Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[Na].[NH:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=O)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.[N:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[N+:17]=[N-:18]>O.CO>[N:16](/[C:19](=[CH:14]\[C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[NH:5][CH:6]=[CH:7]2)/[C:20]([O:22][CH3:23])=[O:21])=[N+:17]=[N-:18]
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: COC(=O)CN=[N+]=[N-]
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC(=O)/C(=C/c1ccc2[nH]ccc2c1)N=[N+]=[N-]
Reaction time: 5 h
Yield: 76.7 %

Procedure:
Under nitrogen, to a sodium methoxide solution (prepared from 15 ml of methanol and 0.66 g (29 mmol) of sodium) a mixture of 1.02 g (7 mmol) of indole-5-carbaldehyde [Helv. Chim. Acta, 1616. (1968)], 3.34 g (29 mmol) of methyl azido-acetate and 7 ml of methanol is added dropwise at 0° C. and the so obtained mixture is stirred at this temperature for 5 h. Then the reaction mixture is diluted with 50 ml of water, and extracted three times with: 50 ml of chloroform. The combined organic layers are washed with 20 ml of water, filtered through a phase separating filter-paper and concentrated to yield 1.3 g (77%) of the title compound. Mp.: 130-133° C. (chloroform).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][S:9][C:4]=2[CH:3]=1.[N+:13]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:13]([C:16]1[CH:21]=[C:20]([C:2]2[CH:12]=[CH:11][C:5]3[NH:6][C:7](=[O:10])[CH2:8][S:9][C:4]=3[CH:3]=2)[CH:19]=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: O=C1CSc2cc(Br)ccc2N1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: O=C1CSc2cc(-c3cccc([N+](=O)[O-])c3)ccc2N1
Temperature: 25 °C

Procedure:
A solution of 7-bromo-4H-benzo[1,4]thiazin-3-one (2 g, 8.2 mmol), 3-nitrophenyl boronic acid (2.72 g, 16.4 mmol), potassium carbonate (6.85 g, 49.2 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.95 g, 0.82 mmol) in dimethoxyethane (100 ml), ethanol (25 ml), and water (25 ml) was heated to reflux for 6 hours. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with water, then brine, dried (MgSO4) and evaporated to obtain crude 7-(3-nitro-phenyl)-4H-benzo[1,4]thiazin-3-one (0.15 g, 6%). Recrystallization of crude sample from EtOAc afforded the title compound: mp 290-292° C.; MS (EI) m/z 286 (M+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[C:8]([Cl:16])=[CH:9][C:10]([Cl:15])=[C:11]([CH2:13][OH:14])[CH:12]=1.O1C[CH2:20][CH2:19][CH2:18]1.[H-].[Na+].C(Br)C=C>O>[CH2:20]([O:14][CH2:13][C:11]1[CH:12]=[C:7]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]([Cl:16])=[CH:9][C:10]=1[Cl:15])[CH:19]=[CH2:18]
Reactant: C1CCOC1
Reactant: OCc1cc(-c2ncccn2)c(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C=CCBr
Product: C=CCOCc1cc(-c2ncccn2)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 250 ml single neck round bottom flask equipped with a reflux condensor and an argon inlet was added 5.10 gm of the 5-pyrimidyl-2,4-dichlorophenylcarbinol and 100 of anhydrous tetrahydrofuran. The system was cooled to 0° C. and after cooling 0.53 gm sodium hydride added. The system was stirred for 20 additional minutes and 2.1 ml of allyl bromide was then added. The system was allowed to come to room temperature over 1/2-hour and stirred there for an additional 2 hours. Afterwards the system was heated at reflux for 17 hours. At this time, water was added to the system and the product extracted with methylene chloride. The methylene chloride was then washed with water and then dried over sodium sulfate. The methylene chloride was removed by stripping to give 5.47 gm of the 5-pyrimidyl-2,4-dichlorophenylcarbinol allylether as an orange liquid and listed as Compound No. 2, Table I.
Reaction SMILES: CC(C)([S@@]([NH:6][C@H:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)[CH3:8])=O)C.Cl.O1CCOCC1.C([O-])(O)=O.[Na+]>CO>[NH2:6][CH:7]([CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:13][CH2:14]1)[CH3:8]
Reactant: C[C@H](N[S@@](=O)C(C)(C)C)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CC(N)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.5 %

