Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:2]=1[CH3:3].Cl[C:13]1[C:14](Cl)=[C:15](Cl)[C:16](Cl)=[C:17]2[C:22](=O)[O:21][C:19](=[O:20])[C:18]=12>OCC1CC2CC1C1C2CCC1.CO>[CH:8]1[CH:7]=[C:6]2[CH:5]=[CH:4][C:2]([CH:3]3[C:22](=[O:21])[C:17]4[C:18](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:19]3=[O:20])=[N:1][C:11]2=[CH:10][CH:9]=1
Reactant: Cc1ccc2ccccc2n1
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Agent: OCC1CC2CC1C1CCCC21
Solvent: CO
Product: O=C1c2ccccc2C(=O)C1c1ccc2ccccc2n1
Temperature: 190 °C
Reaction time: 4 h
Yield: 47.5 %

Procedure:
4.3 g of quinaldine and 8.6 g of tetrachlorophthalic anhydride in 100 ml of 8-hydroxymethyltricyclo[5.2.1.02,6 ]decane [TCD alcohol M®, ex Hoechst] are stirred and heated under nitrogen to 190° C. in a 350 ml glass apparatus equipped with cooler, thermometer, gas inlet pipe and semi-anchor stirrer. The mixture is stirred for 4 hours at 190° C. and the resultant yellow suspension is cooled to 40° C., diluted with 150 ml of methanol and filtered. The filter cake is washed with methanol until colourless and the yellow pigment is dried at 80° C in a vacuum drying cabinet, affording 3.9 g of the yellow quinophthalone pigment of formula ##STR2## which is incorporated in powder form into printing inks and varnishes and gives strong, yellow colorations of good fastness properties.
Reaction SMILES: [F-].[K+].[CH2:3]([C:5]1[N:6]([CH:31]2[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:32]2)[N:7]=[C:8]2[C:13](=[O:14])[NH:12][C:11]([C:15]3[C:16]([O:27][CH2:28][CH2:29][CH3:30])=[N:17][CH:18]=[C:19]([C:21]#[C:22][Si](C)(C)C)[CH:20]=3)=[N:10][C:9]=12)[CH3:4]>CN(C)C=O.C(OCC)(=O)C>[CH2:3]([C:5]1[N:6]([CH:31]2[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[CH2:32]2)[N:7]=[C:8]2[C:13](=[O:14])[NH:12][C:11]([C:15]3[C:16]([O:27][CH2:28][CH2:29][CH3:30])=[N:17][CH:18]=[C:19]([C:21]#[CH:22])[CH:20]=3)=[N:10][C:9]=12)[CH3:4]
Reactant: CCCOc1ncc(C#C[Si](C)(C)C)cc1-c1nc2c(CC)n(C3CN(C(=O)OC(C)(C)C)C3)nc2c(=O)[nH]1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#Cc1cnc(OCCC)c(-c2nc3c(CC)n(C4CN(C(=O)OC(C)(C)C)C4)nc3c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Potassium fluoride (0.38 mmol) was added to a stirred solution of the product of stage f) (0.19 mmol) in aqueous N,N-dimethylformamide (2 ml N,N-dimethylformamide/0.2 ml water) at 0° C. After 10 min the reaction was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was diluted with ethyl acetate and washed with water, 1 N hydrochloric acid (3 times) and brine. The organic layer was dried (MgSO4) and concentrated to give the title compound as a solid; 1H NMR (400MHz, CDCl3): δ=1.05 (t, 3H), 1.30 (t, 3H), 1.43 (s, 9H), 1.88-2.00 (m, 2H), 2H), 3.19 (s, 1H), 4.35 (app t, 2H), 4.52 (app t, 2H), 4.60-4.80 (br s, 2H), 5.22 (t, 1H), 8.39 (s, 1H), 8.80 (s, 1H), 10.75 (br s, 1H); LRMS (TSP—positive ion) 496 (MNH4+).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].C(N(CC)CC)C.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[C:16]([O:7][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:8])[CH:1]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cccc(O)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(OC(=O)c2ccccc2)c1
Temperature: 25 °C

