Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:15]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:22]([O:26][C:27](=[O:30])[CH:28]=[CH2:29])([CH3:25])([CH3:24])[CH3:23].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CC#N>CCOC(C)=O.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:15]1(=[C:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:5]2[CH:6]=[CH:7][C:2](/[CH:29]=[CH:28]/[C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:30])=[CH:3][CH:4]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Brc1ccc(C(=C2CCCCCC2)c2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCCC2)c2ccccc2)cc1
Reaction time: 2 h
Yield: 103.4 %

Procedure:
A stirred suspension of 1 (0.77 g, 2.24 mmol), TEA (1.86 mL, 13.4 mmol), t-butylacrylate (1.96 mL, 13.4 mmol), Pd(OAc)2 (0.12 g, 0.50 mmol), P(o-tolyl)3 (0.28 g, 0.90 mmol) and CH3CN were stirred at reflux under N2. Heating was discontinued after 2 h and the reaction diluted with EtOAc (50 mL) and water (50 mL). The mixture was filtered through a celite pad and the filtrate transferred to a separatory funnel. The organic fraction was washed with 50 mL brine (50 mL), dried (MgSO4), filtered and concentrated to 1.39 g of an amber oil. The crude product was purified by flash chromatography on silica gel with a hexanes to 5% EtOAc:hexanes gradient. The product, 2, was isolated as a colorless, viscous oil (900 mg, 100%). 1H NMR (300 MHz, DMSO-d6): δ 1.52 (s, 9H), 1.59 (s, 8H), 2.31 (br, 4H), 6.51 (d, J=16 Hz, 1H), 7.19-7.38 (m, 7H), 7.56 (d, J=16 Hz, 1H), 7.66 (d, J=8.1 Hz, 2H).
Reaction SMILES: [O:1]([CH2:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:12].[CH3:13]COCC>>[Cl:12][CH2:13][C:9](=[O:10])[CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl
Reactant: O=C(Cl)COc1ccccc1
Reactant: CCOCC
Product: O=C(CCl)COc1ccccc1

Procedure:
The synthesis of 2,4-diamino-4-phenoxymethylfuro[2,3-d]pyrimidin-4-one12 is shown in FIG. 20. Phenoxyacetyl chloride 10 was reacted with CH2N2 in the presence of gaseous hydrogen chloride and ether to produce 1-chloro-3-phenoxy-2-propanone 11. 1-chloro-3-phenoxy-2-propanone 11 was reacted with 2,6-diamino-3H-pyrimidin-4-one 1 to produce 2,4-diamino-4-phenoxymethylfuro[2,3-d]pyrimidin-4-one 12 at a 39% yield.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:21])[CH2:13][C:14]([CH2:16][O:17][C:18](=[O:20])[CH3:19])=O)[CH3:10].[CH2:22]([O:24][C:25](=[O:30])/[CH:26]=[C:27](\[NH2:29])/[CH3:28])[CH3:23]>O1CCOCC1>[CH2:9]([O:11][C:12]([C:13]1[CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:26]([C:25]([O:24][CH2:22][CH3:23])=[O:30])=[C:27]([CH3:28])[NH:29][C:14]=1[CH2:16][O:17][C:18](=[O:20])[CH3:19])=[O:21])[CH3:10]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)/C=C(/C)N
Reactant: CCOC(=O)CC(=O)COC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(C)NC(COC(C)=O)=C(C(=O)OCC)C1c1ccccc1
Yield: 50 %

