Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[O:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[C:16](O)[C:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][N:13]=2)[CH2:8][CH2:7]1.C(O)C.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>O>[O:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[C:16]([N:30]([CH2:31][CH3:32])[CH2:28][CH3:29])[C:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][N:13]=2)[CH2:8][CH2:7]1
Reactant: CCNCC
Reactant: CCOC(=O)Cc1cnc(N2CCOCC2)nc1O
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)Cc1cnc(N2CCOCC2)nc1N(CC)CC
Yield: 69.5 %

Procedure:
Phosphorus oxychloride (11.7 ml) was added to 3.35 g (12.5 mmoles) of ethyl 2-morpholino-4-hydroxypyrimidine-5-acetate, and the mixture was heated under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, and methylene chloride and ice water were added. It was neutralized with sodium hydrogen carbonate. The methylene chloride layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the product were added 15 ml of ethanol and 7.0 g (95.7 mmoles) of diethylamine, and in an autoclave, the mixture was reacted at 120 ° C. for 7 hours. Water was added, and the mixture was extracted with methylene chloride. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give 2.8 g (yield 56%) of the desired compound as an oil.
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[C:6]([Cl:8])[Cl:7])C.O1CCCC1.[OH-].[Li+].Cl>O>[Cl:7][C:6]([Cl:8])=[C:5]([C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)[C:4]([OH:19])=[O:3]
Reactant: CCOC(=O)C(=C(Cl)Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(=C(Cl)Cl)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
P1.2): 650 mg of 3,3-dichloro-2-(4-trifluoromethyl-phenyl)-acrylic acid ethyl ester are introduced into 4 ml of tetrahydrofuran. 100 mg of lithium hydroxide in 1.5 ml of water are then added and the mixture is stirred at room temperature for 16 hours. After a further 4 hours at 40° C., the reaction mixture is poured into water, rendered acidic with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phases are washed twice with water and concentrated. 3,3-Dichloro-2-(4-trifluoromethyl-phenyl)-acrylic acid is obtained.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([C:24](=O)[CH3:25])[CH:21]=[CH:22][CH:23]=3)=[CH:14][C:12]=2[CH:13]=1.Cl.[NH2:28][OH:29].C([O-])([O-])=O.[Na+].[Na+]>CO>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([C:24](=[N:28][OH:29])[CH3:25])[CH:21]=[CH:22][CH:23]=3)=[CH:14][C:12]=2[CH:13]=1
Reactant: CC(=O)c1cccc(-c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=NO)c1cccc(-c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Example 136C (240 mg, 0.5 mmol) and hydroxylamine hydrochloride (139 mg, 2.00 mmol) were dissolved into methanol (2 mL) and treated with Na2CO3 (318 mg, 3.0 mmol). The suspension was stirred at room temperature overnight and then heated at 70° C. three days. The mixture was cooled to room temperature and filtered, the solids being rinsed with 50% MeOH/CH2Cl2. The filtrate was concentrated, then partitioned between water and MeOH/CH2Cl2; some clean product remained undissolved and was separated. The organic phase was concentrated, dissolved in a little methanol, and seeded with the previously collected product. After this material had crystallized, both crops of product were rinsed with methanol and permitted to dry to provide the title compound as a white microcrystalline solid (49% yield). 