Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12])[CH:5]=[O:6].Br[CH2:15][CH2:16][OH:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:17][CH2:16][CH2:15][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12])[CH:5]=[O:6]
Reactant: OCCBr
Reactant: CC(C)Oc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C=O)cc1OCCO

Procedure:
The title compound was prepared analogously to intermediate 2 (4-methoxy-3-propoxy-benzaldehyde) by reaction of 3-hydroxy-4-isopropoxy-benzaldehyde ([CAS RN 94283-73-5], F. R. Hewgill, M. C. Pass Australian J. Chem. 1985, 38, 537-554) with 2-bromo-ethanol in DMF using K2CO3 as base. MS (ISP): 224.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(CCN(C)C)C.[Li]C(CC)C.C1CCCCC1.[CH3:30][Si:31](Cl)([CH3:33])[CH3:32].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:31]([CH3:33])([CH3:32])[CH3:30])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccccc1Cl
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: C[Si](C)(C)c1cccc(Cl)c1C(=O)O
Temperature: -100 °C
Yield: 63 %

Procedure:
2-Chlorobenzoic acid (3.91 g, 25 mmol), THF (60 mL), and TMEDA (8.6 mL, 57 mmol) were stirred under nitrogen and cooled to −100° C. 1.3M s-BuLi in cyclohexane (0.055 mol, 42.3 mL) was added dropwise keeping the temperature below −80° C. After the addition was complete, TMSCl (2.7 g, 25 mmol) was added dropwise and the resulting mixture was allowed to stir and slowly warm to −30° C. 25% citric acid (100 mL) was added and the mixture was extracted with two 50 mL portions of ether, which were then combined and washed three times with water, dried (MgSO4) and concentrated. The crude product was purified by HPLC, eluting with 2:3 ethyl acetate/hexanes. The product was recovered as a white solid in 63% yield. m.p. 129-131° C.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[O:4][C:5]([CH3:9])([CH3:8])[C:6]#[N:7].[CH2:15]([OH:17])[CH3:16].[ClH:18]>C(Cl)Cl>[ClH:18].[F:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[O:4][C:5]([CH3:9])([CH3:8])[C:6](=[NH:7])[O:17][CH2:15][CH3:16]
Reactant: CCO
Reactant: CC(C)(C#N)Oc1ccc(F)cc1F
Agent: Cl
Solvent: ClCCl
Product: CCOC(=N)C(C)(C)Oc1ccc(F)cc1F
Reaction time: 60 h

Procedure:
Through a cooled solution of Example 51B (6.5 g, 33 mmol) and ethanol (9.6 mL, 165 mmol) in methylene chloride (10 ml) was bubbled HCl gas at 0° C. for 30 minutes. The reaction was kept in a refrigerator at 4° C. for 60 hours. The reaction mixture was then concentrated and triturated with diethyl ether to obtain a precipitate of the titled compound. MS (ESI+) m/z 244 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[O:16][Si](C(C)(C)C)(C)C)[CH:4]=[CH2:5].CI.C(Cl)Cl.[O:29]1CCC[CH2:30]1>CO.Cl>[CH3:30][O:29][CH2:5][CH2:4][CH2:3][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[OH:16]
Reactant: C1CCOC1
Reactant: C=CCc1ccc2ccccc2c1O[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: ClCCl
Solvent: CO
Product: COCCCc1ccc2ccccc2c1O
Temperature: 25 °C
Yield: 66 %

