Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>CN(C)C(=O)C>[Cl:13][C:4]1[CH:3]=[C:2]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[O:22])=[CH:19][CH:20]=2)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cnc(Cl)cc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 120 °C
Yield: 33.9 %

Procedure:
A mixture of ethyl 4,6-dichloronicotinate (500 mg, 2.272 mmol) and (4-aminophenyl)(morpholino)methanone (469 mg, 2.272 mmol) in N,N-Dimethylacetamide (5 mL) was treated with DIEA (0.794 mL, 4.54 mmol) and sealed in a large microwave vial and heated in a heating block at 120° C. overnight. The reaction mixture is removed from heating block, cooled to rt and diluted with water and extracted into CH2Cl2. Washed with water and concentrated to give dark oil which was chromatographed (ISCO Companion 40 g silica gel column and eluted with EtOAc/Hexane gradient (0-100%) to give 300 mg of ethyl 6-chloro-4-(4-(morpholine-4-carbonyl)phenylamino)nicotinate as a light yellow solid. LCMS: (M+H)+=390.02, 392.02 (Cl pattern). 1H NMR (400 MHz, CDCl3) δ ppm 1.43 (t, J=7.14 Hz, 3H) 3.74 (br. s, 8H) 4.41 (q, J=7.03 Hz, 2H) 7.00 (s, 1H) 7.30 (d, J=8.35 Hz, 2H) 7.51 (d, J=8.35 Hz, 2H) 8.80 (s, 1H) 9.99 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH3:8].[CH3:15][N:16]([CH3:25])[C:17]1[CH:22]=[C:21](F)[N:20]=[C:19](F)[CH:18]=1>>[CH3:15][N:16]([CH3:25])[C:17]1[CH:22]=[C:21]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH3:8])[N:20]=[C:19]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH3:8])[CH:18]=1
Reactant: CN(C)c1cc(F)nc(F)c1
Reactant: CC(c1ccccn1)c1ccccn1
Product: CN(C)c1cc(C(C)(c2ccccn2)c2ccccn2)nc(C(C)(c2ccccn2)c2ccccn2)c1
Yield: 61 %

Procedure:
NMe2PY5Me2 was synthesized in a similar manner as that of CF3PY5Me2, using 1,1-bis(2-pyridyl)ethane and 4-dimethylamino-2,6-difluoropyridine as the precursors, and purified on a silica column eluted with CH2Cl2:MeOH:triethytamine (20:1:0.1). Yield: 61%. 1H NMR (CDCl3, 400 MHz): □ =8.44 (dd, J=4.81, 0.98 Hz, 4H), 7.28 (dt, J=7.86, 7.80, 1.89 Hz, 4H), 6.95 (ddd, J=7.41, 4.85, 0.98 Hz, 4H), 6.76 (d, J=8.05 Hz, 4H), 6.31 (s, 2H), 2.80 (s, 6H), 2.13 (s, 6H). Anal. Calcd. for C31H30N6: C, 76.52%; H, 6.21%; N, 17.27%. Found: C, 76.22%; H, 6.46%; N, 17.15%. LMS (M+) m/z calcd for [NMe2PY5Me2+H]+, 487.2610, found, 487.3.
