCC1CN(Cc2ccccc2)CCC1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
A suspension of 4-hydroxy-1-(phenylmethyl)-3-piperidinecarboxamide (5.62 g, 23.9 mmol) in THF (65 mL) was treated dropwise with borane-methyl sulphide complex (2M solution in THF, 26.4 mL, 52.8 mmol). After stirring for 0.5 h at room temperature, the reaction mixture was heated at 80° C. for 1.5 h. Methanol (16 mL) was added and heating continued for 0.5 h. The mixture was evaporated and the residue was chromatographed on silica gel, eluting with 10-30% (2M ammonia/methanol)/dichloromethane to give the product (2.67 g, 51%).
Reaction SMILES: C([O:4][CH:5]([CH3:9])[C:6](O)=[O:7])(=O)C.[F:10][C:11]([F:36])([F:35])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[CH:22][N:21]=[C:20]([O:24][C:25]3[C:30]4[N:31]=[C:32]([NH2:34])[S:33][C:29]=4[CH:28]=[CH:27][CH:26]=3)[CH:19]=2)=[CH:14][CH:13]=1.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.CCN(P1(N(CC2C=CC=CC=2)CCCN1C)=NC(C)(C)C)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.C(=O)([O-])[O-].[K+].[K+]>S(Cl)(Cl)=O>[OH:4][CH:5]([CH3:9])[C:6]([NH:34][C:32]1[S:33][C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([O:24][C:20]3[CH:19]=[C:18]([C:15]4[CH:16]=[CH:17][C:12]([C:11]([F:35])([F:10])[F:36])=[CH:13][CH:14]=4)[N:23]=[CH:22][N:21]=3)[C:30]=2[N:31]=1)=[O:7]
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Reactant: CC(=O)OC(C)C(=O)O
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1Cc1ccccc1
Solvent: C=Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(O)C(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (+/−)-2-acetoxypropionic acid (56 uL, 0.5 mmol, Fluka) in thionyl chloride (1 mL) was heated at reflux for 3 h. After evaporation of the solvent, the residue was dissolved in THF, and treated with 4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine, (Example 65), (97 mg, 0.25 mmol) and 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine, polymer bound (BEMP resin) (0.17 g, 0.38 mmol, Aldrich). The reaction mixture was stirred at 25° C. for 16 h. The insoluble material was filtered off and washed with CH2Cl2. The filtrate was concentrated and then dissolved in MeOH. Potassium carbonate (69 mg, 0.5 mmol) was added and the reaction mixture was stirred at 25° C. for 2 h. The solvent was evaporated in vacuum and to the residue was added CH2Cl2 (30 mL). After stirring for 5 min, the precipitate was collected by filtration and purified by silica gel chromatography (3:1 of EtOAc/hexanes) to give the title compound. MS (ESI, pos. ion) m/z: 461 (M+1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:4])=[O:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:38]([O:40][C:41]([C:43]1([NH2:52])[CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1)=[O:42])[CH3:39].CCN(C(C)C)C(C)C>CO.C(Cl)Cl.C(Cl)Cl>[CH2:38]([O:40][C:41]([C:43]1([NH:52][C:7]([C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:2]([CH3:1])(=[O:3])=[O:4])=[O:9])[CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1)=[O:42])[CH3:39]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: CS(=O)(=O)c1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2ccccc2S(C)(=O)=O)Cc2ccccc2C1
Yield: 139.6 %

Procedure:
To a 40 mL vial containing a stirring bar, 2-(methylsulfonyl)benzoic acid (0.4 g, 2.88 mmol) is charged with dry DCM (7 mL). Stirring is initiated. HBTU (922 mg, 2.43 mmol). The 2-aminoindane-2-carboxylic acid ethyl ester (500 mg, 2.44 mmol) is added followed by the DIPEA (0.95 mL, 8 mmol). The reaction is allowed to stir for 36 h. Analysis by tlc of the reaction mixture (silica, 10% MeOH/DCM) indicates complete consumption of the starting amine. The contents of the reaction flask are diluted with EtOAc (50 mL) and transferred to a separatory funnel. This is washed consecutively with dilute aqueous NaHCO3 (25 mL) and brine (25 mL), dried over MgSO4, filtered and evaporated in vacuo to provide 1.32 g of white solid. This material is dissolved in 10 mL of DCM and purified utilizing an ISCO Companion with a 40 g cartridge of silica. The gradient is 15% EtOAc in heptanes for 3 column volumes followed by a linear gradient to 50% over 8 column volumes and then 90% EtOAc for 2 column volumes with a ramp of 1 column volume. 25 mL fractions are collected. Fractions 5 through 8 are combined and evaporated in vacuo. Pumping to a constant weight gives amorphous white solid 0.71 g.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([C:9]([OH:11])=O)[CH2:6][O:7][CH3:8])(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(OCC)(=O)C>[CH3:2][C:1]([NH:4][C@@H:5]([C:9]([NH:34][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:11])[CH2:6][O:7][CH3:8])=[O:3]
