Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:2]([CH:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(CC)CC>CN(C=O)C>[N:1]1[N:2]([CH:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[O:13])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Nc1nccs1
Reactant: CC(C)CC(C(=O)O)n1cc2ccccc2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CC(C(=O)Nc1nccs1)n1cc2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of Compound 1 (640 mg, 2.76 mmol), 2-aminothiazole (284 mg, 2.76 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) (1.0 g, 2.76 mmol) and 0.2 mL of Et3N in DMF (4 mL) was stirred at room temperature for 2 hours to provide the title compound, which was then purified by HPLC. 1H NMR (400 MHz, DMSO-d6) δ: 7.74 (d, J=12.0 Hz, 1H), 7.60 (d, J=12.0 Hz, 1H), 7.51 (d, J=4.0 Hz, 1H), 7.25 (m, 2H), 7.05 (t, J=8.0, 8.0 Hz, 1H), 5.67 (m, 1H), 2.23 (m, 1H), 2.06 (m, 1H), 1.32 (m, 1H), 0.94 (d, J=8.0 Hz, 3H), 0.90 (d, J=8.0 Hz, 3H). [M+H] calc'd for C16H18OS, 314; found, 314.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].N=C1CC(C)CCN1.[CH2:13]([NH:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][N:17]=1)[CH3:14]>>[C:1]([OH:4])(=[O:3])[CH3:2].[CH3:14][CH2:13][N:15]=[C:16]1[CH2:21][CH:20]([CH3:22])[CH2:19][CH2:18][NH:17]1
Reactant: CCNc1cc(C)ccn1
Agent: CC1CCNC(=N)C1
Solvent: CC(=O)O
Product: CCN=C1CC(C)CCN1

Procedure:
The method of preparation of 2-imino-4-methylpiperidine acetate was used to convert 2-(ethylamino)-4-methylpyridine to the title compound except platinum oxide was used as the catalyst. The analysis of the product, obtained as an oil, was found to be consistent with the proposed structure. MH+=141; 1H NMR (D2O): δ3.40-3.10 (m, 2H); 3.00 (q, J=6 Hz, 2H); 2.50-2.40 (m, 1H); 2.10-1.90 (m, 1H); 1.83 (s, 3H); 1.80-1.65 (m, 4H); 1.40-1.20 (m, 1H); 1.02 (t, J=6 Hz, 3H); 0.83 (d, J=6 Hz, 3H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[S:10][C:9]2[C:11]3[C:16]([CH2:17][C:8]=2[C:7]=1[C:18]([NH2:20])=[O:19])=[CH:15][CH:14]=[CH:13][CH:12]=3.C(OCC)C>N1C=CC=CC=1>[C:1]([NH:5][C:6]1[S:10][C:9]2[C:11]3[C:16]([CH2:17][C:8]=2[C:7]=1[C:18]([NH2:20])=[O:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)(=[O:3])[CH3:2]
Reactant: NC(=O)c1c(N)sc2c1Cc1ccccc1-2
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)Nc1sc2c(c1C(N)=O)Cc1ccccc1-2
Reaction time: 2 h
Yield: 87 %

Procedure:
Acetyl chloride (0.039 g, 0.5 mmol) was added dropwise to a stirred solution of 2-amino-4H-indeno[1,2-b]thiophene-3-carboxylic acid amide(0.115 g, 0.5 mmol) in dry pyridine (3 mL) at room temperature. The resulting reaction mixture was stirred under nitrogen for 2 h. Ethyl ether (20 mL) was then added to the reaction mixture. The reaction mixture was allowed to stir an additional 10 minutes. The reaction mixture was then filtered, washed with excess ethyl ether, air dried to give the title compound as light brown solid (0.082 g, 0.435 mmol, 60.3% yield). ESMS m/z: 273 [M+H]+.
Reaction SMILES: OC(C(F)(F)F)=O.[OH:8][NH:9][C:10]([C@H:12]1[CH2:17][C@H:16]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH2:15][N:14]([CH3:25])[C@@H:13]1[C:26]([N:28]1[CH2:33][CH:32]=[C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)=[O:27])=[O:11].[H][H]>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[OH:8][NH:9][C:10]([C@H:12]1[CH2:17][C@H:16]([O:18][C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)[CH2:15][N:14]([CH3:25])[C@@H:13]1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])=[O:11]
Reactant: CN1C[C@@H](Oc2ccncc2)C[C@H](C(=O)NO)[C@H]1C(=O)N1CC=C(c2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CN1C[C@@H](Oc2ccncc2)C[C@H](C(=O)NO)[C@H]1C(=O)N1CCC(c2ccccc2)CC1
Yield: 91.2 %