Procedure:
A suspension of sodium hydride (60% in mineral oil; 0.28 g, 0.007 mole) in dry tetrahydrofuran (5 mL) was stirred at 0°. A solution of the product of Example 122 Part B (2.00 g, 0.006 mole) was added slowly, and the mixture warmed to room temperature. Methyl iodide (0.8 mL, 0.013 mole) was added, the mixture was stirred for 3 hours, then was poured into 1.0N hydrochloric acid. The crude material was isolated by extraction with methylene chloride, dissolved in a mixture of methanol (20 mL) and 1.0N hydrochloric acid (20 mL), and heated at reflux for 20 hours. The cooled solution was extracted with methylene chloride, and the residue was chromatographed with 9:1 petroleum ether/ether to provide the title compound (0.90 g, 66%) as a colorless oil. Mass spectrum: m/z 216.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:22][C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)[CH3:2].[CH3:28][C:29]([CH2:35][CH2:36][CH2:37][CH:38]([CH3:50])[CH2:39][CH2:40][CH2:41][CH:42]([CH3:49])[CH2:43][CH2:44][CH2:45][CH:46]([CH3:48])[CH3:47])=[CH:30][CH2:31]CCO.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:22][CH:5]1[O:4][CH2:1][CH2:2][CH2:31][CH:30]=[C:29]([CH3:28])[CH2:35][CH2:36][CH2:37][CH:38]([CH3:50])[CH2:39][CH2:40][CH2:41][CH:42]([CH3:49])[CH2:43][CH2:44][CH2:45][CH:46]([CH3:48])[CH3:47])(=[O:10])[CH3:9]
Reactant: CC(=CCCCO)CCCC(C)CCCC(C)CCCC(C)C
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1OC(OCCCC=C(C)CCCC(C)CCCC(C)CCCC(C)C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C

Procedure:
3.0 g (7.7 mmol) of β-D-Glucose pentaacetate and 3.24 g (9.99 mmol) of 5,9,13,17-tetramethyloctadec-4-en-1-ol were dissolved in dry acetonitrile (8 mL). 1.95 mL (15.4 mmol) of boron trifluoride diethyl etherate complex was added to the solution with cooling on ice. The reaction mixture was allowed to warm up slowly to room temperature while being stirred overnight before addition of 3.2 mL (23 mmol) of triethylamine at 0° C. The resulting solution was diluted with ethyl acetate, and washed with water, 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over sodium sulfate. After filtration, the filtrate was concentrated to obtain 1-O-(5,9,13,17-tetramethyloctadec-4-enyl)-D-glucopyranoside tetraacetate as a crude product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:12]2[CH:13]=[CH:14][NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>CC(C)=O>[O:30]1[CH2:29][CH:28]1[CH2:26][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:12]2[CH:13]=[CH:14][NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)=[O:10]
Reactant: O=C(Nc1ccccc1O)c1cccc2[nH]ccc12
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(Nc1ccccc1OCC1CO1)c1cccc2[nH]ccc12

Procedure:
Under an inert atmosphere, a solution of 3 g of N-(2-hydroxyphenyl)-1H-indol-4-carboxamide and 1.65 g of potassium carbonate in 100 ml of acetone was refluxed for 24 hours with 4.7 ml of epichlorhydrin and after purifying by chromatography over silica (eluent: ethyl acetate--triethylamine, 9-1) and evaporating to dryness, the residue was triturated in pentane, then filtered and dried under reduced pressure at 60° C. to obtain 2.8 g of N-[2-[(2-oxiranyl)methoxy]phenyl]-1H-indol-4-carboxamide melting at 122° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([CH2:13][CH2:14]O)[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.S(Cl)([Cl:24])=O>O>[CH:1]1([C:7]2[CH:8]=[C:9]([CH2:13][CH2:14][Cl:24])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: OCCc1cccc(C2CCCCC2)c1
Solvent: c1ccncc1
Solvent: O
Product: ClCCc1cccc(C2CCCCC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
33.1 g of β-(m-cyclohexyl-phenyl)-ethanol are mixed with 13.3 ml of absolute pyridine. 12.5 ml of thionyl chloride are added dropwise to this mixture, whilst cooling with ice. Thereafter the reaction mixture is slowly heated to 100°-110°C and is kept at this temperature for 2 hours. The reaction solution is again cooled to room temperature, 29 ml of water are added and the whole is extracted with a mixture of ether and chloroform. The organic phase is washed twice with 2 N sodium carbonate solution, three times with 2 N hydrochloric acid and finally once with 2 N sodium carbonate solution, dried over sodium sulphate, filtered and evaporated. The residue, a brown oil, is distilled in a high vacuum. Hereupon, β-(m-cyclohexyl-phenyl)-ethyl chloride is obtained as a light yellow oil of boiling point 103°-8°C/0.1 mm Hg.
Reaction SMILES: [OH:1][C:2]1[C:9](C=O)=[CH:8][C:7]([CH3:12])=[CH:6][C:3]=1C=O.[OH-:13].[Na+].[OH:15]O>O>[CH3:12][C:7]1[CH:6]=[C:3]([OH:15])[C:2]([OH:1])=[C:9]([CH:8]=1)[OH:13]
Reactant: [OH-]
Reactant: Cc1cc(C=O)c(O)c(C=O)c1
Reactant: OO
Agent: [Na+]
Solvent: O
Product: Cc1cc(O)c(O)c(O)c1
Reaction time: 0.3 h
Yield: 69 %