1HNMR (300 MHz, CDCl3) δ 1.18 (d, 3H), 1.4-2.1 (m, 4H), 2.2-2.6 (m, 3H), 2.34 (s, 3H), 3.00-3.12 (m, 2H), 3.20-3.34 (m, 2H), 6.49 (s, 1H), 7.41-7.48 (m, 3H), 7.56-7.63 (m, 2H), 7.68 (dd, 1H), 7.70 (bs, 1H), 7.88 (dd, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[C@@H:20]([CH2:30][OH:31])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[C@@H:20]([CH:30]=[O:31])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1C[C@H](CO)[C@@H](c2cccc(F)c2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](c2cccc(F)c2)[C@@H](C=O)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of 4.3 mL (49.8 mmol) of oxalyl chloride in 90 mL of CH2Cl2 at −78° C. was treated with 5.4 mL (75.7 mmol) of DMSO maintaining the temperature at less than −60° C. The resulting mixture was stirred cold for 5 min. A solution of 6.4 g (21.6 mmol) of 1-tert-butoxycarbonyl-3-(R)-(hydroxymethyl)-4-(S)-(3-fluoro)phenylpyrrolidine (from Step B) in 10 mL of CH2Cl2 was added maintaining the temperature at less than −60° C. The resulting mixture was stirred cold for 60 min. The mixture was treated with 30 mL (173.1 mmol) of N,N-diisopropylethylamine maintaining the temperature at less than −60° C. The reaction was warmed to 0° C., stirred for 20 min and quenched with 20 mL 0.5 N KHSO4. The mixture was partitioned between 250 mL of CH2Cl2 and 100 mL of H2O and the layers were separated. The aqueous layer was extracted with 250 mL of CH2Cl2. The combined organic phases were dried over MgSO4 and concentrated. Purification by Biotage Flash 75 using 75 L cartridge and 6.0 L of 9:1 v/v heptane/ethyl acetate as the eluant afforded the title compound: 1H NMR (500 MHz, CDCl3) δ 1.48 (s, 9H), 2.48 (1H), 3.17–3.89 (6H), 6.96–7.35 (4H), 9.67 (s, 1H).
Reaction SMILES: ClC(OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].[NH2:14][O:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[CH2:24]([N:26]([CH2:29]C)CC)[CH3:25]>ClCCl>[CH2:24]([NH:26][C:29](=[O:3])[NH:14][O:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH3:25]
Reactant: CC(C)(C)OC(=O)CON
Reactant: CCN(CC)CC
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: CCNC(=O)NOCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 138.7 %

Procedure:
A solution of 4-nitrophenyl chloroformate (12.09 g, 60 mmol) in dichloromethane (200 ml) was stirred at 0° C. for 10 min. A solution of tert-butyl 2-(aminooxy)acetate (Compound XIV-5) (7.36 g, 50 mmol) in dichloromethane (100 ml) and triethylamine (9.06 ml, 65 mmol) were added and the mixture was stirred at room temperature for 0.5 hr. The reaction mixture was washed with water (300 ml) and brine (300 ml). The organic layer was dried over magnesium sulfate and filtered and the filtrate was concentrated in vacuo to give the desired product (15.14 g, 97%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5](C=C)=[CH:4][CH:3]=1.C[N+]1([O-])[CH2:16][CH2:15][O:14]CC1.CC(C)=[O:20].O>CCOC(C)=O.[Os](=O)(=O)(=O)=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:15]([OH:14])[CH2:16][OH:20])=[CH:4][CH:3]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1ccc(Br)cc1
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Solvent: CCOC(C)=O
Solvent: O
Product: OCC(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
4-Bromostyrene (1.00 g, 5.46 mmol) was dissolved in 25 mls of 2:1 water acetone. To this was added 4-methylmorpholine N-oxide (0.704 g, 6.01 mmole) and osmium tetroxide (0.167 g, 0.061 mmole, 2.5% in t-BuOH). This mixture was stirred at room temperature for 16 hours, then diluted with EtOAc, washed once with 1N aq. HCl, once with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by Flash 40 Biotage (40M cartridge, 100% EtOAc as the eluant) to give 335 mgs (28%) of 1-(4-bromophenyl)ethane-1,2-diol as a white solid.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[Na].Cl.Cl[CH2:15][C:16](=[NH:21])[O:17][CH2:18][CH2:19][CH3:20]>C(O)CC>[OH:10][C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:15]=1[C:16](=[NH:21])[O:17][CH2:18][CH2:19][CH3:20]
Reactant: COC(=O)c1ccccc1S
Reactant: CCCOC(=N)CCl
Agent: Cl
Agent: [Na]
Solvent: CCCO
Product: CCCOC(=N)c1sc2ccccc2c1O

Procedure:
16.8 g (0.1 mol) of methyl thiosalicylate are added dropwise to a solution of 4.6 g (0.2 mol) of sodium in 400 ml of anhydrous n-propanol. To this mixture 17.2 (0.1 mol) of propyl chloroacetimidate hydrochloride are slowly added and the resultant mixture is heated under reflux for 6 hours. The reaction mixture is evaporated under vacuum and the residue distributed between water and dichloromethane. The organic phase is dried, evaporated, and the residue recrystallized from ethyl acetate/diisopropylether solution to yield 6.2 g of yellow crystals with an m.p. of 185° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:20])=[CH:11][C:12]([NH:16][C:17](=[O:19])[CH3:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:21][N:22]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[N:23]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[CH3:20][C:10]1[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:25]3[CH:24]=[N:23][N:22]([CH3:21])[CH:26]=3)[CH:7]=2)=[C:14]([CH3:15])[N:13]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:11]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(=O)Nc1cc(C)c(Oc2ccnc(Cl)c2)c(C)n1
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: C1COCCO1
Solvent: O
Product: CC(=O)Nc1cc(C)c(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Temperature: 80 °C
Yield: 100 %

Procedure:
A mixture of N-(5-((2-chloropyridin-4-yl)oxy)-4,6-dimethylpyridin-2-yl)acetamide (598 mg, 2.05 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (554 mg, 2.66 mmol), K2CO3 (850 mg, 6.15 mmol) and Pd(PPh3)4 (118 mg, 0.102 mmol) in dioxane (8 mL) and water (2 mL) was sparged with Ar and heated at 80° C. overnight. The mixture was cooled to RT, diluted with EtOAc, washed with satd. NaHCO3, then brine, dried over Na2SO4 and concentrated to dryness to afford crude N-(4,6-dimethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)acetamide (100% yield assumed) which was used without further purification. MS (ESI) m/z: 338.1 (M+H+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[C@@H:14]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@@H:13]([OH:20])[C@@H:12]([OH:21])[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].CN(C=[O:39])C>>[Si:27]([O:21][C@@H:12]1[C@@H:13]([OH:20])[C@H:14]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[C:10]([CH2:9][O:8][C:1](=[O:39])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:11]1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)O[C@@H]1C(COCc2ccccc2)=C[C@H](O)[C@@H]1O
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: CC(C)(C)O[C@@H]1C(COC(=O)c2ccccc2)=C[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of 25 (8.04 g, 27.5 mmol) and imidazole (7.05 g, 103.55 mmol) in anhydrous DMF (80 ml) was treated with tert-butyldimethylsilyl chloride (6.70 g, 44.45 mmol). The mixture was stirred at room temperature under a blanket of argon for 40 min and quenched by the addition of water (100 ml). The reaction mixture was extracted with ethyl acetate (3×100 ml), and the combined organic extract was washed with brine (2×100 ml) and dried over Na2SO4. The solvent was evaporated and the product purified by flash column chromatography over silica gel to give 9.77 g (87.4%) of pure 26 as an oil. Analysis calculated for C23H38O4Si.0.5 H2O: C, 66.46; H, 9.46. Found: C, 66.41; H, 9.31.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#N)=[C:16]([CH3:22])[CH:15]=1.CN([CH:26]=[O:27])C.[BH4-].[Na+].[OH:30]S(O)(=O)=O>C1COCC1.CCOC(C)=O>[Br:13][C:14]1[CH:15]=[C:16]2[C:17](=[CH:20][CH:21]=1)[C:18](=[O:30])[O:27][CH2:26][CH2:22]2
Reactant: Cc1cc(Br)ccc1C#N
Reactant: CN(C)C=O
