Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:12])[CH3:11])=[C:6]([F:13])[CH:5]=1.Cl[CH2:16]Cl.C[O:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21]>C(OCC)C>[F:24][C:23]([F:26])([F:25])[S:20]([O-:22])(=[O:21])=[O:19].[F:13][C:6]1[CH:5]=[C:4]([C:3]([O:2][CH3:1])=[O:14])[CH:9]=[CH:8][C:7]=1[N+:10]([CH3:16])([CH3:11])[CH3:12]
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: COC(=O)c1ccc(N(C)C)c(F)c1
Reactant: ClCCl
Solvent: CCOCC
Product: COC(=O)c1ccc([N+](C)(C)C)c(F)c1
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 60 h
Yield: 80 %

Procedure:
To a stirred solution of 3.90 g (19.8 mmol) 9 and 70 ml dichloromethane were added 32.5 g (198 mmol) methyltriflate (Aldrich) drop wisely. The reaction mixture was stirred for 2.5 days at room temperature and diethylether was added. The desired compound precipitates and the solvent were decanted. The solid was washed extensively (ten times) with large amounts of diethylether. The solid was dried by use of oil pump vacuum and purified by (C-18) RP-column chromatography (acetonitril/water-gradient 1:99 to 80:20). The desired compound 10 was obtained in 80% yield (5.72 g, 15.84 mmol).
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([C:33]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([OH:43])[CH:36]=2)=O)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH3:23].O>C1COCC1>[CH2:22]([O:24][C:25]1[CH:26]=[C:27](/[C:33](/[C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([OH:43])[CH:36]=2)=[CH:9]\[C:10]#[N:11])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH3:23]
Reactant: CCOc1cc(C(=O)c2ccc(OC)c(O)c2)ccc1OC
Reactant: CCOP(=O)(CC#N)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(/C(=C\C#N)c2ccc(OC)c(O)c2)ccc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of cyanomethylphosphonic acid diethyl ester (8.1 mL, 51.6 mmol) in anhydrous THF (50 mL) was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 51.6 mL, 51.6 mmol) at 0° C. and stirred for 30 min at room temperature followed by addition of (3-ethoxy-4-methoxy-phenyl)-(3-hydroxy-4-methoxy-phenyl)-methanone (5.20 g, 17.2 mmol) in THF (40 mL) and refluxed overnight. The reaction mixture was poured into water (50 mL), extracted with CH2Cl2 (2×60 mL). The combined organic phases were washed with brine (60 mL), dried over MgSO4, and purified via flash column chromatography (EtOAc/Hexane) to give E/Z-3-(3-ethoxy-4-methoxy-phenyl) -3-(3-hydroxy-4-methoxy-phenyl)-acrylonitrile as an off-white solid (5.26 g, 94% yield). The product was used in the next step without further purification.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1F.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1[O:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:14][CH:13]=1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(CCCn3ccnc3)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.4 %

Procedure:
To a solution of 4-[3-(1H-imidazol-1-yl)propyl]phenol (405 mg) and 3-chloro-4-fluoronitrobenzene (370 mg) in N,N-dimethylformamide (4 mL) was added potassium carbonate (415 mg), and the mixture was stirred at room temperature for 16 hrs. Under ice-cooling, water was added and the mixture was extracted with ethyl acetate. The extract washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by basic silica gel column chromatography (eluent, ethyl acetate:hexane=80:20→100:0) to give the title compound (669 mg) as an oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[C:9](=O)[CH2:8][CH2:7][N:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:5]1)[CH3:2].C1(C[NH2:23])C=CC=CC=1.S1C=CC=C1.[H][H]>C(O)C.[Pd].CO>[NH2:23][C@H:9]1[CH2:8][CH2:7][N:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:5][C@H:4]1[O:3][CH2:1][CH3:2]
Reactant: NCc1ccccc1
Reactant: [H][H]
Reactant: CCOC(=O)N1CCC(=O)C(OCC)C1
Agent: [Pd]
Solvent: c1ccsc1
Solvent: CO
Solvent: CCO
Product: CCOC(=O)N1CC[C@H](N)[C@H](OCC)C1

