Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[SH:2][C:3]1[N:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1.[CH3:10]OC(OC)N(C)C.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[CH3:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:10])[N:8]=1
Reactant: Cc1ccnc(S)n1
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nccc(C)n1

Procedure:
2-Mercapto-4-methylpyrimidine hydrochloride (100 g, 617 mmol), dimethylformamide dimethylacetal (100 mL, 754 mmol), diisopropylethylamine (161 mL, 926 mmol) and toluene (200 mL) were combined under argon. The resulting solution was heated to reflux for 4 h. The solvent was removed in vacuo and water and sodium bisulfate were added. The resulting mixture was extracted with ether (3×100 mL). The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford an oil. Vacuum distillation gave Compound 2 as a liquid: 70.5 g, (504 mmol, 82%)
Reaction SMILES: [O:1]=[C:2]([CH3:14])[CH2:3][C:4](ON1C(=O)CCC1=O)=[O:5].[CH3:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][NH:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=1.C(N(CC)CC)C.[Cl-].[Na+]>ClCCl>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][N:22]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:4](=[O:5])[CH2:3][C:2](=[O:1])[CH3:14])=[CH:29][CH:30]=1
Reactant: CC(=O)CC(=O)ON1C(=O)CCC1=O
Reactant: COC(=O)CCNCc1ccc(OC)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCN(Cc1ccc(OC)cc1)C(=O)CC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask with stirbar was charged with 2,5-dioxopyrrolidin-1-yl 3-oxobutanoate (6.47 g, 32.5 mmol), methyl 3-(4-methoxybenzylamino)propanoate (prepared as described in Bew, S. et al, Chem Commun. 2006 (41), 4338-40, 7.7 g, 34.5 mmol) and triethylamine (5 mL, 35.9 mmol) in dichloromethane (125 mL). The solution was stirred overnight at ambient temperature, then shaken in a separatory funnel with saturated aqueous sodium chloride. The organics were then washed with saturated aqueous sodium chloride containing 0.1M HCl and dried over anhydrous sodium sulfate. Filtration and solvent removal provided the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[C@H:22]1[C@H:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:26]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:25]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:24]([CH2:52][O:53][CH2:54][C:55]2C=CC=CC=2)[O:23]1)[CH:2]=[CH2:3].ClCCl.FC(F)(F)S(O[Si](C)(C)C)(=O)=[O:67]>C(OC(=O)C)(=O)C>[C:54]([O:53][CH2:52][C@@H:24]1[C@@H:25]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C@H:26]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C@@H:27]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C@H:22]([C:6]2[CH:7]=[C:8]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH3:21])=[CH:17][CH:18]=3)[C:9]([Cl:11])=[CH:10][C:5]=2[O:4][CH2:1][CH:2]=[CH2:3])[O:23]1)(=[O:67])[CH3:55]
Reactant: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](COC(C)=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -45 °C
Yield: 100 %

Procedure:
To a stirred −55° C. solution of (2S,3S,4R,5R,6R)-2-(2-(allyloxy)-4-chloro-5-(4-ethoxybenzyl)phenyl)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran (19, 8.54 g, 10 mmol) from Step 3 in acetic anhydride (50 mL)/dichloromethane (50 mL) was dropwise added trimethylsilyl trifluoromethanesulfonate (4.7 mL, 26 mmol) at a rate such that the reaction temperature was maintained between −50 and −55° C. The solution was allowed to warm to −45° C. over 1.5 h prior to quenching with saturated sodium hydrogen carbonate solution. The reaction mixture was extracted with dichloromethane and the combined organic layers were washed with saturated sodium hydrogen carbonate solution prior to drying over magnesium sulfate. After filtration and concentration under reduced pressure, the crude residue was purified on a Biotage® purification apparatus (silica gel, 5 to 20% tetrahydrofuran in hexanes gradient) to yield the title compound (20, 7.8 g, 10 mmol, 100%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH2:18][CH:19]=O)[C:15]([CH3:21])=[N:14]1.[NH2:22]/[C:23](/[C:28]#[N:29])=[C:24](\[NH2:27])/[C:25]#[N:26]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH2:18][CH:19]=[N:22][C:23]([C:28]#[N:29])=[C:24]([NH2:27])[C:25]#[N:26])[C:15]([CH3:21])=[N:14]1
Reactant: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1CC=O
Reactant: N#C/C(N)=C(/N)C#N
Product: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1CC=NC(C#N)=C(N)C#N

