Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([NH:13][C:14]([C@@H:16]([NH2:21])[CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4].C(O)(=O)C.[CH3:26][C:27]([CH3:32])([CH3:31])[CH2:28][CH:29]=O>CO>[CH3:26][C:27]([CH2:28][CH2:29][NH:21][C@H:16]([C:14]([NH:13][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:15])[CH2:17][C:18]([OH:20])=[O:19])([CH3:32])[CH3:31]
Reactant: CC(C)(C)CC=O
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NCCC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.6 %

Procedure:
Aspartame (5.88 g), acetic acid (1.20 g) and methanol (100 ml) were charged to a hydrogenation vessel, followed by 3,3-dimethylbutyraldehyde (2.00 g). The vessel was pressure purged with nitrogen (4×), and 0.24 g of 4% palladium on carbon (containing 50% water) was added. After pressure purging the reactor with nitrogen (4×), followed by hydrogen (4×), the mixture was hydrogenated at 50 psig for 12 hours at room temperature. After completion of the reaction, the vessel was purged with nitrogen (4×). The catalyst was removed from the reaction mixture by filtration through powdered cellulose. Methanol (20 ml) was used to rinse the reaction vessel and the filter cake. The combined filtrate and wash was evaporated to dryness. The residue was stirred with 50 ml of deionized water and 50 ml of heptane for 4 hours at room temperature. The crystallized solid was isolated by filtration and washed with 20 ml heptane. The wet product was dried under vacuum at 40° C. to give 7.15 g of neotame (>97% by HPLC).
Reaction SMILES: [O:1]([CH:8]1[CH2:17][CH2:16][C:11]2(OCC[O:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Cl>CCOCC>[O:1]([CH:8]1[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(OC2CCC3(CC2)OCCO3)cc1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: O=C1CCC(Oc2ccccc2)CC1
Reaction time: 8 h

Procedure:
11.7 g (50 mmole) 8-phenoxy-1,4-dioxa-spiro[4.5]decane (25) were dissolved in 250 in ether. 50 ml water and 37.5 ml concentrated hydrochloric acid were added with stirring. The mixture was stirred for 2 hours and allowed to stand overnight. After subsequent phase separation the mixture was extracted with ether and washed with saturated common salt solution, and the solvent was distilled off. 9 g (91% theoretical) of compound (26) were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[N:12]=[C:11]3[CH:19]2[CH2:21][CH2:20]2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[C:13](=[O:18])[N:12]=[C:11]3[CH:19]2[CH2:21][CH2:20]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1nc(C2CC2)c2cc(-c3cccc(Cl)c3)ccc2[nH]1
Reactant: COc1ccc(CCl)cc1
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)nc(C3CC3)c3cc(-c4cccc(Cl)c4)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 6-(3-chlorophenyl)-4-cyclopropyl-1H-quinazolin-2-one (0.5 g, 1.68 mmol) in anhydrous DMF was added potassium hexamethylsilyl amide (0.45 g, 2.1 mmol) at ambient temperature under nitrogen. The reaction mixture was stirred at ambient temperature for 30 minutes, treated with p-methoxy benzyl chloride (0.35 mL, 2.5 mmol), and heated at 55° C. for 5 hours. The mixture was then cooled to room temperature and quenched with a saturated aqueous ammonium chloride solution (10 mL). Methylene chloride (50 mL) was added and organic layer was separated. The aqueous layer was extracted with methylene chloride (2×20 mL) and the combined organic layers were washed with brine and dried (MgSO4). After removal of solvent, the residue was separated on a flash chromatography (silica gel, hexane:ethyl acetate/1:1) to afford 6-(3-chlorophenyl)-4-cyclopropyl-1-(4-methoxybenzyl)-1H-quinazolin-2-one as an off-white solid: mp 173-174° C.; 1H-NMR (DMSO-d6) δ 8.65 (d, 1H, J=1.8 Hz), 8.10 (dd, 1H, J=8.9, 1.8 Hz), 7.93 (d, 1H, J=1.6 Hz), 7.79 (d, 1H, J=7.6 Hz), 7.53 (d, 2H, J=8.4 Hz), 7.46 (t, 1H, J=8.1 Hz), 7.21 (d, 2H, J=8.6 Hz), 6.88 (d, 2H, J=8.6 Hz), 5.41 (s, 2H), 3.73 (s, 3H), 3.18 (m, 1H), 1.18-1.27 (m, 4H); MS (CI) m/z 417([M+H]+, 100%); Anal. Calc. For C25H21ClN2O2: C, 72.02, H, 5.08, N, 6.72. Found: C, 71.88, H, 4.91, N, 6.70.
Reaction SMILES: [OH-].[K+].[CH2:3]([C:5]1[C:10]([F:11])=[CH:9][C:8]([OH:12])=[C:7]([O:13][CH3:14])[CH:6]=1)[CH3:4].[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1F)[C:19]#[N:20]>C(#N)C.CCCCC>[CH2:3]([C:5]1[C:10]([F:11])=[CH:9][C:8]([O:12][C:23]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=2[F:15])=[C:7]([O:13][CH3:14])[CH:6]=1)[CH3:4]
Reactant: CCc1cc(OC)c(O)cc1F
Reactant: N#Cc1ccc(F)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCC
Solvent: CC#N
Product: CCc1cc(OC)c(Oc2ccc(C#N)cc2F)cc1F
Temperature: 85 °C
Reaction time: 8 h