Procedure:
To a 1 L round bottomed flask charged with a magnetic stir bar was added crude tert-butyl 4-((S)-1-((S)-1,1-dimethylethylsulfinamido)ethyl)piperidine-1-carboxylate (29 g) was taken up in MeOH (200 mL) before addition of a 4 N solution of HCl in 1,4-dioxane (24.06 ml, 96 mmol). The resulting solution was then stirred at room temperature for 1 h at rt. The methanol was then removed in vacuo to afford viscous oil which was treated with sat'd aqueous NaHCO3 (˜500 mL) and extracted with ethyl acetate (2×500 mL). This organic phase was combined, dried with MgSO4, filtered, and solvent was then removed in vacuo affording the title compound (22 g) which was used without further purification.
Reaction SMILES: Br[C:2]1[N:3]([CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.ClCC(N(C)C)=O.C([O-])([O-])=O.[Na+].[Na+].[CH3:40][O:41][C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][N:43]=1>O1CCOCC1>[CH:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=3)[N:3]([CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[C:2]=2[C:45]2[CH:44]=[N:43][C:42]([O:41][CH3:40])=[CH:47][CH:46]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC(=O)N(C)C)c2c1
Reactant: COc1ccc(B(O)O)cn1
Agent: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OC)nc3)n(CC(=O)N(C)C)c2c1
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of methyl 2-bromo-3-cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-1H-indole-6-carboxylate (1 eq), prepared as described in Example 3, Step 1, but using 2-chloro-N,N-dimethylacetamide in the alkylation step, in dioxane (0.06 M) was added bistriphenylphosphine-palladium dichloride (0.2 eq). The reaction mixture was left at RT under nitrogen atmosphere for 15 min, at that rime an aqueous solution of Na2CO3 (2 M), (2.93 eq) and 2-methoxy-5-pyridineboronic acid (2.5 eq) were added. The reaction mixture was heated to reflux for 2 h, then was cooled to RT and concentrated in vacuo. The residue was diluted with DCM, filtered and washed with water, brine, dried over Na2SO4, filtered and evaporated in vacuo to give the title compound (85%). 1H NMR (400 MHz; DMSO-d6, 300 K) δ 1.20-1.28 (m, 3H), 1.65-1.85 (m, 7H), 2.50-2.54 (m, 1H), 2.8 (s, 3H), 2.9 (s, 3H), 3.87 (s, 3H), 3.93 (s, 3H), 4.92 (s, 2H), 6.97 (d, J 8.4, 1H), 7.62 (d, J 8.8, 1H), 7.67 (d, J 8.8, 1H), 7.85 (d, J 8.4, 1H), 7.99 (s, 1H), 8.11 (s, 1H); MS (ES+) m/z 450 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]1CC(=C)C[O:10][C@@H:9]1[C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CC[O:29]CC1.S(=O)(O)[O-].[Na+].C(OCC)(=O)C.[C:44]([OH:48])([CH3:47])([CH3:46])[CH3:45]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[OH:48][C:44]1([CH2:47][OH:29])[CH2:46][O:10][C@H:9]([C:15]2[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=2[F:23])[C@@H:8]([NH:7][C:6](=[O:24])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:45]1
Reactant: C=C1CO[C@H](c2cc(F)c(F)cc2F)[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC(O)(CO)CO[C@@H]1c1cc(F)c(F)cc1F
Reaction time: 48 h

