Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:14])[S:10](Cl)(=[O:12])=[O:11].ClCCl.[CH2:18]([O:25][CH2:26][N:27]1[C:32](=[O:33])[C:31]2=[N:34][CH:35]=[N:36][C:30]2=[CH:29][NH:28]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:8][N:9]([CH3:14])[S:10]([N:36]1[C:30]2[CH:29]=[N:28][N:27]([CH2:26][O:25][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:32](=[O:33])[C:31]=2[N:34]=[CH:35]1)(=[O:12])=[O:11]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: O=c1c2ncnc-2c[nH]n1COCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)n1cnc2c(=O)n(COCc3ccccc3)ncc21
Yield: 66.3 %

Procedure:
2.08 g of triethylamine, 2.80 g of N,N-dimethyl sulfamoyl chloride, and 0.22 g of 4-dimethylaminopyridine were added to 50 ml of a dichloromethane solution of 3.04 g of 5-benzyloxymethylimidazo[4,5-d]pyridazin-4-one [CAS NO. 82137-50-6] (R. Paul Gagnier, Michael J. Halat, and Brian A. Otter Journal of Heterocyclic Chemistry, 21, p 481, 1984), and the mixture was heated under reflux for 4 hours. 250 ml of ethyl acetate was added to the solution, and the mixture was washed successively with 50 ml of an aqueous solution of 1N hydrochloric acid, 50 ml of a saturated sodium bicarbonate solution, and 50 ml of a saturated sodium chloride solution. The mixture was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 2.86 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (2:3).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([N:15]2[C:26]3[C:18](=[CH:19][N:20]=[C:21]4[C:25]=3[CH:24]=[CH:23][N:22]4[S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])[NH:17][N:16]2C)([CH3:14])[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:30]1([S:27]([N:22]2[CH:23]=[CH:24][C:25]3[C:21]2=[N:20][CH:19]=[C:18]2[C:26]=3[N:15]([C:11]3([CH3:14])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:16]=[N:17]2)(=[O:29])=[O:28])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CN1Nc2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2N1C1(C)CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)CCNCC1
Reaction time: 1 h
Yield: 92.3 %

Procedure:
A mixture of 4-(6-benzenesulfonyl-2-methyl-6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (280 mg, 0.56 mmol)) in DCM/TFA was stirred for 1 hr. The solvent was evaporated under vacuum and the resulting residue purified by column chromatography (SCX-2, gradient: 0 to 50% [2M NH3 in methanol] in DCM) to afford 205 mg (93%) of 6-benzenesulfonyl-1-(4-methyl-piperidine-4-yl)1,6-dihydro-1,2,3,5,6-pentaaza-as-indacene. 1H NMR (400 MHz, DMSO): δ 9.25 (s, 1H), 8.19-8.17 (m, 3H), 7.76-7.72 (m, 1H), 7.65 (t, 2H), 7.48 (d, 1H), 2.83-2.80 (m, 4H), 2.55 (m, 2H), 2.00 (d, 2H), 1.82 (s, 3H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[N:4]([Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.[F:22][C:23]1[C:28]([CH:29]=O)=[CH:27][CH:26]=[C:25]([NH:31][C:32]2[CH:33]=[N:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)[N:24]=1>>[F:22][C:23]1[N:24]=[C:25]([NH:31][C:32]2[CH:33]=[N:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)[CH:26]=[CH:27][C:28]=1[CH2:29][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[NH:4][CH:3]=1
Reactant: COc1ccc(Nc2ccc(C=O)c(F)n2)cn1
Reactant: Cc1cnc2c(c1)c(I)cn2[Si](C(C)C)(C(C)C)C(C)C
Product: COc1ccc(Nc2ccc(Cc3c[nH]c4ncc(C)cc34)c(F)n2)cn1

Procedure:
[6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine P-3019 is prepared in two steps from 3-iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 8 and 2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridine-3-carbaldehyde 56 as shown in Scheme 11.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:14][C:15]1([O:18][CH2:17]1)[CH3:16]>CN(C)C=O.O>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][CH2:14][C:15]([CH3:17])([OH:18])[CH3:16])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: CC1(C)CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)COC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decan-8-ol (4.90 g) in N,N-dimethylformamide (20 mL) was added 60% sodium hydride in oil (1.24 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Isobutylene oxide (2.52 g) was added to this mixture, and the mixture was stirred at 90° C. for 15 hr. The reaction mixture was cooled to room temperature and diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=90/10→70/30 (volume ratio)] to give the title compound as a colorless oil (5.59 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([NH:11]C(=O)OC(C)(C)C)=[CH:8][C:6]=2[N:7]=1.FC(F)(F)C(O)=O.ClCCl>>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([NH2:11])=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Yield: 99.3 %