Procedure:
A mixture of 21 parts of ethyl 3-ethoxy-4-oxo-1-piperidinecarboxylate, 11 parts of benzenemethanamine, 1 part of a solution of thiophene in ethanol 4% and 320 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 18 parts of ethyl cis-4-amino-3-ethoxy-1-piperidinecarboxylate as a residue (intermediate 69).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([O:17][CH3:18])=[C:6]([C:10]([O:15][CH3:16])=[C:11]([O:13][CH3:14])[CH:12]=1)[C:7]([OH:9])=O)[CH2:2][CH3:3].S(Cl)(Cl)=O.[CH2:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30][NH2:31])[CH3:24].O(C(C)C)C(C)C>>[CH2:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30][NH:31][C:7](=[O:9])[C:6]1[C:10]([O:15][CH3:16])=[C:11]([O:13][CH3:14])[CH:12]=[C:4]([CH2:1][CH2:2][CH3:3])[C:5]=1[O:17][CH3:18])[CH3:24]
Reactant: CCCc1cc(OC)c(OC)c(C(=O)O)c1OC
Reactant: CCN1CCC[C@H]1CN
Solvent: CC(C)OC(C)C
Solvent: O=S(Cl)Cl
Product: CCCc1cc(OC)c(OC)c(C(=O)NC[C@@H]2CCCN2CC)c1OC

Procedure:
3-Propyl-2,5,6-trimethoxybenzoic acid (23 g, 0.09 mol) was treated with thionyl chloride and (2S)-(-)-1-ethyl-2-aminomethylpyrrolidine as described in example 4. Yield 10.6 g (32%). M.p. 68°-70° C. (i-Pr2O). 1H-NMR (CDCl3): δ6.73 (s,1H), 6.40 (b,1H), 3.85 (Sx2,6H), 3.76 (s,3H), 0.9-3.8 (m,21H)ppm.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].C(N([CH:12]([CH3:14])[CH3:13])CC)(C)C.[CH3:15][C:16]1[CH:17]=[C:18]([S:22](Cl)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1>ClCCl>[CH3:1][N:2]([S:22]([C:18]1[CH:19]=[C:12]([CH3:13])[CH:14]=[CH:16][CH:17]=1)(=[O:24])=[O:23])[CH2:3][CH2:4][O:5][S:22]([C:18]1[CH:17]=[C:16]([CH3:15])[CH:21]=[CH:20][CH:19]=1)(=[O:24])=[O:23]
Reactant: CCN(C(C)C)C(C)C
Reactant: CNCCO
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Product: Cc1cccc(S(=O)(=O)OCCN(C)S(=O)(=O)c2cccc(C)c2)c1
Yield: 50.1 %

Procedure:
To a solution of 2-methylaminoethanol (1.0 g, 13 mmol) and diisopropylethylamine (5.8 ml, 33 mmol) in dichloromethane (50 ml) at room temperature was added 3-methylphenylsulfonyl chloride (5.6 g, 29 mmol). The solution was heated to reflux under argon for 12 hours then cooled and partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography to afford the title compound (2.5 g, 50%).
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)C(C)=O.[OH-].[K+].O=[Si]=O.[C:17](=[O:19])=[O:18]>>[NH2:1][C:5]1[CH:6]=[C:7]([C:17]([OH:19])=[O:18])[C:8]([OH:11])=[CH:9][CH:10]=1
Reactant: O=C=O
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=[Si]=O
Agent: [K+]
Agent: [OH-]
Product: Nc1ccc(O)c(C(=O)O)c1
Temperature: 220 °C
Yield: 90 %