Procedure:
To a chilled (0°-5° C.) solution of 5.0 g (0.046 mol) of m-cresol in 20 mL of methylene chloride containing 5.16 g (0.051 mol) of triethylamine was added dropwise a solution containing 6.47 g (0.046 mol) of benzoyl chloride in 20 mL of methylene chloride. A precipitate formed upon addition. The reaction mixture was stirred several hours at room temperature and was then filtered. The filtrate was washed with water (25 mL) and then with brine (25 mL). The organic phase was removed and dried over magnesium sulfate, filtered and evaporated to dryness in a rotary evaporator. The crude product amounted to 9.66 g. An analytical sample (m.p. 51°-54° C.) was obtained by recrystallization from petroleum ether.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[NH2:4].[OH-].[Na+].[Cl-].[C:16]([NH3+])(C)(C)C.S(OC)(OC)(=O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[NH:4][CH3:16]
Reactant: CC(C)(C)[NH3+]
Reactant: Nc1c([N+](=O)[O-])ccc(Cl)c1Cl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Product: CNc1c([N+](=O)[O-])ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2,3-dichloro-6-nitroaniline (1.026 g, 5 mmole), was suspended in toluene (10 ml). To this vigorously stirred suspension was added 50% aqueous sodium hydroxide solution (1.7 g), tertiary-butyl ammonium chloride (0.07 g, 0.25 mmole) and dimethyl sulfate (0.51 ml, 5.4 mmole). After 4 hr stirring at room temperature the intense red solution was washed with water, brine, dried with magnesium sulfate, filtered, evaporated in vacuo. Weight=1.03 g, m.p.=82° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)[CH:5]=[N:4][CH:3]=[N:2]1.CN(C=O)C.[H-].[Na+].[CH2:28](Br)[CH3:29]>O>[CH2:28]([N:16]1[C:17]2[C:12](=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)=[CH:19][CH:18]=2)[CH2:13][CH2:14][C:15]1=[O:20])[CH3:29]
Reactant: CCBr
Reactant: O=C1CCc2cc(OCCCn3cncn3)ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1C(=O)CCc2cc(OCCCn3cncn3)ccc21
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 2 g (7.35 mM) of 6-[3-(1,2,4-triazol-1-yl)propoxy]-3,4-dihydrocarbostyril with 20 ml of DMF was added 350 mg (8.8 mM) of sodium hydride (60% in oil) and the mixture was heated at 60° C. for 30 minutes. Then under ice-cooling condition, 0.6 ml (8.1 mM) of ethyl bromide was added dropwise, further the reaction mixture was stirred at room temperature for 3 hours. To the reaction mixture was added water, then extracted with chloroform, the chloroform layer was washed with water, dried with anhydrous sodium sulfate, and concentrated by removing the solvent by evaporation. The resulting residue was purified by means of a silica gel column chromatography (eluent: dichloromethane:methanol=30:1), then recrystallized from ethyl acetate-n-hexane to yield 1.8 g of 1-ethyl-6-[3-(1,2,4-triazol-1 -yl)propoxy]-3,4-dihydrocarbostyril. Colorless needle-like crystals. Melting point: 97.0°-98.0° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)=O)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[CH3:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH:42]N>>[CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:38]4[C:37](=[C:36]([CH3:35])[CH:41]=[CH:40][CH:39]=4)[NH:42][C:22]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc([N+](=O)[O-])c3)CC2)c1
Reactant: Cc1ccccc1NN
Agent: Cl
Product: Cc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3cccc([N+](=O)[O-])c3)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-(3-{1-[5-(3-nitrophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)propanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 539.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]3=[O:18])[CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:19].[F:20][C:21]([F:30])([F:29])[C:22]1[CH:23]=[C:24]([CH2:27]O)[S:25][CH:26]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1COCC1>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:27][C:24]4[S:25][CH:26]=[C:22]([C:21]([F:30])([F:29])[F:20])[CH:23]=4)=[CH:13][C:12]3=[O:18])[CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:19]
Reactant: Cc1nc2ccc(-n3ccc(O)cc3=O)cc2n1C
Reactant: OCc1cc(C(F)(F)F)cs1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1nc2ccc(-n3ccc(OCc4cc(C(F)(F)F)cs4)cc3=O)cc2n1C
Temperature: 50 °C
Reaction time: 8 h
Yield: 39.3 %

