Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[S:9])([S-:8])[S:2][CH2:3][CH2:4][O:5][CH2:6][CH3:7].[K+].[CH2:11]([S:13][CH:14]1[N:17]([CH:18](Cl)[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[C:16](=[O:33])[CH2:15]1)[CH3:12]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl>[CH2:11]([S:13][CH:14]1[N:17]([CH:18]([S:9][C:1]([S:2][CH2:3][CH2:4][O:5][CH2:6][CH3:7])=[S:8])[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[C:16](=[O:33])[CH2:15]1)[CH3:12]
Reactant: CCOCCSC(=S)[S-]
Reactant: CCSC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Product: CCOCCSC(=S)SC(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1SCC
Reaction time: 1 h
Yield: 30.9 %

Procedure:
A solution of 3.58 g potassium 2-ethoxyethyl trithiocarbonate and 3.7 g benzyltriethylammonium chloride in 100 ml methylene chloride was cooled to 0° C. under a nitrogen atmosphere and a solution of 5.3 g of p-nitrobenzyl 2-(4-ethylthio-2-oxo-1-azetidinyl)-2-chloroacetate in 50 ml methylene chloride was added dropwise. The reaction mixture was stirred for 1 hour, then washed with three 50 ml portions of water, dried over anhydrous sodium sulfate and concentrated in vacuo to an oil. (8.6 g). The crude product was chromatographed on silica gel eluting with 5% ethyl acetate in chloroform to yield 2.3 g of the title compound as an oil. The IR spectrum of a chloroform solution of the title compound had an absorption at 5.65 micron; and the NMR spectrum in deuterochloroform showed peeks at 1.2(m,6H);2.34-3.77(c,10H);4.7,4.98(m,1H); 5.26(s,2H); 6.62,6.86(s,1H); 7.43(m,2H); and 8.16(m,2H). ppm.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH:7]([CH2:22][CH3:23])[C:8]([C:10]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]3[C:11]=2[CH2:12][CH2:13][C:14](=[O:21])[NH:15]3)=[O:9])[CH2:3][CH2:2]1.Br.[H][H]>O.[Pd]>[O:1]1[CH2:6][CH2:5][N:4]([CH:7]([CH2:22][CH3:23])[CH:8]([C:10]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]3[C:11]=2[CH2:12][CH2:13][C:14](=[O:21])[NH:15]3)[OH:9])[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: CCC(C(=O)c1ccc(O)c2c1CCC(=O)N2)N1CCOCC1
Agent: [Pd]
Agent: Br
Solvent: O
Product: CCC(C(O)c1ccc(O)c2c1CCC(=O)N2)N1CCOCC1
Yield: 69.6 %

Procedure:
1.0 g of 5-(2-morpholinobutyryl)-8-hydroxy-3,4-dihydrocarbostyril (IIb) hydrobromide was dissolved in 70 ml of water and 0.2 g of palladium-on-carbon and 0.3 g of palladium black were added to the solution followed by allowing the mixture to catalytically reduce under atmospheric pressure in a hydrogen atmosphere for 10 days at a temperature of 70° C while shaking. After completion of the reduction, the reaction mixture was filtered to remove the catalysts by filtration, and the filtrate was concentrated to dryness under reduced pressure. The resulting residue was dissolved in acetone by heating followed by allowing the solution to cool. The precipitate formed upon cooling was recrystallized from ethanol to obtain 0.7 g of white amorphous 5-(2-morpholino-1-hydroxybutyl)-8-hydroxy-3,4-dihydrocarbostyril (I) hydrobromide 1/2 hydrate having a melting point of 183° - 185° C (with decomposition). The product thus obtained was confirmed by NMR and IR spectral analyses and elemental analysis.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:18][CH3:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[CH2:20]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)[CH2:27][CH2:26]1)[CH2:21][CH2:22][CH2:23][CH3:24]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH2:20]([C@H:25]1[CH2:26][CH2:27][C@H:28]([CH2:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([O:39][C:13](=[O:14])[C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]([CH3:1])[CH2:18][CH3:19])=[CH:17][CH:16]=3)=[CH:37][CH:38]=2)[CH2:29][CH2:30]1)[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CC[C@H](C)CCCCCOc1ccc(C(=O)Cl)cc1