Procedure:
Tert-butyl 2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-ylcarbamate (800 mg) was treated with 5 mL of trifluoroacetic acid/dichloromethane (1:1). The reaction mixture was stirred at room temperature until complete. The reaction mixture was evaporated. The residue was diluted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate (50 mL) and brine (50 mL). The aqueous layer was back-extracted with ethyl acetate (2×60 mL), and then washed with saturated sodium bicarbonate and brine. The combined organic layers were dried over MgSO4, filtered and evaporated to afford 580 mg of 2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([C:18]([F:21])([F:20])[F:19])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl[C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][N:24]=1>>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:23]([N:16]2[CH:17]=[C:13]([C:12]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][O:10][C:11]=3[C:18]([F:21])([F:19])[F:20])[N:14]=[CH:15]2)=[N:24][CH:25]=1
Reactant: FC(F)(F)c1onc(-c2ccc(Cl)cc2)c1-c1c[nH]cn1
Reactant: COC(=O)c1ccc(Cl)nc1
Product: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(Cl)cc4)noc3C(F)(F)F)c2)nc1
Yield: 75 %

Procedure:
As described for Example 4, 3-(4-chloro-phenyl)-4-(1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole (700 mg, 2.2 mmol) instead of 4-(1H-imidazol-4-yl)-3-phenyl-5-trifluoromethyl-isoxazole was converted, using methyl 6-chloronicotinate instead of 4-fluorobenzotrifluoride, to the title compound (750 mg, 75%) which was obtained as a white solid. MS: m/e=449.0 [M+H]+.
Reaction SMILES: [BH4-].[Li+].[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:22](=[O:25])[CH2:23][Cl:24])=[C:15]2[C:20]=1[NH:19][C:18](=[O:21])[CH:17]=[CH:16]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.ClCCl.O>C1COCC1>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:22]([OH:25])[CH2:23][Cl:24])=[C:15]2[C:20]=1[NH:19][C:18](=[O:21])[CH:17]=[CH:16]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(CCl)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=c1ccc2c(C(O)CCl)ccc(OCc3ccccc3)c2[nH]1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
238 mL of a 2 molar solution of lithium borohydride in THF are added dropwise to 52 g (159 mmol) 8-benzyloxy-5-(2-chloro-acetyl)-1H-quinolin-2-one in 650 mL THF at 0° C. It is stirred for two hours at 0° C., then heated to ambient temperature, combined with 200 mL dichloromethane and 75 mL water and stirred for a further hour. The precipitated solid is suction filtered and the organic phase of the filtrate is separated off and freed from the solvent. The residue is combined with the solid from the preceding filtration and repeatedly stirred with diethyl ether and THF. Yield: 51.6 g (99%); mass spectroscopy [M+H]+=330/32.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[CH2:21][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:23][CH3:24])[CH:10]=1.O.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[CH2:28]([O:27][C:25]([N:22]([CH2:21][C:12]1[CH:13]=[C:14]([C:17]([F:18])([F:19])[F:20])[CH:15]=[CH:16][C:11]=1[C:9]1[CH:10]=[C:5]([CH2:4][C:3]([OH:35])=[O:2])[CH:6]=[N:7][CH:8]=1)[CH2:23][CH3:24])=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OC)c1)C(=O)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)O)c1)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
(5-{2-[(N-Benzyloxycarbonyl-N-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-pyridin-3-yl)-acetic acid methyl ester (0.1 g, 0.2 mmol) in THF (2 mL), MeOH (0.5 mL), and H2O (0.5 mL) was treated with lithium hydroxide (0.03 g) and stirred at room temperature until no starting material was seen by analytical LCMS. The reaction was neutralized with citric acid to pH 4 and extracted with EtOAc, and the combined organic layers were washed with H2O, dried over MgSO4, filtered, and concentrated to give Compound 12.
Reaction SMILES: [O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:28])[NH:11][CH:12]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:13]([OH:20])[CH2:14][NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][C:31]=1[C:40]#[N:41].C([O-])(O)=O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:28])[NH:11][CH:12]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:13]([OH:20])[CH2:14][N:15]([S:36]([C:33]2[CH:34]=[CH:35][C:30]([F:29])=[C:31]([C:40]#[N:41])[CH:32]=2)(=[O:37])=[O:38])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2]1
Reactant: CC(C)CNCC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)S(=O)(=O)c1ccc(F)c(C#N)c1
Yield: 92 %