Procedure:
Potassium hydroxide (2.4 g, 43.13 mmol) was added to a solution of 4-ethyl-5-fluoro-2-methoxyphenol (6.1 g, 35.94 mmol) and 3,4-difluorobenzonitrile (5.0 g, 35.94 mmol) in anhydrous acetonitrile (80 mL). The reaction mixture was stirred at 85° C. overnight then concentrated under vacuum. The residue was solubilized in ethyl acetate (300 mL) and diluted by addition of a saturated solution of ammonium chloride (200 mL). The aqueous layer was separated and extracted with ethyl acetate (2×200 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated to dryness to give a brown solid. After trituration in pentane, the title product was obtained as a brown solid (8.10 g, 77%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.CCN(CC)CC.[Si:29]([O:36][C@@H:37]([CH3:63])[C@@H:38]([NH:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]#[N:60])=[C:55]([Cl:61])[C:54]=1[CH3:62])[C:39]([NH:41][NH:42][C:43](=[O:51])[C:44]1[CH:49]=[CH:48][C:47]([I:50])=[CH:46][CH:45]=1)=O)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C(Cl)Cl>[Si:29]([O:36][C@@H:37]([CH3:63])[C@@H:38]([NH:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]#[N:60])=[C:55]([Cl:61])[C:54]=1[CH3:62])[C:39]1[O:51][C:43]([C:44]2[CH:45]=[CH:46][C:47]([I:50])=[CH:48][CH:49]=2)=[N:42][N:41]=1)([C:32]([CH3:34])([CH3:35])[CH3:33])([CH3:30])[CH3:31]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(I)cc2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(I)cc3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a solution of triphenylphosphine (7.2 g, 27.5 mmol) in DCM (300 mL) was added I2 (7.0 g, 27.5 mmol) at 0° C. After I2 was dissolved completely, Et3N (7.7 mL, 55.2 mmol) was added, followed by a solution of N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-4-iodobenzohydrazide (8.6 g, 13.7 mmol) in DCM (100 mL). The reaction mixture was allowed to warm to room temperature and stirred for an additional 60 min. The reaction was quenched with saturated sodium thiosulfate (50 mL) and diluted with DCM (500 mL). The organic layer was separated and washed with water, brine, dried over Na2SO4 and filtered. After the solvent was removed, the residue was purified by flash chromatography to provide the title compound (7.3 g, 88%). 1H NMR (400 MHz, CDCl3, δ in ppm) 8.06 (d, J=8.6 Hz, 2H), 7.88 (d, J=8.6 Hz, 2H), 7.55 (d, J=8.4 Hz, 1H), 6.66 (d, J=8.4 Hz, 1H), 5.56 (d, J=8.8 Hz, 1H), 5.00 (dd, J=2.0, 8.8 Hz, 1H), 4.74 (m, 1H), 2.59 (s, 3H), 1.62 (d, J=6.3 Hz, 3H), 1.07 (s, 9H), 0.28 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: [N+:1]([N:4]=[C:5]1[NH:9][CH2:8][CH2:7][NH:6]1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Cl)=[CH:19][N:18]=1>C(#N)C>[CH:21]1[C:20]([CH2:23][N:6]2[CH2:7][CH2:8][NH:9]/[C:5]/2=[N:4]\[N+:1]([O-:3])=[O:2])=[CH:19][N:18]=[C:17]([Cl:16])[CH:22]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=[N+]([O-])N=C1NCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])/N=C1\NCCN1Cc1ccc(Cl)nc1