Procedure:
A mixture of (2S,3S,5S)—N-hydroxy-1-methyl-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-(pyridin-4-yloxy)piperidine-3-carboxamide TFA salt (4 mg, 0.00001 mol) in 1 mL of MeOH was hydrogenated in the presence of 5% Pd/BaSO4, under balloon pressure of hydrogen, for 2 h. After filtered off the catalyst, the filtration was concentrated to dry to yield the titled compound (4 mg, 100%). MS (ESI): (M+H)+=439.2.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([C:9]([O:11]CC)=O)=[CH:7][N:6]=[C:5]([S:14][CH3:15])[N:4]=1.[CH3:16][NH2:17]>CO>[CH3:15][S:14][C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:11])[N:17]([CH3:16])[CH2:2][C:3]=2[N:4]=1
Reactant: CCOC(=O)c1cnc(SC)nc1CCl
Reactant: CN
Solvent: CO
Product: CSc1ncc2c(n1)CN(C)C2=O
Reaction time: 15 h
Yield: 18 %

Procedure:
79 g (320 mmoles) of 4-chloromethyl-5-ethoxycarbonyl-2-methylthiopyrimidine was dissolved in 300 ml of methanol, and 50 g (640 mmoles) of a 40% methanol solution of methylamine was added dropwise over 15 minutes, and the mixture was stirred for 15 hours. The product was separated by filtration and dried to give 11 g (yield 18%) of 2-methylthio-6-methyl-5-oxo-5,6-dihydro(7H) pyrrolo[3,4-d]pyrimidine. The resulting product (1.5 g; 7.7 mmoles) and 3.4 g (38.5 mmoles) of morpholine were dissolved in 20 ml of n-amyl alcohol, and the solution was heated under reflux for 7 hours. The reaction mixture was cooled, and the precipitated crystals were separated by filtration to give 0.75 g (yield 42%) of the desired compounds.
Reaction SMILES: Cl.[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:17])[CH:11]=1)=[O:9])([CH3:5])([CH3:4])[CH3:3].C[O-].[Na+].[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:12]([OH:17])[CH:11]=1)=[O:9])([CH3:5])([CH3:3])[CH3:4]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)NCC(=O)c1ccc(O)c(O)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)NCC(=O)c1ccc(OC(=O)c2ccccc2)c(O)c1

Procedure:
Using a procedure similar to that described above in Example 58A, 26 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride in 300 ml. of N,N-dimethylformamide under an atmosphere of nitrogen was reacted with 16 g. of sodium methoxide and then with 14 g. of benzoyl chloride. The product was isolated as the free base, 3-hydroxy-4-(benzoyloxy)phenyl tert-butylaminomethyl ketone [20 g.; m.p 150°-165° C. (dec.) (uncorr.)], which was converted to 13 g. of its methanesulfonate, m.p. 245° C. (dec.)(uncorr.). By catalytically hydrogenating this salt, using a procedure similar to that described above in Example 30B, there is obtained 3-hydroxy-4-(benzoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate.
Reaction SMILES: Cl.[CH:2]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]#[N:18]>ClC1C=CC=CC=1>[CH:2]1([NH:8][C:17]([NH:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH3:9])=[NH:18])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NC1CCCCC1
Reactant: Cc1ccccc1NC#N
Agent: Cl
Solvent: Clc1ccccc1
Product: Cc1ccccc1NC(=N)NC1CCCCC1
Reaction time: 8 h
Yield: 26.5 %

