Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:37]=[CH:36][C:12]2[NH:13][C:14]([C:19]3[C:20](=[O:35])[N:21]([NH:30][CH2:31][CH:32]([CH3:34])[CH3:33])[C:22]4[C:27]([C:28]=3[OH:29])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>O1CCCC1.[Pd].[OH-].[OH-].[Pd+2]>[OH:29][C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([NH:30][CH2:31][CH:32]([CH3:33])[CH3:34])[C:20](=[O:35])[C:19]=1[C:14]1[NH:13][C:12]2[CH:36]=[CH:37][C:9]([OH:8])=[CH:10][C:11]=2[S:16](=[O:17])(=[O:18])[N:15]=1
Reactant: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc21
Agent: [Pd+2]
Agent: [Pd]
Agent: O=C[O-]
Solvent: C1CCOC1
Product: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3cc(O)ccc3N2)c(O)c2ccccc21
Yield: 70 %

Procedure:
The product of Example 321B (0.081 g, 0.16 mmol) in tetrahyrofuran (10 mL) was reacted with a catalytic amount of palladium hydroxide on carbon, a catalytic amount of 5% palladium on carbon, and ammonium formate (0.040 g, 0.64 mmol) at 60° C. for 30 minutes. The warm reaction mixture was filtered through celite® (diatomaceous earth) and the filtrate was evaporated under reduced pressure to give the title compound (0.048 g, 72%).
Reaction SMILES: [CH:1]([C:3]1[C:4]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1)=O.[C:22]1([NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28].OS([O-])=O.[Na+]>CC(N(C)C)=O>[NH:28]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:29]=[C:1]1[C:3]1[C:4]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1
Reactant: Nc1ccccc1N
Reactant: CC(C)(C)C(=O)Nc1ncc(-c2ccccc2)cc1C=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)C(=O)Nc1ncc(-c2ccccc2)cc1-c1nc2ccccc2[nH]1
Temperature: 250 °C
Yield: 27.8 %

Procedure:
N-(3-formyl-5-phenylpyridin-2-yl)-2,2-dimethylpropanamide (0.1 g, 0.35 mmol), o-phenylenediamine (0.038 g, 0.35 mmol), and NaHSO3 (0.039, 0.53 mmol) were combined in 3 mL of dimethylacetamide and heated to 250° C. in the SmithSynthesizer™ microwave instrument for 10 minutes. Upon cooling, the solvent was removed and the residue was chromatographed on silica gel eluting with hexanes/ethyl acetate (0 to 100% EtOAc over 20 minutes) to afford N-[3-(1H-benzimidazol-2-yl)-5-phenylpyridin-2-yl]-2,2-dimethylpropanamide (0.036 g). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.37 (s, 9H) 7.32 (m, 2H) 7.45 (m, 1H) 7.56 (t, J=7.60 Hz, 2H) 7.65 (d, J=7.87 Hz, 1H) 7.72 (d, J=7.87 Hz, 1H) 7.86 (dd, J=8.33, 1.19 Hz, 2H) 8.81 (d, J=10.07 Hz, 2H) 12.87 (s, 1H) 13.38 (s, 1H) MS m/z 371 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13](=[O:29])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[F:38][C:39]1[CH:44]=[C:43]([F:45])[CH:42]=[C:41]([F:46])[C:40]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:16][CH:15]=1)=[O:29])=[C:8]([C:40]1[C:39]([F:38])=[CH:44][C:43]([F:45])=[CH:42][C:41]=1[F:46])[CH:7]=[CH:6]2
Reactant: OB(O)c1c(F)cc(F)cc1F
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3c(F)cc(F)cc3F)ccc2c1
Temperature: 100 °C
Yield: 92.7 %