Procedure:
A solution of 5 g of benzaldehyde, 9.4 g of γ-acetoxyacetoacetic acid ethyl ester and 6.5 g of β-aminocrotonic acid ethyl ester in 50 ccs of dioxane is heated to the boil overnight and then cooled. After filtering, light yellow crystals of melting point 104°-106° C. are obtained, yield: 50%.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:11])[CH:9]=[CH2:10].C1(C)C(C(P(C(C2C(C)=CC=CC=2)=O)C(C2C(C)=CC=CC=2)=O)=O)=CC=CC=1.Br[C:46]1[C:47]([NH:55][CH3:56])=[N:48][CH:49]=[C:50]([N+:52]([O-:54])=[O:53])[CH:51]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CN(C=O)C>[CH3:56][NH:55][C:47]1[C:46]([CH:10]=[CH:9][C:8]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11])=[CH:51][C:50]([N+:52]([O-:54])=[O:53])=[CH:49][N:48]=1
Reactant: CNc1ncc([N+](=O)[O-])cc1Br
Reactant: C=CC(=O)OCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1C(=O)P(C(=O)c1ccccc1C)C(=O)c1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCOC(=O)C=Cc1cc([N+](=O)[O-])cnc1NC
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Triethylamine (32 μl), n-butyl acrylate (33 μl), tri(o-toluoyl)phosphine (24 mg), and palladium acetate (5 mg) were added to a tube containing a DMF (3 ml) solution containing 3-bromo-N-methyl-5-nitropyridin-2-amine (45 mg) and the tube was sealed, followed by stirring at 100° C. for 8 hours. The reaction solution was adjusted to room temperature, and n-butyl acrylate (33 μl), tri(o-toluoyl)phosphine (24 mg), and palladium acetate (5 mg) were added again to the tube and the tube was sealed, followed by stirring at 100° C. for 9 hours. Further, the reaction solution was adjusted to room temperature, and water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=16:1 to 3:1), and a yellow solid of n-butyl 3-(2-(methylamino)-5-nitropyridin-3-yl)acrylate (44 mg) was thus obtained.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11](=[O:13])[CH3:12])[CH:5]=1.[CH3:16][C:17]([CH:19]([O:22][CH3:23])[O:20][CH3:21])=O.N1CCCC1>C1(C)C=CC=CC=1>[CH3:21][O:20][CH:19]([O:22][CH3:23])[C:17]1([CH3:16])[CH2:12][C:11](=[O:13])[C:6]2[CH:5]=[C:4]([O:3][C:2]([F:14])([F:15])[F:1])[CH:9]=[CH:8][C:7]=2[O:10]1
Reactant: CC(=O)c1cc(OC(F)(F)F)ccc1O
Reactant: COC(OC)C(C)=O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: COC(OC)C1(C)CC(=O)c2cc(OC(F)(F)F)ccc2O1
Yield: 64.6 %

Procedure:
To a solution of 0.5 g (2.27 mmole) of the compound obtained in step 2 dissolved in 10 ml of toluene were added 0.55 ml (4.54 mmole) of pyruvic aldehyde dimethyl acetal and 80 mg (1.14 mmole) of pyrrolidine. The reactants were heated to reflux for about 12 hours using Dean-Stark apparatus. After completion of the reaction, toluene solvent was removed therefrom under reduced pressure. The residue so obtained was extracted with ethyl acetate and concentrated to give residue, which was purified by silica gel column chromatography using as an eluent a mixture of hexane and ethyl acetate of 10:1 to obtain 0.470 g (yield 65%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([CH:14]=[CH2:15])[N:11]=[C:10]([CH3:16])[N:9]=2)[N:3]=1.[N+](=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N-]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:9]=[C:10]([CH3:16])[N:11]=[C:12]([CH:14]3[CH2:15][CH:19]3[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=2)[N:3]=1
Reactant: C=Cc1cc(-n2nc(C)nc2C)nc(C)n1
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC1c1cc(-n2nc(C)nc2C)nc(C)n1
Reaction time: 2 h

