Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[C:10]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]2[CH3:34])[C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([O:26][CH3:27])=[C:22]([CH2:24][OH:25])[CH:23]=3)=[N:14][C:12]=2[N:13]=1.[P:35](=O)([OH:38])([OH:37])[OH:36]>CC#N>[P:35]([O:25][CH2:24][C:22]1[CH:23]=[C:18]([C:15]2[CH:16]=[CH:17][C:11]3[C:10]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]4[CH3:34])=[N:9][C:8]([N:3]4[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]4[CH3:1])=[N:13][C:12]=3[N:14]=2)[CH:19]=[CH:20][C:21]=1[O:26][CH3:27])([OH:38])([OH:37])=[O:36]
Reactant: COc1ccc(-c2ccc3c(N4CCOC[C@@H]4C)nc(N4CCOC[C@@H]4C)nc3n2)cc1CO
Reactant: O=P(O)(O)O
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(N4CCOC[C@@H]4C)nc(N4CCOC[C@@H]4C)nc3n2)cc1COP(=O)(O)O
Temperature: 25 °C

Procedure:
On a 50 mg scale using a 1:1.1 molar ratio of (5-{2,4-Bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol:Phosphoric acid. 50 mg of (5-{2,4-Bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol was dissolved in the minimal amount of MeCN, this solution was then added drop-wise to a vial containing the phosphoric acid which caused a yellow solid to immediately precipitate. The experiment was then left to stir over night at room temperature before filtering and isolating the precipitate.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][NH:5][CH2:4]1.O1CCCNCC1.[C:16]([OH:27])(=[O:26])[C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1>CO>[C:16]([OH:27])(=[O:26])[C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1.[OH:1][CH2:2][C@@H:3]1[O:8][CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: OCC1CNCCO1
Agent: C1CNCCOC1
Agent: O=C(O)c1ccc(C(=O)O)cc1
Solvent: CO
Product: OC[C@H]1CNCCO1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-hydroxymethylmorpholine and 1,4-oxazepane compound (20.0 g, 2-hydroxymethylmorpholine:1,4-oxazepane compound=75.8:24.2) synthesized in Example 5 were added methanol (100 ml) and terephthalic acid (12.5 g, 0.075 mol) and the mixture was stirred for 30 min. Methanol was evaporated under reduced pressure. To the residue was added 2-propanol (50 ml) and the mixture was subjected twice to azeotropic distillation with dehydrating. To the residue after azeotropic distillation with dehydrating was added ethyl acetate (100 ml) at 40° C., and the mixture was cooled to 10° C. After crystallization, the mixture was cooled to 0° C. and stirred for 1 hr. The crystals were collected by filtration, washed withed twice with ethyl acetate (25 ml) and dried (1 mmHg, 40° C.) to give (R)-2-hydroxymethylmorpholine terephthalate (10.1 g) (2-hydroxymethylmorpholine:terephthalic acid=2:1, yield from (S)-epichlorohydrin: 33.5%). The obtained (R)-2-hydroxymethylmorpholine terephthalate was analyzed by HPLC to find an optical purity of 99% ee.