Procedure:
A suspension of cyclohexylamine hydrochloride (310 mg, 2.28 mmol) and (2-methylphenyl)cyanamide (365 mg, 2.76 mmol) in dry chlorobenzene was heated at 125°-135° for 4 hrs. The solvent was evaporated in vacuo with heating, and the residue partitioned between CH2Cl2 and 20×8 ml 10% HCl. The aqueous extracts were made alkaline to pH 9-9.5, and the white precipitate collected after standing at 4° C. overnight. Two recrystallizations from EtOH/H2O gave 140 mg (22%) of white needles, mp 145°-146°, 1H (CD3OD) 1.149-2.054 (m, 10 H), 2.164 (s, 3 H), 3.50 (m, 1 H), 6.875 (d, 1H, J=7.5 Hz), 6.968 (t, 1H, J=7.5 Hz), 7.118 (t, 1H, J=7.5 Hz), 7.177 (d, 1H, J=7.5 Hz). Anal. Calcd for C14H21N3:C, 72.69; H, 9.15; N, 18.16. Found: C, 72.72; H, 9.24; N, 18.18.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C1COCC1.O>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]([S:25]([C:22]3[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=3)(=[O:27])=[O:26])[CH:9]=[N:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2nc[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cnc3cc([N+](=O)[O-])ccc32)cc1
Reaction time: 16 h

Procedure:
To a stirring solution of 5-nitrobenzimidazole (7.5 g, 46 mmol) in THF (300 mL) and water (150 mL) was added K2CO3 (15.9 g, 115 mmol), followed by p-toluenesulfonyl chloride (11.4 g, 46 mmol). After stirring for 16 h, solvents were removed in vacuo and the residue was partitioned between ethyl acetate and water. The layers were separated and the organic phase was washed with brine, then dried with MgSO4, filtered and concentrated in vacuo. The crude solid was dissolved in choloroform and chromatographed over a silica gel column with a gradient of chloroform through 10% methanol/chloroform. The product containing fractions were combined and concentrated in vacuo to give 11.4 g (79%) of light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([F:8])[C:5]2[O:9][C:10]3[C:15]([C@@:16]4([CH2:21][CH2:20][O:19]/[C:18](=[N:22]\C(=O)C5C=CC=CC=5)/[NH:17]4)[C:4]=2[CH:3]=1)=[CH:14][C:13]([NH:31][C:32]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][N:33]=1)=[CH:12][CH:11]=3.N.CO>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([F:8])[C:5]2[O:9][C:10]3[C:15]([C@@:16]4([CH2:21][CH2:20][O:19][C:18]([NH2:22])=[N:17]4)[C:4]=2[CH:3]=1)=[CH:14][C:13]([NH:31][C:32]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][N:33]=1)=[CH:12][CH:11]=3
Reactant: Cc1cccnc1Nc1ccc2c(c1)[C@@]1(CCO/C(=N\C(=O)c3ccccc3)N1)c1cc(Cl)nc(F)c1O2
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cccnc1Nc1ccc2c(c1)[C@@]1(CCOC(N)=N1)c1cc(Cl)nc(F)c1O2
Temperature: 50 °C

Procedure:
To a solution of (S,Z)—N-(3-chloro-1-fluoro-7-((3-methylpyridin-2-yl)amino)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazinan]-2′-ylidene)benzamide (0.069 g, 0.130 mmol) in THF (2 mL) was added ammonia, 2.0M solution in methanol (10 ml, 20.00 mmol) and heated in a sealed tube at 50° C. for 15 h. The reaction was concentrated and purified by HPLC to afford (S)-3-chloro-1-fluoro-N7-(3-methylpyridin-2-yl)-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine as a white solid. MS m/z=426.1 [M+H]+.
Reaction SMILES: [Cl:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[S:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].ClC1C=C(C=CC=1)C(OO)=[O:19]>C(Cl)Cl>[Cl:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[S:8]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)CSC1CCCCC1Cl
Solvent: ClCCl
Product: COC(=O)CS(=O)C1CCCCC1Cl
Temperature: 5 °C
Reaction time: 20 h