Procedure:
Dissolve trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (752 mg, 1.4 mmol), 2,4,6-trifluorophenylboronic acid (493 mg, 2.8 mmol), potassium phosphate (1.8 g, 8.4 mmol)) and tetrakis(triphenylphosphine)palladium (324 mg, 0.3 mmol) in dry dimethylformamide (DMF, 25 mL) and heat at 100° C. for 20 minutes. Purify reaction on an SCX column to yield 674 mg (93%) of the title compound. Mass spectrum (ion spray): m/z=520.2 (M+H).
Reaction SMILES: C([O:8][C:9]1[C:14]2[N:15]([CH:18]3[CH2:20][CH2:19]3)[CH:16]=[N:17][C:13]=2[CH:12]=[C:11]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[N:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CCO.CN(C=O)C.[OH-].[OH-].[Pd+2]>[CH:18]1([N:15]2[C:14]3[C:9](=[O:8])[NH:10][C:11]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=4)=[CH:12][C:13]=3[N:17]=[CH:16]2)[CH2:19][CH2:20]1
Reactant: COc1ccc(-c2cc3ncn(C4CC4)c3c(OCc3ccccc3)n2)cc1OC
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc(-c2cc3ncn(C4CC4)c3c(=O)[nH]2)cc1OC
Temperature: 65 °C
Reaction time: 0.67 h

Procedure:
To a solution of 4-(benzyloxy)-3-cyclopropyl-6-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-c]pyridine 2.36 (270 mg, 0.67 mmol) in EtOH (6.5 mL) and DMF (2.1 mL) was added ammonium formate (670 mg, 10.6 mmol) and Pd(OH)2 on carbon (20 wt. % Pd, 70 mg). The mixture was heated to 65° C. and stirred for 40 min. The mixture was diluted with DMF (10 mL) and EtOH (10 mL) and was filtered through Celite. The filtrate was concentrated in vacuo and the resulting crude solid was purified by silica gel chromatography (0% to 15% MeOH in DCM) to provide 3-cyclopropyl-6-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-c]pyridin-4(5H)-one 2.37.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14](=[NH:17])[NH:15][OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:25]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=O)#[N:26].CN(C=O)C>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]1[N:17]=[C:30]([C:29]2[CH:33]=[CH:34][CH:35]=[C:27]([C:25]#[N:26])[CH:28]=2)[O:16][N:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=N)NO
Reactant: N#Cc1cccc(C(=O)Cl)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCCC1c1noc(-c2cccc(C#N)c2)n1
Temperature: 25 °C
Yield: 22.3 %

Procedure:
In a 50 mL round bottom flask equipped with stir bar, added 2-(N-hydroxycarbamimidoyl)-piperidine-1-carboxylic acid tert-butyl ester (327 mg, 1.34 mmol), dichloromethane (5 mL) and triethylamine (0.56 mL, 4.03 mmol). To this stirred mixture was added a solution of 3-cyanobenzoyl chloride (222 mg, 1.34 mmol) in dichloromethane (3 mL). The resulting reaction mixture was stirred at room temperature for 2 h. DMF (5 mL) was added to the reaction mixture and stirred at 120° C. for 2 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (50 mL). The organic phase was successively washed with water (30 mL) and brine (20 mL), dried (sodium sulfate), filtered and concentrated in vacuo. The crude residue was purified on silica gel using 20% ethyl acetate in hexanes to isolate 106 mg of the title compound as a white solid. 1H-NMR (CDCl3), δ(ppm): 8.42 (s, 1H), 8.35 (d, 1H), 7.86 (dd, 1H), 7.67 (t, 1H), 5.56 (bs, 1H), 4.11 (bd, 1H), 3.04 (bs, 1H), 2.32 (d, 1H), 1.97 (m, 1H), 1.69 (t, 1H), 1.48 (m, 12H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]1([CH2:17][CH2:18][CH2:19][OH:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl.O>[C:11]1([CH2:17][CH2:18][CH:19]=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCCCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=CCCc1ccccc1
Reaction time: 0.08 h
Yield: 47.3 %