Procedure:
To a suspension of 1-(1,2-dimethyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (200 mg) in THF (5 ml) were added (4-(trifluoromethyl)thiophen-2-yl)methanol (157 mg), 1,1′-(azodicarbonyl)dipiperidine (257 mg) and tributylphosphine (0.25 ml) at room temperature, and the mixture was stirred at 50° C. overnight. After cooling, the mixture was purified by NH silica gel column chromatography (EtOAc/MeOH), followed by preparative HPLC (C18, mobile phase: H2O/CH3CN (0.1% TFA included)). The desired fraction was neutralized with saturated NaHCO3 solution, and extracted with EtOAc. The organic layer was separated, dried over MgSO4 and concentrated in vacuo to give the title compound (129 mg) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[C:4]([CH3:10])[N:3]=1.Cl.[F:12][C:13]1([F:20])[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][CH:16]2[CH2:17][CH2:18][C:13]([F:20])([F:12])[CH2:14][CH2:15]2)[C:5]([CH3:9])=[C:4]([CH3:10])[N:3]=1
Reactant: NC1CCC(F)(F)CC1
Reactant: Cc1nc(Cl)nc(Cl)c1C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)nc(NC2CCC(F)(F)CC2)c1C
Temperature: 50 °C
Yield: 68.2 %

Procedure:
To the solution of 2,4-dichloro-5,6-dimethylpyrimidine (0.585 g, 3.304 mmol) in N,N-dimethylformamide (10 mL), (4,4-difluorocyclohexyl)amine hydrochloride (0.652 g, 3.800 mmol) and triethylamine (1.338 g, 13.218 mmol) were added, and reaction mixture was heated at 50° C. overnight. Volatiles were removed under reduced pressure, and the residue was poured into water (300 mL). The product was extracted with ether (3×50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica eluting with a mixture of hexane/ethyl acetate (gradient 4:1-2:1) to provide 621 mg (68%) of the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.18-1.24 (m, 1H), 1.60-1.72 (m, 2H), 1.80-2.10 (m, 8H) 2.21 (s, 3H), 4.00-4.10 (m, 1H), 6.73 (d, J=7.79 Hz, 1H); MS (ESI) m/z 318.6 (M+1)+.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH3:7])[C@:5]([CH2:14][OH:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4](=[O:16])[N:3]1[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=1.[CH3:29][C:30]([CH3:43])([O:32][C:33]([NH:35][C@@H:36]([CH:40]([CH3:42])[CH3:41])[C:37](O)=[O:38])=[O:34])[CH3:31].Cl.CN(C)CCCN=C=NCC.O>CN(C)C1C=CN=CC=1.ClCCl>[C:21]([C:20]1[CH:23]=[CH:24][C:17]([N:3]2[C:4](=[O:16])[C@@:5]([CH2:14][O:15][C:37](=[O:38])[C@@H:36]([NH:35][C:33]([O:32][C:30]([CH3:29])([CH3:43])[CH3:31])=[O:34])[CH:40]([CH3:42])[CH3:41])([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:6]([CH3:7])[C:2]2=[O:1])=[CH:18][C:19]=1[C:25]([F:28])([F:26])[F:27])#[N:22]
Reactant: CN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)[C@@]1(CO)c1ccccc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OC[C@@]1(c2ccccc2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C