Reaction SMILES: [F:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.C(N(CC)CC)C.[CH:14]1([C:17]2[N:22]=[C:21]([C:23]3[NH:40][C:26]4=[N:27][C:28]([N:31]5[CH2:36][CH2:35][CH2:34][C@@H:33]([C:37](O)=[O:38])[CH2:32]5)=[CH:29][CH:30]=[C:25]4[N:24]=3)[CH:20]=[CH:19][N:18]=2)[CH2:16][CH2:15]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH:14]1([C:17]2[N:22]=[C:21]([C:23]3[NH:40][C:26]4=[N:27][C:28]([N:31]5[CH2:36][CH2:35][CH2:34][C@@H:33]([C:37]([N:4]6[CH2:5][CH2:6][C@H:2]([F:1])[CH2:3]6)=[O:38])[CH2:32]5)=[CH:29][CH:30]=[C:25]4[N:24]=3)[CH:20]=[CH:19][N:18]=2)[CH2:15][CH2:16]1
Reactant: O=C(O)[C@@H]1CCCN(c2ccc3nc(-c4ccnc(C5CC5)n4)[nH]c3n2)C1
Reactant: F[C@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C([C@@H]1CCCN(c2ccc3nc(-c4ccnc(C5CC5)n4)[nH]c3n2)C1)N1CC[C@H](F)C1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
(S)-3-Fluoropyrrolidine (175 μmol) was added to a vial followed by N,N-dimethylformamide (200 μL), triethylamine (35 μL, 250 μmol) and (R)-1-(2-(2-cyclopropylpyrimidin-4-yl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylic acid (200 μL, 50 μmol, 0.25 M in N,N-dimethylformamide) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HATU) (250 μL, 100 μmol, 0.4 M solution in N,N-dimethylformamide). The reaction mixture was shaken at 50° C. for 16 h. The solvent was evaporated by Speedvac and the residue was purified via preparative HPLC to afford the title compound. MS API-ES+ (M+H) 436; HPLC retention time 2.521 min (Method C).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]3[CH2:14][CH:9]([CH2:10][C:11]=2[C:12]=1[F:13])C=C3.C[N+]1([O-])[CH2:21][CH2:20][O:19]CC1.CC(C)=[O:25]>O.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]3[CH2:14][CH:9]([CH2:10][C:11]=2[C:12]=1[F:13])[CH:21]([OH:25])[CH:20]3[OH:19]
Reactant: Fc1ccc2c(c1F)CC1C=CC2C1
Reactant: CC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: OC1C2Cc3c(ccc(F)c3F)C(C2)C1O
Reaction time: 18 h

Procedure:
5,6-Difluorotricyclo[7.2.1.02,7]dodeca-2(7),3,5,10-tetraene (714 mg, 3.72 mmol) and N-methyl morpholine N-oxide (553 mg, 4.10 mmol) were stirred in acetone (20 mL) and H2O (3 mL). To this was added a solution of osmium tetraoxide (OsO4 (0.2 mL, 2.5%wt. soln. In t-butanol (t-BuOH), 0.02 mmol). After 18 hours, the mixture was concentrated to an oil, dissolved in a minimum of CH2Cl2 and filtered through a silica pad (3×3 mm) eluting with 20% EtOAc/hexanes. Product containing fractions were concentrated to an oil (850 mg, 100%). (TLC 20% EtOAc/hexanes Rf 0.37). 1H NMR (CDCl3) δ6.88 (ddd, J=9.3,8.5,7.6 Hz, 1H), 6.78 (m, 1H), 4.01 (AB d, 2H), 3.06 (brs, 1H), 2.92 (AB dd, J=17.9,5.0 Hz, 1H), 2.75 (br AB, J=17.9 Hz, 1H), 2.44 (br s, 1H), 2.32 (2-OH), 2.26 (m, 1H), 1.50 (d, J=7.8 Hz, 1H). GCMS m/e 226 (M+).
Reaction SMILES: C(OC(=O)[CH:7]([C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[NH2:22])[C:8]([O:10]C(C)(C)C)=O)(C)(C)C.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([CH:34]=O)=[CH:26][CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCOCC>CC(O)=O.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>[Br:21][C:18]1[CH:17]=[C:16]2[C:15]([CH2:7][C:8](=[O:10])[N:22]2[CH2:34][C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:24]=[CH:25][CH:26]=2)=[CH:20][CH:19]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc(Br)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC[SiH](CC)CC
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: O=C1Cc2ccc(Br)cc2N1Cc1ccnc2ccccc12
Reaction time: 0.5 h

Procedure:
2-(2-Amino-4-bromo-phenyl)-malonic acid di-tert-butyl ester (1.93 g, 5.0 mmol) and 4-quinolinecarboxaldehyde (890 mg, 5.50 mmol) were dissolved in 20 ml of AcOH under an atmosphere of dry N2. To this solution was added 95% NaHB(OAc)3 (1.45 g, 6.5 mmol) and the solution was stirred for 30 minutes. The reaction mixture was concentrated under vacuum and then stirred in 60 ml of a 1:1 solution of DCM/water. To this mixture was slowly added NaHCO3 until the pH˜8. The DCM layer was then washed with saturated aqueous NaHCO3 and dried over Na2SO4, filtered and concentrated under vacuum to give a golden oil which was subsequently dissolved in a solution of 20 ml of TFA and 2.5 ml of triethylsilane under an atmosphere of dry N2. The mixture was stirred overnight after which time the reaction mixture was concentrated under vacuum and then partitioned between DCM and saturated aqueous NaHCO3. The DCM layer was dried over Na2SO4, filtered and concentrated under vacuum to give a brown solid which, after trituration with Et2O, gives the tilted compound as a white solid.