Reactant: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: O=C1OCCc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A 250-mL, three-necked, round-bottomed flask equipped with a septum, nitrogen inlet needle, and thermocouple was charged with diisopropylamine (3.10 g, 30.6 mmol) and 30 mL of THF. The reaction mixture was cooled at −20° C. while n-BuLi (2.5 M, 12.2 mL, 30.6 mmol) was added dropwise via syringe keeping the internal temperature below 0° C. The resulting reaction mixture was stirred at 0° C. for 15 min. The reaction mixture was then cooled at −40° C. while 4-bromo-2-methylbenzonitrile (4.00 g, 20.4 mmol) in 10 mL of THF was added dropwise via syringe over 1 h. An internal temperature of ca. −40° C. was maintained during the addition. The resulting reaction mixture was stirred at −40° C. for 30 min and then charged with DMF (2.98 g, 40.8 mmol, ca. 50 ppm water) in one portion. The reaction mixture was stirred at −40° C. for 15 min. The reaction mixture was quenched with MeOH (5 vol., 20 mL) and then charged with NaBH4 (0.770 g, 20.4 mmol) in one portion and allowed to warm to room temperature. After complete reduction of intermediate aldehyde (as judged by HPLC analysis), the reaction mixture was carefully quenched with 5 M HCl (with cooling) to adjust the pH to 2-3. The reaction mixture was extracted with EtOAc and then solvent-switched to EtOH (40 mL). H2SO4 (98%, 20.0 g, 204 mmol) was added in one portion and the resulting reaction mixture was stirred at reflux for 24 h. After complete cyclization (monitored by HPLC analysis), the reaction mixture was cooled to room temperature and then solvent-switched to EtOAc. The resulting organic layer was washed with water, brine, and solvent-switched to MTBE. Precipitation from 1:1 MTBE:heptane afforded 6-bromo-3,4-dihydro-1H-isochromen-1-one.
Reaction SMILES: [F:1][C:2]([F:15])([O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11])[CH:3]([F:5])[F:4].[O:16]([C:23]1[CH:24]=[C:25]([NH:29][CH2:30][CH:31](O)[C:32]([F:35])([F:34])[F:33])[CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[O:16]([C:23]1[CH:24]=[C:25]([N:29]2[CH2:30][CH:31]([C:32]([F:33])([F:34])[F:35])[O:11][CH:10]2[C:9]2[CH:12]=[CH:13][CH:14]=[C:7]([O:6][C:2]([F:15])([F:1])[CH:3]([F:4])[F:5])[CH:8]=2)[CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: OC(CNc1cccc(Oc2ccccc2)c1)C(F)(F)F
Solvent: Cc1ccccc1
Product: FC(F)C(F)(F)Oc1cccc(C2OC(C(F)(F)F)CN2c2cccc(Oc3ccccc3)c2)c1
Yield: 91.7 %

Procedure:
A toluene solution (5 mL) of 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (0.45 g, 2.0 mol) and N-(3-phenoxyphenyl)-3-amino-1,1,1-trifluoro-2-propanol (0.60 g, 2.0 mmol) was refluxed in the presence of molecular sieves and Znl2 (˜5 mg) for 18 h under N2. The reaction mixture was filtered to remove the sieves, and the filtrate was diluted with ethyl acetate. The organic layer was washed with brine. dried (MgSO4) and evaporated to give 0.92 g (92%) of the desired 3-(3-phenoxyphenyl)-2-[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]-5-(trifluoromethyl) oxazolidine product as a colorless oil. The formation of the desired product was monitored by the disappearance of the aldehyde peak (δ˜10) in the 1H NMR spectrum. HRMS calcd. 502.1253 [M+H]+, found: 502.1220.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][CH:16]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:15][CH2:14][C:13]=3[CH:12]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].[OH:27]C1C=C2C(=CC=1)C(=O)C(C1C=CC=CC=1)CC2.ClC1C=CC([N+]([O-])=O)=CN=1.[F-].[K+]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:27])[CH:16]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)C3)nc1
Reactant: O=C1c2ccc(O)cc2CCC1c1ccccc1
Agent: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [F-]
Agent: [K+]
Product: O=C1c2ccc(Oc3ccc([N+](=O)[O-])cn3)cc2CCC1c1ccccc1

Procedure:
6-(5-Nitro-pyridin-2-yloxy)-2-phenyl-3,4-dihydro-2H-naphthalen-1-one was prepared as described for 5-nitro-2-(6-phenyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-pyridine in Example 23(d) using 50 mg 6-hydroxy-2-phenyl-3,4-dihydro-2H-naphthalen-1-one, 33 mg 2-chloro-5-nitropyridine and 37 mg potassium fluoride. 1H NMR (400 MHz, d6-DMSO) δ: 9.07 (d, 1H, J 2.8 Hz), 8.68 (dd, 1H, J 9.0, 2.9), 8.01 (d, 1H, J 8.5), 7.37 (d, 1H, J 9.1 Hz), 7.21-7.38 (m, 7H), 3.96-4.04 (m, 1H), 3.15-3.23 (m, 1H), 2.98-3.04 (m, 1H), 2.39-2.48 (m, 1H), 2.25-2.31 (m, 1H).