Reactant: CCCCC[C@H]1CC[C@H](CCc2ccc(O)cc2)CC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCC[C@H]1CC[C@H](CCc2ccc(OC(=O)c3ccc(OCCCCC[C@@H](C)CC)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude (S)-4-(6-methyloctyloxy)benzoyl chloride obtained was dissolved in 20 ml of toluene and then added dropwise to a solution of 0.26 g of 4-[2-(trans-4-pentylcyclohexyl)ethyl]phenol in 2 ml of pyridine. The reaction mixture was stirred at room temperature overnight, then poured into ice-water and extracted with diethyl ether. The extract was washed four times with 25 ml of 3N hydrochloric acid each time, then washed with 25 ml of 2N sodium carbonate solution and several times with water, dried over magnesium sulphate and concentrated. Chromatography of the residual oil on silica gel with toluene gave 0.2 g of (S)-4-(6-methyloctyloxy)benzoic acid 4-[2-(trans-4-pentylcyclohexyl)ethyl]phenyl ester. The product was recrystallized several times from ethanol until the phase transition temperatures were constant. M.p. (C-S) 58°, transition S-S*C 58.5° C., transition S*C -Ch 93° C., cl.p. (Ch-I) 140° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@H:10]([NH:11][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH2:9][CH2:8][N:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6]1)=[O:4].[C:27](=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([O:2][C:3]([C@H:5]1[C@H:10]([NH:11][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH2:9][CH2:8][N:7]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:6]1)=[O:4])[CH3:27]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N[C@H](C)c1ccccc1
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N[C@H](C)c1ccccc1
Yield: 22.6 %

Procedure:
In a dry flask (3S,4R)-4-[(R)-1-phenyl-ethylamino]-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (13.78 g, 38.0 mmol) was dissolved in ethanol (400 mL) along with 3 Å molecular sieves (1.04 g). The mixture was heated to reflux over 2.5 hours. Potassium carbonate (26.3 g) was added and refluxing continued for 4 additional hours. The reaction mixture was cooled, filtered through a bed of celite, and concentrated in vacuo to give a crude oil (16.05 g). Purification by flash column chromatography (20-50% ethyl acetate/hexanes) provided a colorless oil (3.24 g, 23%). Unepimerized ethyl ester was also isolated (7.55 g, 53%). 1H NMR (300 MHz, CDCl3), δ: 7.30 (m, 4H), 7.23 (m, 1H), 4.20 (m, 3H), 3.97 (bs, 1H), 3.82 (q, 1H, J=6), 2.89 (m, 2H), 2.66 (t, 1H, J=11), 2.31 (bs, 1H), 1.72 (m, 1H), 1.43 (s, 9H), 1.31 (m, 7H), 1.11 (m, 1H).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C([NH2:16])CCC>ClCCl>[C:1]([O-:6])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([NH2:16])=[O:5].[NH4+:16]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCCCN
Solvent: ClCCl
Product: NC(=O)c1ccccc1C(=O)[O-]
Product: [NH4+]
Reaction time: 0.17 h
Yield: 72.1 %

Procedure:
A heterogenous mixture of phthalic anhydride (10.0 g, 67.5 mmol) and 100 mL of dichloromethane was cooled in an ice bath. n-Butyl amine (12.345 g, 168.78 mmol) was added dropwise. The temperature was not allowed to rise above 15° C. during the addition. When a small amount of the amine had been added a homogenous solution resulted. After a short time, a white precipitate formed. As more amine was added, the precipitate redissolved and a solution again formed. Upon completion of the addition the reaction was allowed to stir in an ice bath for 10 minutes. A white precipitate again formed. The mixture was allowed to stir at 0° C. for 50 minutes and at room temperature for 10 minutes. The precipitate was filtered off and washed with a small amount of dichloromethane. Washing with hexanes and drying in air afforded 8.86 g of compound AM-1. NMR was in agreement with the proposed structure.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[N:8][C:7]([C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11])=[CH:6][CH:5]=1)[CH3:2].[Cl:17][C:18]1[CH:23]=C[C:21]([OH:24])=[CH:20][CH:19]=1.F[C:26](F)(F)[C:27](O)=O>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[C:2]([CH:23]=1)[CH2:1][N:3]([C:4]1[N:9]=[N:8][C:7]([C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11])=[CH:6][CH:5]=1)[CH2:26][CH3:27]
Reactant: CCCCOC(=O)c1ccc(NCC)nn1
Reactant: O=C(O)C(F)(F)F
Reactant: Oc1ccc(Cl)cc1
Product: CCCCOC(=O)c1ccc(N(CC)Cc2cc(Cl)ccc2O)nn1

Procedure:
The title compound was prepared from butyl 6-(ethylamino)pyridazine-3-carboxylate and 4-chlorophenol using a similar method to that of reference example 3, except 0.4 equivalents of trifluoroacetic acid were added to the reaction mixture.
