Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C@H:17]2[CH2:19][C@H:18]2[CH2:20][CH2:21][O:22][C:23]2[C:28]([F:29])=[CH:27][C:26]([CH2:30][C:31](O)=[O:32])=[C:25]([F:34])[CH:24]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][NH:36][CH3:37].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:35][N:36]([CH3:37])[C:31](=[O:32])[CH2:30][C:26]1[C:25]([F:34])=[CH:24][C:23]([O:22][CH2:21][CH2:20][C@@H:18]2[CH2:19][C@@H:17]2[CH:14]2[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:12][CH2:13]2)=[C:28]([F:29])[CH:27]=1
Reactant: CNC
Reactant: O=C(O)Cc1cc(F)c(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OCc3ccccc3)CC2)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)Cc1cc(F)c(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OCc3ccccc3)CC2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {4-[2-((1S,2R)-2-{1-[(benzyloxy)carbonyl]piperidin-4-yl}cyclopropyl)ethoxy]-2,5-difluorophenyl}acetic acid (313 mg, 0.661 mmol) in 2.5 ml anhydrous DMF at RT was added dimethylamine (2.0 M solution in THF, 0.661 ml, 1.32 mmol) and N, N-diisopropylethylamine (0.562 ml, 3.31 mmol). 0-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (503 mg, 1.32 mmol) was then added to the solution and the mixture stirred at RT overnight. The reaction was quenched by addition of water (12 ml) and the mixture extracted with ethyl acetate (12 ml). The layers were separated and the organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Biotage column, 25 g) using a gradient eluent of 0-50% ethyl acetate in hexanes (800 ml) to afford the title compound. LC/MS (m/z): 501.4 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9].[F:23]C1C=CC(S(Cl)(=O)=O)=CC=1>>[F:23][C:6]1[CH:5]=[CH:4][C:3]([S:8]([NH:11][C@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:2][CH:7]=1
Reactant: O=C(O)[C@@H](Cc1ccccc1)NS(=O)(=O)c1ccccc1F
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: O=C(O)[C@@H](Cc1ccccc1)NS(=O)(=O)c1ccc(F)cc1

Procedure:
Following the 14a synthetic method, using 4-fluorobenzenesulfonyl chloride (97.31 mg, 0.5 mmol) instead of 2-fluorobenzenesulfonyl chloride gave 16a as a colorless oil; (108.48 mg, 67.1%). [α]D25: −19.1 (c=0.41, CHCl3); 1H-NMR (300 MHz, CDCl3): δ 7.77-7.73 (m, 2H), 7.24-7.21 (m, 7H), 6.92 (d, J=9 Hz, 1H), 4.21-4.14 (m, 1H), 3.15-2.90 (m, 2H); 13C NMR (300 MHz, acetone-d6): δ 171.55, 166.28, 162.95, 137.53, 136.53, 129.74, 129.62, 129.39, 128.24, 126.68, 115.93, 115.63, 57.29, 38.49; HRMS (ESI): calcd for: C15H14FNO4S [M+Na]+=346.0520, obsd [M+Na]+=346.0513.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1.Cl>N1C=CC=CC=1>[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11]([CH:1]([OH:4])[CH:2]([OH:3])[S:11]([C:8]2[CH:9]=[CH:10][C:5]([CH3:15])=[CH:6][CH:7]=2)(=[O:13])=[O:12])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCO
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)C(O)C(O)S(=O)(=O)c2ccc(C)cc2)cc1
Yield: 83 %

Procedure:
19.8 g (0.3 mol) of ethylene glycol are dissolved in 150 ml of distilled pyridine and then the solution is cooled with an ice bath. p-Toluenesulfonyl chloride (123 g, 0.65 mol) is added slowly with mechanical stirring. The temperature must remain below 20° C. during the addition. When approximately 90 g have been added, stirring becomes difficult and the mixture is diluted with 200 ml of pyridine. The reaction mixture is left stirring for 2 h 30. An aqueous HCl solution (12N HCl (170 ml) in ice (500 ml)) is added. The solid formed during this addition is filtered off. This solid is dissolved in refluxing methanol (250 ml) and then the new precipitate formed after returning to ambient temperature is filtered off. Finally, the white solid obtained is dried under vacuum and the pure product is obtained (92.4 g, yield 83%).
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14]Br)[CH3:11]>C(O)C>[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH3:2])[CH3:11]
Reactant: CCOC(CBr)OCC
Reactant: Cc1ccccc1S
Agent: [Na]
Solvent: CCO
Product: CCOC(CSc1ccccc1C)OCC
Yield: 89 %