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=[O:4].[P:7]([O-:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].N1C=CC=CC=1.[C:21](Cl)(=[O:23])[CH3:22]>ClCCl>[C:21]([O:4][CH:3]([P:7]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])=[O:14])[C:2]([OH:6])=[O:5])(=[O:23])[CH3:22]
Reactant: CCOP([O-])OCC
Reactant: CC(=O)Cl
Reactant: O=CC(=O)O
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(OC(C)=O)C(=O)O
Temperature: 60 °C
Reaction time: 5 h

Procedure:
Glyoxylic acid monohydrate (4.0 g, 43.45 mmol) was suspended in diethyl phosphite (5.59 mL, 1.0 equiv), warmed to 60° C., and held there for 5 h. The reaction was cooled, diluted with dichloromethane (40 mL), and treated with pyridine (3.51 mL, 1.0 equiv) and acetyl chloride (3.09 mL, 1.0 equiv). A significant exotherm was noted. The reaction was stirred at room temperature for 2 h. The reaction was washed with 1M hydrochloric acid (2×20 mL), then saturated sodium bicarbonate. The organics were dried over magnesium sulfate, and concentrated to give <2 g as an oil. The aqueous washes were combined and extracted with dichloromethane (4×). The organics were dried over magnesium sulfate and concentrated to give 5.85 g (53%) as an oil which solidified upon standing. 1H-NMR (CDCl3, 500 MHz) δ 1.36 (t, J=7.0, 6H), 2.21 (s, 3H), 4.28 (m, 4H), 5.54 (d, J=17.7, 1H), 8.90 (bs, 1H). Mass spec.: 255.10 (MH)+.
Reaction SMILES: B.[CH2:2]([S:9][C:10]1[CH:49]=[CH:48][CH:47]=[CH:46][C:11]=1[C:12]([NH:14][CH2:15][C:16]([CH3:45])([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)[CH2:17][NH:18][C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>C1COCC1.O>[CH2:2]([S:9][C:10]1[CH:49]=[CH:48][CH:47]=[CH:46][C:11]=1[CH2:12][NH:14][CH2:15][C:16]([CH3:45])([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)[CH2:17][NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(CNC(=O)c1ccccc1SCc1ccccc1)(CNC(=O)c1ccccc1SCc1ccccc1)Cc1ccc([N+](=O)[O-])cc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(CNCc1ccccc1SCc1ccccc1)(CNCc1ccccc1SCc1ccccc1)Cc1ccc([N+](=O)[O-])cc1

Procedure:
27.6 ml of a 1M borane solution in THF was added dropwise to a solution of 2,98 g [69] (4.6 mmol) in 10 ml THF at 0° C., reflux-heated for two hours, cooled and 10 ml of a 1:1 mixture of HCl in water was added and the solvlent was removed in a rotary evaporator. After neutralising with 1N NaOH the mixture was extracted with dichloromethane, and dried over sodium sulphate and the solvent was removed, leaving a faintly yellow oil.