Reaction SMILES: C(C1(C(O)=O)[CH2:8][CH2:7][CH:6]([CH:9]([CH3:11])[CH3:10])[CH2:5][CH2:4]1)C.[Li]C.[CH3:17][C:18]([CH3:20])=[O:19].[CH2:21]1[CH2:26]NC(=O)C1.[Br:27][Br-]Br>C(OCC)C.CO>[Br:27][CH2:17][C:18]([C:20]1([CH2:26][CH3:21])[CH2:4][CH2:5][CH:6]([CH:9]([CH3:10])[CH3:11])[CH2:7][CH2:8]1)=[O:19]
Reactant: CC(C)=O
Reactant: CCC1(C(=O)O)CCC(C(C)C)CC1
Reactant: O=C1CCCN1
Agent: [Li]C
Solvent: CCOCC
Solvent: CO
Product: CCC1(C(=O)CBr)CCC(C(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
1-Ethyl-4-isopropyl-cyclohexanecarboxylic acid (800 mg, 4.7 mmol) in ethyl ether (about 20 mL) at 0° C. was treated with MeLi (5.5 mL in ethyl ether; 8.8 mmol) and stirred overnight at RT following a method analogous to General Procedure A1 to generate the corresponding methyl ketone (600 mg) after quenching the reaction with water, aq extractive workup, evaporation of the solvent and purification of the crude ketone. The resulting ketone (600 mg, 3 mmol) was treated with pyrrolidone hydrotribromide (1.6 g, 3.3 mmol) in MeOH (10 mL) and stirred at RT overnight following a method analogous to General Procedure B1 to produce 2-bromo-1-(1-ethyl-4-isopropyl-cyclohexyl)-ethanone (600 mg, 55% overall yield for two steps) after evaporation of the solvent, extractive workup with EtOAc and aq sodium bicarbonate, drying of the organic portion and removal of the solvent under vacuum.
Reaction SMILES: [N:1]1([CH:6]2[CH2:15][CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)/[C:7]/2=[N:16]\[OH:17])[CH:5]=[CH:4][N:3]=[CH:2]1.CCCCC.[H-].[Na+].[CH2:25]([O:27][C:28](=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32]Br)[CH3:26]>CN(C=O)C>[CH2:25]([O:27][C:28](=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32][O:17]/[N:16]=[C:7]1/[CH:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:15][CH2:14][C:13]2[C:8]/1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:26]
Reactant: O/N=C1\c2ccccc2CCC1n1ccnc1
Reactant: CCOC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: CCOC(=O)CCCCO/N=C1\c2ccccc2CCC1n1ccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(+-)-(E)-2-(1H-imidazol-1-yl)-1,2,3,4-tetrahydronaphtalen-1-one oxime (500 mg; 2.2 mmoles) dissolved in dry DMF (27 ml) is added, under dry nitrogen atmosphere, to a pentane-washed sodium hydride suspension (160 mg NaH 55%; 3.6 mmoles), in dry DMF (10 ml). The resulting reaction mixture is stirred at r.t. for 2 hours. Then ethyl-5-bromopentanoate (0.530 ml; 3.3 mmoles) is added at r.t. and the reaction mixture is stirred at r.t. for 3 hrs., the solvent evaporated in vacuo, and the residue carefully taken up with ice-cooled water and extracted with ethyl acetate. The collected organic phases are dried over Na2SO4 and evaporated to give an oily crude material which is chromatographed over silica gel. By eluting with CH2Cl2 /MeOH (95:5), the pure title compound is obtained as a slight yellow oil (250 mg). 1H-NMR (200MH2, CDCl3) ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[NH:7][CH:8]([CH2:36][C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)[C:9]([N:11]1[CH2:16][CH2:15][C:14]([C:27](=[O:35])[NH:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])([CH3:4])([CH3:3])[CH3:2].C(O)C.[H][H]>O1CCCC1.[Pd]>[C:1]([O:5][C:6](=[O:42])[NH:7][C@@H:8]([CH2:36][C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)[C:9]([N:11]1[CH2:12][CH2:13][C:14]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=2)([C:27](=[O:35])[NH:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:15][CH2:16]1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(Cc1cccs1)C(=O)N1CCC(Cc2ccc([N+](=O)[O-])cc2)(C(=O)NC2CCCCC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)N1CCC(Cc2ccc(N)cc2)(C(=O)NC2CCCCC2)CC1

Procedure:
To a solution of {2-[4-Cyclohexylcarbamoyl-4-(4-nitro-benzyl)-piperidin-1-yl]-2-oxo-1-thiophen-2-ylmethyl-ethyl}-carbamic acid tert-butyl ester (9.77 mmol; 5.85 g) (prepared as in Example 1, substituting 4-nitrobenzylbromide for 4-biphenylmethyl bromide and cyclohexylamine for cyclohexylmethylamine), in tetrahydrofuran (20 mL) and ethanol (40 mL) was added 10% palladium on carbon (2 g), and the resulting mixture was hydrogenated under 50 psi of hydrogen pressure overnight at room temperature. The catalyst was removed via filtration, and the filtrate was evaporated to yield (S)-{2-[4-(4-aminobenzyl)-4-cyclohexylcarbamoyl-piperidin-1-yl]-2-oxo-1-thiophen-2-ylmethyl-ethyl}-carbamic acid tert-butyl ester. MS (ESI) m/z 569.40 [M+H]+.