Procedure:
To a solution of (1-benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester 19 in CH2Cl2 (4 mL) was added 4-fluoro-3-cyanobenzenesulfonyl chloride (92 mg, 0.42 mmol) followed by NaHCO3 (40 mg) and satd. NaHCO3 (0.4 mL) and stirred at RT for 1 h. The reaction mixture was diluted with ethyl acetate (25 mL) and washed with water, brine and dried with Na2SO4 and concentrated to furnish crude product (240 mg). The crude product was purified by column chromatography using 1/1 ethyl acetate/hexane to provide 200 mg product (92% yield).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:5][C:6]1[N:11]=[C:10]([CH:12]=[O:13])[CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cccc(CO)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCCOc1cccc(C=O)n1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
Activated manganese dioxide (2.40 g, 27.6 mmol) was added to a solution of (6-butoxy-pyridin-2-yl)methanol (0.52 g, 2.85 mmol, obtained from Example 17(c)) in anhydrous dichloromethane (5 mL). The resulting solution was heated to reflux for 2 h and then cooled to r.t. and 50 mL of dichloromethane added. The black solid was removed by filtration through silica gel and washed with dichloromethane. The combined filtrate was concentrated in vacuo providing the title compound (0.43 mg, 84%) as a light yellow oil.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4C)[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][C:22]1[CH:23]=[CH:24][C:25](=[O:28])[NH:26][CH:27]=1.N1NC(=O)C=CC=1>>[CH3:21][C:22]1[CH:23]=[CH:24][C:25](=[O:28])[N:26]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:10][C@H:11]([N:13]5[CH2:14][CH2:15][CH2:16][CH2:17]5)[CH2:12]4)[S:8][C:4]=3[CH:3]=2)[CH:27]=1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: Cc1ccc(=O)[nH]c1
Agent: O=c1cccn[nH]1
Product: Cc1ccc(=O)n(-c2ccc3nc([C@H]4C[C@H](N5CCCC5)C4)sc3c2)c1