Reactant: NCc1ccccc1
Reactant: COC[C@@H](NC(C)=O)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: COC[C@@H](NC(C)=O)C(=O)NCc1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
Into a 2 L, four-necked RB flask was charged 1250 ml of ethyl acetate and 25 g of N-acetyl-O-methyl-D-serine under nitrogen atmosphere. The reaction mass was cooled to −20° C. and added 16.5 g of N-methylmorpholine. Isobutyl chloroformate (22.3 g) was slowly added to the reaction mass. After stirring for 30 min benzylamine (17.5 g) was slowly added to the reaction mass and stirred for 30 min. Temperature of the reaction mass was raised to 25-30° C. and stirred for 1 h. Reaction mass was quenched with 100 ml of 1N HCl and transferred into a separating funnel. Organic layer was washed with brine and dried over sodium sulphate. Solvent was partially distilled of from the mass under vacuum. The residue was kept under stirring and filtered the solid. The wet solid was recrystallized from ethyl acetate to get 35 g of pharma grade lacosamide. Chiral HPLC purity is >99.9% and the related impurities are <0.5%.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH2:15][CH2:14][C:13](=[O:16])[CH:12]=1.[Cl-].[Cl-].[Cl-].[Ce+3].[BH4-].[Na+]>C(O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH2:15][CH2:14][CH:13]([OH:16])[CH:12]=1
Reactant: O=C1C=C(c2ccc3ccccc3c2)CC1
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CCO
Product: OC1C=C(c2ccc3ccccc3c2)CC1
Reaction time: 0.5 h

Procedure:
A solution of 3-(naphthalen-2-yl)cyclopent-2-enone (2.22 g, 10.7 mmol) in ethanol (250 mL) was treated with cerium trichloride (2.63 g, 10.7 mmol, 1 eq.) followed portion wise by sodium borohydride (0.48 g, 12.8 mmol, 1.2 eq.) at room temperature. The reaction mixture was stirred for 0.5 h, then quenched with saturated aqueous ammonium chloride (125 mL) and concentrated to remove ethanol. The concentrate was diluted with water (125 mL) and extracted with dichloromethane (3×125 mL). The combined organic extracts were dried over magnesium sulphate, filtered, and concentrated in vacuo to afford in a quantitative yield as a white solid which was not further purified. 1H NMR (400 MHz, CDCl3) δ ppm 1.89-1.97 (1H, m, CH), 2.48-2.57 (1H, m, CH), 2.75-2.83 (1H, m, CH), 3.00-3.09 (1H, m, CH), 3.27 (1H, q, J 1.3 Hz, CH), 5.04-5.09 (1H, m, OH), 6.36 (1H, q, J 1.9 Hz, CH), 7.39-7.50 (2H, m ArH), 7.70 (1H, dd, J 1.6, 8.5 Hz, ArH), 7.75-7.88 (3H, m, ArH), 7.99 (1H, s, ArH).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH:29]=O)=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl.[BH3-]C#N.[Na+]>CO.C1COCC1.O.[OH-].[K+]>[CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:21][CH:22]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2C=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: Nc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2CNc2ccccc2)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(2,6-Dichlorobenzoyl)-4-(2-formylphenyl)-L-phenylalanine methyl ester (49.1 mg) was dissolved in a mixture of anhydrous MeOH (1 mL) and anhydrous THF (0.5 mL). Aniline (58.8 μL), HCl (53.8 μL of 4M in dioxane) and 3 Å molecular sieves were then added and the mixture was stirred under N2 at room temperature for 1 h. NaCNBH3 (4.06 mg) was added and the mixture was stirred for an additional 72 h. The pH of the mixture was brought to approximately 2 with 1N HCl to quench the reaction. The mixture was diluted with water and neutralized with 1M KOH. This was then extracted with CH2Cl2 and the combined organic extracts were dried (K2CO3) and evaporated. The residue was purified by preparative TLC (silica gel) using CH2Cl2 as eluent to give N-(2,6-dichlorobenzoyl)-4-[2-[(phenylamino)methyl]phenyl]-L-phenylalanine methyl ester (21.2 mg). ESMS: m/z 533 (MH+).