Reaction SMILES: [C:1]([O:5][NH:6][C:7]([C:9]1[C:18]([CH3:19])=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([CH3:21])([CH3:20])[NH:16]2)=[CH:11][CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][NH:6][C:7]([C:9]1[C:18]([CH3:19])=[C:17]2[C:12]([CH2:13][CH2:14][C:15]([CH3:21])([CH3:20])[NH:16]2)=[CH:11][CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(C(=O)NOC(C)(C)C)ccc2c1NC(C)(C)C=C2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)NOC(C)(C)C)ccc2c1NC(C)(C)CC2
Yield: 0.1 %

Procedure:
A solution of 7-tert-butyloxycarbamoyl-1,2-dihydro-2,2,8-trimethylquinoline (114 mg, 0.39 mol) in 4 mL of ethyl acetate was hydrogenated under an atmosphere of hydrogen with Pd-C 10% (11 mg) at rt for 7 h. Filtration over Celite afforded 60 mg (60%) of 7-tert-butyloxycarbamoyl-1,2,3,4-tetrahydro-2,2,8-trimethylquinoline. The title compound was prepared by General Method 12 (EXAMPLE 147) from 7-tert-butyloxycarbamoyl-1,2,3,4-tetrahydro-2,2,8-trimethylquinoline (60 mg, 0.206 mmol) to afford 30 mg (77%) of 7-amino-1,2,3,4-tetrahydro-2,2,8-trimethylquinoline as a light reddish oil. Data for 7-amino-1,2,3,4-tetrahydro-2,2,8-trimethylquinoline: 1 H NMR (400 MHz, CDCl3) 6.70 (d, J=7.9, 1H), 6.09 (d, J=7.9, 1H), 3.30 (bs, 3H), 2.71 (t, J=6.7, 2H), 1.89 (s, 3H), 1.65 (t, J=6.7, 2H), 1.21 (s, 6H).
Reaction SMILES: [CH:1]([C:3]1[N:4]([S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)=[O:2].[BH4-].[Na+].O>CO>[OH:2][CH2:1][C:3]1[N:4]([S:14]([N:17]([CH3:19])[CH3:18])(=[O:15])=[O:16])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: CN(C)S(=O)(=O)n1cc(-c2ccccc2)nc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(C)S(=O)(=O)n1cc(-c2ccccc2)nc1CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Formyl-N,N-dimethyl-4-phenyl-1H-imidazole-1-sulfonamide (221 mg, 0.79 mmol) was dissolved in anhydrous MeOH (10 mL) and NaBH4 (89 mg, 2.37 mmol) was added in portions. Gas evolved and the suspension was stirred at room temperature. After 30 min, the crude reaction mixture was poured into H2O and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to give crude 2-(hydroxymethyl)-N,N-dimethyl-4-phenyl-1H-imidazole-1-sulfonamide, which was used directly in the next reaction.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.O[C@@H:32]1[C@@H:37]([NH:38][C:39](=[O:48])[O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:36][C@H:35]2[C@@H:33]1[CH2:34]2.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.CO>[O:25]=[C:23]1[C:22]2[C:21](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20](=[O:30])[N:24]1[C@H:36]1[C@@H:37]([NH:38][C:39](=[O:48])[O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:32][C@H:33]2[C@@H:35]1[CH2:34]2
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(N[C@H]1C[C@@H]2C[C@@H]2[C@@H]1O)OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(N[C@H]1C[C@@H]2C[C@@H]2[C@H]1N1C(=O)c2ccccc2C1=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
A solution of triphenylphosphine (6.4 g, 24.292 mmol), phthalimide (6.2 g, 42.511 mmol) and benzyl (1S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]hexan-3-ylcarbamate (3.0 g, 12.146 mmol) in toluene (250 mL) was stirred at −78° C. for 30 minutes under nitrogen protection, followed by the addition of diisopropyl azodicarboxylate (8.6 mL, 42.511 mmol) dropwise. The resulting mixture was stirred at −78° C. for another 1 hour and then at room temperature overnight. The reaction mixture was treated with 10 mL of methanol, and the solvents were removed under reduced pressure. The crude material was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:2) to afford the title compound (3.0 g, 65%) as a light yellow oil. MS (ES+) C22H20N2O4 requires: 376, found: 399 [M+23]+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[CH3:19][NH:20][O:21][CH3:22].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CCOC(C)=O>[CH:1]([O:4][C:5]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:6]=1[C:7]([N:20]([O:21][CH3:22])[CH3:19])=[O:9])([CH3:2])[CH3:3]
