Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18](CC#N)=[C:17]([C:24]([F:27])([F:26])[F:25])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CCN(C(C)C)C(C)C.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.[C:53]([OH:56])(=[O:55])[CH3:54]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:54][C:53]([OH:56])=[O:55])=[C:17]([C:24]([F:27])([F:25])[F:26])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CC#N)c(C(F)(F)F)c2)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CC(=O)O)c(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 4-(N-tert-butyloxy-carbonyl-4-piperidinyloxy)-2-trifluoromethylphenylacetonitrile (0.26 g, 0.87 mmol) from Step 5 above in acetic acid (10 mL) was added concentrated aqueous HCl (5 mL). The mixture was refluxed for 4 h. The solvents were removed under reduced pressure and the residue was stripped from DMF (2×). The residue was then dissolved in DMF (5 mL). DIEA (0.45 mL, 2.6 mmol) and di-tert-butyldicarbonate (0.21 g, 9.6 mmol) were added. The mixture was stirred at ambient temperature for 3 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (50 mL) and 0.25 M aqueous citric acid (25 mL). The organic phase was washed with water (2×25 mL), dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give 4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-trifluoromethylphenylacetic acid as an amorphous solid (HPLC retention time=10.1 min (method A)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[C:13]([NH:19][C:20](=[O:22])[CH3:21])[NH:14][C:15](=O)[C:16]=3[N:17]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:34]>O1CCOCC1>[Cl:34][C:15]1[C:16]2[N:17]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:9]=[CH:10][C:11]=2[N:12]=[C:13]([NH:19][C:20](=[O:22])[CH3:21])[N:14]=1
Reactant: CC(=O)Nc1nc2ccc(-c3ccc(F)cc3)nc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc(Cl)c2nc(-c3ccc(F)cc3)ccc2n1
Temperature: 80 °C
Yield: 52.6 %

Procedure:
To a suspension of N-[6-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-pyrido[3,2-d]pyrimidin-2-yl]-acetamide (0.77 g, 2.58 mmol) and DIEA (1.34 mL, 7.74 mmol) in dioxane (25 mL) was added POCl3 (0.73 mL, 7.74 mmol). The mixture was heated to 80° C. for 30 minutes. After the removal of solvent, the residue was dissolved in ethyl acetate (200 mL) and the solution was filtered through a short column with silica gel. The column was additionally washed with ethyl acetate. The filtrate and washings were combined and concentrated. The precipitate formed was isolated by filtration to give the pure title compound as a brown solid (0.43 g, yield 43%) which was characterised as follows: MS (m/z) 317.0 [M+H]+.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[C:16]([O:17][CH2:18][O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=[C:13]([O:23][CH2:24][O:25][CH3:26])[C:12]=1[O:27][CH3:28])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][CH2:10][C:11]1[C:16]([O:17][CH2:18][O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=[C:13]([O:23][CH2:24][O:25][CH3:26])[C:12]=1[O:27][CH3:28]
Reactant: COCOc1cc(OC)c(OCOC)c(CCO[Si](C)(C)C(C)(C)C)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COCOc1cc(OC)c(OCOC)c(CCO)c1OC
Reaction time: 0.5 h

Procedure:
15.0 Milligrams of 2-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]ethyl tert-butyldimethylsilyl ether was dissolved in 2 ml of anhydrous tetrahydrofuran, under argon gas stream conditions, 0.1 ml of tetrahydrofuran solution of 1 mole of tetra-n-butylammonium fluoride was added thereto and stirred for 30 minutes, the reaction of removal of the protecting group was completed quantitatively. The solvent was removed by evaporation under reduced pressure, and the residue obtained was treated on a silica gel thin layer chromatography and purified by developing with 30% ethyl acetate-n-hexane to yield 9.0 mg of 1-(2-hydroxyethyl)-2,5-dimethoxy-3,6-bis(methoxymethoxy)benzene.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[S:11][N:10]=[N:9][C:8]=1[C:12]([O:14]CC)=[O:13])=[O:5])[CH3:2].Cl>C(O)C>[CH2:1]([O:3][C:4]([NH:6][C:7]1[S:11][N:10]=[N:9][C:8]=1[C:12]([OH:14])=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)Nc1snnc1C(=O)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Nc1snnc1C(=O)O