Procedure:
In ethanol (50 mL) was dissolved sodium metal (1.6 g, 66 mmol) at 23° C. 2-Methylbenzenethiol (8.1 mL, 68 mmol) was slowly added to this solution, followed by bromoacetaldehyde diethylacetal (9.50 mL, 63 mmol). The reaction mixture was stirred at reflux for 18 h. The solvent was then evaporated in vacuo and the residue was washed with H2O (100 mL) and extracted with ether (100 mL). The organic solution was dried (MgSO4), concentrated in vacuo and purified by distillation to afford the title compound (13.48 g, 82% yield): 1H NMR (400 MHz, CDCl3) δ ppm: 7.33 (1H, d, J=7.9 Hz), 7.16–7.08 (3H, m), 4.65 (1H, t, J=5.6 Hz), 3.66 (2H, q, J=7.0 Hz), 3.55 (2H, q, J=7.0 Hz), 3.09 (2H, d, J=5.6 Hz), 2.38 (3H, s), 1.20 (6H, t, J=7.0 Hz). LCMS (M+H)+ m/z 241 (t=2.65 min.).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-])=O)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>C(O)C.C1COCC1.[Pd]>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH2:13])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)N1CCc2cc(N)ccc21
Yield: 67.9 %

Procedure:
The solution of 1-acetyl-5-nitroindoline (1.0 g, 4.85 mmol) in ethanol-THF (100 mL: 30 mL) was hydrogenated over 5% Pd/C (600 mg) at atmosphere pressure for 2 h, filtered through Celite and concentrated in vacuo to give a white solid which was recrystallized from ethanol. White crystalline solid (580 mg, 68%) was obtained. Mp 185-186.5° C. (lit 184-185° C., [21]); 1H NMR (270 MHz, DMSO): δ 7.73 (1H, d, J=8.6 Hz, ArH), 6.45 (1H, s broad, w1/2=1.8 Hz, ArH), 6.33 (1H, dd, J=8.6, 1.8 Hz, ArH), 4.82 (2H, s, NH2), 3.97 (2H, t, J=8.4 Hz, CH2), 2.99 (2H, t, J=8.4 Hz, CH2), 2.07 (3H, s, CH3); APCI-MS 175 (M−H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=O.C([O-])(=O)C.[NH4+].[N+:16]([CH3:19])([O-:18])=[O:17].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:19]/[N+:16]([O-:18])=[O:17])[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1ccc(C=O)cc1C
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(/C=C/[N+](=O)[O-])cc1C
Yield: 66.2 %

Procedure:
A solution of 3,4-dimethylbenzaldehyde (20 mL, 0.15 mol), ammonium acetate (12.5 g, 0.16 mol), glacial acetic acid (65 mL), nitromethane (34 mL, 0.63 mol), and acetic anhydride (3.0 mL, 0.032 mol) is refluxed for 2 hours. The reaction is concentrated to an oil, then dichloromethane (100 mL) is added, and the solution is washed with water (2×) and brine. The organic phase is dried (MgSO4), and concentrated to a dark green solid. This material is re-crystallized (treated with Darco) from 50% cyclohexane/hexanes to afford 17.6 g (66% yield) of the desired compound. 1H NMR (CDCl3) δ 8.08 (dd, J=2.4 Hz, 13.5 Hz, 1H), 7.61 (dd, J=2.4 Hz, 13.5 Hz, 1H), 7.31-7.36 (m, 2H), 7.25 (d, J=7.8 Hz, 1H), 2.36 (s, 3H), 2.35 (s, 3H); MS 329 (MH+).
Reaction SMILES: [C:1]1([S:7][CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[Si](C)(C)[CH3:14]>CO>[C:1]1([S:7][CH2:8][C:9]([O:11][CH3:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CSc1ccccc1
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)CSc1ccccc1
Reaction time: 16 h

Procedure:
A room temperature solution of (phenylsulfanyl)acetic acid (8.4 g, 50.0 mmol) in methanol (100 mL) was treated with chlorotrimethylsilane (13 mL, 100.0 mmol), stirred for 16 hours, and concentrated. The concentrate was dissolved in 5:1/hexanes:diethyl ether, filtered through a pad of silica gel (80 g), rinsed with 5:1/hexanes:diethyl ether, and concentrated to provide the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:20][C:21]([CH3:23])=[CH2:22]>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[O:10][CH2:22][C:21]([CH3:23])=[CH2:20]
Reactant: C=C(C)CCl
Reactant: Cc1cc(Br)cc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(C)COc1c(C)cc(Br)cc1Br