Reactant: CNOC
Reactant: CC(C)Oc1cc(C(F)(F)F)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1ccc(C(F)(F)F)cc1OC(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 80 %

Procedure:
To a suspension of 2-isopropoxy-4-trifluoromethyl-benzoic acid isopropyl ester (35 mg, 0.12 mmol) in THF (1 ml) was added a solution of 0.5 N-LiOH (2 eq), and the resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was acidified with 1N HCl, and then extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was vacuum dried to yield the 2-isopropoxy-4-trifluoromethyl-benzoic acid. To an ice-cold suspension of 2-isopropoxy-4-trifluoromethyl-benzoic acid and N,O-dimethylhydroxylamine hydrochloride (13 mg, 0.132 mmol) in CH2Cl2 (1 mL) was added N-methylmorpholine (0.015 ml, 0.132 mmol), and the resulting mixture was stirred for 5 minutes, to which were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (26 mg, 0.132 mmol). The resulting mixture was stirred for 2 hours at room temperature, and then diluted with EtOAc. The organic layer was washed with 1N HCl, water, and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by chromatography (Hex/EtOAc=3/1) to give the title compound (28 mg, 80%).
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([CH2:7][N:8]1[CH:12]=[CH:11][N+:10]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])=[C:9]1[NH2:22])=[O:6])[CH3:3].[C:23]([O-])(=O)[CH3:24].[Na+].C(OC(=O)C)(=O)C.C(=O)(O)[O-].[Na+]>>[CH2:2]([O:4][C:5]([C:7]1[N:8]2[CH2:12][CH2:11][N:10]([C:13]3[C:14]([CH3:21])=[CH:15][C:16]([CH3:20])=[CH:17][C:18]=3[CH3:19])[C:9]2=[N:22][C:23]=1[CH3:24])=[O:6])[CH3:3]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)Cn1cc[n+](-c2c(C)cc(C)cc2C)c1N
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1c(C)nc2n1CCN2c1c(C)cc(C)cc1C
Temperature: 160 °C
Yield: 41 %

Procedure:
A mixture of 3-ethoxycarbonylmethyl-1-(2,4,6-trimethyl-phenyl)-2-aminoimidazolium bromide (1.0 g, 2.7 mmol), sodium acetate (0.55 g, 6.75 mmol) and acetic anhydride (5.0 mL) was heated at 160° C. for 12 hr. Upon cooling, the mixture was poured into a flask containing ice. While stirring, excess sodium bicarbonate was added to the above mixture in small portions, and the resulting mixture was stirred at room temperature for 6 hr. Then, the mixture was extracted with dichloromethane (2×40 mL). The organic extracts were washed with water and dried over anhydrous sodium sulfate. Solvents were removed in vacuo and the residue was subjected to chromatography using ethyl acetate/hexanes (1:4) as eluent to afford the title compound as a light yellow oil which solidified upon cooling (0.344 g, 41% yield). 1H NMR (CDCl3, 300 MHz) δ 6.89 (s, 2H), 4.32 (q, J=7.1 Hz, 2H), 4.36–4.26 (m, 2H), 4.15–4.08 (m, 2H), 2.39 (s, 3H), 2.26 (s, 3H), 2.20 (s, 6H), 1.35 (t, J=7.1 Hz, 3H). Mass spec.: 314.15 (MH+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:7]=1[C:15]([O:17][CH3:18])=[O:16].C[O-].[Na+].[F:22][C:23]([F:30])([F:29])[C:24](OCC)=[O:25].Cl>CC(OC)(C)C.CO.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH2:13][C:24](=[O:25])[C:23]([F:30])([F:29])[F:22])=[CH:8][C:7]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1cc(C(C)=O)ccc1-c1ccco1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc(C(=O)CC(=O)C(F)(F)F)ccc1-c1ccco1