Procedure:
A suspension of sodium thiocyanate (24.30 g, 0.30 mole) in acetonitrile (120 ml), maintained at 19° C., was treated dropwise over 22 minutes with a solution of ethyl chloroformate (28.7 ml, 0.30 mole) in acetonitrile (25 ml). The resultant mixture was stirred for 25 minutes at 20° C. and then ethyl diazoacetate (31.5 ml, 0.30 mole) was added. After stirring for 24 hours, 6.0 N hydrochloric acid (300 ml) was added with cooling. Acetonitrile solvent was removed in vacuo and the residual aqueous suspension was extracted several times with ether. Combined ether extracts were washed with water, dried (Na2SO4) and evaporated to leave 51.0 g of ethyl 5-ethoxycarbonylamino-1,2,3-thiadiazole-4-carboxylate. This ester was hydrolyzed by refluxing for 6 hours in a mixture of ethanol (80 ml) and aqueous 6 N hydrochloric acid (400 ml) to yield the title acid; m.p. 179°-180° dec. after crystallization from nitromethane.
Reaction SMILES: [C:1]([C:3]1[N:7](COCC[Si](C)(C)C)[N:6]=[C:5]2[CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][C:4]=12)#[N:2].Cl>CCO>[N:6]1[NH:7][C:3]([C:1]#[N:2])=[C:4]2[CH2:18][NH:17][CH2:16][C:5]=12
Reactant: CC(C)(C)OC(=O)N1Cc2nn(COCC[Si](C)(C)C)c(C#N)c2C1
Agent: Cl
Solvent: CCO
Product: N#Cc1[nH]nc2c1CNC2
Temperature: 90 °C

Procedure:
To a stirred solution of the product obtained in Step E (250 mg, 0.686 mmol) in EtOH (4 mL) was added 1N HCl (8 mL). The resulting mixture was heated at 90° C. under nitrogen for 3 h. Solvents were removed and the crude product was subjected to column chromatography on a silica gel Biotage 40S® column, eluting with 5 to 14% MeOH (containing 10% conc. NH4OH) in CH2Cl2 to give the title compound. LC-MS: 135.1 (M+H).
Reaction SMILES: Cl.[Na+].[CH:3]1[C:16]2[NH:15][C:14]3[CH:13]=[CH:12][CH:11]=[C:10]([C:17]([O-:19])=[O:18])[C:9]=3[O:8][C:7]=2[C:6]([C:20]([O-:22])=[O:21])=[CH:5][CH:4]=1.[Na+]>O>[CH:3]1[C:16]2[NH:15][C:14]3[CH:13]=[CH:12][CH:11]=[C:10]([C:17]([OH:19])=[O:18])[C:9]=3[O:8][C:7]=2[C:6]([C:20]([OH:22])=[O:21])=[CH:5][CH:4]=1
Reactant: O=C([O-])c1cccc2c1Oc1c(cccc1C(=O)[O-])N2
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cccc2c1Oc1c(cccc1C(=O)O)N2

Procedure:
A two-fold stoichiometric excess of 1N hydrochloric acid is added to a solution of phenoxazine-4,6-dicarboxylic acid sodium salt in water. The solution is then extracted with ether, and the extract is dried and the solvent removed under reduced pressure to afford phenoxazine-4,6-dicarboxylic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=O)[CH3:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=1)([O-:17])=[O:16].C([BH3-])#N.[Na+].[OH-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][N:26]2[CH2:27][CH2:28][N:29]([CH:11]([CH3:12])[CH2:10][C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:30][CH2:31]2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: CC(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc(CCN2CCNCC2)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CCO
Product: CC(Cc1ccc([N+](=O)[O-])cc1)N1CCN(CCc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 1 h