Procedure:
A solution of 2,4-dibromo-6-methyl-phenol (Compound 3,62 g, 0.23 mol) in 700 mL of acetone was treated with potassium carbonate (38.7 g, 0.28 mol), sodium iodide (3.4 g, 0.023 mol) and 3-chloro-2-methylpropene (34 mL, 0.35 mol) and the resulting suspension was refluxed for 18 hours. The solids were filtered and the filtrate was evaporated in vacuo to afford the title compound as a dark yellow oil. 1H-NMR (300 MHz, CDCl3): δ 7.53(d, 1H, J=2.7 Hz), 7.27(d, 1H, J=1.9 Hz), 5.17(s, 1H), 5.02(s, 1H), 4.28(s, 2H), 2.30(s, 3H), 1.92(s, 3H).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:9][C:10]1([CH3:27])[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]2[CH:15]=[C:14](/[C:22](/[CH3:26])=[CH:23]\[CH2:24][OH:25])[CH:13]=[CH:12][C:11]1=2.N1C=CN=C1>CN(C=O)C>[C:4]([Si:1]([CH3:3])([CH3:2])[O:25][CH2:24]/[CH:23]=[C:22](\[C:14]1[CH:13]=[CH:12][C:11]2[C:10]([CH3:27])([CH3:9])[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=2[CH:15]=1)/[CH3:26])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C/C(=C/CO)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C/C(=C/CO[Si](C)(C)C(C)(C)C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.4 %

Procedure:
tert-Butyldimethylsilyl chloride (2.7 g, 17.5 mmol) was added to the solution of Intermediate 2 (3 g, 11.6 mmol) and imidazole (1.6 g, 23.2 mmol) in 10 mL of DMF. The mixture was then stirred for 16 h at room temperature. After quenching with water, the mixture was extracted with ether (3×10 mL), washed with brine (1×10 mL), dried (MgSO4) and concentrated to give a crude brown oil. The crude product was purified by flash chromatography using 10% EtOAc in hexane to give the title compound (3 g, 70% yield) as a colorless oil:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:30][C:31](=[O:36])[CH2:32][C:33](=[O:35])[CH3:34])([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:30][C:31](=[O:36])[CH2:32][CH:33]([OH:35])[CH3:34])([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1
Reactant: CC(=O)CC(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)CC(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.7 %

Procedure:
To a solution of (R)—N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-oxobutanamide (Example 251, 51 mg, 0.1 mmol), in MeOH (1 mL) was added NaBH4 (10 mL, 0.26 mmol). The reaction mixture was stirred at rt for 1 h and concentrated under reduced pressure. The residue was purified by preparative HPLC (Axia luna column, 30×100 mm, 40-100% MeOH/H2O with 0.1% TFA over 10 min, flow rate 40 mL/min, monitoring at 220 nm) to yield N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-hydroxybutanamide (Example 330) as a pale yellow oil (28 mg, 55% yield). LCMS: RT=2.66 min [M+H] 512.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 7.13-7.23 (3H, m), 7.02-7.08 (2H, m, J=4.96, 4.56, 4.56, 2.43, 2.43 Hz), 6.96-7.02 (2H, m), 6.85-6.93 (4H, m), 6.67 (2H, d, J=7.07 Hz), 5.87 (1H, t, J=2.78 Hz), 4.10-4.20 (1H, m), 3.95 (1H, dd, J=12.76, 10.74 Hz), 3.73 (1H, dd, J=12.76, 10.74 Hz), 2.32-2.38 (2H, m), 1.22 (3H, d, J=6.32 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:19][C:18]3[C:13](=[C:14]([O:22]C)[CH:15]=[C:16]([O:20][CH3:21])[CH:17]=3)[C:11](=[O:12])[CH:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:21][O:20][C:16]1[CH:17]=[C:18]2[C:13]([C:11](=[O:12])[CH:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[O:19]2)=[C:14]([OH:22])[CH:15]=1
Reactant: COc1ccc(-c2cc(=O)c3c(OC)cc(OC)cc3o2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1ccc(-c2cc(=O)c3c(O)cc(OC)cc3o2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.2 %