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.[CH:18](=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1.C(OCC)(=O)C>C1COCC1.O>[OH:27][CH:18]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:1]1=[O:9]
Reactant: O=C1CCCCCCC1
Reactant: COc1cccc(C=O)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(C(O)C2CCCCCCC2=O)c1
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
To a solution of cyclooctanone (4.0 g) in THF (40 ml) was added LDA (23 ml, 1.5M solution in cyclohexane) at −78° C. under N2, and then after 30 minutes, a solution of m-anisaldehyde (4.1 g) in THF (10 ml) was added in the solution. After being stirred for 2 hours at the same temperature, the solution was poured into the mixture of ethyl acetate and water. The organic layer was washed with 1N-HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 2-{hydroxy-(3-methoxyphenyl)methyl}cyclooctanone (6.9 g).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:17][CH:16]=2)[C:12]#N)=[CH:7][CH:6]=1)[CH2:2][CH3:3].O=[CH:26][C:27](=C)[CH3:28]>>[CH3:28][C:27]1[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[CH:6][CH:7]=2)[N:14]([C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:17][CH:16]=2)[CH:26]=1
Reactant: CCCOc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1
Reactant: C=C(C)C=O
Product: CCCOc1ccc(-c2cc(C)cn2-c2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(4-propoxyphenyl)-α-(4-sulfamoylanilino)acetonitrile [prepared as described in step (ii) above] and methacrolein as starting materials, the title compound was obtained as a pale brown powder (yield 5%), melting at 142-145° C.
Reaction SMILES: [Cl:1][C:2]([Cl:17])([Cl:16])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1)=[O:4].ClC1C=CC=C(C(OO)=[O:26])C=1.C(OC(C)C)(C)C>C(Cl)Cl>[Cl:17][C:2]([Cl:1])([Cl:16])[C:3]([NH:5][C:6]1[CH:7]=[N+:8]([O-:26])[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1)=[O:4]
Reactant: O=C(Nc1cnc2c(c1)CCCC2)C(Cl)(Cl)Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: O=C(Nc1cc2c([n+]([O-])c1)CCCC2)C(Cl)(Cl)Cl
Yield: 98.9 %

Procedure:
To a solution of 24.03 g of Compound 2 obtained in the above step (2) in 40 ml of methylene chloride is added 21.2 g of 80% m-chloroperbenzoic acid at room temperature, and the resultant mixture is stirred for 45 minutes. The reaction mixture is mixed with isopropyl ether and the crystals are filtered to give 25.06 g of the titled compound 3 as crystals. Yield: 99% mp.: 244° to 246° C. (dec.)
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7].[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[Li].C1(C)C=CC=CC=1.O>O1CCCC1>[CH3:1][C:2]1[CH:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]([C:20]2[C:21]([CH3:26])=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=2[CH3:18])=[NH:13])[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7]
Reactant: CC1=C(C)C(c2ccccc2C#N)C(C)=C1C
Reactant: [Li]c1c(C)cc(C)cc1C
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC1=C(C)C(c2ccccc2C(=N)c2c(C)cc(C)cc2C)C(C)=C1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 108.1 %

Procedure:
To a solution of 2-(2,3,4,5-tetramethylcyclopentadienyl)benzonitrile (6.3 mmol) in tetrahydrofuran (25.5 mL) was added dropwise a solution of 2,4,6-trimethylphenyllithium (12.5 mmol) in tetrahydrofuran (55.6 mL) at −78° C. under a nitrogen atmosphere. The temperature of the mixture was raised to room temperature and the mixture was stirred for 5 hrs. To the reaction mixture solution were added toluene and water to separate an organic layer and an aqueous layer. The organic layer was dried and the solvent was distilled off to give 2-(2,3,4,5-tetramethylcyclopentadienyl)-α-(2,4,6-trimethylphenyl) -benzenemethanimine (2.34 g) as a brown oily substance.