Procedure:
Methyl [(2-chlorocyclohexyl)thio]acetate (2.5 g, 0.0112 mole) was added to methylene chloride (35 ml) and the mixture was cooled to 5° C. with an ice bath. 3-Chloroperoxybenzoic acid (85%, 2.3 g, 0.0112 mole) was added, and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was cooled to 5° C. with an ice bath, and filtered. Solid sodium thiosulfate was added to the filtrate and the mixture was stirred for several minutes then filtered. The filtrate was dried over anhydrous magnesium sulfate. After filtering, the filtrate was concentrated in a rotary evaporator to give the product as a solid. The structure was supported by NMR.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH:15]=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].O>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCC.COC(C)(C)C>[CH:15]([C@H:12]1[CH2:13][CH2:14][C@H:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:10][CH2:11]1)=[CH:1][CH2:3][CH2:4][CH3:5]
Reactant: N#Cc1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Agent: CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: COC(C)(C)C
Solvent: O
Product: CCCC=C[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 3.6 g of butyltriphenylphosphonium bromide in 40 ml of t-butyl methyl ether was placed at room temperature while gassing with argon in a sulphonation flask provided with a thermometer, mechanical stirrer, dropping funnel and solid substance addition tube, treated with 1.01 g of potassium t-butylate and stirred at room temperature for a further 1 hour. The deep orange, heterogeneous mixture was subsequently cooled to -60° C. and treated within 15 minutes with a solution of 1.28 g of trans-4-(p-cyanophenyl)cyclohexanecarboxaldehyde in 10 ml of t-butyl methyl ether. The mixture was stirred for a further 60 minutes while warming slowly to -30° C., then poured into 100 ml of water and extracted three times with 50 ml of diethyl ether each time. The organic phases were washed once with 50 ml of water, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residue (3.45 g) on silica gel with ethyl acetate/petroleum ether (vol. 3:97) gave 1.52 g (99%) of p-[trans-4-(1-pentenyl)cyclohexyl]benzonitrile (trans-1-pentenyl/cis-1-pentenyl ratio about 5:95) as a colourless oil; Rf-value (ethyl acetate/petroleum ether vol. 3:97) 0.19.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].C(=O)(O)[O-].[Na+].O>CC(C)=O>[CH2:1]([O:8][C:9]([NH:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)CCCNC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
A solution of benzylchloroformate (9.4 g, 5.5 mmol) in acetone (15 ml) was added dropwise to a mixture of 4-aminobutanoic acid (5.2 g, 5 mmol), sodium bicarbonate (8.6 g, 10 mmol), water (25 ml) and acetone (25 ml) causing vigorous effervescence. The solution was allowed to stir overnight. The acetone was removed using a rotary evaporator to leave an aqueous phase which was washed with ether (2×25 ml). The resulting aqueous layer was acidified to pH2 with dilute hydrochloric acid and then extracted with dichloromethane (3×50 ml). The dichloromethane extracts were combined, dried over magnesium sulphate and volatile components removed under reduced pressure to leave 4-[(benzyloxycarbonyl)amino]butanoic acid as a white solid in a good state of purity. This material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:35]([F:38])([F:37])[F:36])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][C:28](=[O:30])[NH:27][CH2:26]4)=[O:24])=[C:19]([C:31]([F:34])([F:33])[F:32])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[H-].[Na+].[F:41][C:42]([F:47])([F:46])[CH2:43][CH2:44]I.CC#N>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:35]([F:36])([F:37])[F:38])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][C:28](=[O:30])[N:27]([CH2:44][CH2:43][C:42]([F:47])([F:46])[F:41])[CH2:26]4)=[O:24])=[C:19]([C:31]([F:33])([F:34])[F:32])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)cc2C(F)(F)F)CN1
Reactant: FC(F)(F)CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)cc2C(F)(F)F)CN1CCC(F)(F)F
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)phenyl)carbonyl]imidazolidin-4-one (80 mg, 0.14 mmol, 1.00 equiv) in N,N-dimethylformamide (5 ml), sodium hydride (11 mg, 0.28 mmol, 2.00 equiv, 60%), 1,1,1-trifluoro-3-iodopropane (153 mg, 0.68 mmol, 5.00 equiv). The resulting solution was stirred overnight at r t. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 2×10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×10 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 17.8 mg (19%) of 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)phenyl)carbonyl]-3-(3,3,3-trifluoropropyl)imidazolidin-4-one as a light yellow solid. (ES, m/z): [M+CH3CN]+ 711.0; 1H NMR (300 MHz, CD3OD): δ8.12-8.22 (m, 2H), 7.99 (s, 1H), 7.89 (d, J=5.4 Hz, 2H), 7.71 (d, J=5.1 Hz, 1H), 5.12 (s, 1H), 4.70 (s, 1H), 4.16-4.47 (m, 3H), 3.86 (s, 1H), 3.57-3.74 (m, 2H), 2.39-2.67 (m, 2H).
Reaction SMILES: [H-].[Na+].[C:3]([O:12][CH2:13][CH3:14])(=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6].[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19](S(C)(=O)=O)[N:18]=1.O>CN(C)C=O>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19]([O:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]([O:12][CH2:13][CH3:14])=[O:11])[N:18]=1
Reactant: CCOC(=O)c1ccccc1O
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1Oc1nc(OC)cc(OC)n1
Temperature: 100 °C
Yield: 85.6 %