Reaction SMILES: [F:1][C:2]1([F:16])[C:7](O)(O)[CH2:6][CH2:5][N:4](C(=O)C(F)(F)F)[CH2:3]1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([BH3-])#N.[Na+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:17]([NH:24][CH:7]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1([F:1])[F:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(N1CCC(O)(O)C(F)(F)C1)C(F)(F)F
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: FC1(F)CNCCC1NCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.5 %

Procedure:
In a 100 mL flask, 2.00 g (8.0 mmol) of 3,3-difluoro-4,4-dihydroxy-1-trifluoroacetylpiperidine 13 (J. Org Chem. 2010, 75, 929-932) and 2.15 g (20.0 mmol; 2.5 equiv) of benzylamine were dissolved in 50 mL of toluene. The mixture was heated under reflux with a Dean Stark trap during 15 hours. After cooling to room temperature, the solvent was removed in vacuo. The resulting oil was dissolved in 25 mL of absolute methanol and 0.56 g (8.8 mmol; 1.1 equiv) of sodium cyanoborohydride and 0.48 g (8.0 mmol; 1 equiv) of acetic acid were slowly added at room temperature. The solution was stirred during 4 hours at room temperature. After removing the solvent under vacuum, the crude oil was redissolved in 50 mL of dichloromethane and poured in 50 mL of a saturated aqueous NaHCO3 solution and was subsequently extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine and dried over MgSO4. Filtration of the solids and evaporation of the solvent resulted in a crude oil which was purified via flash chromatography (EtOAc, Rf=0.03) yielding 1.32 g (5.8 mmol; 73% yield) of benzyl-(3,3-difluoro-piperidin-4-yl)amine 14 as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[CH2:23]([N:25]1[CH2:30][CH2:29][C:28]2([C:41]3[C:33](=[CH:34][C:35]4[CH2:36][CH2:37][NH:38][C:39]=4[CH:40]=3)[O:32][CH2:31]2)[CH2:27][CH2:26]1)[CH3:24].C(N(CC)CC)C>S(Cl)(Cl)=O.C1COCC1>[CH2:23]([N:25]1[CH2:30][CH2:29][C:28]2([C:41]3[C:33](=[CH:34][C:35]4[CH2:36][CH2:37][N:38]([C:20]([C:17]5[CH:16]=[CH:15][C:14]([C:3]6[CH:4]=[CH:5][C:6]([C:8]7[O:9][C:10]([CH3:13])=[N:11][N:12]=7)=[CH:7][C:2]=6[CH3:1])=[CH:19][CH:18]=5)=[O:22])[C:39]=4[CH:40]=3)[O:32][CH2:31]2)[CH2:27][CH2:26]1)[CH3:24]
Reactant: CCN1CCC2(CC1)COc1cc3c(cc12)NCC3
Reactant: Cc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)o1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN1CCC2(CC1)COc1cc3c(cc12)N(C(=O)c1ccc(-c2ccc(-c4nnc(C)o4)cc2C)cc1)CC3
Temperature: 45 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
A stirred suspension of 2'-methyl-4'-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl-4-carboxylic acid (D11, 0.53 g, 1.8 mmole) in thionyl chloride (8 ml) was heated at about 45° C. for 30 minutes, then concentrated in vacuo. The yellow solid was dissolved in THF (10 ml)/dichloromethane (5 ml) and added to a stirred solution of 1'-ethyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D109, 0.46 g, 1.8 mmole) and triethylamine (0.50 ml, 3.6 mmole) in THF (15 ml) at 5° C. under argon. The solution was stirred at room temp. for 2 h, then concentrated in vacuo. The residue was treated with 10% Na2CO3 solution and extracted with ethyl acetate. The extract was dried (Na2SO4), concentrated in vacuo and the residue chromatographed on silica gel eluting with 3% methanol/chloroform and the yellow oil obtained passed through a short basic alumina column eluting with ethyl acetate to afford the title compound as a beige foam (0.62 g, 68%). This was converted to its hydrochloride (mp 269-273° C.) and mesylate (mp 275-279° C.) salts.