Procedure:
2-(2,6-Dichloro-4-trifluoromethylphenyl)-5-methyl-2H-1,2,3-triazole-4-acetaldehyde was treated with diaminomaleonitrile in a similar manner to Example 1, to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-[2-(2-amino-1,2-dicyanoethenylimino)ethyl]-5-methyl-2H-1,2,3-triazole, which was cyclised in a similar manner to Example 1a, to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-[(4,5-dicyano-1H-imidazol-2-yl)methyl]-5-methyl-2H-1,2,3-triazole (Compound 33).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([O:22]C1C=CC=CC=1)=O.[CH3:29][N:30]([CH3:32])[NH2:31]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([NH:31][N:30]([CH3:32])[CH3:29])=[O:22]
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Reactant: CN(C)N
Product: CN(C)NC(=O)c1c(Nc2ccc(I)cc2F)n(C)c(=O)n(C)c1=O

Procedure:
Example 45 was synthesized following a similar procedure described in the synthesis of Example 5 by reaction of compound 2A and 1,1-dimethylhydrazine. 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=8.0 Hz, 1 H) 7.58 (d, J=8.0 Hz, 1 H) 6.99 (t, J=8.0 Hz, 1 H) 3.33 (s, 3 H) 3.08 (s, 3 H) 2.60 (s, 6 H). [M+H] calc'd for C15H17FIN5O3, 462; found, 462.
Reaction SMILES: [F:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:14])=O>C1COCC1.CN(C=O)C>[F:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccnc1F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cl)c1cccnc1F

Procedure:
A homogeneous mixture of 2-fluoronicotinic acid (Aldrich, 0.45 g, 3.2 mmol), in anhydrous THF (12 mL), was treated with oxalyl chloride (0.56 mL, 6.4 mmol) followed by anhydrous DMF (2 drops). After heating at reflux for 1.5 hours, the reaction mixture was concentrated in vacuo to afford 2-fluoronicotinoyl chloride as a residue which was used without further purification. The residue was dissolved in anhydrous THF (8 mL), anhydrous DCM (2 mL), pyridine (1 mL) and DMF (to a total volume of 16 mL). This homogeneous 2-fluoronicotinoyl chloride mixture (2 mL) was then added to a rapidly stirred mixture of o-toluidine (Aldrich, 0.17 mL, 1.6 mmol) in anhydrous THF (2 mL). After 15 hours, the reaction was quenched with water, and then extracted with 10% isopropanol in chloroform. The organic layer was washed once with sat. aq. NaHCO3, once with sat. aq. NaCl, then dried over anhydrous Na2SO4 and concentrated in vacuo to afford the desired product (0.084 g, 91%) as a pale orange solid which was used without further purification. MS(ESI+) m/z 231 (M+H)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].[CH2:9]([O:11][C:12](=[O:24])[C:13]1[C:18](F)=[CH:17][CH:16]=[C:15]([N+:20]([O-:22])=[O:21])[C:14]=1[NH2:23])[CH3:10].Cl>C1COCC1>[CH2:9]([O:11][C:12](=[O:24])[C:13]1[C:18]([O:6][CH2:5][C:4]([F:8])([F:7])[F:3])=[CH:17][CH:16]=[C:15]([N+:20]([O-:22])=[O:21])[C:14]=1[NH2:23])[CH3:10]
Reactant: CCOC(=O)c1c(F)ccc([N+](=O)[O-])c1N
Reactant: OCC(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(OCC(F)(F)F)ccc([N+](=O)[O-])c1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
420 mg NaH (60% suspension in oil) were added to a solution of 2.16 mL (29.8 mmol) 2,2,2-trifluoro-ethanol in 5 mL THF. When the gas evolution ceased, 1.0 g (4.38 mmol) 2-Amino-6-fluoro-3-nitro-benzoic acid ethyl ester was added. The resulting mixture was stirred at 0° C. for 30 minutes and at room temperature for further 30 minutes. To this mixture were added 2 mL of a 6 M aqueous HCl-solution, and most of the solvent was removed under reduced pressure. The residue was mixed with 20 mL water and the resulting solid was collected and washed with water and then hexane. The obtained yellow crystalline material was dried under reduced pressure at 35° C. Yield: 1.22 g.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([Cl:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][N:27]=1>>[Cl:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:26]4[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][N:27]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Cc1ccnc(Br)c1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1
Product: Cc1ccnc(C(=O)c2cn(-c3cccc(-c4cccnc4Cl)c3)cn2)c1