Procedure:
The title compound was prepared according to the procedure described in Example 22, substituting the product of Example 62A for the product of Example 1E and substituting 5-methyl-2(1H)-pyridone for 3(2H)-pyridazinone. 1H NMR (300 MHz, CDCl3) δ ppm 8.03 (d, J=9.15 Hz, 1H) 7.87-7.90 (m, 1H) 7.44 (td, J=9.00, 2.03 Hz, 1H) 7.29 (dt, J=9.00, 2.37 Hz, 2H) 7.15 (s, 1H) 6.63 (d, J=9.15 Hz, 1H) 3.61-3.73 (m, 1H) 3.03-3.16 (m, 1H) 2.43-2.78 (m, 6H) 2.12 (s, 3H) 1.81-1.91 (m, 4H) 1.51-1.61 (m, 2H). MS: (M+H)+=366.
Reaction SMILES: C(O[C:6]1([F:38])[C:33](CC=O)=[CH:32][C:31]([F:37])=[CH:30][CH:7]1[O:8][CH2:9][CH2:10][C@@H:11]1[CH2:13][C@@H:12]1[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:16][CH2:15]1)(C)(C)C.[C:39]([OH:45])([C:41](F)(F)F)=[O:40]>ClCCl>[CH2:23]([O:22][C:20]([N:17]1[CH2:16][CH2:15][CH:14]([C@H:12]2[CH2:13][C@H:11]2[CH2:10][CH2:9][O:8][C:7]2[C:6]([F:38])=[CH:33][C:32]([CH2:41][C:39]([OH:45])=[O:40])=[C:31]([F:37])[CH:30]=2)[CH2:19][CH2:18]1)=[O:21])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC1(F)C(CC=O)=CC(F)=CC1OCC[C@@H]1C[C@@H]1C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cc1cc(F)c(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OCc3ccccc3)CC2)cc1F
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Benzyl 4-{(1R,2S)-2-[2-(2-tert-butoxy-2-oxoethyl-2,5-difluorophenoxy)ethyl]cyclopropyl}piperidine-1-carboxylate (0.350 g, 0.661 ml) was dissolved in dichloromethane (1.5 ml) and TFA (1.5 ml) added. The mixture was stirred at RT for 3.5 h and the volatiles removed under vacuum to afford the title compound. LC/MS (m/z): 474.3 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][CH2:5][C:4]=2[CH:3]=1.[Br:16]Br.S([O-])(O)=O.[Na+]>P(OC)(OC)(OC)=O>[Br:16][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[C:4](=[CH:3][C:2]([I:1])=[CH:15][CH:14]=3)[CH2:5][CH2:6][C:7]=2[CH:8]=1
Reactant: BrBr
Reactant: Ic1ccc2c(c1)CCc1ccccc1-2
Agent: O=S([O-])O
Agent: [Na+]
Solvent: COP(=O)(OC)OC
Product: Brc1ccc2c(c1)CCc1cc(I)ccc1-2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
9.5 g (27.9 mmol) of 2-iodo-9,10-dihydrophenanthrene are dissolved in 40 ml of trimethyl phosphate, and a solution of 2 ml (39 mmol) of bromine in 10 ml of trimethyl phosphate is added dropwise at 20° C. After 90 min, the batch is added to ice-water, excess bromine is reduced by addition of sodium hydrogensulfite soln., and the precipitated product is filtered off with suction, taken up in toluene, washed with sat. sodium hydrogen-carbonate soln. and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is recrystallised from heptane/toluene, giving 2-bromo-7-iodo-9,10-dihydrophenanthrene as colourless crystals.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([C:9]([CH:11]=[CH2:12])=[O:10])C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[N:22]([CH3:28])[C:21]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:16][CH:15]=1.[OH-].[Na+]>C(#N)C.O.C1(C)C=CC=CC=1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:24](/[CH:12]=[CH:11]/[CH:9]=[O:10])=[C:23]([CH:25]([CH3:27])[CH3:26])[N:22]([CH3:28])[C:21]=2[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:16][CH:15]=1
Reactant: C=CC(=O)N(C)C
Reactant: CC(C)c1cc(-c2ccc(F)cc2)c(-c2ccccc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1c(/C=C/C=O)c(-c2ccc(F)cc2)c(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.64 m((18 mmol) of phosphorus oxychloride are taken in 10 ml of anhydrous acetonitrile. Under argon, a solution of 1.85 g (16.8 mmol) of 90% strength dimethylaminoacrolein in 7 ml of acetonitrile is first added dropwise at -10° C. to 0° C., and a solution of 1.76 g (6 mmol) of 3-(4-fluorophenyl)-5-isopropyl-1-methyl-2-phenyl-pyrrole (Example 3) in 7 ml of acetonitrile is then added at -5° C. to 0° C. The mixture is heated under reflux overnight. It is now added to a suspension of 4.4 g of sodium hydroxide in 65 ml of water and 65 ml of toluene at 10° C. such that the temperature does not rise above 25° C. After the mixture has been stirred at room temperature for 1.5 hours, it is filtered over kieselguhr and the phases are separated.
Reaction SMILES: [NH2:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl[C:12]([O:14][CH3:15])=[O:13].[OH-].[Na+]>C1COCC1.O>[CH3:15][O:14][C:12]([NH:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:13]
Reactant: NC1(C(=O)O)CCCCC1
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)NC1(C(=O)O)CCCCC1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A suspension of 39.9 g (279 mmol) of 1-aminocyclohexane-1-carboxylic acid in a mixture of 75 ml of THF and 75 ml of water was treated dropwise with 23.8 ml of methyl chloroformate, dissolved in 40 ml of THF, such that the temperature of the suspension did not rise above 50° C. In the course of this, the pH of the solution was kept between 8.5 and 9.5 by addition of 25% strength sodium hydroxide solution. After stirring at pH 8 for 30 minutes, the mixture was diluted with water, the THF was removed in vacuo and the aqueous phase was washed twice with methyl tert-butyl ether. The aqueous phase was adjusted to pH 2 using 6 N hydrochloric acid and extracted successively with methyl tert-butyl ether and dichloromethane. The combined organic phases were concentrated in vacuo. The residue was triturated with diethyl ether and the product was filtered off. 47.85 g (85%) of 1-methoxycarbonylaminocyclohexane-1-carboxylic acid were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:29]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15](=[O:28])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])[CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:30][C:31]([O:33]CC)=[O:32].O[Li].O>C1COCC1.CO.O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:29]=1[C:9]1([CH2:10][CH2:11][N:12]([C:15](=[O:28])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:25])([F:27])[F:26])[CH2:13][CH2:14]1)[CH2:8][CH:7]2[CH2:30][C:31]([OH:33])=[O:32]
Reactant: CCOC(=O)CC1CC2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2c(Br)cccc21
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC1CC2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 120 h
Yield: 48.6 %