Procedure:
After washing with petroleum ether, 3.9 grams (0.079 mole) of 60% sodium hydride in mineral oil was suspended in 15 mL of dimethylformamide. The suspension was cooled, and a solution of 10.8 grams (0.065 mole) of ethyl salicylate in 20 mL of dimethylformamide was added dropwise with stirring. Upon completion of addition, the reaction mixture was stirred at ambient temperature for one hour, and then 10.5 grams (0.048 mole) of 4,6-dimethoxy-2-methylsulfonylpyrimidine (prepared as in Example 1, Steps A-C) was added. Upon completion of addition, the reaction mixture was heated at 100° C. for 2.5 hours. The reaction mixture was cooled and poured into 250 mL of water. The mixture was extracted with ethyl acetate, and the extract was dried with magnesium sulfate. The mixture was filtered, and the filtrate was subjected to column chromatography on silica gel. Elution was accomplished using in succession 25% hexane in methylene chloride and 30% ethyl acetate in hexane. The appropriate fractions were combined and concentrated under reduced pressure to yield 12.5 grams of ethyl 2-(4,6-dimethoxypyrimidin-2-yloxy)benzoate. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH:24]1[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:25][CH:24]1[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)CC1CNCCN1C(=O)OC(C)(C)C
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CC(C)CC1CN(Cc2cccc(-c3ccnc(Cl)n3)c2)CCN1C(=O)OC(C)(C)C