Procedure:
This compound is prepared by method C using compound 12l and 2-bromo-4-methylpyridine
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[N:10]1[C:19]2[C:18](=O)[CH2:17][CH2:16][CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[N:10]1[C:19]2[CH:18]([NH:5][CH2:4][C:3]3[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=3[NH2:1])[CH2:17][CH2:16][CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: NCc1ccccc1N
Reactant: O=C1CCCc2cccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Nc1ccccc1CNC1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 64 h
Yield: 53.1 %

Procedure:
Using General Procedure B: To a solution of 2-aminobenzylamine (0.36 g, 2.9 mmol) and 6,7-dihydro-5H-quinolin-8-one (0.43 g, 2.9 mmol) in CH2Cl2 (15 mL) was added NaBH(OAc)3 (0.92 g, 4.4 mmol) and the mixture stirred at room temperature for 64 h. Purification of the crude material by column chromatography on silica gel (2% MeOH/CH2Cl2) gave (5,6,7,8-tetrahydroquinolin-8-yl)-(2-aminobenzyl)-amine (0.39 g, 52%) as a yellow oil. 1H NMR (CDCl3) δ1.80 (m, 1H), 1.94 (m, 2H), 2.17 (m, 1H), 2.79 (m, 2H), 3.84 (m, 1H), 3.87 (d, 1H, J=11.7 Hz), 4.02 (d, 1H, J=12.0 Hz), 6.64 (d, 1H, J=7.8 Hz), 6.67 (t, 1H, J=7.8 Hz), 7.09 (m, 3H), 7.38 (d, 1H, J=3.0 Hz), 8.38 (d, 1H, J=3.9 Hz).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:9]=1[C:10](O)=[O:11]>C1COCC1.CCOCC>[F:7][C:8]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:9]=1[CH2:10][OH:11]
Reactant: Cc1ccc(F)c(C(=O)O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(F)c(CO)c1
Temperature: 0 °C

Procedure:
To a 1M solution of lithium aluminum hydride in THF (57 mL) at 0° C. is added a solution of 2-fluoro-5-methylbenzoic acid (8.0 g, 52 mmol) in 160 mL of ether drop-wise. The reaction is then heated at reflux for 1.5 hr. The reaction is then cooled to 0° C. and is quenched with H2O (4 mL), aqueous 40% NaOH (4 mL) and H2O (4 mL). The resultant slurry is then filtered through celite and MgSO4. The filtrate is then concentrated and purified by silica gel flash column chromatography to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2OC)=[C:4]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1.Br.[OH-:24].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[N:3]=[C:4]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[C:5]([C:10]2[CH:15]=[CH:14][C:13](=[O:24])[NH:12][CH:11]=2)=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: [OH-]
Reactant: COc1ccncc1-c1cc(C#N)c(N)nc1-c1ccco1
Agent: Br
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1cc(-c2ccc(=O)[nH]c2)c(-c2ccco2)nc1N