Reaction SMILES: [C:1]([C:3]1([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[CH2:8][CH:7](C(OC)=O)[C:6](=[O:13])[CH2:5][CH2:4]1)#[N:2].C(O)(=O)C.S(=O)(=O)(O)O>O>[C:1]([C:3]1([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[CH2:8][CH2:7][C:6](=[O:13])[CH2:5][CH2:4]1)#[N:2]
Reactant: COC(=O)C1CC(C#N)(c2ccc(OC)c(OC)c2)CCC1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C2(C#N)CCC(=O)CC2)cc1OC
Yield: 67.3 %

Procedure:
A mixture of 29 g. (0.0915 mole) of methyl 5-cyano-5-(3,4-dimethoxyphenyl)-2-oxocyclohexanecarboxylate (prepared in Example 10) in 600 ml. of acetic acid and 300 ml. of 10% sulfuric acid is stirred mechanically on a steam bath for about 24 hours. The mixture is then allowed to cool and diluted with water. This mixture is extracted thoroughly with benzene. The organic layer is successively washed with water, sodium bicarbonate solution and brine and evaporated to dryness. The solid residue is recrystallized from a mixture of ethyl acetate and cyclohexanone to give 15.96 g. (67.3% yield) of 4-cyano-4-(3,4-dimethoxyphenyl)cyclohexanone, having a melting point of 112.5° to 114.5°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9](SC)[NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)[CH:18]([CH3:20])[CH3:19])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[NH3:28]>>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[NH:28])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)[CH:18]([CH3:20])[CH3:19])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: CSC(=Nc1cccc(F)c1)Nc1ccc(C(C(C)C)n2ccnc2)cc1
Product: CC(C)C(c1ccc(NC(=N)Nc2cccc(F)c2)cc1)n1ccnc1
Temperature: 40 °C
Yield: 46 %

Procedure:
A solution of methyl N′-(3-fluorophenyl)-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]-phenyl]carbamimidothioate (0.0094 mol) in NH3/CH30H (60 ml) was stirred and heated in autoclave at 40° C. for 3 days. The solvent was evaporated and the residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 94/6/0.2 to 90.10/0.5). The pure fractions were collected and evaporated. The residue was crystallized from 2-propanone and (C2H5)2O and filtered off, yielding 0.89 g (46%) N′-(3-fluorophenyl)-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]guanidine (compound 744).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH2:24]([NH:27][C:28]1[CH2:32][S:31][C:30](=[O:33])[N:29]=1)[C:25]#[CH:26].CC(C)([O-])C.[K+]>C(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:32]2/[C:28]([NH:27][CH2:24][C:25]#[CH:26])=[N:29][C:30](=[O:33])[S:31]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: C#CCNC1=NC(=O)SC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
To a suspension of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (15 g) and 4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one (8.18 g) in ethanol (150 mL) was added potassium tert-butoxide (5.95 g), and the reaction mixture was stirred at 80° C. for 30 min. The reaction mixture was concentrated, saturated aqueous ammonium chloride solution/ethyl acetate were added to the residue, and the organic layer was separated, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the residue was washed with diisopropyl ether to give the title compound (9.96 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1.[NH2:12][C@H:13]([C:16]([OH:18])=[O:17])[CH2:14][SH:15].[OH-].[Na+]>C(OCC)C.C(O)C>[NH2:12][C@@H:13]([CH2:14][S:15][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([O:3][CH3:2])=[CH:5][CH:6]=1)[C:16]([OH:18])=[O:17]
Reactant: N[C@@H](CS)C(=O)O
Reactant: COc1ccc(CCl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: COc1ccc(CSC[C@H](N)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