Procedure:
To a solution of tert-butyl[(2R,3S)-5-methylene-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl]carbamate (203 mg, 0.59 mmol) in tert-butyl alcohol (6 mL), acetone (3 mL) and water (1.5 mL) was added osmium tetroxide (0.113 mL of 2.5% solution in tert-butyl alcohol, 0.009 mmol). The resultant mixture was stirred at room temperature for 10 minutes and then treated with N-methylmorpholine N-oxide (92 mg, 0.79 mmol) and stirred. After two days, the reaction mixture was treated with aqueous sodium bisulfite solution (5 mL, 2.0/V) followed after 10 min by ethyl acetate. The organic layer was washed successively with 2N hydrochloric acid and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and evaporated to yield tert-butyl [(2R,3S)-5-hydroxy-5-(hydroxymethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl]carbamate which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=O)=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11](=[O:12])[N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:27])([F:26])[F:28])=[N:20][C:21]([C:22]([N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)=[O:24])=[C:15]2[CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCCC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 73.6 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (150 mg, 0.27 mmol), pyrrolidine (38.4 mg, 0.54 mmol) and bis(2-oxo-3-oxazolidinyl) phosphonic chloride (0.138 g, 0.54 mmol) were dissolved in 8 mL of dichloromethane under stirring, and triethylamine (0.25 mL, 1.62 mmol) was then added to the solution. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-oxo-3-[1-(pyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 12a (120 mg, yield 74%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].[C:36]([O:41][CH2:42]Cl)(=[O:40])[CH:37]([CH3:39])[CH3:38].[CH3:44]N(C=O)C>CCOC(C)=O>[C:36]([O:41][CH:42]([N:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]2[C:16]([C:17](=[O:18])[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=2[F:33])=[CH:15]1)[CH3:44])(=[O:40])[CH:37]([CH3:39])[CH3:38]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Reactant: CN(C)C=O
Reactant: CC(C)C(=O)OCCl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(C)OC(=O)C(C)C)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 10 °C
Reaction time: 3 h
Yield: 63.3 %

Procedure:
To a mixture of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.5 g, 1.02 mmol) and potassium hydroxide (115 mg, 2.04 mmol) in anhydrous DMF (4 mL) was added a solution of chloromethyl isobutyrate (37 mg, 0.25 mmol) in anhydrous DMF (1 mL) over 30 min at 10° C. The reaction was stirred at 10° C. for 3 h, then diluted with EtOAc (40 mL) and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=5/1 to 4/1) to afford the title compound as a white solid (0.39 g, 63.3%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@@H:12]([CH2:13][O:14][C:15](=[O:17])[NH2:16])[N:11]([OH:18])[C:10]1=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:30]>C(#N)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C@@H:12]([CH2:13][O:14][C:15](=[O:17])[NH2:16])[N:11]([O:18][CH2:28][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[C:10]1=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(O)[C@@H]1COC(N)=O
Reactant: O=C(CBr)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(OCC(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1COC(N)=O

Procedure:
In 40 ml of acetonitrile is dissolved 650 mg of (3S,4S)3-(tert-butoxycarbonylamino)-4-carbamoyloxymethyl-1-hydroxy-2-azetidinone, and 0.39 ml of triethylamine and 712 mg of p-nitrobenzyl bromoacetate are added to the solution under ice-cooling with stirring. The reaction solution is stirred at room temperature (15°-25° C.) for 3.5 hours. The solvent is distilled off under reduced pressure, and 50 ml of a mixed solution (1:1) of ethyl acetate and tetrahydrofuran and 50 ml of water are added to the residue. The organic layer is separated, washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The remaining crystals are treated with 15 ml of a mixed solution (1:2) of ether and hexane and filtered to give 98 mg (88.6%) of the above-identified comoound as crystals, m.p. 189°-191° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:15])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:16][O:17]C(Cl)Cl.Cl>ClCCl.C(OCC)(=O)C.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH3:15])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:7][C:8]=1[CH:16]=[O:17]
Reactant: COC(Cl)Cl
Reactant: COc1ccc(C2(C)CCOCC2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(C2(C)CCOCC2)cc1C=O
Reaction time: 0.33 h
Yield: 122.3 %

Procedure:
A solution of 4-(4-methoxyphenyl)-4-methyltetrahydro-2H-pyran (0.518 g, 2.51 mmol) in dichloromethane (12.0 mL) was cooled to −15° C., and titanium tetrachloride (1.22 mL, 11.0 mmol) was added dropwise thereto. After stirring the mixture for 20 minutes, dichloromethyl methyl ether (0.336 mL, 3.77 mmol) was added dropwise thereto. After stirring the mixture for 1 hour, 1 mol/L hydrochloric acid was added to stop the reaction. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with water and then with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was then evaporated under reduced pressure to obtain 0.719 g of the crude product containing the captioned compound.
Reaction SMILES: [NH2:1][O:2][CH:3]([CH3:8])[CH2:4][CH2:5][C:6]#[N:7].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14](S(Cl)(=O)=O)=[CH:13][CH:12]=1.[CH:21](N(C(C)C)CC)(C)C.S(Cl)(Cl)(=O)=O.[OH-].[Na+]>C1COCC1.CN(C1C=CN=CC=1)C.C(OCC)C>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:21][NH:1][O:2][CH:3]([CH3:8])[CH2:4][CH2:5][C:6]#[N:7])=[CH:13][CH:12]=1
Reactant: CC(CCC#N)ON
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O=S(=O)(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(CNOC(C)CCC#N)cc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 64 %