Procedure:
To a solution of 5b (10.0 g, 32.1 mmol) in 200 mL anhydrous CH2Cl2 was added dropwise a 1 M solution of BBr3 (35.3 mL, 35.3 mmol) over 15 min at room temperature with magnetic stirring. A thick yellow precipitate formed rapidly during the addition. After stirring 5 h, the reaction was quenched by adding 200 mL EtOH, and the solvent was then evaporated in vacuo. The yellow residue was triturated with 300 mL boiling 50% EtOH. After cooling to room temperature, the yellow solid was collected on a Büchner funnel, rinsed with 500 mL 50% EtOH and air dried. Recrystallization from 1.5 L EtOH provided 8.16 g (85.4%) of the title product as fine, pale-yellow needles; mp 176-177° C. (lit.25 mp 174-175° C.); 1H NMR (CDCl3) δ 3.88 (s, 3 H), 3.89 (s, 3 H), 6.36 (d, 1 H, J=2.1 Hz), 6.48 (d, 1 H, J=2.1 Hz), 6.57 (s, 1 H), 7.01 (d, 2 H, JAB=9.0 Hz), 7.84 (d, 2 H, JAB=9.0 Hz), 12.81 (s, 1 H); EI-MS m/z 298 (M+, 100). Anal. calcd for C17H14O5: C, 68.45; H, 4.73. Found: C, 68.25; H, 4.77.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([NH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH3:36])[CH:34]=2)[N:29]=[C:28]([C:37](O)=[O:38])[N:27]=1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:40]([NH2:44])[CH:41]([CH3:43])[CH3:42].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(N(CC)CC)C.O>[C:1]([O:5][C:6]([NH:8][C:9]([NH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH3:36])[CH:34]=2)[N:29]=[C:28]([C:37]([NH:44][CH2:40][CH:41]([CH3:43])[CH3:42])=[O:38])[N:27]=1)=[N:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1ccc2nc(C(=O)O)nc(N[C@H]3CCCC[C@H]3NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2c1
Reactant: CC(C)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2nc(C(=O)NCC(C)C)nc(N[C@H]3CCCC[C@H]3NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 400 mg of 4-{[(1S,2R)-2-({[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)cyclohexyl]amino}-6-methylquinazoline-2-carboxylic acid, 0.15 ml of isobutylamine, 285 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 200 mg of 1-hydroxybenzotriazole in 7 ml of N,N′-dimethylformamide, 0.41 ml of triethylamine was added, and then the mixture was stirred at room temperature for 24 hours. The reaction solution was mixed with water and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform) to obtain 242 mg of the desirable compound as a white powder.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=2[O-:18])=[CH:8][CH:7]=1)=[O:5])C.N1C=CC=CC=1C1C=CC(C(O)=O)=CC=1.[OH-].[Na+]>O1CCOCC1>[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=2[O-:18])=[CH:8][CH:7]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(-c2cccc[n+]2[O-])cc1
Agent: O=C(O)c1ccc(-c2ccccn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2cccc[n+]2[O-])cc1
Yield: 87.8 %

Procedure:
2-(4-Ethoxycarbonylphenyl)pyridine N-oxide (260 mg) synthesized from 4-(2-pyridyl)benzoic acid in the same manner as in the above Referential Example was dissolved in 1,4-dioxane (10 ml), a 1N aqueous solution (2.00 ml) of sodium hydroxide was added, and the mixture was heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid (6 ml) was added to the residue, and precipitate formed was collected by filtration to obtain the title compound (202 mg) as a colorless amorphous solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8](N)[CH2:9][NH2:10].C=O>C(Cl)Cl>[O:7]1[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[CH:8]=[CH:9][NH:10]1
Reactant: NCCN
Reactant: Oc1ccccc1
Agent: C=O
Solvent: ClCCl
Product: C1=Cc2ccccc2ON1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a suitably equipped glass resin reactor equipped with stirrer is charged 450 parts phenol, 450 parts methylene chloride and 144 parts of ethylene diamine. The temperature of the reaction mixture is adjusted to 25° C. and 595 parts of 50% formalin is added while maintaining the temperature below 30° C. The reaction mixture is stirred for 2 hours at 30° C. after formaldehyde addition is complete. The reaction mixture is heated to atmospheric reflux and refluxed for 3 hours. The reaction mixture is allowed to cool and separate into two layers. The upper water layer is withdrawn and discarded. The lower organic layer is reheated to atmospheric reflux and distilled to remove solvent. Heating is continued with the gradual application of vacuum until a temperature of 70° C. at about 5.0 kPa pressure is reached. The very viscous product is removed from the reactor and allowed to cool. The light yellow semi-solid product has 67% closed dihydrobenzoxazine ring. Upon standing, the clear amorphous product slowly crystallizes to an opaque, grainy solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.[Br:12]Br>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:12])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C)cc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1