Procedure:
A solution of 4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methyl-6-vinylpyrimidine (2-3, 500 mg, 2.323 mmol 1.0 eq.) in toluene (35 mL) was heated under nitrogen to 120° C. To the reaction mixture was added ethyl diazoacetate (0.602 mL, 5.81 mmol, 2.5 eq.) dropwise. Upon complete addition, heating was continued for 2 hours. A mix of trans (major) and cis (minor) products were observed. Toluene was removed by roto-evaporation and the resulting residue purified by silica gel column chromatography (0-100% ethyl acetate in hexanes). The major product peak was collected and concentrated to afford ethyl 2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidin-4-yl)cyclopropanecarboxylate (2-4). 1H NMR (500 MHz, CDCl3) δ 7.59 (s, 1H), 4.18 (m, 2H), 2.89 (s, 3H), 2.62 (s, 3H), 2.60 (m, 1H), 2.41 (s, 3H), 2.36 (m, 1H), 1.71 (m, 1H), 1.66 (m, 1H), 1.28 (t, 3H, J=6.4 Hz). LRMS m/z (M+H) 302.3 found, 302.2 required.
Reaction SMILES: [CH:1]1([NH:4][S:5]([C:8]2[C:9]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C1([O:24][C:25](=O)[NH:26][C:27]2[N:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[N:28]=2)C=CC=CC=1.N12CCCCC1C=NCCC2.Cl>C(#N)C.O>[CH:1]1([NH:4][S:5]([C:8]2[C:9]([S:14]([NH:17][C:25]([NH:26][C:27]3[N:28]=[C:29]([O:35][CH3:36])[CH:30]=[C:31]([O:33][CH3:34])[N:32]=3)=[O:24])(=[O:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: NS(=O)(=O)c1ccccc1S(=O)(=O)NC1CC1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: C1=NCCCN2CCCCC12
Agent: Cl
Solvent: O
Solvent: CC#N
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2S(=O)(=O)NC2CC2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a solution of 0.14 g of the product of Example 1 and 0.15 g of phenyl(4,6-dimethoxypyrimidin-2-yl)carbamate in 2 ml of dry acetonitrile was added 0.1 ml of 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU). The solution was stirred for 15 minutes at room temperature, diluted with 2 ml of water and acidified with 5% hydrochloric acid. The precipitated product was collected by filtration, washed successively with water, diethyl ether, and 1-chlorobutane, and dried in vacuo at 40° C. to afford 0.19 g of the subject compound, m.p. 197.5°-199° C. (dec.).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:8][CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)(=[O:19])=[O:18]
Reactant: OCC1CCCCO1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCCCO1
Reaction time: 0.5 h
Yield: 102 %

Procedure:
A stirred solution of 13.9 g of 3,4,5,6-tetrahydro-2H-pyran-2-methanol and 18.2 g of triethylamine in 250 ml of methylene chloride was cooled to -10° C. and 15.1 g of methansulfonyl chloride was added dropwise over 5 minutes while maintaining the temperature at -10° C. to 0° C. using a cooling bath. The bath was removed and the mixture was stirred for 1/2 hour while the temperature reached 16° C. The reaction mixture was washed successively with 150 ml of ice water, 150 ml of 10% hydrochloric acid solution, 150 ml of saturated sodium bicarbonate solution and 150 ml of saturated sodium chloride solution, then dried (MgSO4) and evaporated under vacuum at 50° C. to give 23.7 g of a yellow oil, which was Claisen distilled to yield 19.7 g of the desired product; b.p. 110° C. (0.2 mm).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH:3]=1.[CH2:19]([CH:21]1[O:23][CH2:22]1)Br.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4]([O:13][CH2:14][C:15]([F:16])([F:17])[F:18])[CH:3]=1)[CH:21]1[O:23][CH2:22]1
Reactant: BrCC1CO1
Reactant: COC(=O)Cc1ccc(O)cc1OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(OCC2CO2)cc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of methyl 4-hydroxy-2-(2,2,2-trifluoroethoxy)phenylacetate (0.60 g, 2.4 mmol) from Step 4 of Example 32 in DMF (7 mL) was added epibromohydrin (0.50 g, 3.6 mmol) and Cs2CO3 (1.55 g, 4.8 mmol). The mixture was stirred at ambient temperature for 3 h. EtOAc was added (15 mL) and the solid was removed by filtration. The filtrate solvents were removed under reduced pressure and the residue was partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give methyl 4-(glycidyloxy)-2-(2,2,2-trifluoroethoxy)-phenylacetate as a pale yellow oil (HPLC retention time=8.3 min (method A)).
Reaction SMILES: OS(O)(=O)=O.[S:6]1[CH:10]=[CH:9][C:8]([C:11](O)([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:12][CH:13]([CH3:15])[CH3:14])=[C:7]1[C:21]1[S:22][CH:23]=[CH:24][CH:25]=1.C(Cl)Cl>O>[CH2:12]([C:11]1([CH2:16][CH:17]([CH3:19])[CH3:18])[C:25]2[CH:24]=[CH:23][S:22][C:21]=2[C:7]2[S:6][CH:10]=[CH:9][C:8]1=2)[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CC(O)(CC(C)C)c1ccsc1-c1cccs1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: CC(C)CC1(CC(C)C)c2ccsc2-c2sccc21
Temperature: 25 °C