Procedure:
Under a nitrogen atmosphere throughout: 5.3 Parts of 2-hydroxy-5-methylisophthalaldehyde prepared in Example 15 or 16 were slurried with a solution of 2.6 parts of sodium hydroxide in 32 parts of water, and a solution of 9.8 parts of 27.2% by weight hydrogen peroxide in 35 parts of water was added over four minutes. The temperature rose to 85° C. initially and was then maintained at 40°-50° C. with external cooling. After a further 18 minutes the pH was 7.8. The solution was filtered to remove 1.05 parts of unchanged starting material, and the filtrate was continuously extracted with ether to give 2.5 parts of 5-methylpyrogallol, m.pt. 114°-121° C., equivalent to 69% yield.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12](Cl)=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][OH:22])=[CH:19][CH:18]=1.CN(C)C.O>O1CCCC1>[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:22][C:12](=[O:13])[CH:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=2)[CH3:15])=[CH:19][CH:18]=1
Reactant: CC(C)Cc1ccc(C(C)C(=O)Cl)cc1
Reactant: Cc1ccc(CO)cc1
Agent: CN(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(COC(=O)C(C)c2ccc(CC(C)C)cc2)cc1
Yield: 84.5 %

Procedure:
To a solution of 5.4 g of 2-(4-isobutylphenyl)propionic acid chloride and 3.5 g of p-methylbenzyl alcohol in 30 ml of tetrahydrofuran was added 3.7 g of trimethylamine, dropwise under cooling, and reacted at room temperature for 2 hours. After the reaction was complete, the crystals produced were removed by filtration. The filtrate was freed of solvent by distillation to leave a residue, to which was added water. The resulting mixture was extracted with ether, and the extract was dehydrated and freed of solvent by distillation to give an oily residue. This residue was then distilled in vacuo to yield 6.3 g of 2-(4-isobutylphenyl)propionic acid-p-methylbenzyl ester as a colorless oil, boiling at 139°-140° C./0.1 mmHg. Mass spectrum: parent ion 310 m/e.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.[CH3:17][C:18]1[CH:19]=[C:20]([CH2:30][OH:31])[CH:21]=[CH:22][C:23]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[O:16]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[CH:9][C:10]([C:11]([N:27]2[CH2:26][CH2:25][N:24]([C:23]3[CH:22]=[CH:21][C:20]([CH2:30][OH:31])=[CH:19][C:18]=3[CH3:17])[CH2:29][CH2:28]2)=[O:13])=[CH:14][CH:15]=1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1
Reactant: Cc1cc(CO)ccc1N1CCNCC1
Product: Cc1cc(CO)ccc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2)CC1
Yield: 52.2 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (378 mg) described in Preparation Example 16 and [3-methyl-4-(piperazin-1-yl)phenyl]methanol (323 mg) described in Preparation Example 98 and by the reaction and treatment in the same manner as in Example 87, the title compound (351 mg) was obtained.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:12])[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[C:13]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[OH:25])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>C(O)C>[C:19]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:2][CH:3]([OH:12])[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: OC(CCl)CCc1cccnc1
Reactant: Oc1ccccc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OC(CCc1cccnc1)COc1ccccc1-c1ccccc1
Yield: 34.9 %