Procedure:
(±)-(E)-ethyl 2-(7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate (13 mg, mmol) was dissolved in THF (0.4 mL) and MeOH (0.8 mL). A solution of LiOH.H2O (10 mg) in water (0.4 mL) was added. The mixture was stirred at rt for 5 d. The reaction mixture was submitted directly to preparative HPLC to afford (±)-(E)-2-(7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid (6 mg, %) as a solid. LC-MS Method 1 tR=1.92, min, m/z=522, 524.
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]>ClCCl.C(OCC)(=O)C>[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
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC[C@@H](NC(C)=O)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.6 %

Procedure:
To a cold solution (−2° C.) of 1.94 g of Intermediate 6, in 40 mL of dichloromethane was added dropwise 2.12 g of acetic anhydride maintaining the temperature below 5° C. The reaction mixture was stirred at room temperature for 3 hours and the organic phase was washed with water (2×20 mL), sodium bicarbonate solution (2×20 mL), brine and dried over sodium sulfate. The solvent was removed under vacuum and a white solid was obtained. The product was dissolved in 20 mL of ethyl acetate at reflux temperature and cooled slowly to 0° C. The solid was collected by filtration and dried yielding 1.6 g of lacosamide as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:15])[C:11]=1[N+:12]([O-])=O)[C:5]([O:7][CH3:8])=[O:6].Cl>CO.[Fe]>[NH2:12][C:11]1[C:2]([CH3:1])=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][C:10]=1[CH3:15]
Reactant: COC(=O)c1cc(C)c([N+](=O)[O-])c(C)c1
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(C)c(N)c(C)c1
Temperature: 80 °C
Yield: 91.1 %

Procedure:
To a solution of methyl 3,5-dimethyl-4-nitrobenzoate (10.0 g, 0.0478 mol) in methanol (100 mL), iron powder (15.7 g, 0.2869 mol) and 37% HCl (1.72 g, 0.0478 mol) is added at 0° C. The reaction is heated at 80° C. for 16 hours. The mixture is cooled to room temperature and filtered through Celite™ bed and washed with methanol followed by evaporation of filtrate to dryness to afford the title compound as a brown solid (7.8 g, 99%). Mass spectrum (m/z): 180.2 (M+1).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:23])[CH2:8][NH:7][CH2:6][CH2:5][N:4]1[CH2:9][C@@H:10]([C:12]1[CH:21]=[CH:20][C:15]2[C:16](=[O:19])[O:17][CH2:18][C:14]=2[C:13]=1[CH3:22])[OH:11].[CH3:24][C:25]1[C:33]2[CH2:32][O:31][C:30](=[O:34])[C:29]=2[CH:28]=[CH:27][C:26]=1[C@@H:35]1[CH2:37][O:36]1>>[CH3:2][C:3]1([CH3:23])[CH2:8][N:7]([CH2:37][C@@H:35]([C:26]2[CH:27]=[CH:28][C:29]3[C:30](=[O:34])[O:31][CH2:32][C:33]=3[C:25]=2[CH3:24])[OH:36])[CH2:6][CH2:5][N:4]1[CH2:9][C@@H:10]([C:12]1[CH:21]=[CH:20][C:15]2[C:16](=[O:19])[O:17][CH2:18][C:14]=2[C:13]=1[CH3:22])[OH:11]
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reactant: Cc1c([C@@H](O)CN2CCNCC2(C)C)ccc2c1COC2=O
Agent: Cl
Product: Cc1c([C@@H](O)CN2CCN(C[C@H](O)c3ccc4c(c3C)COC4=O)C(C)(C)C2)ccc2c1COC2=O

Procedure:
5,5′-{(2,2-dimethylpiperazine-1,4-diyl)bis[(1R)-1-hydroxyethane-2,1-diyl]}bis(4-methyl-2-benzofuran-1 (3H)-one) was prepared in a similar fashion to that described for the synthesis of EXAMPLE 1 starting from 5-[(R)-2-(2,2-dimethylpiperazin-1-yl)-1-hydroxyethyl]-4-methyl-2-benzofuran-1 (3H)-one hydrochloride (INTERMEDIATE 4) and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1 (3H)-one (INTERMEDIATE 2).