Procedure:
A solution of 0.45 g of (S)-4-[2,5-dioxo-4-(hydroxymethyl)-3-methyl-4-phenylimidazolidin-1-yl]-2-trifluoromethylbenzonitrile, 0.33 g of (2S)-2-[(1,1-dimethylethoxy)carbonylamino]-3-methylbutanoic acid, 0.185 g of 4-dimethylamino pyridine and 0.45 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 70 mL of dichloromethane is stirred for 1 hour then poured into water and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and evaporated. The crude product is purified by chromatography over silica gel while eluting with 70/30 heptane/ethyl acetate mixture to provide the desired compound.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7]O.C(O[CH:12]=[C:13]([C:30]([C:32]1([CH3:35])[CH2:34][CH2:33]1)=[O:31])[C:14]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][C:17]=1[C:26]([F:29])([F:28])[F:27])=[O:15])C>>[CH3:25][S:22]([C:19]1[CH:20]=[CH:21][C:16]([C:14]([C:13]2[CH:12]=[N:7][O:31][C:30]=2[C:32]2([CH3:35])[CH2:34][CH2:33]2)=[O:15])=[C:17]([C:26]([F:29])([F:28])[F:27])[CH:18]=1)(=[O:24])=[O:23]
Reactant: NO
Reactant: CCOC=C(C(=O)c1ccc(S(C)(=O)=O)cc1C(F)(F)F)C(=O)C1(C)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: CC1(c2oncc2C(=O)c2ccc(S(C)(=O)=O)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
Sodium acetate (1.0 g) was added to a stirring mixture of hydroxylamine hydrochloride (0.85 g) and 2-ethoxymethylene-1-(4-methylsulphonyl-2-trifluoromethylphenyl)-3-(1-methylcyclopropyl)-propane-1,3-dione (4.2 g) in industrial methylareal spirit (200 ml). The mixture was stirred at room temperature for 3 hours. The mixture was evaporated to dryness and then suspended in ethyl acetate (100 ml). The resultant suspension was washed with water (100 ml), dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 4-(4-methylsulphonyl-2-trifluoromethylbenzoyl)-5-(1-methylcyclopropyl) isoxazole (compound 99, 3.5 g) as a white Solid, m.p. 141°-142° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].[N-:28]=[N+:29]=[N-:30].[Na+].O>CN(C)C=O>[N:28]([CH2:2][C:3]([N:5]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4])=[N+:29]=[N-:30]
Reactant: COc1ccccc1CN(C(=O)CCl)c1ccccc1Oc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1CN(C(=O)CN=[N+]=[N-])c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
A solution of 1.51 g of N-chloroacetyl-N-(2-methoxybenzyl)-2-phenoxyaniline synthesized in the same manner as in Example 1 and 770 mg of sodium azide in 10 ml of dimethylformamide was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with 5% hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate−hexane=1:4) to give 1.55 g of N-azidoacetyl-N-(2-methoxybenzyl)-2-phenoxyaniline as an oil.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([OH:9])[CH2:7][Cl:8])(=[O:3])[CH3:2].[CH:10]([O:12][CH2:13][CH3:14])=[CH2:11].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[C:1]([O:4][CH2:5][CH:6]([O:9][CH:10]([O:12][CH2:13][CH3:14])[CH3:11])[CH2:7][Cl:8])(=[O:3])[CH3:2]
Reactant: C=COCC
Reactant: CC(=O)OCC(O)CCl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(C)OC(CCl)COC(C)=O
Yield: 97.9 %