Reaction SMILES: [CH3:1][C:2]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:9][CH:10]=1)([CH3:5])[CH2:3][NH2:4].[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:32]=2)[C:29](O)=[O:30])[N:20]=1>>[CH3:5][C:2]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:9][CH:10]=1)([CH3:1])[CH2:3][NH:4][C:29](=[O:30])[C:28]1[CH:32]=[C:24]([C:21]2[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=2)[CH:25]=[N:26][CH:27]=1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC(C)(CN)c1coc(-c2ccccc2)n1
Product: CC(C)(CNC(=O)c1cncc(-c2noc(C(F)(F)F)n2)c1)c1coc(-c2ccccc2)n1
Yield: 13 %

Procedure:
This compound was synthesized from 2-methyl-2-(2-phenyloxazol-4-yl)propan-1-amine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (19 mgs, 13% yield). 1H NMR (CDCl3) δ 9.45 (t, J=9.0 Hz, 1H), 9.35 (s, 1H), 8.42 (s, 1H), 8.03 (s, 2H), 7.51-7.40 (m, 4H), 3.62 (bs, 2H), 1.42 (s, 6H). MS (ESI) m/z: Calculated for C22H18F3N5O3: 457.14. found: 458.1 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:16][C:17]#[CH:18])[C:6](=[O:19])[C:5]=1[CH3:20])([OH:3])=O.Cl.[CH3:22][NH:23][CH3:24].N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[CH3:22][N:23]([CH3:24])[C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:16][C:17]#[CH:18])[C:6](=[O:19])[C:5]=1[CH3:20])=[O:3]
Reactant: C#CCn1c(-c2ccccc2)nc(C(=O)O)c(C)c1=O
Reactant: CNC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C#CCn1c(-c2ccccc2)nc(C(=O)N(C)C)c(C)c1=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 31.7 %

Procedure:
To a stirred solution of 0.87 g (3.2 mmol) of crude 6-carboxy-5-methyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone, 0.32 g (3.9 mmol) of dimethylamine hydrochloride and 2 mL of pyridine in 10 mL of THF was added 0.74 g (3.6 mmol) of solid N,N'-dicyclohexylcarbodiimide. The mixture was stirred at room temperature for 4 days and filtered to remove insoluble material. The filtrate was diluted with 150 mL of ethyl acetate, washed with 50 mL of 5% aqueous HCl and 50 mL of saturated aqueous sodium bicarbonate and dried over MgSO4. Removal of the solvent left 0.40 g of crude product which was purified by flash chromatography on a 30 g column of silica gel, eluted with 60, 80 and 100% ethyl acetate in hexanes to furnish 0.30 g (32%) of 6-dimethylaminocarbonyl-5-methyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone (compound 19), mp 137°-140 ° C. 1H-NMR (CDCl3)δ2.15(3H,s), 2.40(1H, t), 3.00(3H,s), 3.10(3H,s), 4.65(2H,d), 7.55(3H,m), 7.70 (2H,m).