Procedure:
7.8 g (60 mmol) of 2-nitroiminoimidazolidine and 12.1 g (87.5 mmol) of potassium carbonate were dissolved in 60 ml of acetonitrile in a reflux flask. The mixture is heated to a temperature sufficient for achieving reflux operating condition. 8.1 g (50.0 mole) of 2-chloro-5-chloromethyl pyridine is dissolved in 40 ml of acetonitrile, and is dropwisely and continuously added into the flask under the reflux condition for a period of 0.5 hr, i.e. the addition rate is about 1.5 ml/minute (the addition rate at the onset of the reaction corresponds to 0.0278 equivalent of 2-chloro-5-chloromethyl pyridine per equivalent of 2-nitroiminoimidazolidine per minute) After completion of the reaction, the mixture is subjected to filtration. The filtrate is concentrated, and is further purified.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[OH:15].[Cl:16][C:17]1[N:18]=[C:19]([C:24](O)=[O:25])[NH:20][C:21]=1[CH2:22][CH3:23].O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>>[Cl:16][C:17]1[N:18]=[C:19]([C:24]([NH:1][C@@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4][C@H:3]2[OH:15])=[O:25])[NH:20][C:21]=1[CH2:22][CH3:23]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)nc1Cl
Yield: 92 %

Procedure:
The same operation as in Example (196b) was performed using tert-butyl trans(±)-4-amino-3-hydroxypiperidine-1-carboxylate synthesized in Example (201a) (600 mg, 2.77 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (2405d) (484 mg, 2.77 mmol), 1-hydroxybenzotriazole hydrate (562 mg, 4.16 mmol), WSC hydrochloride (798 mg, 4.16 mmol) and triethylamine (580 μL, 4.16 mmol), to obtain 950 mg of the title compound (92%) as a colorless solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([I:29])[CH:23]=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:28][C:25]1[CH:26]=[CH:27][C:22]([F:21])=[CH:23][C:24]=1[I:29]
Reactant: Cc1ccc(F)cc1I
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)c(I)c1
Yield: 57.6 %

Procedure:
N-Bromosuccinimide (0.61 g, 3.4 mmol) and VAZO (0.10 g, 0.41 mmol) were added to a solution of 4-fluoro-2-iodotoluene (0.75 g, 3.2 mmol) in carbon tetrachloride (45 mL). The resulting suspension was stirred and heated under reflux for 18 hours. It was then cooled and filtered, the solid was rinsed with carbon tetrachloride (5 mL), and the combined filtrates were concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with hexanes) to provide 322 (0.58 g, 58% yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.51 (dd, J=8.0, 2.5 Hz, 1H); 7.38 (dd, J=8.4, 5.7 Hz, 1H); 7.00 (dt, J=8.2, 2.7 Hz, 1H); 4.54 (s, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][C:11](F)=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1.[CH3:18][NH2:19]>O>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][C:11]([NH:19][CH3:18])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1
Reactant: CN
Reactant: O=C1CCCCN1c1ccc(F)c([N+](=O)[O-])c1
Solvent: O
Product: CNc1ccc(N2CCCCC2=O)cc1[N+](=O)[O-]

Procedure:
4.1 g (0.017 mol) of 4-(2-oxo-piperidin-1-yl)-2-nitro-fluoro-benzene are stirred in 50 ml methylamine solution (40% in H2O) in a sealed vessel for 1 hour at ambient temperature. Then the mixture is diluted with water, suction filtered and dried.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([OH:11])[CH:5]=1.Br[CH2:14][CH2:15]Br.[OH-].[K+]>CO>[O:10]1[CH2:15][CH2:14][O:11][C:6]2[CH:5]=[C:4]([C:3]([O:2][CH3:1])=[O:12])[CH:9]=[CH:8][C:7]1=2
Reactant: COC(=O)c1ccc(O)c(O)c1
Reactant: BrCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)OCCO2
Yield: 13 %

Procedure:
A mixture of 3,4-dihydroxybenzoic acid methyl ester (5.2 g, 31 mmol), 1,2-dibromoethane (2.9 mL, 34 mmol), and pulverized KOH (3.8 g, 68 mmol) in MeOH was heated at reflux for 30 hrs. After removal of the solvent under reduced pressure, the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water, dried over MgSO4, concentrated in vacuo and purified by purified by column chromatography on silica gel eluting with 40% ethyl acetate in hexane to yield methyl 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (780 mg, 13%) along with the unreacted starting material (2.6 g). 1H NMR (DMSO-d6, 600 MHz) δ 7.45 (d, 1H, J=8.4 Hz), 7.39 (s, 1H), 6.96 (d, 1H, J=8.4 Hz), 4.33-4.28 (m, 4H), 3.80 (s, 3H); MS (ES+) m/z 195.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[C:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc(Cl)cc1
Product: CC(=O)Oc1ccc(Cl)cc1