Procedure:
Prepared according to the method described in Example 24b) from (±)-α-(chloromethyl)-3-pyridinepropanol (1.0 g, Example 24a), 2-phenylphenol (0.92 g), ethanol (45 ml) and aqueous sodium hydroxide (1.0 M, 5 ml) with heating at reflux for 1 hour. After work up the residue was purified by column chromatography over silica eluting with hexane:acetone (2:1) to give the title compound as a colourless oil (0.60 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9]C(=O)OC(C)(C)C)=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.ClC1C=CC=CC=1C(OO)=[O:25].Cl.O1CCOCC1>C(Cl)Cl.CO>[NH2:9][CH2:8][C:5]1[C:4]([C:17]([F:20])([F:19])[F:18])=[CH:3][C:2]([CH3:1])=[N+:7]([O-:25])[CH:6]=1
Reactant: Cc1cc(C(F)(F)F)c(CNC(=O)OC(C)(C)C)cn1
Reactant: O=C(OO)c1ccccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(C(F)(F)F)c(CN)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
To a round-bottomed flask was added tert-butyl ((6-methyl-4-(trifluoromethyl)pyridin-3-yl)methyl)carbamate (1.0 equiv.) which was dissolved in DCM (0.7 M). To this solution was added in-chloroperoxybenzoic acid (1.3 equiv.) and the mixture was stirred at room temperature for 12 h. The solvent was removed to afford a crude solid which was dissolved in MeOH and 4 N HCl in dioxane (4.2 equiv.) was added at room temperature. The mixture was stirred for 24 h and some precipitate begun to form. The volatile solvents were removed under reduced pressure to afford a crude residue. The residue was dissolved in methanaol and the resulting mixture was loaded on a Strata ion-exchange column. The column was washed successively with water, acetonitrile, MeOH and 7 N ammonia in MeOH. The product eluted with the 7 N ammonia in MeOH eluent and product containing eluent was concentrated under reduced pressure to afford 5-(aminomethyl)-2-methyl-4-(trifluoromethyl)pyridine 1-oxide (90% yield) as the free base; MS(ESI) m/z 207.0[M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][C:12]([CH:15]=O)([CH3:14])[CH3:13].[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:17]1([CH:15]([NH:8][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]([CH3:13])([CH3:14])[CH3:11])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1
Reactant: NC(=O)c1ccc(F)cc1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CC(C)(C)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)C(NC(=O)c1ccc(F)cc1)n1nnc2ccccc21

Procedure:
4-Fluorobenzamide, pivaldehyde, benzotriazole and p-toluenesulfonic acid were processed as described in Example 53A to provide the desired product.
Reaction SMILES: [OH-].[K+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]=O)[CH:4]=1.[C:11](#[N:13])[CH3:12]>>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH2:12][C:11]#[N:13])[CH:4]=1.[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]=[CH:12][C:11]#[N:13])[CH:4]=1
Reactant: CC#N
Reactant: O=Cc1cccnc1
Agent: [K+]
Agent: [OH-]
Product: N#CC=Cc1cccnc1
Product: N#CCCc1cccnc1
Temperature: 0 °C