Procedure:
Oxalyl chloride (2.90 g; 2.29 mmol) in methylene chloride (50 mL), cooled to −78° C., was treated with dimethylsulfoxide (3.4 mL) in 10 mL of methylene chloride. After stirring for 5 min, 3-phenyl-1-propanol (2.72 g; 20 mmol) in 20 mL of methylene chloride was added, and the resulting mixture was stirred at −78° C. for 15 min, treated with 14 mL of triethylamine, stirred an additional 15 min, and poured into 100 mL of water. The layers were separated, the organic phase was dried and concentrated, and the crude residue was purified on a silica gel column, eluting with 10% ethyl acetate in hexane, to obtain 1.27 g (47%) of the aldehyde as a clear oil. 1H NMR (300 MHz, CDCl3): δ 2.80 (m, 2H); 2.98 (m, 2H); 7.27 (m, 5H); 9.81 (2, 1H).
Reaction SMILES: [CH3:1][C:2]([NH:4][C@@H:5]([C:9](NCC1C=CC=CC=1)=[O:10])[CH2:6][O:7][CH3:8])=[O:3].C[O:20]C(=O)[C@@H](CO)N.C(OP(OCC)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C(OC(=O)C)(=O)C.CN(C1C=CC=CN=1)C.[OH-].[Li+]>CO.C(N(CC)CC)C>[C:2]([NH:4][C@H:5]([CH2:6][O:7][CH3:8])[C:9]([OH:10])=[O:20])(=[O:3])[CH3:1]
Reactant: COC[C@@H](NC(C)=O)C(=O)NCc1ccccc1
Reactant: COC(=O)[C@H](N)CO
Agent: CCOP(OCC)(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccccn1
Agent: [Li+]
Solvent: CC(=O)OC(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Product: COC[C@@H](NC(C)=O)C(=O)O

Procedure:
Another method for the preparation of Lacosamide of Formula-I was described in the Journal Bioorganic & Medicinal Chemistry, 16(19), 8968-8975 (2008), wherein D-serine methyl ester is treated with diethoxytriphenylphosphorane to give 9:1 mixture of (R)-aziridine-2-carboxylic acid methyl and ethyl ester of Formula-XIV. The mixture of compound of Formula-XIV on acetylation with acetic anhydride in the presence of triethylamine and dimethylaminopyridine gives a mixture of (R)-1-acetylaziridine-2-carboxylic acid methyl and ethyl ester of Formula-XV. The mixture of compound of Formula-XV is treated with methanol in the presence of borontrifluoride etherate BF3.Et2O to give a mixture of (2R)-2-acetamido-3-methoxypropanic acid methyl and ethyl ester of Formula-XVI. The compound of Formula-XVI on hydrolysis with lithium hydroxide yields the compound (2R)-2-acetamido-3-methoxypropanoic acid of Formula- XVII; which on reaction with benzylamine in presence of tetrahydrofuran and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride followed by purification of the product using flash column chromatography (10:90 MeOH/CHCl3) yields compound Lacosamide of Formula-I. The reaction sequence is as given in Scheme-4;
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([CH2:10]I)[O:8][C@@H:7]([N:12]2[CH:20]=[C:18]([CH3:19])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:6]1)(=[O:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(O)=O.N(C(OCC)=O)=NC(OCC)=O.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO>[C:1]([O:4][C@H:5]1[C:9](=[CH2:10])[O:8][C@H:7]([N:12]2[CH:20]=[C:18]([CH3:19])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CI
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=C1O[C@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1OC(C)=O
Reaction time: 0.5 h
Yield: 127.4 %

Procedure:
A mixture of 7 (1.08 g, 2.63 mmol), Ph3P (897 mg, 3.42 mmol) and AcOH (301 μL, 5.26 mmol) in THF (10 mL) was cooled to 0 under positive pressure of dry Ar. To this was added dropwise diethyl azodicarboxylate (2.3 M solution in toluene, 1.49 mL, 3.42 mol). After stirring for 30 min, the mixture was partitioned between CH2Cl2 and sat. aqueous NaHCO3. The organic layer was dried (Na2SO4) and evaporated. The residue was treated with K2CO3 (727 mg, 5.26 mmol) in MeOH (5 mL) for 1 h. The mixture was partitioned between CHCl3 and brine. The organic layer was dried (Na2SO4), evaporated, and chromatographed on a silica gel column (hexane/EtOAc=4/1). This gave 8 (892 mg, 83%) as an oil.
Reaction SMILES: CS(O)(=O)=O.[F:6][C:7]1[C:8]([NH2:27])=[N:9][CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:15](=[O:26])[O:16][C:17]2[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:18]=2[C:19]=1[CH3:20].Br[C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:20][C:19]1[C:18]2[CH:21]=[CH:22][C:23]([O:25][C:29]3[N:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:24][C:17]=2[O:16][C:15](=[O:26])[C:14]=1[CH2:13][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([NH2:27])[C:7]=1[F:6]
Reactant: Cc1c(Cc2ccnc(N)c2F)c(=O)oc2cc(O)ccc12
Reactant: Brc1ncccn1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Cc2ccnc(N)c2F)c(=O)oc2cc(Oc3ncccn3)ccc12
Temperature: 115 °C
Reaction time: 3.5 h
Yield: 89.5 %