Procedure:
4-Chlorophenyl acetate is prepared by acylation of 4-chlorophenol with acetic anhydride using Schotten Baumann conditions.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>N1C=CC=CC=1>[C:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc(Cl)cc1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(Cl)cc1

Procedure:
Into a reaction flask equipped with a magnetic stirrer and thermometer was charged 257.2 grams (2.0 moles) of p-chlorophenol, 245 grams (2.4 moles) of acetic anhydride and 200 milliliters of pyridine and the resulting reaction mixture was then heated to a temperature of 23° C.-47° C. After completion of the reaction, work-up and distillation at reduced pressure, p-chlorophenyl acetate was obtained (93 percent of theoretical). The nuclear magnetic resonance (NMR) spectrum was consistent with the chemical structure.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>CC(C)=O>[CH2:20]([O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10])[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: Cc1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a mixture of 4-methyl-2-nitro-phenol (1.50 g, 9.80 mmol) and K2CO3 (2.03 g, 14.7 mmol) in acetone (23 mL) was added allyl bromide (1.24 ml, 14.7 mmol). The reaction mixture was stirred at room temperature overnight. It was then heated at 40° C. for 6 hrs. Inorganic salts were filtered and washed with acetone. The filtrate was concentrated and the residue was purified by flash chromatograph eluting with hexane/EtOAc (95:5) to give 1.67 g (88%) of the desired product. MS (DCI/NH3) m/z: 211.0 (M+NH4)+; 1H NMR (300 MHz, DMSO-D6) δ ppm 2.30 (s, 3 H) 4.67–4.75 (m, 2 H) 5.27 (m, 1 H) 5.42 (m, 1 H) 5.97 (m, 1 H) 7.24 (d, J=8.48 Hz, 1 H) 7.45 (dd, J=8.65, 2.20 Hz, 1 H) 7.69 (d, J=2.37 Hz, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[CH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[C:21](I)[C:20]([Cl:24])=[CH:19][N:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:21]2[C:20]([Cl:24])=[CH:19][N:18]=[C:17]([Cl:16])[CH:22]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Clc1cc(I)c(Cl)cn1
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2cc(Cl)ncc2Cl)CC1

Procedure:
The title compound is prepared from 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester and 2,5-dichloro-4-iodo-pyridine following a procedure analogous to that described for Intermediate 27. LC (method 7): tR=1.66 min; Mass spectrum (ESI+): m/z=355 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.B.O1CCCC1.C([Li])CCC.[C:17]1(=[O:22])[CH2:21][CH2:20][CH2:19][CH2:18]1>>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:17]1([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C1CCCC1
Reactant: c1cocn1
Agent: B
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ncco2)CCCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
An ambient solution of oxazole (1.00 g, 14.5 mmol) and borane.tetrahydrofuran complex (14.5 mL, 14.5 mmol, 1 M in tetrahydrofuran) was stirred for 30 min. The reaction was cooled to −78° C., and n-butyllithium (9.5 mL, 15.2 mmol, 1.6 M in hexane) was added dropwise. After 30 minutes, cyclopentanone (1.42 mL, 16.0 mmol) was added dropwise. After 30 minutes, the cold (−78° C.) reaction was quenched by the addition of 5% acetic acid in ethanol (70 mL) and warmed to room temperature. The solution was diluted with diethyl ether (10 0 mL) and saturated NaHCO3 (50 mL). Layers were separated, and the organics were washed with brine (1×50 mL), dried over Na2SO4, concentrated, under reduced pressure, and purified by chromatography on SiO2 gel, eluting with 50% ethyl acetate in hexane, to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.59-1.71 (m, 2H), 1.72-1.84 (m, 2H), 1.84-1.96 (m, 2H), 1.98-2.09 (m, 2H), 5.40 (s, 1H), 7.11 (s, 1H), 8.02 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH3:2].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)=[O:12])[CH3:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1ccc(Br)cc1
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: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2ccc(OC)cc2)cc1
Temperature: 100 °C
Yield: 95.8 %