To a mixed solution of diethyl ether (400 ml) and conc. hydrochloric acid (400 ml) was added in drops 4-methoxybenzyl chloride (280 g, 1780 mmol) dissolved in diethyl ether (400 ml) for 2 h, and the mixture was stirred for 1 h. The organic layer was separated and added to a solution which was prepared by dissolving L-cysteine (197 g, 1625 mmol) and 2N aqueous sodium hydroxide solution (980 ml) in ethanol (1890 ml). The mixture was stirred for 2 h at room temperature. After completion of the reaction, the mixture was cooled to 0° C., and neutralized to pH 7 using 3N aqueous hydrochloric acid solution. The resulting solid was filtered and dried to give (R)-2-amino-3-(4-methoxy-benzylsulfanyl)-propionic acid (250 g, 1035 mmol, Yield 64%).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH3:6][S:7](Cl)(=[O:9])=[O:8]>C1COCC1>[C:1]([NH:5][S:7]([CH3:6])(=[O:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Product: CC(C)(C)NS(C)(=O)=O
Temperature: 0 °C

Procedure:
t-Butylamine (105 ml, 1.0 mole) was dissolved in THF (about 950 ml) and cooled to 0° C. Methanesulfonylchloride (57.2 g) was added and the solution allowed to warm to room temperature overnight. The mixture was filtered and the filtrate stripped to dryness. The resulting residue was dissolved in methylene chloride and washed with 1N HCl followed by washing first with water and then with brine (water saturated with NaCl). The methylene chloride layer was dried over Na2SO4, filtered, and stripped to dryness. The resulting residue was dissolved in pentane, and the solid which crystallized was collected and dried.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[NH:10][C:9]([C:11](O)=[O:12])=[C:8]([CH3:14])[CH:7]=1)([OH:3])=[O:2].C(OCC)(OCC)OCC>O>[CH:11]([C:9]1[NH:10][C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:7][C:8]=1[CH3:14])=[O:12]
Reactant: Cc1cc(CCC(=O)O)[nH]c1C(=O)O
Solvent: CCOC(OCC)OCC
Solvent: O
Product: Cc1cc(CCC(=O)O)[nH]c1C=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100.5 %

Procedure:
A solution of 5-(2-carboxy-ethyl)-3-methyl-1H-pyrrole-2-carboxylic acid (e.g, 6.59 mmol) in trfluoroacetic acid (6 mL) was stirred at room temperature for 10 minutes. It was then cooled to 0° C. and to it was added triethyl orthoformate (6 mL). The mixture was stirred at 0° C. for 10 minutes and at room temperature for 10 minutes. The reaction was poured into water (50 mL) and extracted with ethyl acetate. The extract was dried and concentrated to give 1.2 g of 3-(5-formyl-4-methyl-1H-pyrrol-2-yl)-propionic acid as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ 12.17 (brs, 1H), 11.50 (brs, 1H), 9.44 (s, 1H, CHO), 5.85 (s, 1H), 2.74 (t, J=7.4 Hz, 2H, CH2), 2.54 (t, J=7.4 Hz, 2H, CH2, CH2), 2.23 (s, 3H, CH3). MS 182 [M++1].
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][CH3:16])=[C:6]([C:17]([O:19]CC)=[O:18])[C:5]=1[C:22]([O:24]CC)=[O:23])[CH3:2].[OH-].[Na+]>C(O)C.O>[CH2:15]([O:14][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:22]([OH:24])=[O:23])[C:6]=1[C:17]([OH:19])=[O:18])[CH3:16]
Reactant: CCOC(=O)c1c(C(=O)OCC)c(OCC)c2ccccc2c1OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1c(C(=O)O)c(C(=O)O)c(OCC)c2ccccc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
Diethyl 1,4-bis(ethyloxy)-2,3-naphthalenedicarboxylate (24.8 g, 68.8 mmol) was suspended in ethanol (200 ml) and treated with sodium hydroxide (8.3 g, 206.4 mmol) dissolved in 200 ml of water. A further 50 ml of ethanol added to aid stirring. Heated to reflux, 100° C. All in solution on heating. Refluxed for 8 hours. Cooled to room temperature and stood overnight. Solvent was evaporated to almost dryness. Water was added and stirred in an ice bath. Acidified with 2M HCl solution (˜150 ml). The white precipitate was filtered, washed with water and dried in a vacuum oven to give the title compound as a white solid (18.77 g, 61.7 mmol).