Procedure:
574 g. of this ester were dissolved in 1200 ml. of carbontetrachloride and, while boiling and exposing to a U.V. lamp, treated dropwise with a solution of 109 ml. of bromine in 400 ml. of carbontetrachloride. After all of the bromine had been dropped in, the mixture was heated for a further hour, concentrated in vacuo and the residue crystallized from low boiling petroleum ether, yielding as colorless fine crystals, 4-(bromo-methyl)benzoic acid methyl ester, which melted at 52°. For the reaction of this ester with 1-methyl-1,2-dicarbobenzoxy-hydrazine, the following procedure was followed:
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][C:24]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([OH:36])[CH:32]([NH:37][C:38](=[O:47])[CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:31]1)=[O:29])([CH3:26])[CH3:25].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH3:26][C:24]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C:33](=[O:36])[CH:32]([NH:37][C:38](=[O:47])[CH2:39][O:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:31]1)=[O:29])([CH3:23])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(NC(=O)COc2ccccc2)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(=O)C(NC(=O)COc2ccccc2)C1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 103.3 %

Procedure:
Dess-Martin periodinane (0.53 g, 1.25 mmol) was added to a stirred solution of 4-hydroxy-3-[(phenoxyacetyl)amino]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (0.36 g, 1.0 mmol) in DCM (4 mL). The mixture was stirred at 80° C. for 5 minutes under microwave irradiation and a saturated solution of Na2CO3 was added. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo to yield 4-oxo-3-[(phenoxyacetyl)amino]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (0.36 g, 100% yield, 28% pure) that was used in the next step without further purification. C18H24N2O5 LCMS: Rt 2.55, m/z 249 [M+H-BOC]+ (using method, LC-MS Method 3).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1.BrCCCC[N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32].C(N(CC)CC)C>CN(C)C=O>[CH2:16]([C:31]1[CH:30]=[CH:29][CH:28]=[C:25]2[C:26]([NH:22][C:23](=[O:32])[C:24]=12)=[O:27])[CH2:4][CH2:5][CH3:13].[O:1]=[C:2]1[N:6]([CH:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCc1cccc2c1C(=O)NC2=O
Temperature: 50 °C
Reaction time: 18 h

Procedure:
4-(2-keto-1-benzimidazolinyl)piperidine (1.04 g, 4.79 mmol), N-(4-bromobutyl)-phthalimide (1.59 g, 5.64 mmol) and triethylamine (986 mL, 7.07 mmol) were combined in 10 mL of N,N-dimethylformamide. The reaction mixture was stirred at 50° C. for 18 hours, and then concentrated in vacuo. The residue was partitioned between dichloromethane and saturated sodium bicarbonate. The phases were separated and the organic phase was dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The resulting solid was purified by “flash” chromatography (95:5:0.5 of dichloromethane:methanol:ammonium hydroxide). The product fractions were evaporated to dryness and reconcentrated twice from diethyl ether to give the title compound as a solid.
Reaction SMILES: O[C:2]([CH3:18])([CH3:17])[C:3]#[C:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([O:15][CH3:16])=[C:11]([CH:14]=1)[C:12]#[N:13])=[O:6].C(NCC)C.C([OH:26])C>>[CH3:17][C:2]1([CH3:18])[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:15][CH3:16])=[C:11]([CH:14]=2)[C:12]#[N:13])=[CH:4][C:3]1=[O:26]
Reactant: COc1ccc(C(=O)C#CC(C)(C)O)cc1C#N
Reactant: CCO
Solvent: CCNCC
Product: COc1ccc(C2=CC(=O)C(C)(C)O2)cc1C#N
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred solution of 5-(4-hydroxy-4-methylpent-2-ynoyl)-2-methoxybenzonitrile (0.9 g, 3.70 mmol) in ethanol (10 mL), a solution of diethyl amine (0.38 mL, 3.70 mmol) in EtOH (2.0 mL) was added dropwise at RT and the reaction mixture was stirred for additional 1 h. The ethanol was then was removed, and the mixture diluted with EtOAc (40 mL). The combined organic layers were washed with water (5 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford 5-(5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)-2-methoxybenzonitrile (0.9 g, 100%) as a yellow semi solid.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[C:7]([O:11][C:12]([N:14]1[CH2:18][CH:17]([OH:19])[CH:16]([OH:20])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>O.C1COCC1>[C:7]([O:11][C:12](=[O:13])[N:14]([CH2:18][CH:17]=[O:19])[CH2:15][CH:16]=[O:20])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CC(O)C(O)C1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CC=O)CC=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium periodate (20.31 g, 94.96 mmol) in H2O (118 mL) was added to a cooled solution of 3,4-dihydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (19.3 g, 94.6 mmol) in THF (158 mL) over a 30 minute period. The resulting white suspension was allowed to stir at room temperature for 3 h. The suspension was filtered and the filtrate concentrated under vacuum to remove the THF. The resulting aqueous solution was used directly in the next reaction.