Procedure:
A solution of 30.5 g (0.20 mol) of 3-chloro-2-hydroxy-1-propyl acetate (prepared in Example 1), 22 g (0.30 mol) of ethyl vinyl ether, and 7.5 g (0.030 mol) of pyridinium p-toluenesulfonate in 150 mL of methylene chloride was stirred at room temperature for 6 hours. The solution was then washed with 75 mL of water, dried and stripped of solvent in vacuo to give 44.0 g (98.0%) of 3-chloro-2-(1-ethoxyethoxy)-1-propyl acetate: 1H NMR (CDCl3) δ1.05-1.37 (overlapping t and d, 6H, --CH2CH3 and --CHCH3); 2.07 (s, 3H, --COCH); 3.53 and 4.12 (m. 7H, --CH2CHCH2 and --CH2CH3); 4.72 (q, J=4 Hz, 1H, --CHCH3); IR (film) 1740 cm-1 (--COCH3 ). The unpurified product was used in the next step.
Reaction SMILES: [C:1]([O:7][C@H:8]([CH2:20][C@H:21]1[C@H:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:23](=[O:31])[O:22]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:6])[CH2:2][C:3]([OH:5])=O.CN(C(O[N:40]1N=N[C:42]2C=CC=[CH:46][C:41]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)(C)C>C(#N)C>[CH2:25]([C@@H:24]1[C:23](=[O:31])[O:22][C@H:21]1[CH2:20][C@@H:8]([O:7][C:1](=[O:6])[CH2:2][C:3]([NH:40][CH:41]([CH3:46])[CH3:42])=[O:5])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCCCCCCCCCC[C@@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)OC(=O)CC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CC(C)N
Product: CCCCCCCCCCC[C@@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)OC(=O)CC(=O)NC(C)C
Yield: 84.9 %

Procedure:
A solution of 33.5 mg of (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl hydrogen malonate (Example N) in 2 ml of acetonitrile was treated with 60 mg of HBTU and 75 mg of iso-propylamine. After stirring the reaction mixture was filtered, the filtrate was concentrated and the residue was chromatographed on silica gel with hexane/methylene chloride/ethyl acetate (2:2:1). There were obtained 31.1 mg of (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl-N-isopropylmalonamate, m.p. 59°.
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:27]2([CH2:32][NH2:33])[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:33][CH2:32][C:27]2([C:21]3[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:19]([O:18][CH3:17])[CH:20]=3)[CH2:28][CH2:29][CH2:30][CH2:31]2)=[O:14])=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(Cc2ccccc2)cc1
Reactant: COc1ccc(C2(CN)CCCC2)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(C2(CNC(=O)c3ccc(Cc4ccccc4)cc3)CCCC2)cc1OC
Reaction time: 16 h
Yield: 56.1 %

Procedure:
4-Benzyl-benzoic acid (21.2 mg, 0.100 mmol) and C-[1-(3,4-Dimethoxy-phenyl)-cyclopentyl]-methylamine (23.5 g, 0.100 mmol) were dissolved in acetonitrile (1 mL) containing triethylamine (41.8 μL, 0.300 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (38.0 mg, 0.100 mmol) was added and the solution was allowed to stir for 16 hours. The mixture was then purified by reverse phase preparative liquid chromatography to yield the pure product (24.1 mg, 0.0561 mmol, 56.1%) ESI-MS m/z calc. 429.2, found 430.4 (M+1)+. Retention time of 3.75 minutes.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH:4]([CH2:9][C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1>>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5]2[N:18]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][C:4]=2[CH2:3]1
Reactant: CC1CCC(=O)C(CC(=O)c2ccccc2)C1
Reactant: Nc1ccc(C(=O)O)cc1
Product: CC1CCc2c(cc(-c3ccccc3)n2-c2ccc(C(=O)O)cc2)C1
Yield: 73 %