Procedure:
4-Nitrophenylacetone (33 mg, 0.18 mmol) and 1-[2-(4-nitrophenyl)ethyl]piperazine hydrochloride (50 mg, 0.18 mmol) were added to Titanium(IV) Isopropoxide (110 μl, 0.37 mmol) and stirred for 1 hour. Ethanol was added followed by sodium cyanoborohydride (23 mg, 0.37 mmol) and stirred at room temperature overnight. Poured into 1N NaOH and extracted with ethyl acetate then washed with brine, dried and evaporated to dryness. The residue was purified by mass directed HPLC to yield 1-[2-(4-nitrophenyl)ethyl]-4-[1-(4-nitrophenyl)propan-2-yl]piperazine. LC-MS (IE, m/z): 399 [M+1]+. 1H-NMR (500 MHz, DMSO) δ ppm 8.19 (t, J=8.5 Hz, 4H), 7.56 (d, J=9.7 Hz, 2H), 7.54 (d, J=9.7 Hz, 2H), 2.76-4.4 (m, 15H), 1.02 (d, J=6.1 Hz, 3H). (0.24 μM)
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:11]=[CH:10][NH:9][C:7](=O)[C:5]=2[CH:6]=1.C(=O)([O-])[O-].[Na+].[Na+].P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:10]1[N:9]=[CH:7][C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[N:11]=1
Reactant: O=c1[nH]cnc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Clc1ncc2ccccc2n1

Procedure:
A portion of the quinazolinone (4.46 gm, 0.02 moles) was refluxed in phosphorous oxychloride (20 mL) for one hour. After cooling, the solution was carefully poured into cold 20% sodium carbonate solution (500 mL). The solid chloroquinazoline was isolated by filtration, washed with water and dissolved in methylene chloride (400 mL). The solution was dried over magnesium sulfate, filtered and stripped to give the chloroquinazoline as a pale yellow solid in a yield of 3.7 gm, 76.5%. The 4-chloroquinazoline (3.7 gm, 0.015 moles) was refluxed in ethanol with N-2-aminoethylmorpholine (3.99 gm, 0.031 moles) for one hour. Once cooled, the solution was stripped and the residue was dissolved in water (400 mL). The solution was made basic by the addition of sodium carbonate and the product was extracted into methylene chloride (2×100 mL). The combined extracts were washed with water (50 mL) and were then dried over magnesium sulfate. After filtration, the extracts were stripped to give the product as a tan solid. The solid was recrystallized from ethyl acetate (25 mL) and hexane (50 mL). The product, 203-93 was isolated as an off white solid in a yield of 2.86 gm, 56.0%.
Reaction SMILES: C[O:2][C:3]1[C:8]([N:9]2[CH2:30][CH2:29][C:12]3([C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)=[CH:7][CH:6]=[CH:5][N:4]=1.[Na+].[I-].C[Si](Cl)(C)C.Cl.S(=O)(O)[O-].[Na+]>C(#N)C.[Cl-].[Na+].O.CCOC(C)=O>[OH:2][C:3]1[C:8]([N:9]2[CH2:10][CH2:11][C:12]3([C:16](=[O:17])[N:15]([C:18]4[CH:19]=[CH:20][C:21]([O:24][C:25]([F:27])([F:28])[F:26])=[CH:22][CH:23]=4)[CH2:14][CH2:13]3)[CH2:29][CH2:30]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: O=S([O-])O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(c1cccnc1O)CC2
Temperature: 25 °C
Yield: 64.6 %