Procedure:
4-(aminooxy)pentanenitrile (1.3 mmol, 150 mg) and 4-methoxybenzenesulfonylchloride (1.3 mmol, 272 mg) were combined in anhydrous THF with diisopropylethylamine (1.4 mmol, 0.69 mL) and a few crystals of DMAP. The reaction was stirred at 50° C. for 15 hours. The reaction was diluted in diethyl ether, washed with 1N HCl, 1N NaOH and brine and dried over mangesium sulfate. NMR analysis revealed that the isolated crude was the double sulfonyl chloride addition product. The aqueous NaOH fraction was acidified to neutral pH, extracted into ethyl acetate and dried over magnesium sulfate. The solvent was removed under vacuum leaving a very clean 195 mg (52%) crude product. Rf=0.4 (0.1:1 hexanes/ethyl acetate); H1-NMR (CDCl3): δ 7.82 (2H,d), 7.01 (2H,d), 6.84 (1H,s), 4.17 (1H,m), 3.88 (3H,s), 2.42 (2H,m), 1.88 (2H,m), 1.23 (3H,d).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][C:5](C)=[CH:6][C:7](=[O:17])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.OCC1OC=CC(=O)C=1O.C(Br)C1C=CC=CC=1>>[OH:1][CH2:2][C:3]1[O:4][CH:5]=[CH:6][C:7](=[O:17])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(CO)o1
Agent: BrCc1ccccc1
Agent: O=c1ccoc(CO)c1O
Product: O=c1ccoc(CO)c1OCc1ccccc1

Procedure:
The title compound was prepared by the method outlined for 2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one, using 7.1 g (50 mmol, 1 eq.) of 2-hydroxymethyl-3-hydroxy-pyran-4(1H)-one and 9.5 g benzyl bromide (55 mmol 1.1 eq.) to yield the crude product as an organic oil. Further purification by column chromatography on silica gel (eluant: 10% CH3OH/90% CHCl3) furnished the pure product (9.4 g, 81%) as a bright yellow oil. (Looker and Clifton (1986).
Reaction SMILES: [F:1][C@@:2]([CH3:29])([C:6]([NH:8][C@@H:9]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][O:19][CH3:20])[C:13]2[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=2[C:11]2[CH:25]=[CH:26][CH:27]=[CH:28][C:10]1=2)=[O:7])[C:3]([OH:5])=O.[F:30][C:31]([F:38])([C:34]([F:37])([F:36])[F:35])[CH2:32][NH2:33]>>[F:1][C@:2]([CH3:29])([C:3]([NH:33][CH2:32][C:31]([F:38])([F:30])[C:34]([F:37])([F:36])[F:35])=[O:5])[C:6]([NH:8][C@@H:9]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][O:19][CH3:20])[C:13]2[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=2[C:11]2[CH:25]=[CH:26][CH:27]=[CH:28][C:10]1=2)=[O:7]
Reactant: COCCN1C(=O)[C@@H](NC(=O)[C@](C)(F)C(=O)O)c2ccccc2-c2ccccc21
Reactant: NCC(F)(F)C(F)(F)F
Product: COCCN1C(=O)[C@@H](NC(=O)[C@](C)(F)C(=O)NCC(F)(F)C(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Using (S)-2-fluoro-N—[(S)-5-(2-methoxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-2-methyl-malonamic acid and 2,2,3,3,3-pentafluoropropylamine, the title compound was prepared in the same manner as described for example 1c. White solid (71%). MS: m/e=532(M+H+).
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:32])=[C:7]([CH:15]([C:17]2[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[C:19]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:18]=2[OH:31])Br)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(O)(=O)C>C(O)C>[C:1]([C:5]1[C:6](=[O:32])[C:7](=[CH:15][C:17]2[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[C:19]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:18]=2[OH:31])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(C(Br)c2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)C1=CC(=Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)C(=O)C(C(C)(C)C)=C1
Reaction time: 0.33 h