Procedure:
H2SO4 (1.45 mL) was added dropwise to 4-(2,2′-bithiophene-3-yl)-2,6-dimethylheptan-4-ol (IIb) (0.688 g, 2.23 mmol) under stirring at room temperature. After stirring for 12 h, CH2Cl2 (15 mL) and water (15 mL) were added. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were successively washed with saturated NaHCO3 and brine. After drying over MgSO4, the solvent was removed in vacuo. The crude oil was purified with column chromatography (eluent hexane) to afford a pure dark yellow oil (Ib) (0.240 g, 35.0%). 1H-NMR (CDCl3): δ=7.12 (d, J=4.8 Hz, 2H), 6.92 (d, J=4.8 Hz, 2H), 1.85 (d, J=5.8 Hz, 4H), 1.08-0.78 (m, 2H), 0.50 (d, J=7.1 Hz, 12H). 13C-NMR (CDCl3): δ=158.45, 137.29, 124.99, 122.66, 53.69, 49.30, 25.46, 25.14.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21](O)=[O:22])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CN(C)C=O.[CH2:29]([NH2:32])[CH2:30][CH3:31].O>N1C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][C:21]([NH:32][CH2:29][CH2:30][CH3:31])=[O:22])=[CH:18][CH:19]=2)(=[O:11])=[O:12])=[CH:6][CH:5]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1ccc(S(=O)(=O)Cc2ccc(CC(=O)O)cc2)cc1
Reactant: CCCN
Solvent: c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=O)Cc1ccc(CS(=O)(=O)c2ccc(C(C)C)cc2)cc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of [4-(4-isopropyl-benzenesulfonylmethyl)-phenyl]-acetic acid (1 g, 3.00 mmol) in pyridine (15 ml)/N,N-dimethylformamide (15 ml) N,N′-carbonyldiimidazole (0.54 g, 3.31 mmol) was added and the mixture heated to 50° C. for 1 h. At 0° C. propylamine was added. The mixture was stirred at room temperature for 16 h. Then, the mixture was poured into water. The precipitate was collected and dried in a vacuum oven at 70° C. to give the product as a yellow powder (0.89 g, 2.39 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.CN(C(ON1N=[N:37][C:32]2[CH:33]=[CH:34][CH:35]=[N:36][C:31]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.N1CCC[C@@H]1C#N.CN1CCOCC1>C1COCC1>[Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([N:36]3[CH2:35][CH2:34][CH2:33][C@@H:31]3[C:32]#[N:37])=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#C[C@H]1CCCN1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)[C@H](C(=O)N1CCC[C@@H]1C#N)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 16.2 %