Procedure:
To a solution of 8-(2-methoxy-pyridin-3-yl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 9, 40 mg, 0.095 mmol) in acetonitrile (2 mL) at 0° C. was added NaI (28.5 mg, 0.19 mmol). TMSCl (24 uL, 0.19 mmol) was added, and the mixture was stirred and allowed to warm to rt over overnight. 1N Hydrochloric acid (1 mL), 38% aqueous sodium bisulfite solution (0.5 mL), brine and EtOAc (10 mL) were added, and the mixture was stirred for 30 min. The phases were separated, and the aqueous phase was extracted with additional EtOAc. The combined organic phases were washed with sat. NaHCO3, brine, dried (Na2SO4), filtered and evaporated under reduced pressure to yield the title compound as a light green solid (25 mg, 65%). MS (ESI): 408.3 (MH+).
Reaction SMILES: CC(C)([O-])C.[K+].F[C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[C:17]([F:20])([F:19])[F:18])[C:11]([OH:13])=[O:12].[CH2:21]([OH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>CS(C)=O>[CH2:21]([O:28][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[C:17]([F:20])([F:19])[F:18])[C:11]([OH:13])=[O:12])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)c(F)c1
Reactant: OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)c1ccc(C(F)(F)F)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Potassium tert-butoxide (816 mg, 7.28 mmol) was added to a solution of 3-fluoro-4-trifluoromethyl-benzoic acid (682 mg, 3.28 mmol) and benzyl alcohol (471 mg, 4.36 mmol) in DMSO (7.3 ml), and the mixture was stirred at room temperature for 16 hours. The reaction solution was made acidic by adding concentrated hydrochloric acid, and the precipitated insoluble matter was then filtered off. The resulting solid was washed with water and then dried to give 3-benzyloxy-4-trifluoromethyl-benzoic acid as a crude compound.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16](Cl)=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)C(C)C)(C)C.[Cl:30][C:31]1[N:32]([CH2:39][C:40]([OH:44])([CH3:43])[CH2:41][OH:42])[CH:33]=[C:34]([N+:36]([O-:38])=[O:37])[N:35]=1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:42][CH2:41][C:40]([OH:44])([CH3:43])[CH2:39][N:32]3[CH:33]=[C:34]([N+:36]([O-:38])=[O:37])[N:35]=[C:31]3[Cl:30])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: O=C(Cl)N1CCN(c2ccc(OC(F)(F)F)cc2)CC1
Reactant: CC(O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(O)(COC(=O)N1CCN(c2ccc(OC(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 55.6 %

Procedure:
4-(4-Trifluoromethoxyphenyl)piperazine-1-carbonylchloride (0.26 g, 0.85 mmol), N,N-diisopropylethylamine (0.30 ml, 1.7 mmol) and 4-dimethylaminopyridine (21 mg, 0.17 mmol) were added to a suspension of 2-chloro-1-(2,3-dihydroxy-2-methylpropyl)-4-nitroimidazol prepared in Example 3 (0.30 g, 1.3 mmol) in toluene (5 ml) followed by stirring at 100° C. for 2.5 hours. The mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=9/1) to afford 3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 4-(4-trifluoromethoxyphenyl)piperazine-1-carboxylate (0.24 g, yield 55%) as a light yellow oil.
Reaction SMILES: [C:1]1([CH2:11][C:12](=[CH2:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[SH:25][CH2:26][CH2:27][OH:28]>C(OCC)C>[OH:28][CH2:27][CH2:26][S:25][CH2:18][CH:12]([CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: C=C(Cc1cccc2ccccc12)C(=O)OCC
Reactant: OCCS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCOC(=O)C(CSCCO)Cc1cccc2ccccc12
Temperature: 25 °C

Procedure:
2.04 g of ethyl 2-(1-naphthyl)methyl-2-propenoate was dissolved in 714 μl of 2-mercaptoethanol, and 102 mg of potassium tert-butoxide was added thereto at room temperature under stirring. The mixture was stirred at room temperature for 15 minutes. 500 μl of 2-mercaptoethanol was added thereto and the mixture was stirred for 15 minutes. Then, the reaction solution was diluted with 150 ml of diethyl ether. The diethyl ether layer was washed with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 2.81 g of ethyl (2RS)-3-(2-hydroxyethyl)thio-2-(1-naphthylmethyl)propionate as colorless oily substance.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[OH:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1>>[CH3:37][O:36][C:33]1[CH:34]=[CH:35][C:30]([O:29][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=2)=[CH:31][CH:32]=1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Reactant: COc1ccc(O)cc1
Product: COc1ccc(OCc2ccc(-c3nccnc3NS(=O)(=O)c3ccccc3C(F)(F)F)cc2)cc1
Yield: 48 %

Procedure:
Following the general method as outlined in Example 1 (Method 8), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 4-hydroxyanisole, the title compound was isolated as a yellow solid in 48% yield (91% purity by HPLC).
Reaction SMILES: Cl.[NH2:2][OH:3].[F:4][C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)=O.[OH-].[Na+].Cl>O.C(O)C>[F:4][C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[C:8](=[N:2][OH:3])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: O=C(c1cccc(F)c1)c1cccc(F)c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=C(c1cccc(F)c1)c1cccc(F)c1
Temperature: 20 °C
Yield: 96.7 %