Procedure:
Intermediate 1 was coupled with 2-Isobutyl-piperazine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 445.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].[CH:7]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[O:9][C:8]=1[CH2:15]Br.C[C]C>[Ag]=O>[CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][O:5][CH2:15][C:8]1[O:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(CBr)o1
Reactant: CC(C)=CCO
Agent: O=[Ag]
Agent: C[C]C
Product: CC(C)=CCOCc1ccc([N+](=O)[O-])o1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Freshly prepared silver oxide (34.8 g, 0.15 mol) was added to a mixture of 3-methyl-2-buten-1-ol (21.0 g, 25 mL, 0.24 mol) and 5-nitro-2-furfuryl bromide (18.8 g, 0.1 mol) and stirred at room temperature for 12 h. Silver salts were removed by filtration and the filter cake was washed with ether (200 mL). The filtrate and the washings were combined and evaporated to remove ether and excess 3-methyl-2-buten-1-ol. The oil obtained was purified by column chromatography (silica gel, hexane:ethyl acetate, 7:1). Fractions containing the product were collected and evaporated to give a light yellow oil. Yield 5.5 g. 1H NMR (CDCl3) ε 1.69 and 1.77 (s, 6H, CH3), 4.09 [d, 2H, (CH3)2C=CHCH2 --OCH2)], 4.64 [s, 2H, (CH3)2C=CHCH2 --OCH2)], 5.38 (t, 1H, (CH3)2C=CH--), 6.6 and 7.27 (d, 2H, ArH).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:28](I)[CH2:29][CH3:30]>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([O:8][C:9]([N:11]([CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)[CH2:28][CH2:29][CH3:30])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCI
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)OCc2ccccc2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.3 %

Procedure:
tert-Butyl 4-((benzyloxycarbonylamino)methyl)piperidine-1-carboxylate (0.950 g, 2.726 mmol) was dissolved in dry DMF (25 mls). To this was added sodium hydride (0.164 g, 4.090 mmole, 60% dispersion in mineral oil) and the reaction mixture was stirred at room temperature for 30 minutes. Propyl iodide (0.695 g, 4.090 mmole) was then added and the mixture stirred at room temperature for 16 hours, then diluted with brine (200 mls), extracted twice with EtOAc, extracts washed twice with brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting oil was purified by flash chromatography (100 g Biotage Snap cartridge, 30% EtOAc/Hexanes) to give 0.280 g (26%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([CH3:19])([CH3:18])[C:6](=[O:17])[CH:7](Br)[O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[CH3:2].[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1>C(#N)C>[CH2:1]([O:3][C:4](=[O:20])[C:5]([CH3:19])([CH3:18])[C:6](=[O:17])[CH:7]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)[CH3:2]
Reactant: CCOC(=O)C(C)(C)C(=O)C(Br)Oc1ccc(Cl)cc1
Reactant: c1nc[nH]n1
Solvent: CC#N
Product: CCOC(=O)C(C)(C)C(=O)C(Oc1ccc(Cl)cc1)n1cncn1
Yield: 77.8 %

Procedure:
34 g (0.091 mol) of 4-bromo-4-(4-chlorophenoxy)-2,2-dimethyl-3-keto-butanoic acid ethyl ester were dissolved in 240 ml of acetonitrile. 24 g (0.345 mol) of 1,2,4-triazole were added and the mixture was heated for 48 hours under reflux. The solvent was then distilled off in vacuo, the residue was dissolved in 200 ml of methylene chloride and the solution was washed three times with 50 ml of water each time, dried over sodium sulphate and concentrated. The oil which remained was boiled up with 100 ml of petroleum ether, whereupon it crystallized. The solid was filtered off and dried. 24.9 g (78% of theory) of 4-(4-chlorophenoxy)-2,2-dimethyl-3-keto-4-(1,2,4-triazol-1-yl)-butanoic acid ethyl ester of melting point 88°-89° C. were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].Cl[CH2:15][CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19]>>[O:19]=[S:18]1(=[O:20])[CH2:17][CH2:16][CH2:15][N:1]1[C:2]1[CH:12]=[C:11]([N:13]2[CH2:15][CH2:16][CH2:17][S:18]2(=[O:20])=[O:19])[CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1ccc(N)cc1N
Reactant: O=S(=O)(Cl)CCCCl
Product: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1N1CCCS1(=O)=O

Procedure:
Using ethyl 2,4-diaminobenzoate (2.21 g) and 3-chloropropane-1-sulfonyl chloride (4 mL) and by the reaction and treatment in the same manner as in Preparation Example 16, the title compound (1.33 g) was obtained.