Procedure:
(R)-2-(6-Chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (10 mg, 0.032 mmol), HATU (15 mg, 0.039 mmol), (R)-pyrrolidine-2-carbonitrile hydrochloride (4 mg, 0.032 mmol), and N-methylmorpholine (90 μL, 0.097 mmol) were combined in THF (0.5 mL). The reaction mixture was stirred under nitrogen at 40° C. for 10 min and then at room temperature for 30 min. The solution was concentrated and purified by preparative HPLC (10-50% AcCN/H2O with 0.035% TFA) to afford the title compound as a white solid (2 mg, 18%). 1H NMR (500 MHz, CD3OD) δ 0.94 (d, J=6.9 Hz, 3H), 1.06 (d, J=6.3 Hz, 3H), 1.03-1.12 (m, 1H), 2.12-2.17 (m, 2H), 2.25-2.27 (m, 2H), 2.59-2.63 (m, 1H), 3.72-3.74 (m, 1H), 3.83-3.86 (m, 1H), 4.92 (d, J=5.9 Hz, 1H), 5.06 (d, J=13.2 Hz, 1H), 5.46 (d, J=11.8 Hz, 1H), 7.86 (s, 1H), 8.25 (s, 1H). [M+H] calc'd for C19H20ClN5O2, 386; found, 386.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][C@@H:10](C(O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P([N:35]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.C(O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[NH2:35][C@@H:10]1[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][C@H:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@H]1C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Solvent: OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@H](N)CN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
(3R*,5S*)-1-(tert-Butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3-carboxylic acid (575 mg) was suspended in toluene (10 ml), diphenylphosphoryl azide (0.52 ml) and triethylamine (0.34 ml) were added and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was cooled to room temperature, benzyl alcohol (0.52 ml) and triethylamine (0.34 ml) were added and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was washed with water, 5% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate and saturated brine in this order, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure. The obtained residue was dissolved in methanol (5 ml), 10% palladium-carbon (50% containing water) (70 mg) was added, and the mixture was subjected to catalytic reduction at ambient temperature under a hydrogen atmosphere (1 atm) for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (370 mg) as an oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:25]=[CH:24][C:7]([CH2:8][CH2:9][C:10]([NH:12][CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:11])=[CH:6][CH:5]=1)[CH3:2].I[CH2:27][CH2:28][CH3:29].N12CCCC1=NCCC2>O1CCCC1>[CH2:1]([N:3]([CH2:27][CH2:28][CH3:29])[C:4]1[CH:25]=[CH:24][C:7]([CH2:8][CH2:9][C:10]([NH:12][CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:11])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCCI
Reactant: CCNc1ccc(CCC(=O)NC(C(=O)OCC)C(=O)OCC)cc1
Agent: C1CN=C2CCCN2C1
Solvent: C1CCOC1
Product: CCCN(CC)c1ccc(CCC(=O)NC(C(=O)OCC)C(=O)OCC)cc1
Reaction time: 36 h

Procedure:
Working as in Example F, but starting with 10 g of diethyl 4-ethylaminobenzylacetamidomalonate, 5.6 ml of 1-iodopropane and 7.2 ml of 1,5-diazabicyclo-[4.3.0] non-5-ene in 70 ml of tetrahydrofuran, and after reacting for 36 hours followed by purification by flash chromatography (eluent: 97/3 CH2Cl2/MeOH by volume), 2.8 g of a solid are obtained, which solid is recrystallized from 26 ml of cyclohexane. 2.9 g of diethyl 4-(ethylpropylamino)benzylacetamidomalonate are thus obtained in the form of a white solid melting at 84-86° C.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[O:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].ClC1C=C(C=CC=1)C(OO)=[O:31]>C(Cl)Cl>[OH:1][CH:2]([C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[O:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N+:14]=1[O-:31])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCC(O)c1cccc(OCc2ccc3ccccc3n2)c1
Solvent: ClCCl
Product: CCCCCC(O)c1cccc(OCc2ccc3ccccc3[n+]2[O-])c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.9 %