Procedure:
3-3′-Difluorobenzophenone oxime may be prepared according to the following procedure: a solution of 1.6 g of hydroxylamine hydrochloride in 8 cm3 of water is poured dropwise into a solution of 5.0 g of 3,3′-difluorobenzophenone in 10 cm3 of ethanol, and then 1.2 g of sodium hydroxide pellets are added in small fractions. The reaction mixture, heated under reflux for 10 minutes, is cooled to 20° C. and then acidified with 7.5 cm3 of 4 N hydrochloric acid. Once triturated, the oily precipitate obtained becomes a white solid which is filtered, washed with water and then dried at 35° C. under reduced pressure (2.7 kPa). 5.17 g of 3,3′-difluorobenzophenone oxime are obtained in the form of a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH3:20])[CH:18]=[N:19][C:4]=2[CH:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][O:25][C:24]2[CH:28]=[C:29](B3OC(C)(C)C(C)(C)O3)[CH:30]=[CH:31][C:23]1=2>>[CH3:20][N:17]1[C:5]2[C:6]([O:8][C@@H:9]([C@H:11]3[CH2:15][NH:14][C:13](=[O:16])[CH2:12]3)[CH3:10])=[N:7][C:2]([C:29]3[CH:30]=[CH:31][C:23]4[N:22]([CH3:21])[CH2:27][CH2:26][O:25][C:24]=4[CH:28]=3)=[CH:3][C:4]=2[N:19]=[CH:18]1
Reactant: CN1CCOc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Product: C[C@@H](Oc1nc(-c2ccc3c(c2)OCCN3C)cc2ncn(C)c12)[C@H]1CNC(=O)C1

Procedure:
Following General Procedure B, beginning with (R)-4-((R)-1-(6-chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 2.06 (22.1 mg, 0.075 mmol) and 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (25 mg, 0.091 mmol) (R)-4-((R)-1-(3-methyl-6-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3B.06 was synthesized.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]2[C:22]([CH3:25])([CH3:24])[N:10]3[CH2:11][CH2:12][C:13]4[C:18]([C:9]3=[CH:8][C:7]=2[CH:6]=[CH:5][C:4]=1[O:26][CH3:27])=[CH:17][C:16]1[O:19][CH2:20][O:21][C:15]=1[CH:14]=4.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:23]2[C:22]([CH3:24])([CH3:25])[N:10]3[CH2:11][CH2:12][C:13]4[C:18]([CH:9]3[CH2:8][C:7]=2[CH:6]=[CH:5][C:4]=1[O:26][CH3:27])=[CH:17][C:16]1[O:19][CH2:20][O:21][C:15]=1[CH:14]=4
Reactant: COc1ccc2c(c1OC)C(C)(C)N1CCc3cc4c(cc3C1=C2)OCO4
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1OC)C(C)(C)N1CCc3cc4c(cc3C1C2)OCO4
Temperature: 0 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 9,10-dimethoxy-8,8-dimethyl-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (600 mg, 1.64 mmol) in methanol (50 mL) was added sodium borohydride (65 mg, 1.7 mmol) in small portions at 0° C. After stirring at 0° C. for 2 h, the mixture was concentrated in vacuo. The resulting residue was extracted with diethyl ether (2×50 mL), washed with water (2×25 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 9,10-dimethoxy-8,8-dimethyl-5,8,13,13a-tetrahydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (0.5 g, 83%). LC/MS m/e calcd for C22H25NO4 (M+H)+: 368.45, observed: 368.1; 1H NMR (400 MHz, MeOD) δ ppm 1.51 (s, 3 H) 1.72 (s, 3 H) 2.63-2.84 (m, 3 H) 2.84-2.93 (m, 1 H) 3.06 (dd, J=16.17, 3.79 Hz, 1 H) 3.21-3.28 (m, 1 H) 3.83 (s, 3 H) 3.86 (s, 3 H) 4.09 (dd, J=11.37, 3.54 Hz, 1 H) 5.88 (s, 2 H) 6.58 (s, 1 H) 6.75 (s, 1 H) 6.80-6.85 (m, 1 H) 6.86-6.91 (m, 1 H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([O:10][CH:11]2[CH2:16][NH:15][CH2:14][C:13]3[O:17][CH:18]=[CH:19][C:12]2=3)[CH:6]=[CH:7][C:8]=1[Cl:9].C(=O)([O-])[O-].[Cs+].[Cs+].[C:26]([O:30][C:31]([NH:33][CH2:34][CH2:35]Br)=[O:32])([CH3:29])([CH3:28])[CH3:27]>CN(C=O)C>[C:26]([O:30][C:31]([NH:33][CH2:34][CH2:35][N:15]1[CH2:16][CH:11]([O:10][C:5]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=2)[C:12]2[CH:19]=[CH:18][O:17][C:13]=2[CH2:14]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: Clc1ccc(OC2CNCc3occc32)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCN1Cc2occc2C(Oc2ccc(Cl)c(Cl)c2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 26.3 %