Procedure:
3-(3-Pyridinyl)propionitrile is prepared in this example. A three-neck flask carrying a magnetic stir bar is fitted with a thermometer, pressure equalizing addition funnel, and a reflux condenser carrying an argon inlet. Freshly powdered potassium hydroxide (6.6 g, 0.1 mol) and anhydrous acetonitrile (150 ml) are charged into the flask and heated at reflux while 3-pyridinecarboxaldehyde (10.7 g, 0.1 mol) in anhydrous acetonitrile (50 ml) is added dropwise over a period of about five minutes and refluxing continued for about another three minutes. The resulting hot reaction mixture is poured into an ice/water mixture (100 g), and the resulting solution is extracted with CH2Cl2 (3×100 ml), dried with Na2SO4, and evaporated to give crude 3-(3-pyridinyl)acrylonitrile, which is purified by column chromatography over silica gel using CHCl3 as the eluent; yield 3.3 g (25.6%).
Reaction SMILES: [CH3:1][P:2]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=O)[O:3][CH3:4].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:28]>>[CH3:1][P:2]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[S:28])[O:3][CH3:4]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COP(C)(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Product: COP(C)(=S)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A mixture of methyl P-methyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinate (1.5 g, 4.7 mmol) and phosphorus pentasulfide (0.52 g, 1.2 mmol) is heated to 150°-160° under nitrogen for 3-4 hours. After cooling, the residue is purified by preparative thin-layer chromatography (on silica gel, eluting with 20% ethyl acetate/hexane) to give methyl P-methyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinothioate.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[H-].[Na+].Br[C:29]1[N:30]([CH2:37][C@:38]2([CH3:41])[CH2:40][O:39]2)[CH:31]=[C:32]([N+:34]([O-:36])=[O:35])[N:33]=1>CN(C)C=O>[CH3:40][C@@:38]1([CH2:41][O:21][C:18]2[CH:19]=[CH:20][C:15]([N:12]3[CH2:11][CH2:10][CH:9]([O:8][C:7]4[CH:22]=[CH:23][C:4]([O:3][C:2]([F:1])([F:24])[F:25])=[CH:5][CH:6]=4)[CH2:14][CH2:13]3)=[CH:16][CH:17]=2)[O:39][C:29]2=[N:33][C:32]([N+:34]([O-:36])=[O:35])=[CH:31][N:30]2[CH2:37]1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Br)CO1
Reactant: Oc1ccc(N2CCC(Oc3ccc(OC(F)(F)F)cc3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]1(COc2ccc(N3CCC(Oc4ccc(OC(F)(F)F)cc4)CC3)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 72.5 °C
Reaction time: 0.33 h
Yield: 32.7 %

Procedure:
4-[4-(4-Trifluoromethoxyphenoxy)piperidin-1-yl]phenol (693 mg) was dissolved in N,N-dimethylformamide (3 ml), then under ice-cooling condition, sodium hydride (86 mg) was added, the reaction mixture was stirred at 70-75° C. for 20 minutes. The reaction mixture was ice-cooled, a solution prepared by dissolving (R)-2-bromo-4-nitro-1-(2-methyl-2-oxiranylmethyl)imidazole (720 mg) prepared in example 6 in N,N-dimethylformamide (3 ml) was added and stirred at 70-75° C. for 20 minutes. The reaction mixture was turned back to a room temperature, ice-water (25 ml) was added, and extracted 3 times with dichloromethane (50 ml). The organic layers were combined, after being washed with water 3 times, the organic layer was dried over anhydrous magnesium sulfate. After being filterated under a reduced pressure, the filtrate was concentrated, and the obtained residue was purified by use of a silica gel column chromatography (eluent: dichloromethane/ethyl acetate=3/1). Recrystallized from ethyl acetate/diisopropyl ether, there was obtained (R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole (343 mg, yield: 33%) as pale yellow powder product.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.Cl.[CH2:23]([O:25][C:26](=[O:30])[CH2:27][CH2:28][NH2:29])[CH3:24].C(OCC)C>C(Cl)Cl>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:29][CH2:28][CH2:27][C:26]([O:25][CH2:23][CH3:24])=[O:30])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)CCNS(=O)(=O)c1ccc(CBr)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of the 4-bromomethylphenylsulfonylchloride (10 g, 37 mmol) in CH2Cl2 (200 mL) at 0° C. was added diisopropylethylamine (16 mL, 93 mmol) followed by ethyl-3-aminopropionate hydrochloride (5.1 g, 37 mmol)). The reaction was stirred for 10 minutes at 0° C. and the solvent was evaporated at room temperature under reduced pressure. The residue was dissolved in ethyl acetate and washed with 1N HCl (3×), H2O, aqueous NaHCO3 (3×), brine (3×) and dried over MgSO4. The solvent was concentrated to give a syrup. Addition of ethyl ether induced crystallization of the product as a white solid (10 g, 30 mmol, 81%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:15])[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.OC1C2N=NNC=2C=CC=1.[C:33]([C:37]1[N:42]=[C:41]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:40]=[C:39]([CH:49]2[CH2:52][CH2:51][CH2:50]2)[N:38]=1)([CH3:36])([CH3:35])[CH3:34].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][CH2:11][C:12]([N:46]1[CH2:47][CH2:48][N:43]([C:41]2[CH:40]=[C:39]([CH:49]3[CH2:52][CH2:51][CH2:50]3)[N:38]=[C:37]([C:33]([CH3:36])([CH3:35])[CH3:34])[N:42]=2)[CH2:44][CH2:45]1)=[O:14])[CH3:15])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(CCCC(=O)O)C(=O)OC(C)(C)C
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCNCC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(CCCC(=O)N1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1)C(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
6 g of 4-(tert-butoxycarbonyl-methyl-amino)-butyric acid (27.6 mmol) and 5.53 g of triethylamine (54.6 mmol) were dissolved in 100 ml of dimethylformamide. 4.1 g of hydroxybenzotriazole (HOBt, 30.35 mmol), 7.6 g of 2-tert-butyl-4-(piperazin-1-yl)-6-cyclobutyl-pyrimidine (27.7 mmol), and 5.8 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodimide hydrochloride (EDCl, 30.26 mmol) were added at room temperature, and the reaction mixture was stirred for 16 h. The reaction mixture was partitioned between water and ethyl acetate, the organic phase dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using dichloromethane. Fractions containing the product were combined and the solvent evaporated to yield 13.1 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:13]CN(C(C)C)C(C)C.[Cl:22][C:23]1[N:28]=[C:27](Cl)[C:26]([Cl:30])=[CH:25][N:24]=1>CS(C)=O.C(Cl)Cl>[Cl:22][C:23]1[N:28]=[C:27]([NH:1][C:2]2[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:3]=2[C:4]([NH:6][CH3:13])=[O:5])[C:26]([Cl:30])=[CH:25][N:24]=1
Reactant: Cc1cc(C)c(N)c(C(N)=O)c1
Reactant: CCN(C(C)C)C(C)C
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CS(C)=O
Solvent: ClCCl
Product: CNC(=O)c1cc(C)cc(C)c1Nc1nc(Cl)ncc1Cl