Procedure:
A mixture of 4-bromobenzoic acid ethyl ester (2.7 mL, 16.5 mmol), 4-methoxy phenylboronic acid (2.5 g, 16.5 mmol) and sodium carbonate (7.7 g, 72.6 mmol) in toluene:ethanol:water (75 mL:37 mL:37 mL) was flushed with nitrogen for 1 hour. After addition of the tetrakis(triphenylphosphine)palladium(0) catalyst (0.95 g, 0.82 mmol), the reaction was heated at 100° C. overnight. After cooling, the mixture was filtered through Celite which was then washed with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown solid. Purification of the residue by flash chromatography with a solvent gradient from 25% to 50% of dichloromethane in hexane provided the title compound (4.05 g, 95.8%) as a pale yellow solid, m.p. 101–103° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:16][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
4-bromobenzenesulfonyl chloride (200 mg, 0.783 mmol) was dissolved in MC (10 ml), followed by dropwise addition of tert-butylamine (0.41 ml, 3.91 mmol) at 0° C., and then the resulting mixture was stirred at room temperature under nitrogen stream for 1 hour. Distilled water (15 ml) was added to the resulting reaction liquid, followed by extraction with MC (30 ml×2). The organic layer was dried over anhydrous sodium sulfate, followed by filtration and concentration, and then the residue thus obtained was dried under vacuum, to obtain 228 mg of white solid (100%).
Reaction SMILES: [OH:1][CH:2]([C:9]1[CH:10]=[CH:11][C:12]2[O:13]C(C3C=CC=CC=3)[O:15][CH2:16][C:17]=2[N:18]=1)[CH2:3][NH:4][C:5]([CH3:8])([CH3:7])[CH3:6].[ClH:25]>CC(C)=O.O>[ClH:25].[ClH:25].[OH:15][CH2:16][C:17]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]([CH:2]([OH:1])[CH2:3][NH:4][C:5]([CH3:7])([CH3:6])[CH3:8])[N:18]=1
Reactant: CC(C)(C)NCC(O)c1ccc2c(n1)COC(c1ccccc1)O2
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)NCC(O)c1ccc(O)c(CO)n1

Procedure:
One and five-tenths grams (4.8 m moles) of the above intermediate 6-(1-hydroxy-2-t-butylaminoethyl)-2-phenyl-4H-pyrido[3,2-d]-1,3-dioxin is dissolved in 20 ml. of acetone-water (1:1 v/v) and is treated with 1 ml. of 12N hydrochloric acid. After heating the solution to reflux for 5 hrs. the mixture is concentrated to an oil and dissolved in 100 ml. of ethanol. The water is azeotroped with 3 × 100 ml. portions of ethanol and the free base of the product generated by the addition of triethylamine. The solution is concentrated in vacuo to an oily slurry and the free base extracted from the triethylamine hydrochloride by extraction with acetone. The acetone extracts are combined, concentrated to an oil and the oil dissolved in 10 ml. of dry ethanol. Ethanol (0.184 ml.) containing hydrogen chloride (188 gm. HCl/ml. ethanol) is added and the solution added dropwise to 2 l. of dry isopropyl ether. The product is filtered and dried, 1.05 g. Further purification by recrystallization from methanol-acetone provides 950 mg. of the product which by infrared and nuclear magnetic resonance spectroscopy and thin-layer chromatography are identical to that in U.S. Pat. No. 3,700,681.
Reaction SMILES: CC([O-])(C)C.[K+].Cl[CH:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28].Cl>CN(C=O)C.O>[F:20][C:21]1[CH:26]=[C:25]([CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28]
Reactant: CCOC(=O)C(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(c1ccccc1)c1ccc([N+](=O)[O-])c(F)c1
Temperature: -45 °C
Reaction time: 0.33 h
Yield: 44.4 %

Procedure:
9.8 g of potassium tert-butylate were dissolved in 90 mL of DMF and cooled to −45° C. To this, a mixture of ethyl 2-chloro-2-phenylacetate (43.8 mmol, 8.7 g) and 1-fluoro-2-nitrobenzene (43.8 mmol, 4.6 mL) was gently added dropwise and stirring was continued for a further 20 minutes. The reaction mixture was set to pH 4 with aq. 16% strength. HCl, diluted with 25 mL of water, and extracted with EA (3×50 mL). Following combination of the organic phases, they were washed with water and sat. aq. NaCl solution, dried over MgSO4 and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel: mesh 100-200, eluent: 10% EA in cyclohexane) and yielded 5.9 g (44.9%) of the desired product.