Procedure:
A mixture of 5.0 g (0.015 mol) 2-[3-(1-hydroxyhexyl)phenoxymethyl]quinoline and 3.0 g (0.017 mol) m-chloroperoxybenzoic acid in 100 ml CH2Cl2 was stirred at room temperature for a period of 24 hours. The reaction mixture was extracted with dilute NaHCO3 solution, washed with water, dried over MgSO4 and concentrated to dryness under reduced pressure. The residue was triturated with large amounts of ether to obtain a solid. This solid was filtered, washed with ether and dried to give the desired compound (2 g).
Reaction SMILES: [NH2:1][CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:3]([NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+].[N:35]#[C:36]Br>O.O1CCOCC1>[C:36]([NH:1][CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:3]([NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:35]
Reactant: N#CBr
Reactant: NC(c1ccccc1)C(NC(=O)Nc1ccc(C(F)(F)F)cc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#CNC(c1ccccc1)C(NC(=O)Nc1ccc(C(F)(F)F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of [S--(R*,R*)] and [R--(R*,R*)]-N-(2-amino-1,2-diphenylethyl)-N'-[4-(trifluoromethyl)phenyl]urea (0.3 g, 0.75 mmol) in water (5 mL) and 1,4-dioxane (5 mL) is added solid sodium bicarbonate (0.06 g, 0.75 mmol) followed by cyanogen bromide (0.1 g, 0.75 mmol). The resulting mixture is stirred 1.5 hour at room temperature before diluting with water and filtering. The solid product is washed with water (2×) and t-butyl-methyl ether (2×). Dry in vacuo at 43° C. for 2 hours, mp 153° C. -154° C. IR (KBr) 3350, 2225, 1674, 1554, 1326, 1115, 699 cm-1 ; NMR (DMSO-d6), 4.61 (m, 1H), 5.04 (m, 1H), 7.19 (m, 10H), 7.57 (m, 6H), 9.04 (s, 1H). Analysis calculated for C23H19F3N4O.0.31H2O: C, 64.24; H, 4.60; N, 13.03. Found: C, 64.24; H, 4.60; N, 12.67.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[C:6](#[N:15])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)C>[OH:3][NH:2][C:6](=[NH:15])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NO
Reactant: N#CC=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N=C(/C=C/c1ccccc1)NO
Reaction time: 0.5 h

Procedure:
To a solution of hydroxylamine hydrochloride (690 mg, 10 mmol) in ethanol was added NaOH (400 mg, 10 mmol), followed by cinnamonitrile (1.3 g, 10 mmol). This mixture was heated to reflux for 16 h. The ethanol was removed in vacuo, the residue was acidified with 3M HCl (5 mL) and the solution was boiled for 30 minutes. The cooled solution was made basic (pH 8) with NH4OH, and partitioned between water and ethyl acetate. The organics were concentrated to give a sticky white mass which was used without further purification.
Reaction SMILES: [NH:1]1[CH:5]([C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])[CH2:4][CH2:3][C:2]1=[O:14].C(=O)([O-])[O-].[K+].[K+].[C:21](Cl)(=[O:25])[O:22][CH2:23][CH3:24]>C(#N)C>[CH2:23]([O:22][C:21]([N:11]1[CH2:10][CH2:9][N:8]([C:6]([CH:5]2[NH:1][C:2](=[O:14])[CH2:3][CH2:4]2)=[O:7])[CH2:13][CH2:12]1)=[O:25])[CH3:24]
Reactant: O=C1CCC(C(=O)N2CCNCC2)N1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)N1CCN(C(=O)C2CCC(=O)N2)CC1
Temperature: 0 °C
Yield: 84.3 %

Procedure:
A mixed solution of 2.1 g of 1-(2-pyrrolidone-5-carbonyl)piperazine, 2.5 g of anhydrous potassium carbonate and 120 ml of acetonitrile was cooled with ice water and 1.1 g of ethyl chlorocarbonate in 10 ml of acetonitrile was dropped therein with stirring. After dropping, the mixture was stirred overnight at room temperature. The solvent was evaporated from the reaction mixture in vacuo, methylene chloride was added to the residue, and insoluble matter was removed therefrom by filtration. The solvent was evaporated in vacuo from the filtrate to give 2.3 g of oily product. This was crystallized from ethyl acetate and further recrystallized to give 2.1 g of desired product, m.p. 147°-148.5° C.