Procedure:
A solution of 2-amino-3,5-dimethyl-benzamide (573 mg), DIEA (580 mL), and 2,4,5-trichloropyrimidine (660 mg) in DMSO was heated at 65° C. for 4.5 h, then diluted with DCM, washed with brine twice, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography to provide 460 mg of 2-(2,5-dichloropyrimidin-4-ylamino)-3,5,N-trimethyl-benzamide: 1H NMR (300 MHz, CDCl3) δ 9.3 (bs, 1H), 8.2 (s, 1H), 7.3 (s, 1H), 7.2 (s, 1H), 6.2 (bs, 1H), 3.0 (d, 3H), 2.4 (s, 3H), 2.3 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([F:32])=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:11]([F:30])=[CH:12][C:13]([F:29])=[C:14]([C@:16]4([CH3:28])[C:22]([F:24])([F:23])[C:21]([CH3:26])([CH3:25])[O:20][CH2:19][C:18](=S)[NH:17]4)[CH:15]=3)=[N:7][C:6]=2[CH:31]=1.[NH3:33].C(OO)(C)(C)C>>[F:1][C:2]1[C:3]([F:32])=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:11]([F:30])=[CH:12][C:13]([F:29])=[C:14]([C@:16]4([CH3:28])[C:22]([F:24])([F:23])[C:21]([CH3:26])([CH3:25])[O:20][CH2:19][C:18]([NH2:33])=[N:17]4)[CH:15]=3)=[N:7][C:6]=2[CH:31]=1
Reactant: N
Reactant: CC1(C)OCC(=S)N[C@](C)(c2cc(-c3nc4cc(F)c(F)cc4o3)c(F)cc2F)C1(F)F
Agent: CC(C)(C)OO
Product: CC1(C)OCC(N)=N[C@](C)(c2cc(-c3nc4cc(F)c(F)cc4o3)c(F)cc2F)C1(F)F
Yield: 24 %

Procedure:
In a manner analogous to that described in Example 2c), the ammonolysis of (R)-5-[5-(5,6-difluoro-benzo oxazol-2-yl)-2,4-difluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-thione (83 mg, 175 μmol) with ammonia (7M in methanol; 1.72 ml) and tert-butylhydroperoxide (70% in water; 183 μl) yielded the title compound (19 mg, 24% yield). MS (ISP): m/z=458.2 [M+H]+.