Procedure:
Under a nitrogen atmosphere, 3-(3-fluoro-2-aminopyridin-4-ylmethyl)-7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran methanesulfonate (7.6 g, 19.2 mmol) and 2-bromopyrimidine (4.0 g, 24.9 mmol) were dissolved in DMF (122 mL), potassium carbonate (5.8 g, 42.2 mmol) was added, and the mixture was stirred at 115° C. for 3.5 hours. The reaction mixture was cooled to 28° C., water (122 mL) was added dropwise over a period of 0.5 hours at that temperature, and the mixture was stirred for 2 minutes. The mixture was further cooled to 0° C. and stirred for 1 hour, and the precipitated crystals were collected by filtration. The obtained crystals were washed with water (61 mL) and acetonitrile (61 mL) in that order, and dried under reduced pressure to obtain the title compound as crystals (6.5 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:17]=[C:16]([C:18](OCC)=[O:19])[NH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:23]([CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:24]=[S:25].C(N(CC)CC)C.CCCCCC>[N-]=C=S.C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][N:23]1[C:24](=[S:25])[N:15]2[C:13]3[N:14]=[C:10]([C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=4)[S:11][C:12]=3[CH:17]=[C:16]2[C:18]1=[O:19])[CH3:33]
Reactant: CCOC(=O)c1cc2sc(-c3ccc([N+](=O)[O-])cc3)nc2[nH]1
Reactant: CCOC(=O)CCCN=C=S
Agent: [N-]=C=S
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCN1C(=O)c2cc3sc(-c4ccc([N+](=O)[O-])cc4)nc3n2C1=S
Temperature: 130 °C
Reaction time: 18 h

Procedure:
As depicted in Scheme 27 below, ethyl 2-(4-nitrophenyl)-4H-pyrrolo[2,3-d]thiazole-5-carboxylate (0.1 mmol) is placed in a heavy-walled glass tube equipped with a threaded Teflon plug, and ethyl 4-isothiocyanatobutyrate (1.03 mmol, 10 molequivalents) and triethylamine (2 mmol, 20 molequivalents) are added thereto. The glass tube is sealed and the reaction mixture is heated at 130° C. while stirring overnight (18 hours). Additional isothiocyanate (10 drops, 10 molequivalents) is added thereafter and heating is continued while stirring at 130° C. for 6 additional hours. The mixture is then dissolved in chloroform and the purified final product is isolated by column chromatography on silica, using a 9:1 hexane:ethyl acetate mixture as eluent.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:7][S:8][C:4]=2[CH:3]=1.[Cu](C#N)[C:18]#[N:19]>CN1CCCC1=O.Cl>[C:18]([C:2]1[CH:16]=[CH:15][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:7][S:8][C:4]=2[CH:3]=1)#[N:19]
Reactant: Brc1ccc2c(-c3ccccc3)csc2c1
Reactant: N#C[Cu]C#N
Agent: Cl
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2c(-c3ccccc3)csc2c1