Procedure:
Three tenths of a part of the di-(3,5-di-tert-butyl-2-hydroxyphenyl) bromomethane produced above is dissolved in 20 parts of ethanol and placed in the reaction vessel just above described. One part of 5 percent aqueous sodium hydroxide solution is added and a slow current of nitrogen is passed through the solution for 20 minutes. The reaction mixture is poured into a vessel containing crushed ice, neutralized with acetic acid and extracted with ether. The ether is evaporated and the residue crystallized twice from aqueous ethanol to yield (3,5-di-tert-butyl-2-oxo-3,5-cyclohexadien-1-ylidene)-(3,5-di-tert-butyl-2-hydroxyphenyl) methane.
Reaction SMILES: C(O)C.O1CCCC1.[O:9]1[CH2:13][CH2:12][O:11][CH:10]1[C:14]1[CH:15]=[CH:16][C:17]([CH:20]=[O:21])=[N:18][CH:19]=1.[BH4-].[Na+]>O>[O:9]1[CH2:13][CH2:12][O:11][CH:10]1[C:14]1[CH:15]=[CH:16][C:17]([CH2:20][OH:21])=[N:18][CH:19]=1
Reactant: O=Cc1ccc(C2OCCO2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: OCc1ccc(C2OCCO2)cn1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 78.3 %

Procedure:
To an ethanol (20 mL) and tetrahydrofuran (20 mL) solution of 5-[1,3]dioxolan-2-yl-pyridine-2-carbaldehyde (1.73 g, 9.66 mmol) described in Manufacturing Example 154-1-3 was added sodium borohydride (731 mg, 19.3 mmol), which was stirred for 25 minutes at room temperature. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:2) to obtain the title compound (1.37 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].Br[CH2:20][CH2:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.Br>C(#N)C>[Br-:10].[C:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N+:5]([CH2:20][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)=[CH:4]1)([OH:18])=[O:17]
Reactant: Clc1nc[nH]c1Cl
Reactant: BrCCc1cccc2ccccc12
Reactant: O=C(O)CCCCCBr
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: O=C(O)CCCCCn1c[n+](CCc2cccc3ccccc23)c(Cl)c1Cl
Product: [Br-]

Procedure:
4,5-dichloroimidazole (1.00 g, 7.36 mmol) was dissolved in acetonitrile. Potassium hydroxide (0.828 g, 14.72 mmol) was added to the solution and allowed to reflux for 30 min. 1 equivalent of 6-bromohexanoic acid (1.44 g, 7.36 mmol) was added to the solution and refluxed for 5 h. Solution was filtered to remove the KBr precipitate and placed back onto reflux. An equivalent of 1-(2-bromoethyl)naphthalene (1.73 g, 7.36 mmol) was added to solution and refluxed for 2.5 h. The solution was neutralized with 6M HBr, volatiles removed in vacuo, and the resulting product will be collected and analyzed.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5](=[O:8])[NH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[O:15]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>C(#N)C>[CH3:1][O:2][C:3]1[N:4]([CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:23]=2)[C:5](=[O:8])[NH:6][N:7]=1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: COc1n[nH]c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1n[nH]c(=O)n1Cc1cccc(Oc2ccccc2)c1
Reaction time: 5.5 h
Yield: 18.2 %

Procedure:
To a solution of 575 mg (5 mmol) of 5-methoxy-2,4-dihydro-3H-1,2,4-triazol-3-one in 7 ml of dry acetonitrile was added 726 mg (5.25 mmol) of potassium carbonate was added. A solution of 1.32 g (5 mmol) of 3-phenoxybenzylbromide in 9 ml of dry acetonitrile was added dropwise thereto at 55° C. After the mixture was stirred at the same temperature for additional 5.5 hours, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. To the resultant solid residue (1.36 g) was added a mixture of equal amounts of tert-butyl methyl ether and n-hexane. The mixture was cooled and the deposited solid was washed, ice-cooled, collected by filtration, and dried to obtain a residue. The residue was recrystallized from tert-butyl methyl ether to obtain 0.27 g of 5-methoxy-4-(3-phenoxybenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one as white powder.