Reaction SMILES: O.O.O.O.O.[O-][Si]([O-])=O.[Na+].[Na+].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Si:19](Cl)(Cl)(Cl)[Cl:20]>>[Cl:20][Si:19].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cl[Si](Cl)(Cl)Cl
Agent: O=[Si]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Oc1ccccc1
Product: [Si]Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
About 0.5 mol of fine granular sodium metasilicate pentahydrate, 0.5 mol of phenol and 1 mol of silicon tetrachloride are slowly added while agitating at ambient temperature and pressure for 1 to 2 hours; the reaction is complete in 2 to 8 hours, thereby producing white granules of phenol chlorosilicon acid resinous product and sodium chloride. To this resinous product, 1 mol of a nitrile, acetonitrile, is added while agitating and keeping the temperature below the boiling temperature of the mixture for 1 to 2 hours; the reaction is complete in 2 to 8 hours, thereby producing an organic silicon acid resinous product. The resinous product is washed with water and filtered to remove the salt.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH:11]([OH:24])[C:12](=[NH:23])[NH:13][O:14][C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][CH3:10])(C)(C)C.FC(F)(F)C(O)=O>COCCOCCOC.ClCCl>[NH2:7][CH:8]([CH2:9][CH3:10])[CH:11]([C:12]1[N:23]=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:14][N:13]=1)[OH:24]
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)C(=N)NOC(=O)c1ccccc1
Solvent: ClCCl
Solvent: COCCOCCOC
Solvent: O=C(O)C(F)(F)F
Product: CCC(N)C(O)c1noc(-c2ccccc2)n1
Yield: 29.9 %

Procedure:
A solution of (3) (1.5 g, 4.3 mmol) in diglyme was heated at 150° C. in a microwave reactor (Smith Creator, S00219) for 40 minutes. Solvent evaporated under vacuum in Genevac Evaporator at 80° C. for 3 hours to give a brown solid. This was taken in dichloromethane (40 ml) and treated with trifluoroacetic acid at room temperature for 2 hours. Solvent evaporated to dryness under reduced pressure, crude taken in water, washed with DCM, aqueous layer basified with 1M NaOH solution and extracted with dichloromethane. Organic layer dried over Na2SO4 and evaporated under reduced pressure to give 2-amino-1-(5-phenyl-[1,2,4]oxadiazol-3-yl)-butan-1-ol (300 mg) as a pale brown solid. 1HNMR (CDCl3) 8.14-8.10 (m, 2H), 7.59-7.47 (m, 3H), 4.83 & 4.65 (d, J=5 Hz, 1H), 3.18-3.05 (2m, 1H), 1.71-1.20(m, 2H), 1.05-0.97 (2×t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH3:21])[CH:16]=[N:15][C:14]=2[N:13]([CH3:22])[C:11]1=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9].C[N+]1([O-])CC[O:27]CC1.[OH2:31].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)(C)(C)C.CC(C)=O.[Os](=O)(=O)(=O)=O>[OH:31][CH:8]([CH2:9][OH:27])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH3:21])[CH:16]=[N:15][C:14]=2[N:13]([CH3:22])[C:11]1=[O:12]
Reactant: O
Reactant: C=CCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(C)(C)O
Product: Cn1cnc2c1c(=O)n(CCCCCCCC(O)CO)c(=O)n2C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
A solution of 1-(8-nonenyl)-3,7-dimethylxanthine (810 mg, 2.7 mmol), 4-methylmorpholine-N-oxide (340 mg, 2.9 mmol) and 2.5 % osmium tetroxide in t-butanol (3 drops) in acetone (20 ml) and water (20 ml) was stirred for 24 hours. Saturated aqueous sodium dithionite solution (5 ml) was added. After stirring for 15 minutes, the reaction was extracted with 25% ethanol-dichloromethane (4×50 ml). The combined organic phases were dried over sodium sulfate and the solvents evaporated under vacuum. The solid residue was recrystallized (ethanol-chloroform) to give 1-(8,9-Dihydroxynonyl)-3,7-dimethylxanthine (490 mg, 54% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[Br:11]Br.C(OCC)(=O)C>C(Cl)(Cl)Cl.C(O)(=O)C>[Br:11][C:7]1[C:2]([OH:1])=[N:3][CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=1
Reactant: BrBr
Reactant: O=[N+]([O-])c1ccc(O)nc1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cnc(O)c(Br)c1
Yield: 54.7 %

Procedure:
2-Hydroxy-5-nitropyridine (10.0 g, 71 mmol) in chloroform (200 ml) and acetic acid (10 ml) was treated with bromine (3.7 ml, 72 mmol) and then refluxed for 24 hrs. More bromine (3.7 ml, 72 mmol) was added and the mixture refluxed for a further 48 hrs, then cooled. Ethyl acetate (150 ml) was added and the solid formed removed by filtration, washed with ethyl acetate (50 ml) and dried to give the product as an off-white powder (8.5 g).