Procedure:
Combine 6-bromo-3-phenylbenzothiophene (0.5 g, 1.73 mmol) and copper cyanide (0.56 g, 6.23 mmol) and reflux 3 h in 1-methyl-2-pyrrolidinone (1.73 mL). Add ferric chloride (2.11 g, 7.79 mmol) in concentrated HCl (1.73 mL) and stir 1.5 h. Cool the mixture and partition between diethyl ether and brine. Dry the organic layer over Na2SO4, filter and evaporate onto silica gel. Purify the residue by chromatography on silica gel eluting with hexane/EtOAc (1:0 to 3:2 gradient) to give the desired intermediate that is used without further-purification (0.27 g, 67%). MS (GCMS) m/z: 235 M+.
Reaction SMILES: ClC1C=C(C(C2(C)C3C(=CC=[C:19]([O:22]C)C=3)C(=O)N2)CC=C)C=CC=1Cl.Cl.[Cl:27][C:28]1[CH:29]=[C:30]([CH:35]([CH:51]2[C:59]3[C:54](=[CH:55][CH:56]=[C:57]([O:60][CH:61]([CH3:63])[CH3:62])[CH:58]=3)[C:53](=[O:64])[N:52]2[CH3:65])[CH2:36]CN2CCC(N3CCCNC3=O)CC2)[CH:31]=[CH:32][C:33]=1[Cl:34]>>[Cl:27][C:28]1[CH:29]=[C:30]([CH:35]([CH:51]2[C:59]3[C:54](=[CH:55][CH:56]=[C:57]([O:60][CH:61]([CH3:63])[CH3:62])[CH:58]=3)[C:53](=[O:64])[N:52]2[CH3:65])[CH2:36][CH:19]=[O:22])[CH:31]=[CH:32][C:33]=1[Cl:34]
Reactant: C=CCC(c1ccc(Cl)c(Cl)c1)C1(C)NC(=O)c2ccc(OC)cc21
Reactant: CC(C)Oc1ccc2c(c1)C(C(CCN1CCC(N3CCCNC3=O)CC1)c1ccc(Cl)c(Cl)c1)N(C)C2=O
Agent: Cl
Product: CC(C)Oc1ccc2c(c1)C(C(CC=O)c1ccc(Cl)c(Cl)c1)N(C)C2=O

Procedure:
The intermediate 3-(3,4-dichlorophenyl)-3-(6-isopropoxy-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde was prepared from 3-[1-(3,4-dichlorophenyl)but-3-enyl]-5-methoxy-3-methyl-2,3-dihydro-1H-isoindol-1-one (described at Example 30 sub-part c.) by treating the ether as described in Example 31 sub-part a. to give the corresponding alcohol, followed by a sequence similar to that described in Example 42 sub-parts a.-b.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](O)=[O:46])([CH3:44])[CH3:43])=[CH:33][C:32]=2[CH3:49])=[C:28]([CH:50]([CH3:52])[CH3:51])[NH:27][N:26]=1)(=O)C.[NH2:53][CH2:54][CH2:55][CH2:56][OH:57].NC(C)(C)C(N)=O>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](=[O:46])[NH:53][CH2:54][CH2:55][CH2:56][OH:57])([CH3:44])[CH3:43])=[CH:33][C:32]=3[CH3:49])=[C:28]([CH:50]([CH3:52])[CH3:51])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)NC(C)(C)C(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCCCO
Agent: CC(C)(N)C(N)=O
Product: Cc1cc(OCCC(=O)NC(C)(C)C(=O)NCCCO)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 78 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)ethyl-carbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole and 3-amino-1-propanol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methylpropionamide, respectively.
Reaction SMILES: [C:1]([C:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[S:5][C:4]=1[NH:12][C:13](=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)#[N:2].C(C1C2CCNCC=2SC=1N[C:35](=[O:44])[CH:36]=CC1C=NC=CC=1)#N.ClC(OCC)=S>>[C:35]([N:8]1[CH2:9][CH2:10][C:11]2[C:3]([C:1]#[N:2])=[C:4]([NH:12][C:13](=[O:22])/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:5][C:6]=2[CH2:7]1)(=[O:44])[CH3:36]
Reactant: N#Cc1c(NC(=O)C=Cc2cccnc2)sc2c1CCNC2
Reactant: N#Cc1c(NC(=O)C=Cc2ccccc2)sc2c1CCNC2
Agent: CCOC(=S)Cl
Product: CC(=O)N1CCc2c(sc(NC(=O)/C=C/c3ccccc3)c2C#N)C1

Procedure:
The following compounds 35 and 36 can be prepared according to the general procedure F described below starting from N-(3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-phenyl-acrylamide (compound B1) or N-(3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(pyridin-3-yl)-acrylamide (compound B2) and ethyl chlorothioformate.
Reaction SMILES: [CH3:1][O:2][C@H:3]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:4]([N:6]1[CH2:13][C:12]2[C:11]([NH:14][C:15](=[O:29])[C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[N:10][N:9](C(OCC)=O)[C:8]=2[CH2:7]1)=[O:5]>CO.C(N(CC)CC)C>[CH3:1][O:2][C@H:3]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:4]([N:6]1[CH2:13][C:12]2[C:11]([NH:14][C:15](=[O:29])[C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)=[CH:20][CH:21]=3)=[N:10][NH:9][C:8]=2[CH2:7]1)=[O:5]
Reactant: CCOC(=O)n1nc(NC(=O)c2ccc(N3CCN(C)CC3)cc2)c2c1CN(C(=O)[C@H](OC)c1ccccc1)C2
Solvent: CCN(CC)CC
Solvent: CO
Product: CO[C@@H](C(=O)N1Cc2[nH]nc(NC(=O)c3ccc(N4CCN(C)CC4)cc3)c2C1)c1ccccc1
Yield: 46.8 %