Procedure:
p-Acetaminophenol 15 g, potassium hydroxide 60 g, and quartz sand 90 g were added into a 500 ml autoclave, and CO2 was introduced to perform a carboxylation reaction under a reaction pressure of 5.0 MPa and heated to 220° C., maintained for 1 hour, then the reaction was terminated, cooled to 80° C., and 1500 ml distilled water was added to dissolve potassium 5-aminosalicylate. After decolorization, the aqueous phase was acidified with 20˜30% hydrochloric acid until pH=4, cooled and then filtered to obtain the product of 5-aminosalicylic acid, the content is 97% and the yield is 90%.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:31][CH:30]=2)O1>>[CH:13]1([C:9]2[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6](=[O:20])[N:5]3[C:10]=2[C:11]([CH3:12])=[C:2]([C:29]2[CH:30]=[CH:31][C:32]([NH:35][S:36]([CH3:39])(=[O:37])=[O:38])=[CH:33][CH:34]=2)[CH:3]=[CH:4]3)[CH2:15][CH2:14]1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: CC1(C)OB(c2ccc(NS(C)(=O)=O)cc2)OC1(C)C
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(NS(C)(=O)=O)cc3)ccn2c1=O
Yield: 77.8 %

Procedure:
Methyl 1-cyclopropyl-9-methyl-8-(4-(methylsulfonamido)-phenyl)-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (74 mg, 0.25 mmol) and N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl)-methane-sulfonamide (96 mg, 0.32 mmol). Compound precipitated from solution and was filtered off and dried in vacuo to afford the title compound as a yellow solid (83 mg, 77%). ESI-MS m/z: 427 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[O:19])[N:11]([CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[C:10]2=[O:27])[CH:6]=[CH:7][CH:8]=1.ClC1C=C(C=CC=1)C(OO)=[O:33]>C(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[O:19])[N:11]([CH2:20][C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)[C:10]2=[O:27])[CH:6]=[CH:7][CH:8]=1)=[O:33]
Reactant: CSc1cccc(-n2c(=O)n(Cc3ccncc3)c(=O)c3cccnc32)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1cccc(-n2c(=O)n(Cc3ccncc3)c(=O)c3cccnc32)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 48.1 %

Procedure:
1-(3-Methylthiophenyl)-3-(4-pyridylmethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (100 mg, 0.27 mmole), prepared, e.g., as described in Example 5B, was dissolved in methylene chloride (20 ml) and cooled to 0° C. m-Chloroperoxybenzoic acid (45 mg, 0.27 mmole) was added to the solution. The solution was stirred for 2 hours at 0° C. The solution was then washed with a 10% solution of Na2SO3 (2 ml) followed by a wash with saturated NaHCO3 (10 ml). The organic and aqueous phases were separated and the organic phase was dried with MgSO4. The solvents were removed and the residue purified by preparative thin-layer chromatography (ethyl acetate as eluent) yielding 51 mg (0.13 mmole, 48% yield) of 1-(3-methylsulfinylphenyl)-3-(4-pyridylmethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, as a white solid, (mp 218°-219° C.).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]2[O:19][CH2:18][CH2:17][O:16]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([Br:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Br-:27].[CH2:20]([N:12]1[CH:13]=[CH:14][N+:10]([CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:11]1[CH:15]1[O:16][CH2:17][CH2:18][O:19]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc(CCCn2ccnc2C2OCCO2)cc1
Product: [Br-]
Product: c1ccc(CCC[n+]2ccn(Cc3ccccc3)c2C2OCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
A reaction mixture of 18 g (70 mmol) of 1-(3-phenylpropyl)-2-(1,3-dioxolan-2-yl)imidazole and 11.93 g (70 mmol) of benzyl bromide was stirred at room temperature for 8 h. The mixture was triturated with ethyl acetate, decanted and dried to afford 26.1 g (87%) of 3-benzyl-2-(1,3-dioxolan-2-yl)-1-(3-phenylpropyl)imidazolium bromide (Formula VI: A=1-(3-phenylpropyl)imidazole; Y=2-(1,3-dioxolan-2-yl; R1 =R6 =H; Z- =Br-).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].O1CCCC1.[CH3:17][CH2:18][O:19][C:20]([C@H:22]1[CH2:26][CH2:25][C:24](=[O:27])[N:23]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:21].[Cl-].[NH4+]>C(OCC)(=O)C>[CH2:18]([O:19][C:20](=[O:21])[C@H:22]([NH:23][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:25][C:24](=[O:27])[C:4]1[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=1)[CH3:17]
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: Fc1cc([Mg]Br)cc(F)c1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](CCC(=O)c1cc(F)c(F)c(F)c1)NC(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 5 h