Reaction SMILES: [Na].FS(O)(=O)=O.[CH2:7]([O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH2:16])=[NH:15])[CH:8]([CH3:10])[CH3:9].C([O:23][CH:24]=[C:25]([C:31](OCC)=O)[C:26]([O:28][CH2:29][CH3:30])=[O:27])C.C(O)(=O)C>C(O)C>[O:23]=[C:24]1[NH:16][C:14]([C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][CH2:7][CH:8]([CH3:10])[CH3:9])=[N:15][CH:31]=[C:25]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)COc1ccccc1C(=N)N
Agent: O=S(=O)(O)F
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccccc2OCC(C)C)[nH]c1=O
Temperature: 0 °C
Yield: 84.9 %

Procedure:
To a solution of sodium (161 mg., 7 mg-atoms) in ethanol (10 ml.) was added 2-isobutoxybenzamidine fluorosulfonate (1.02 g., 3.5 mmole). The mixture was warmed to give a clear solution to which was added a solution of diethyl ethoxymethylenemalonate (756 mg., 3.5 mmole) in ethanol (2 ml.). The solution was heated under reflux for 3 hours. The cooled mixture was added to ice-water (50 ml.) and was acidified to pH 5 with glacial acetic acid. After brief stirring, the solid was collected by filtration, washed with water, and dried to give the title compound (0.94 g., 86%), m.p. 90°-91°.
Reaction SMILES: [Si]([O:8][C:9]1[S:17][C:16]2[CH2:15][CH2:14][N:13]([CH:18]([C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH2:12][C:11]=2[CH:10]=1)(C(C)(C)C)(C)C.C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39].O>CC(C)=O.CN(C)C1C=CN=CC=1>[CH3:39][C:38]([O:8][C:9]1[S:17][C:16]2[CH2:15][CH2:14][N:13]([CH:18]([C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH2:12][C:11]=2[CH:10]=1)=[O:40]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)[Si](C)(C)Oc1cc2c(s1)CCN(C(C(=O)C1CC1)c1ccccc1F)C2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)Oc1cc2c(s1)CCN(C(C(=O)C1CC1)c1ccccc1F)C2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
2-(Tert-butyldimethylsilyloxy)-5-(α-cyclopropylformyl-2-fluorobenzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (3.0 g) prepared by example 2 was dissolved in acetone (10.0 mL) and the solution was cooled to 0° C. Triethylamine (1.02 g) was then added dropwise followed by adding 4-dimethylaminopyridine (DMAP) (0.025 g) and the mixture was stirred for 10 minutes at the same temperature. Acetic anhydride (0.83 g) in acetone was then added and the reaction was monitored by Thin Layer Chromatography (TLC) (petroleum ether/ethyl acetate=10/1 or 5/1). After the reaction was completed, cold water (7.5 mL) was then added to the reaction mixture. After the reaction mixture was stirred for 15 minutes, the reaction mixture was cooled to −5° C. and further stirred for 3 hours. Solid precipitate was collected by filtration followed by washing with a mixture of pre-cooled acetone/water (1:1 v/v) (10 ml). The obtained prasugrel free base was dried under vacuum at 50° C. for 24 hours. The yield was 85%.
Reaction SMILES: [H-].[Na+].[C:3]([C@@H:11]1[CH2:15][CH:14]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[N:13](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:12]1=[O:37])(=O)C1C=CC=CC=1.C=O>C1(C)C=CC=CC=1>[C:20]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:19]=[CH:18][C:17]([CH2:16][C@H:14]2[N:13](/[CH:29]=[CH:30]/[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:12](=[O:37])[C:11](=[CH2:3])[CH2:15]2)=[CH:22][CH:21]=1
Reactant: O=C(c1ccccc1)[C@@H]1CC(Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Agent: C=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (2.03 g, 46.3 mmol) in 40 mL of anhydrous toluene is cooled to 0° C. by ice bath, add a solution of (S)-3-Benzoyl-5-biphenyl-4-ylmethyl-1-((E)-but-1-enyl)-pyrrolidin-2-one (4a, R1=1-butenyl, R4=phenyl) (14.7 g, 35.7 mmol) in anhydrous toluene dropwise, stir for 30 min, then add paraformaldehyde (2.2 g, 71.4 mmol) in portions, heat to reflux under nitrogen atmosphere for 4 h, cool to room temperature, quench with saturated NH4Cl aqueous solution, extract with toluene, the combined organic extracts are washed with saturated Na2CO3 aqueous solution and brine, dry over anhydrous Na2SO4 and concentrate to obtain (R)-5-Biphenyl-4-ylmethyl-1-((E)-but-1-enyl)-3-methylene-pyrrolidin-2-one (1a, R1=1-butenyl). 1HNMR (400 MHz, CDCl3): 1.07 (t, 3H, CH3H), 2.12 (m, 2H, CH2H), 2.57 (m, 2H, 3-CH2), 2.65 (m, 1H, 5-CH2), 3.16 (m, 1H, 5-CH2), 4.14 (m, 1H, 4-CH), 5.22 (s, 1H, C═CHH), 5.27 (m, 1H, CH═CH), 5.91 (d, 1H, HC═CHH), 6.85 (d, 1H, HC═CH—N), 7.14˜7.51 (9H, m, aromatic).