Reaction SMILES: Cl[C:2]1[C:3]([F:11])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[C:5]#[N:6].[H][H].C(N(CC)CC)C.S(=O)(=O)(O)[OH:22]>CO.[C].[Pd]>[F:10][C:7]1[CH:8]=[CH:9][CH:2]=[C:3]([F:11])[C:4]=1[C:5]([NH2:6])=[O:22]
Reactant: O=S(=O)(O)O
Reactant: [H][H]
Reactant: N#Cc1c(F)ccc(Cl)c1F
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: NC(=O)c1c(F)cccc1F

Procedure:
For example, when 3-chloro-2,6-difluorobenzonitrile is dissolved in methanol and reacted with hydrogen gas in the presence of palladium-carbon catalyst and triethylamine under the hydrogen pressure of 5 kg/cm2, the DFBN is obtainable. The DFBN is then heated and dissolved at 70° C. and dropwise added to 90% sulfuric acid, and the reaction is performed at 70° to 80° C. to obtain a 2,6-difluorobenzamide. The product is then dissolved in 1,2-dichloroethane and an oxyalyl chloride is dropwise added to the solution at 20° to 40° C., and the reaction is performed under reflux to obtain 2,6-difluorobenzoyl isocyanate. A dioxane solution of 3,5-dichloro-4-(3-chloro-5-trifluoromethyl-2-pyridyloxy) aniline is dropwise added to a dioxane solution of the isocyanate at 40° to 50° C. and the reaction was performed to obtain N-(2,6-difluorobenzoyl)-N'-[3,5-dichloro-4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenyl]urea having a melting point of 203° to 205° C. This derivative is effective to combat a various kinds of undesirable insects, as disclosed in the Japanese Unexamined Patent Publication 125677/1979, U.S. Pat. Nos. 4,173,637, 4,173,638 and 4,310,530.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:16])[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.Cl.[CH3:18][C:19]1[N:20]([C:24]2[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=2)[CH:21]=[CH:22][N:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([O:16][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([N:20]3[CH:21]=[CH:22][N:23]=[C:19]3[CH3:18])=[CH:31][CH:30]=2)[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:7]=1
Reactant: COC1(c2cc(O)cc(F)c2)CCOCC1
Reactant: Cc1nccn1-c1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1(c2cc(F)cc(OCc3ccc(-n4ccnc4C)cc3)c2)CCOCC1
Temperature: 120 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
A mixture of 4-(5-fluoro-3-hydroxyphenyl)-4-methoxy-3,4,5,6-tetrahydro-2H-pyran (1.4 g, 6.8 mmol), 4-(2-methylimidazol-1-yl)benzyl chloride hydrochloride (1.65 g, 6.8mmol) and potassium carbonate (7.2 g, 68 mmol) in dry DMF (10 ml) was stirred at 120° C. for 2 hours. The mixture was poured into water (100 ml) and extracted with ethyl acetate - benzene (300 ml, 2:1 v/v). The organic phase was washed with water (100 ml), brine (100 ml), dried (MgSO4) and evaporated. Purification of the residual yellow solids by column chromatograghy on silica gel (100 g) eluting with CH2Cl2 /methanol=10:1 and recrystallization from ethyl acetate-hexane gave 4-[5-fluoro-3-[4-(2-methylimidazol-1-yl)benzyloxy]phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-pyran (1.0 g, 39%) as off-white solids.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[N:17]=2)=[CH:12][CH:11]=1.[C:33](=O)([O:36]C)[O:34][CH3:35]>>[CH3:35][O:34][C:33](=[O:36])[CH2:22][C:20]1[CH:19]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=2)[N:17]=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)[CH:21]=1
Reactant: COC(=O)OC
Reactant: Cc1cc(-c2ccc(F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: COC(=O)Cc1cc(-c2ccc(F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
A solution of LDA (1.8 M in THF/heptane/ethyl benzene, 1.1 mL, 2.0 mmol) was added slowly to a stirred solution of 2-(4-fluoro-phenyl)-4-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (260 g, 0.8 mmol) under N2 at −78° C. After 30 minutes dimethyl carbonate (200 μL, 2.0 mmol) was added. After stirring at −78° C. for an additional 30 minutes, the solution was allowed to warm slowly and stirred at 0° C. for 30 minutes. The reaction was quenched with saturated aqueous NH4Cl (2 mL). The mixture was partitioned between CH2Cl2 and H2O. The aqueous layer was extracted with CH2Cl2 (2×). The combined extracts were washed with brine, then dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography on silica gel (40-80% CH2Cl2 in heptane) to give the product as a white solid (130 mg, 42%). 1H NMR (300 MHz, CDCl3) δ 8.23 (d, J=7.91 Hz, 2H), 8.13 (dd, J=5.46, 8.85 Hz, 2H), 7.75 (d, J=8.29 Hz, 2H), 7.64 (d, J=2.64 Hz, 2H), 7.19 (t, J=8.67 Hz, 2H), 3.78 (s, 2H), 3.76 (s, 3H). MS m/e 390.2 (M+H).