Procedure:
3,4,5-Trifluorophenyl magnesium bromide (0.35 M diethylether solution, 55 mL) was dropwise added to a tetrahydrofuran solution (100 mL) of (R)-5-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (CAS Register No. 128811-48-3, 4.1 g) over 20 min at −40° C. This reaction solution was stirred at −40° C. for 5 hr. To this solution, a saturated ammonium chloride aqueous solution and ethyl acetate were added. The reaction solution was heated to room temperature. The organic layer was separated, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane ethyl acetate=1:0 to 1:1) to give 4.8 g of (R)-2-tert-butoxycarbonylamino-5-oxo-5-(3,4,5-trifluorophenyl)pentanoic acid ethyl ester. A 4 N hydrochloric acid ethyl acetate solution (30 mL) was added to an ethyl acetate solution (30 mL) of the obtained (R)-2-tert-butoxycarbonylamino-5-oxo-5-(3,4,5-trifluorophenyl)pentanoic acid ethyl ester. This solution was stirred for 16 hr. The reaction solution was concentrated under reduced pressure. To the residue, ethyl acetate and a saturated sodium hydrogencarbonate aqueous solution were added. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To an ethyl acetate solution (50 mL) of the residue, 10% palladium-carbon (100 mg) was added. The resulting reaction solution was stirred under 1 atm of hydrogen atmosphere for 6 hr. The reaction solution was filtered through Celite. The filtrate was concentrated under reduced pressure to give 2.91 g of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([C:6](OC)=[C:7](OC(=O)C)[C:8](=[O:13])[N:9]2C)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[NH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:13]
Reactant: COc1c(OC(C)=O)c(=O)n(C)c2cc(N)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: O=c1ccc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
To a mixture of 0.95 g of 7-amino-3-acetoxy-4-methoxy-1-methyl-2(1H)-quinolinone (3.6 mmol) in 20 ml of DMF were added 0.55 g of potassium carbonate (4.0 mmol) and 0.56 g of methyl iodide (4.0 mmol) and stirred at room temperature for 1 hour. The reaction mixture was added to water and extracted with toluene, the organic layer was concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (hexane/ethyl acetate=1/1 as an eluent) gave 0.45 g of the title compound (9). (yield=45%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([CH:24]=[O:25])=[C:5]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH2:32]([Mg]Cl)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O.[CH2:42]1COCC1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH2:23][CH3:42])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[C:6]([CH:24]([OH:25])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[C:5]2[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CS(=O)(=O)c1ccc(Cn2c(C=O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Reactant: C1CCOC1
Solvent: O
Product: CCS(=O)(=O)c1ccc(Cn2c(C(O)Cc3ccccc3)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Reaction time: 0.17 h

Procedure:
To a solution (5 ml) of 6-bromo-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbaldehyde (500 mg) in THF was added dropwise a solution (1M, 1.2 ml) of benzylmagnesium chloride in THF at room temperature, and the mixture was stirred for 10 min. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from diisopropyl ether to give the title compound (400 mg).
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11](=[O:15])[CH2:12][N+:13]#[C-:14])([CH3:9])([CH3:8])[CH3:7].[P:16](Cl)(=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19].C1C=CC=CC=1>CCCCCC.O>[C:6]([O:10][C:11](=[O:15])[CH:12]([P:16]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:23])[N+:13]#[C-:14])([CH3:9])([CH3:8])[CH3:7]
Reactant: [C-]#[N+]CC(=O)OC(C)(C)C
Reactant: CCOP(=O)(Cl)OCC
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: c1ccccc1
Product: [C-]#[N+]C(C(=O)OC(C)(C)C)P(=O)(OCC)OCC