Procedure:
4-(3,4-Dichlorophenyloxy)-4,5,6,7-tetrahydrofuro-[2,3-c]pyridine hydrochloride (Example 119) (100 mg) was dissolved in 2 mL of DMF and then 256 mg of cesium carbonate and 87 mg of N-(tert-butoxycarbonyl)-2-bromoethylamine were added successively thereto. This reaction solution was heated at 80° C. with stirring overnight and poured over 30 mL of ice water followed by extracting with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom in vacuo. The residue was purified by silica gel column chromatography to give 35 mg of the objective product as an oily substance.
Reaction SMILES: [P:1]([O-:5])([O-:4])([O-:3])=[O:2].[C:6]([OH:27])(=[O:26])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].Cl.C([O:34]C(C1C=CC(O)=CC=1)=O)CC(C)C>CS(C)=O.O.[Cl-].[Ca+2].[Cl-].C([C@H](N)C(O)=O)CC(N[C@H](C(NCC(O)=O)=O)CS)=O.C(OCC)(=O)C>[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[CH3:25][CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=[CH:19][CH2:18][CH:17]=[CH:16][CH2:15][CH:14]=[CH:13][CH:12]=[CH:11][CH:10]([OH:34])[CH2:9][CH2:8][CH2:7][C:6]([OH:27])=[O:26]
Reactant: CC(C)CCOC(=O)c1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCCCCCCC(=O)O
Agent: Cl
Agent: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCCCCC=CCC=CCC=CC=CC(O)CCCC(=O)O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Into 5 μl of a solution of the test compound in dimethylsulfoxide, 750 μl of a 1/15M phosphate buffer (pH 7.4) which was prepared by dissolving a wrapper of phosphate buffer powder (Yatron) in 10 ml of water, 40 μl of a 30 mM aqueous calcium chloride solution, 50 μl of a 20 mM aqueous GSH (glutathione, reduced form) solution, 50 μl of a 40 mM aqueous ATP (adenosine-5-triphosphate) solution and 100 μl of guinea pig polymorphonuclear leukocyte enzyme were added, followed by stirring at 25° C. for 5 minutes. To initiate the reaction, 5 μl of arachidic acid (10 mg/ml ethanol) were added to said mixture and the mixture was stirred at 25° C. for 5 minutes. 50 μl of 2N hydrochloric acid were added to the reaction mixture to terminate the reaction. 2.0 ml of ethyl acetate containing an internal standard substance (internal standard substance: 2 μg/ml of isoamyl paraben) were then added to the reaction mixture. The resulting mixture was extracted for 1 minute by a mixer, followed by centrifugal separation at 3000 rpm for 5 minutes. The ethyl acetate layer was separated, evaporated to dryness under reduced pressure and then dissolved in 200 μl of acetonitrile. By high-performance liquid chromatography, the amount of 5-HETE formed was determined. From the determination of 5-HETE of the control without the test compounds and that of the test compounds, an inhibition rate (%) was found and the 50% inhibition concentration of the test compounds against 5-lipoxygenase was determined. The results are shown in Table 12.