Reaction SMILES: [C:1]([C@@H:9]1[CH2:13][CH:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[N:11](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:35])(=O)C1C=CC=CC=1.C=O.C1CCN2C(=NCCC2)CC1.[Cl-].[Li+]>O1CCCC1.C1(C)C=CC=CC=1>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=[CH:16][C:15]([CH2:14][C@H:12]2[N:11](/[CH:27]=[CH:28]/[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:10](=[O:35])[C:9](=[CH2:1])[CH2:13]2)=[CH:20][CH:19]=1
Reactant: O=C(c1ccccc1)[C@@H]1CC(Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Agent: C=O
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Temperature: 25 °C

Procedure:
(S)-3-Benzoyl-5-biphenyl-4-ylmethyl-1-((E)-styryl)-pyrrolidin-2-one (4a, R1=styryl, R4=phenyl) (1.0 g, 2.2 mmol) is dissolved in 5 mL of anhydrous tetrahydrofuran, add paraformaldehyde (80 mg, 2.6 mmol), DBU (434 mg, 2.8 mmol) and anhydrous Lithium chloride (186 mg, 4.4 mmol), reflux overnight under nitrogen atmosphere. The reaction mixture is cooled to room temperature, add 20 mL of toluene, wash with 5% HCl(aq), saturated Na2CO3 and brine, dry over anhydrous Na2SO4, evaporate the solvent under vacuum to give (R)-5-Biphenyl-4-ylmethyl-3-methylene-1-((E)-styryl)-pyrrolidin-2-one (1a, R1=styryl). Spectroscopic data as Example 23, Method 1.
Reaction SMILES: [C:1]([C@@H:9]1[CH2:13][CH:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[N:11](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:35])(=O)C1C=CC=CC=1.C=O.C(N(CC)CC)C.[Cl-].[Li+]>O1CCCC1.C1(C)C=CC=CC=1>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=[CH:16][C:15]([CH2:14][C@H:12]2[N:11](/[CH:27]=[CH:28]/[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:10](=[O:35])[C:9](=[CH2:1])[CH2:13]2)=[CH:20][CH:19]=1
Reactant: O=C(c1ccccc1)[C@@H]1CC(Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Agent: C=O
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Temperature: 25 °C

Procedure:
(S)-3-Benzoyl-5-biphenyl-4-ylmethyl-1-((E)-styryl)-pyrrolidin-2-one (4a, R1=styryl, R4=phenyl) (1.0 g, 2.2 mmol) is dissolved in 5 mL of anhydrous tetrahydrofuran, add paraformaldehyde (80 mg, 2.6 mmol), triethyl amine (288 mg, 2.8 mmol) and anhydrous Lithium chloride (186 mg, 4.4 mmol), reflux overnight under nitrogen atmosphere. The reaction mixture is cooled to room temperature, add 20 mL of toluene, wash with 5% HCl(aq), saturated Na2CO3 and brine, dry over anhydrous Na2SO4, evaporate the solvent under vacuum to give (R)-5-Biphenyl-4-ylmethyl-3-methylene-1-((E)-styryl)-pyrrolidin-2-one (1a, R1=styryl). Spectroscopic data as Example 23, Method 1.