Procedure:
1 ml of an approximately 2 molar solution of butyllithium in hexane is added over a period of 15 minutes to a solution, cooled to -10° C., of 282 mg (2 mmols) of isocyanoacetic acid tert.-butyl ester in 3 ml of dry hexane (distilled over sodium), whilst stirring vigorously and in a nitrogen atmosphere. The suspension which forms is stirred for a further 10 minutes and a solution of 413 μl (2 mmols) of diethyl phosphorochloridate in 5 ml of dry hexane is then added over a period of 15 minutes. The reaction mixture is stirred for a further 30 minutes, then treated with 20 ml of benzene and 5 ml of water and stirred vigorously for a further 10 minutes. The organic phase is washed with 3 times 5 ml of saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated in vacuo. The residue is chromatographed on silica gel. Benzene/ethyl acetate, 3:1, elutes diethylphosphono-isocyanoacetic acid tert.-butyl ester as a pale yellow oil; IR spectrum (in methylene chloride): characteristic bands at 3.4; 4.64; 5.70; 7.30; 8.00; 8.70 and 9.80μ.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]([CH:30]=[CH:31][N:32]=1)[C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=[O:17].[CH3:33][C:34]([CH3:63])([O:36][C:37](=[O:62])[CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][CH2:52][C:53]1[CH:54]=[C:55]([CH:59]=[CH:60][CH:61]=1)[C:56](O)=[O:57])[CH3:35].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.NC1C=CC(N(CC)CC)=CC=1C1C=C(C=CN=1)C(NCC1C=CC=C(C(F)(F)F)C=1)=O>[CH2:9]([N:8]([CH2:11][CH3:12])[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:56]([C:55]2[CH:54]=[C:53]([CH2:52][CH2:51][CH2:50][O:49][CH2:48][CH2:47][O:46][CH2:45][CH2:44][O:43][CH2:42][CH2:41][O:40][CH2:39][CH2:38][C:37]([O:36][C:34]([CH3:63])([CH3:35])[CH3:33])=[O:62])[CH:61]=[CH:60][CH:59]=2)=[O:57])=[C:3]([C:13]2[CH:14]=[C:15]([C:16](=[O:17])[NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)[CH:30]=[CH:31][N:32]=2)[CH:4]=1)[CH3:10]
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCCc1cccc(C(=O)O)c1
Reactant: CCN(CC)c1ccc(N)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCC(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 0.42 h
Yield: 77.3 %

Procedure:
To a solution of 2-(2-amino-5-(diethylamino)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide (1.77 g, 4.0 mmol), 3-(2,2-dimethyl-4-oxo-3,7,10,13,16-pentaoxanonadecan-19-yl)benzoic acid (1.70 g, 3.86 mmol) and DIPEA (1.47 g, 11.4 mmol) in DMF (20 ml) was added HATU (1.56 g, 4.10 mmol). The reaction mixture was stirred for 30 minutes, at which time additional 2-(2-amino-5-(diethylamino)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide (0.06 g, 0.14 mmol) was added. After stirring an additional 25 minutes, the reaction mixture was concentrated under vacuum. The residue was dissolved in DCM (200 mL), washed with water (4×50 mL), dried (Na2SO4) and concentrated to dryness. Purification by flash chromatography on silica gel (50% to 100% EtOAc in hexanes) gave the title compound (2.58 g) as an oil.
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([CH:25]=O)=[CH:17]1.[CH:27]([C:29]1[N:30]=[C:31]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[S:32][C:33]=1[CH3:34])=O>>[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([CH2:25][N:2]2[C:27]([C:29]3[N:30]=[C:31]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[S:32][C:33]=3[CH3:34])=[C:4]3[C:3]([N:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]3=[O:15])=[N:1]2)=[CH:17]1
Reactant: Cc1sc(NC(=O)OC(C)(C)C)nc1C=O
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Reactant: O=Cc1csc2ccccc12
Product: Cc1sc(NC(=O)OC(C)(C)C)nc1-c1c2c(=O)n(C)c(=O)n(CC(C)C)c2nn1Cc1csc2ccccc12