Procedure:
A solution of 2-amino-6-(2-furyl)-5-(4-methoxy-3-pyridyl)-3-pyridinecarbonitrile (1.0 g, 3.42 mmol) in acetic acid (6 ml)-conc. hydrobromic acid (10 ml) was stirred at 100° C. for 1.5 hours. After cooling as it was, the reaction solution was adjusted to pH 12 to 13 with 5 N sodium hydroxide and washed with ethyl acetate. The organic layer was extracted with 1 N sodium hydroxide (×2), and then the combined aqueous layer was neutralized with 5 N hydrochloric acid. The resulting solid was collected by filtration, to give the title compound (760 mg) as yellow crude crystals. After suspending the product in methanol, 4 N HCl/ethyl acetate was added thereto to dissolved and it subjected to silica gel column chromatography (elution solvent; dichloromethane, dichloromethane:methanol=40:1, 20:1, 10:1). The resulting crude objective compound was suspended in water, and then neutralized with 5 N sodium hydroxide. The solid was collected by filtration and washed with water, to give the title compound (486 mg, 51%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH2:11][CH2:12][CH2:13][OH:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH2:5][NH:11][CH2:12][CH2:13][OH:14])[C:3]=1[OH:10]
Reactant: O=Cc1cccc(Br)c1O
Reactant: NCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCNCc1cccc(Br)c1O
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a solution of 3-bromo-2-hydroxybenzaldehyde (Preparation 98) (9.6 g, 47.8 mmol) in tetrahydrofuran (250 ml) at 0° C. under nitrogen was added 2-aminoethanol (3.02 ml, 50.1 mmol) then finely powdered sodium triacetoxyborohydride (10.6 g, 50.1 mmol) and the resulting mixture was stirred at 0° C. for 1 h, then stirred overnight and concentrated in vacuo. The residue was triturated under dichloromethane (˜200 mL) and insoluble material was filtered off. The organic phase was concentrated in vacuo and the residue purified using an SCX column to give the title compound as a white solid (10.1 g). MS (ES) C9H1079BrNO2 requires 243 found 244 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Br[CH2:11][CH2:12][O:13][C:14]([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O>[C:14]([O:13][CH2:12][CH2:11][N:7]1[CH2:8][CH2:9][CH:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: OCCC1CCNCC1
Reactant: CC(C)(C)OCCBr
Solvent: CN(C)C=O
Product: CC(C)(C)OCCN1CCC(CCO)CC1
Yield: 68.3 %

Procedure:
4-(2-hydroxyethyl)piperidine (1.94 g, 15 mmol) in dimethylformamide (20 ml) was reacted with 2-(2-bromoethoxy)-2-methylpropane (3.13 g, 17.3 mmol) at 50° C. for 15 hours. The mixture was cooled and the solid removed by filtration. The solid was washed with ethyl acetate and the organics were washed with water, dried (magnesium sulphate) and concentrated to give 2-(1-(2-tert-butoxy ethyl)piperidin-4-yl)ethanol as a yellow oil (2.35 g, 100% yield):
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:9]([CH2:10][C:11]#[N:12])[CH2:8][CH2:7][C:6]1=[O:13])=[O:4].[CH2:14](Br)[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1([CH2:16][CH:15]=[CH2:14])[CH:9]([CH2:10][C:11]#[N:12])[CH2:8][CH2:7][C:6]1=[O:13])=[O:4]
Reactant: C=CCBr
Reactant: COC(=O)C1C(=O)CCC1CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCC1(C(=O)OC)C(=O)CCC1CC#N
Reaction time: 5 h
Yield: 69.4 %