Reaction time: 2 h

Procedure:
4-(2-furyl)-3-(methoxycarbonyl)phenyl-1-ethanone (1.36 g, 5.57 mmol) was dissolved in MTBE (30 ml) at room temperature under nitrogen. Ethyl trifluroroacetate (0.87 g, 6.1 mmol) was added followed by a suspension of sodium methoxide (0.36 g, 6.7 mmol) in methanol (5 ml). After 2 hours of stirring, ethyl trifluoroacetate (2.03 g, 14.3 mmol) was added, followed by sodium methoxide (0.87 g, 6.1mmol). After an additional 18 hours, the mixture was poured into stirring ethyl acetate and dilute hydrochloric acid. The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and evaporated to give the title compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]=[O:38]>C1COCC1>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH:26]([CH:37]([OH:38])[CH2:36][CH2:35][CH2:34][CH2:33][Cl:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=CCCCCCl
Reactant: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C(O)CCCCCl)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 0.32 mL (2.2 mmol) of diisopropylamine in 10 mL of THF at 0° C. was treated with 0.92 mL (2.3 mmol) of 2.5 M n-butyllithium in sol'n in hexanes. The resulting solution was stirred at 0° C. for 10 min, then cooled to −78° C. A solution of 0.51 g (1.8 mmol) of (1-tert-butoxycarbonylpiperidin-4-yl)acetic acid, ethyl ester (from Piperidine 35, Step A) in 2 mL of THF was added. After stirring for 30 minutes, a solution of 0.26 g (2.1 mmol) 5-chloropentanal in 2 mL of THF was added (J. Org. Chem. 1981, 46, 2007). The reaction was stirred for 1.75 hours at −78° C. and 3.5 hours at 0° C. After quenching the reaction with saturated NH4Cl, volatiles were removed under reduced pressure. The residue was partitioned between 100 mL of Et2O and 100 mL of H2O. After separating phases, the organic layer was washed with 100 mL of 0.5 N HCl and 100 mL of 1 N NaHCO3, dried over MgSO4 and concentrated. The residue was purified with a 40M Biotage column using 3:1 v/v of hexanes/EtOAc as the eluant to afford impure title compound: RF: 0.27 (7:3 v/v hexanes/EtOAc); 1H-NMR (500 MHz) δ 1.24–2.08 (m, 23H), 2.38 (t, J=6.2, 1H), 2.63–2.71 (m, 2H), 3.53–3.56 (m, 2H), 3.92 (m, 1H), 4.09–4.19 (m, 4H).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH2:8]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:16](=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C[O-].[Na+].O>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[C:16](=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][OH:18]
Reactant: OCCNCCO
Reactant: O=C1CCCCCCCCCCCCCCCO1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: O=C(CCCCCCCCCCCCCCCO)N(CCO)CCO
Temperature: 80 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
A 200-ml flask equipped with a stirrer was charged with 16.6 g (158 mmol) of diethanolamine and 20.1 g (79 mmol) of cyclohexadecanolide, to which 0.21 g (3.9 mmol) of sodium methoxide was added. The contents were stirred at 80° C. for 18 hours. After completion of the reaction, water was added, and solids deposited were collected by filtration and recrystallized from methanol, thereby obtaining 23.3 g (yield: 82%) of N,N-bis(2-hydroxyethyl)-16-hydroxyhexadecanamide.