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 1-benzothiophene-3-carbaldehyde, followed by tert-butyl 4-formyl-5-methyl-1,3-thiazol-2-ylcarbamate.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[CH:6]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12])=[O:7]>C1COCC1>[CH:1]1([C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])=[O:7])[CH2:3][CH2:2]1.[CH:1]1([CH:6]([OH:7])[C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])[CH2:3][CH2:2]1
Reactant: N#Cc1cccc(C=O)c1
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: N#Cc1cccc(C(=O)C2CC2)c1
Product: N#Cc1cccc(C(O)C2CC2)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
The key intermediate 3-(Cyclopropanecarbonyl)benzonitrile was prepared as follows; a) Cyclopropylmagnesium bromide (1M in THF, 6 ml, 6 mmol) was added to a solution of 3-formylbenzonitrile in THF (12 ml) at −78° C. and stirred at 0° C. for 5 hours. The reaction was quenched with saturated NH4Cl solution (30 ml), extracted with EtOAc, washed with water (×2) and brine, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica (EtOAc/Hexanes 20/80-50/50) to give 3-(cyclopropyl(hydroxy)methyl)benzonitrile (778 mg, 91%). b) 2-Iodoxybenzoic acid (IBX) was added to a solution of 3-(cyclopropyl(hydroxy)methyl)benzonitrile (171 mg, 1 mmol) in EtOAc (5 ml) at room temperature and stirred at 80° C. for 2 hours. After cooling to 0° C., the precipitated materials were filtered off and washed with EtOAc (3 ml×2), then the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica (EtOAc/Hexanes 5/95-30/70) to give 3-(cyclopropanecarbonyl)benzonitrile (225 mg, 100%).
Reaction SMILES: [F:1][C:2]([P:8]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])(=[O:12])[O:9]CC)([F:7])[C:3]([F:6])([F:5])[F:4].[CH2:20]([P:24]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23]>CCCCCC>[F:7][C:2]([P:8]([C:13]([F:18])([F:19])[C:14]([F:17])([F:16])[F:15])(=[O:9])[O-:12])([F:1])[C:3]([F:6])([F:5])[F:4].[CH2:29]([P+:24]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:2][CH3:3])[CH2:30][CH2:31][CH3:32]
Reactant: CCCCP(CCCC)CCCC
Reactant: CCOP(=O)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Solvent: CCCCCC
Product: CCCC[P+](CC)(CCCC)CCCC
Product: O=P([O-])(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
Ethyl bis(pentafluoroethyl)phosphinate (1.538 g; 4.7 mmol) is added to cooled (0° C.) tributylphosphine (0.953 g; 4.7 mmol) in a 25 ml glass flask. The reaction mixture is stirred at 0° C. for 1 h, with initially a two-phase system and later the formation of a solid being observed. The reaction mixture is diluted with 10 ml of n-hexane, warmed and stirred at room temperature for 5.5 h. The readily volatile constituents are removed in vacuo (10−3 mbar) at 35° C. Tributylethylphosphonium bis(pentafluoroethyl)phosphinate, [(C4H9)3PC2H5][(C2F5)2P(O)O], (2.262 g; 4.2 mmol) is isolated as colourless solid in a yield of 89% and a purity of 98%.