Procedure:
Following the general methods as outlined under Intermediate 13, starting from 4-methyl-2-(2-oxo-2-phenylethyl)cyclohexanone and 4-aminobenzoic acid, the title compound was isolated in 73% yield (95% purity by HPLC). MS(ESI+): 332.5; MS(ESI−): 330.4.
Reaction SMILES: [CH2:1](OC(=O)C1C=CC(CC)=CC=1)[CH3:2].Cl[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:25]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][N:42]([CH2:45][CH3:46])[CH2:43][CH3:44])=[CH:35][CH:34]=4)[N:27]=3)=[CH:24][NH:23][N:22]=2)=[CH:17][CH:16]=1>>[CH2:43]([N:42]([CH2:45][CH3:46])[CH2:41][CH2:40][O:39][C:36]1[CH:37]=[CH:38][C:33]([NH:32][C:28]2[N:27]=[C:26]([C:25]3[C:21]([C:18]4[CH:19]=[CH:20][C:15]([CH2:1][CH3:2])=[CH:16][CH:17]=4)=[N:22][NH:23][CH:24]=3)[CH:31]=[CH:30][N:29]=2)=[CH:34][CH:35]=1)[CH3:44]
Reactant: CCOC(=O)c1ccc(CC)cc1
Reactant: CCN(CC)CCOc1ccc(Nc2nccc(-c3c[nH]nc3-c3ccc(Cl)cc3)n2)cc1
Product: CCc1ccc(-c2n[nH]cc2-c2ccnc(Nc3ccc(OCCN(CC)CC)cc3)n2)cc1

Procedure:
The title compound is prepared as described in Example 1 using 4-ethyl-benzoic acid ethyl ester (see Example 11) and 4-(2-diethylamino-ethoxy)-phenylamine (see Example 3).
Reaction SMILES: [CH3:1][NH:2][NH2:3].C([O-])([O-])=O.[K+].[K+].C(O[CH:13]=[C:14]([C:20]([CH:22]([F:24])[F:23])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>O.C1(C)C=CC=CC=1>[F:23][CH:22]([F:24])[C:20]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:2]([CH3:1])[N:3]=1
Reactant: CNN
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cn(C)nc1C(F)F
Temperature: -5 °C
Reaction time: 1.5 h
Yield: 82.6 %

Procedure:
40% Methylhydrazine (565 g, 4.91 moles) in aqueous solution and K2CO3 (237 g, 1.72 moles) are dissolved in water (2134 g) and mixed to make a clear solution. Toluene (2292 g) is added to make a two phase system, and then cooled to −10-0° C. Crude ethyl 2-ethoxymethylenedifluoroacetoacetate (Formula VI) (˜1010 g, ˜4.91 moles) in toluene (1500 g) is then added dropwise with effective agitation while maintaining at the same temperature. The agitation is kept constant for 1-2 hours until GC shows the content of ethyl 2-ethoxymethylenedifluoroacetoacetate <0.2%. Two phases are separated and the organic phase is concentrated until GC shows toluene content <5%. A mixture of toluene (757 g) and petroleum ether (3028 g) (bp. 60-90° C.) is added in and then heated up to 50-60° C. to make a solution. The yellowish solid precipitated after the solution is slowly cooled down to 10-15° C. The solid is collected by filtration and dried in a vacuum oven to give a yellowish solid (828 g, Yield=82.5%). The product only contains 0.01% of the positional isomer of formula XI and 0.01% of the des-difluoro-impurity of Formula XII.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[CH:13][N:14](C)[C:10]=2[C:9]=1[C:18]#[N:19].Cl.[N:21]([O-])=O.[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[N:21][N:14]([CH3:13])[C:10]=2[C:9]=1[C:18]#[N:19]
Reactant: Cn1cnc2ccc(-c3ccccc3Cl)c(C#N)c21
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1nnc2ccc(-c3ccccc3Cl)c(C#N)c21
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
The intermediate of Example 8B (126 mg, 0.49 mmol) was stirred in THF (3 mL) with water (2 mL) and 1N HCl (1 mL) at 0° C. Sodium nitrite (37 mg, 0.54 mmol) in water (0.5 mL) was added dropwise, and the reaction stirred for 30 min. The solution was quenched with sat. NaHCO3 solution and extracted with EtOAc. Organics were dried (MgSO4) and concentrated in vacuo. Purification by silica gel chromatography (40% EtOAc/hexanes) gave 102 mg (78%) of the title compound as a pale orange solid. 1H NMR (400 MHz, CDCl3): δ 8.31 (d, 1H, J=8.4 Hz), 7.39-7.58 (m, 5H), 4.61 (s, 3H). MS (ES) [m+H] calc'd for C14H9N4Cl, 269, 271; found 269, 271.