Reaction SMILES: [N+]1([O-])C=CC=CC=1.Br[C:9]1[C:10]([C:15]#[N:16])=[N:11][CH:12]=[CH:13][CH:14]=1.C[Si](C#N)(C)C.[CH3:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>C(#N)C.C(N(CC)CC)C>[C:15]([C:10]1[C:9]([C:27]2[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=2)=[CH:14][CH:13]=[CH:12][N:11]=1)#[N:16]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ncccc1Br
Agent: C[Si](C)(C)C#N
Agent: [O-][n+]1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(-c2cccnc2C#N)cc1

Procedure:
Synthetic Scheme XXVIII shows the 4-step preparation of the alkylating reagent 2-cyano-3-(4-bromomethylphenyl)pyridine (75) from 3-bromopyridine (76) (Aldrich). In step 1, the pyridine 76 was reacted with hydrogen peroxide in acetic acid at reflux to give the pyridine N-oxide 77. In step 2, the N-oxide 77 was converted to 3-bromo-2-cyanopyridine (78) by reaction with trimethysilylcyanide and triethylamine in acetonitrile at reflux. In step 3, the nitrile 78 was coupled with 4-methylphenylboronic acid (52) (Scheme XXIV) using Snieckus conditions (Scheme XIII) to give 2-cyano-3-(4-methylphenyl)pyridine (79). In step 4, 79 was brominated with NBS/AIBN in carbon tetrachloride at reflux to give the desired alkylating reagent 75. ##STR82##
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C([Li])CCC.CON(C)[C:17]([C:19]1[CH:27]=[CH:26][C:22]2[O:23][CH2:24][O:25][C:21]=2[CH:20]=1)=[O:18]>O1CCCC1>[O:23]1[C:22]2[CH:26]=[CH:27][C:19]([C:17](=[O:18])[CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=3)=[CH:20][C:21]=2[O:25][CH2:24]1
Reactant: Cc1cccc(C)n1
Reactant: CON(C)C(=O)c1ccc2c(c1)OCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc(CC(=O)c2ccc3c(c2)OCO3)n1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
To a −60° C. solution of 2,6-dimethyl pyridine (48 mL, 457 mmol) in tetrahydrofuran (800 mL) was added n-butyl lithium (183 mL, 2.5 M in hexanes, 457 mmol) over 30 minutes. The resulting red solution was stirred at −60° C. for 1 hour, and then treated with a solution of benzo[1,3]dioxole-5-carboxylic acid methoxy-methyl-amide of Step A (415 mmol) in tetrahydrofuran (200 mL) over 1 hour. The resulting reaction mixture was slowly warmed to −20° C. over 3 hours, and then poured over ice (1 kg). The liquid phase was decanted and the ice was washed with methyl tert-butyl ether (1L). The combined organic extracts were washed with saturated aqueous sodium chloride (3×100 mL), dried with magnesium sulfate and concentrated in vacuo to yield the title compound crude (102 g). Recrystallization from toluene yielded the title compound as a yellow solid (57 g, 49% over two steps).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:14])[C:6](=[O:13])[NH:7]2.[N+:15]([O-])([O-:17])=[O:16].[K+]>OS(O)(=O)=O>[N+:15]([C:11]1[C:2]([Br:1])=[C:3]2[C:8](=[CH:9][C:10]=1[Br:12])[NH:7][C:6](=[O:13])[C:5](=[O:14])[NH:4]2)([O-:17])=[O:16]
Reactant: O=c1[nH]c2cc(Br)cc(Br)c2[nH]c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(Br)c([N+](=O)[O-])c(Br)c2[nH]c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
The method of Cheeseman, supra. was adapted. 5,7-Dibromo-1,4-dihydroquinoxaline-2,3-dione (74 mg, 0.23 mMol) was dissolved in concentrated H2SO4 (1 mL) at 0° C. for 30 mins., and then KNO3 (28 mg, 0.27 mMol, Baker) was added to this solution. The mixture was stirred at 0° C. for 3 h and then at room temperature for 30h. It was poured into ice water (8 g) and the precipitate was collected by filtration, was dissolved into 1N KOH (5 mL), and the red precipitate was removed by filtration. The solution then was acidified to pH=2 with 4N HCl to obtain a cream precipitate, which was collected by filtration, then was dried in the air at 50° C. for 4 h, affording the pure 6-nitro-5,7-dibromo-1,4-dihydro-2,3-quinoxalinedione (71 mg, 84.5%), as a yellow powder; mp: 318°-20° C. (dec.). IR (KBr, cm-1): 3468, 3131, 3062, 2931, 1712, 1593, 1537. NMR (1H, DMSO-d6): δ 7.392 (s, 1H), 11.566 (s, 1H), 12.274 (s, 1H). HRMS: calcd. for C8H3N3O4Br2 m/z: 362.8489, found: 362.8478.