Procedure:
5-Cyanomethyl-2-oxo-cyclopentanecarboxylic acid methyl ester (100 mg, 0.58 mmol) and allyl bromide (121 mg, 1 mmol) were dissolved in acetone (5ml). Potassium carbonate (138 mg, 1 mmol) was added to the solution. The mixture was heated under refluxing with stirring for 5 hours and then was cooled and was filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by a silica gel column chromatography (ethyl acetate: n-hexane=1: 4) to obtain 89 mg of 1-allyl-5-cyanomethyl-2-oxo-cyclopentanecarboxylic acid methyl ester as viscous oily product. Yield: 69%. Infrared spectrum(cm-1): 2235, 1755, 1730, 1640, 925. NMR spectrum (CDCl3) δ : 1.60 - 3.05 (m, 9H), 3.73 (s, 3H), 4.88 - 6.07 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[CH:11]=[CH:12][O:13][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:6]([O:5][P:4](/[CH:9]=[CH:10]/[CH:11]=[CH:12][OH:13])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(/C=C/C=CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOP(=O)(/C=C/C=CO)OCC
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A mixture of E-4-t-butyldiphenylsilyloxy-1,3-butadienyl phosphonic diethyl ester (11 g, 26.4 mmol) and tetrabutylammonium fluoride trihydrate (10 g, 31 mmol) in tetrahydrofuran (100 ml) is stirred 2 hours at 20° C. The reaction mixture is concentrated in vacuo, diluted with ethyl acetate and washed with brine. The title product is obtained by flash chromatography on silica gel (4.6 g, 80%).
Reaction SMILES: [I-].[CH:2]1([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:37][O:38][C:39](=[O:50])[C:40]([C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([Cl:49])[CH:43]=1)=O>O1CCCC1>[CH3:37][O:38][C:39](=[O:50])[C:40]([C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([Cl:49])[CH:43]=1)=[CH:7][CH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)C(=O)c1ccc(Cl)c(Cl)c1
Reactant: c1ccc([P+](CC2CCCC2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(=CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 49.2 %

Procedure:
A suspension of cyclopentylmethyl triphenylphosphonium iodide (prepared in Example 3, 3.95 g, 8.37 mmol) in dry tetrahydrofuran (10 mL) was cooled to 0° C. and then treated dropwise with a 1.0M solution of sodium bis(trimethylsilyl)amide (8.4 mL, 8.37 mmol). The bright orange reaction mixture was stirred at 0° C. for 45 min. The reaction mixture was then treated with a solution of (3,4-dichloro-phenyl)-oxo-acetic acid methyl ester (1.30 g, 5.58 mmol) in tetrahydrofuran (4 mL). The resulting reaction mixture was allowed to warm to 25° C. where it was stirred for 64 h. The reaction mixture was then concentrated in vacuo to remove tetrahydrofuran. The residue was diluted with water (150 mL) and then extracted with diethyl ether (1×200 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 19/1 hexanes/ethyl acetate) afforded the 3 cyclopentyl-2-(3,4-dichloro-phenyl)-acrylic acid methyl ester (821.1 mg, 49%) as a yellow oil consisting of a 4.5:1 mixture of (E):(Z) isomers. The isomeric mixture was used without further separation and characterization.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH2:20][C:19](=O)[N:18]([CH:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:24])[C:17]=3[CH:30]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1(C)C=CC=CC=1.COCCOC>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH2:20][C:19](=[S:40])[N:18]([CH:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:24])[C:17]=3[CH:30]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C)N1C(=O)COc2ccc(OC3CN(C(=O)OC(C)(C)C)C3)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)N1C(=S)COc2ccc(OC3CN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 25 °C
Yield: 74.5 %