Procedure:
A solution of ethyl 5-[(2R)-2-methoxy-2-phenylethanoyl]-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate (3.94 g, 7.2 mmol) in methanol (MeOH, 130 ml) and triethylamine (Et3N, 13 ml) was stirred at room temperature for 16 hours (some precipitation occurred). The solid was separated and washed with Et2O, to give 1.6 g of the title compound. Solution was evaporated up to few milliliters, and a second fraction of solid product was separated (1.62 g). The two fractions were joined and analyzed by LC-MS (purity around 90% 254 and 220 nM). After chromatographic purification (short silica gel column, DCM/MeOH 45:5) 2.83 g (83%) of the title compound were obtained as a white solid. M.p 289° C.; [M+H]+ 475;
Reaction SMILES: [CH2:1]([CH:5]([C:11]([O-])=O)[C:6]([O:8]CC)=[O:7])[CH:2]([CH3:4])[CH3:3].C=O.C([O-])([O-])=O.[K+].[K+].[Li+].[OH-]>O.C(#N)C>[CH3:3][CH:2]([CH3:4])[CH2:1][C:5](=[CH2:11])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(CC(C)C)C(=O)[O-]
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C=C(CC(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
To neat ethyl isobutylmalonate (25 g, 0.13 mol) at 0° C. was slowly added ice cold diethylamine (15.1 mL, 0.15 mol). After stirring for 15 minutes, formalin (11.1 mL of 37% aqueous formaldehyde) was added dropwise and the mixture was allowed to stir at 25° C. for 3 days. The reaction was treated with a solution of 20 g of K2CO3 in 40 mL H2O and extracted with ether (2×100 mL). The combined ether layers were washed with brine, dried over MgSO4, and evaporated at 20° C. on a rotary evaporator. The crude product ethyl 4-methyl-2-methylenepentanoate (containing some ether) was dissolved in 250 mL of absolute ethanol and treated with acetonitrile (250 mL), 1M LiOH (9.7 g in 250 mL of H2O, 0.23 mol). After stirring overnight, the organic solvents were evaporated and the aqueous residue was extracted with ethyl acetate (2×150 mL). The combined extracts were washed with brine, dried (MgSO4), and evaporated to afford 10.5 g of 4-methyl-2-methylenepentanoic acid as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[C:9](=[NH:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CC(C)([O-])C.[Na+]>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].C1(P(C2C=CC=CC=2)C2C=CC=CC=2OC2C=CC=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[C:16]1([C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:22][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Clc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Clc1ccc(N=C(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75.7 %

Procedure:
An oven-dried test tube was charged with tris(dibenzylideneacetone)dipalladium (4.6 mg, 0.005 mmol), bis(2-(diphenylphosphino)phenyl)ether [DPE-phos] (8.2 mg, 0.015 mmol) and 4-bromochlorobenzene (191 mg, 1.0 mmol), capped with a rubber septum, evacuated, and refilled with argon. Benzophenone imine (190 mg, 1.05 mmol) and toluene (2 mL) were added via syringe. The resulting solution was stirred at rt for 5 minutes. The tube was opened and sodium tert-butoxide (135 mg, 1.4 mmol) was added. The tube was again capped with the septum, and additional toluene (2 mL) was added via syringe to wash the solid from the test tube wall into the solution. The solution was stirred at room temperature with a gentle argon purge for 5 minutes, then heated at 80° C. for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, washed with saturated aqueous sodium chloride (2 mL), and the organic layer was concentrated in vacuo. The product was isolated as a yellow solid (221 mg, 76%) by flash chromatography on silica gel using 5% ethyl acetate in hexanes as eluent.