Procedure:
To a solution of 3-[4-(1-ethoxycarbonyl-ethyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxy]-azetidine-1-carboxylic acid tert-butyl ester (0.700 g, 1.66 mmol) in toluene (15 mL) and DME (15 mL) was added Lawesson's reagent (1.058 g, 2.66 mmol) and the mixture was heated to reflux for 4 h. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 15% EtOAc in petroleum ether) to give 3-[4-(1-ethoxycarbonyl-ethyl)-3-thioxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxy]-azetidine-1-carboxylic acid tert-butyl ester (0.540 g, 74%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 6.94 (d, J=8.8 Hz, 1H), 6.67 (br, 1H), 6.39 (m, 1H), 6.36 (m, 1H), 4.88 (d, J=15.2 Hz, 2H), 4.74 (m, 1H), 4.27 (m, 2H), 4.19 (m, 2H), 3.97 (m, 2H), 1.68 (d, J=7.2 Hz, 3H), 1.45 (s, 9H), 1.14 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].CN(C=O)C.C([O-])(=O)C.[Na+].Br[CH2:16][C:17]([C:19]1[N:20]=[CH:21][C:22]([NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[N:23][CH:24]=1)=[O:18]>C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:28][C:27]([CH3:30])([CH3:29])[C:26]([NH:25][C:22]1[N:23]=[CH:24][C:19]([C:17](=[O:18])[CH2:16][O:3][C:1](=[O:4])[CH3:2])=[N:20][CH:21]=1)=[O:31]
Reactant: CC(=O)O
Reactant: CC(C)(C)C(=O)Nc1cnc(C(=O)CBr)cn1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCC(=O)c1cnc(NC(=O)C(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
A 500 mL round bottomed flask equipped with a magnetic stirrer, addition funnel, thermocouple probe and nitrogen inlet/outlet was charged with 4.40 mL (76.86 mmol) of acetic acid, 140 mL of DMF and 7.000 g (85.33 mmol) of sodium acetate. Then, 23.30 g (77.62 mmol) of the compound obtained in step 5 was added portionwise over 45 min. After stirring at room temperature for an additional 1 h, HPLC analysis indicated complete reaction. The reaction mixture was diluted with 350 mL of ethyl acetate and 100 mL of saturated sodium bicarbonate was added with stirring. The organic layer was separated, washed with 3×100 mL of water and concentrated at 30° C./60 mmHg to a volume of ca. 60 mL. The resulting slurry was diluted with 200 mL of heptane, concentrated at 30° C./60 mmHg to a volume of ca. 150 mL, and stirred at 50° C. for 30 min. After cooling to room temperature, the solid was collected by filtration, washed with 40 mL of 10% ethyl acetate in heptane and dried by suction, then under reduced pressure (house vacuum) for 24 h, to give 19.52 g (90.0% yield) of the title compound as an off-white solid; 98.81% pure as determined by HPLC analysis (same conditions as in step 4, retention time 6.78 min).
Reaction SMILES: [C:1]([N:3]=[C:4](OCC)[C:5]([CH3:14])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:6])#[N:2].[NH2:18][C:19]12[CH2:25][C:22]([C:26]([NH2:28])=[O:27])([CH2:23][CH2:24]1)[CH2:21][CH2:20]2>C(O)C.CN(C)C1C=CN=CC=1>[C:1]([N:3]=[C:4]([NH:18][C:19]12[CH2:25][C:22]([C:26]([NH2:28])=[O:27])([CH2:21][CH2:20]1)[CH2:23][CH2:24]2)[C:5]([CH3:6])([O:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:14])#[N:2]
Reactant: CCOC(=NC#N)C(C)(C)Oc1ccccc1
Reactant: NC(=O)C12CCC(N)(CC1)C2
Agent: CN(C)c1ccncc1
Solvent: CCO
Product: CC(C)(Oc1ccccc1)C(=NC#N)NC12CCC(C(N)=O)(CC1)C2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of ethyl N-cyano-2-methyl-2-phenoxypropanimidoate (CI-1) (300 mg, 1.29 mmol) and 4-aminobicyclo[2.2.1]heptane-1-carboxamide (BA-7) (217 mg, 1.29 mmol) in ethanol (3 mL) was added 4-(dimethylamino)pyridine (47 mg, 0.387 mmol). The mixture was stirred at room temperature for 5 hours and then heated to 75° C. and stirred overnight. After concentration, the residue was purified by preparative reverse phase HPLC [Waters 2767; Benetnach 10-C18 20×250 mm, 10 μm; 35-85% acetonitrile/water (0.05% trifluoroacetic acid), 30 mL/minute; detection at 214 and 254 nm] to give the titled compound. 1H NMR (400 MHz, CD3OD) δ ppm 7.34 (t, J=7.8 Hz, 2H), 7.14 (t, J=7.4 Hz, 1H), 7.0 (d, J=8.4 Hz, 2H), 2.10-2.15 (m, 4H), 2.01-2.03 (m, 4H), 1.79-1.83 (m, 2H), 1.72 (s, 6H); LCMS (ESI+) m/z 341.7 (M+H)+.