Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]([C:21]([OH:23])=[O:22])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24](OC(OCC)N(C)C)[CH3:25]>>[CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(OCC)N(C)C
Reactant: O=C(O)C1Cc2ccccc2N(C(=O)OCc2ccccc2)C1
Product: CCOC(=O)C1Cc2ccccc2N(C(=O)OCc2ccccc2)C1

Procedure:
The title compound is prepared analogously to Example 1s) starting from 1.5 g of N-benzyloxycarbonyl-1,2,3,4-tetrahydroquinoline-3(R,S)-carboxylic acid and 3.7 ml of N,N-dimethylformamide diethyl acetal and is purified by means of FC (100 g of silica gel, mobile phases D and B). This gives the title compound: Rf (A)=0.75; MS: (M)+ =339.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][C:13]([O:15]C)=O.Cl.[NH2:18][OH:19].[OH-].[Na+].OP([O-])(O)=O.[K+]>CO.O>[OH:19][NH:18][C:13](=[O:15])[CH2:12][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: COC(=O)CCc1ccc2ccccc2n1
Reactant: NO
Agent: Cl
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(CCc1ccc2ccccc2n1)NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a solution of methyl 3-(2-quinolinyl)propanoate (4) (0.111 g, 0.52 mmol) and hydroxylamine hydrochloride (0.144 g, 2.07 mmol) in methanol (3 ml), a solution of NaOH (0.165 g, 4.13 mmol) in water (0.5 ml) was added and the resulting mixture was stirred at room temperature for 30 minutes. The pH of the reaction medium was brought to 7 with saturated KH2PO4, the mixture was extracted with ethyl acetate (3×−15 ml), and the combined extracts were dried (Na2SO4). The solvent was evaporated under reduced pressure, the residue was washed with small amount of ethyl acetate and crystallized from acetonitrile to give the title compound (0.054 g, 48.1%). M.p. 159-160° C. 1H NMR (DMSO-d6, HMDSO), δ: 2.45-2.57 (m, 2H, overlapped with a signal of DMSO); 3.15 (t, J=7.2 Hz, 2H); 7.44 (d, J=8.4 Hz, 1H); 7.54 (ddd, J=8.2, 7.6, and 1.2 Hz, 1H); 7.71 (ddd, J=8.6, 7.0, and 1.4 Hz, 1H); 7.92 (d, J=8.6 Hz, 2H); 8.25 (d, J=8.4 Hz, 1H); 8.71 (s, 1H); 10.44 (s, 1H). HPLC analysis on Omnispher 5 C18: impurities ˜2.3% (column size 4.6×150 mm; mobile phase-5% acetonitrile+95% 0.1M phosphate buffer (pH 2.5); detector UV 230 nm; sample concentration 0.5 mg/ml; flow rate 1.5 ml/min). Anal. Calcd for C12H12N2O2 containing 2% of inorganic impurities: C, 65.32; H, 5.48; N, 12.70. Found, %: C, 65.42; H, 5.39; N, 12.43.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[C:16]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccc(OC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
To a 500 ml flask were added 45.6 grams (0.374 mol) 4-hydroxylbenzaldehyde, 150 ml of acetone and 25.8 grams (0.187 mol) potassium carbonate. Then, 52.1 ml (0.449 mol) of benzoyl chloride (BzCl) was added therein dropwise slowly at a temperature of about 0° C. After the addition, the mixture was warmed up to room temperature and the reaction lasted 2 hours. The residue was extracted 3 times with ethyl acetate (150 ml×3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated till dry to obtain 76.08 grams (0.336 mol) 4-benzoyloxybenzaldehyde. Next, 35.7 ml (0.37 mol) of 4-fluoroaniline was added dropwise to a solution of the obtained 4-benzoyloxybenzaldehyde in 300 ml of ethyl acetate. The reaction lasted 1 hours. The reaction mixture was filtered. The obtained solid was recrystallized from anhydrous ethanol to obtain 60.3 grams (0.189 mol) white solid, namely compound II-1. 1H NMR (400 MHz, CDCl3): δ 7.09-7.14 (m, 2H, Cpr-H), 7.23-7.28 (m, 2H, Cpr-H), 7.37-7.39 (m, 2H, Cpr-H), 7.54-7.59 (m, 2H, Cpr-H), 7.67-7.71 (m, 1H, Cpr-H), 7.99-8.02 (m, 2H, Cpr-H), 8.24-8.26 (m, 2H, Cpr-H), 8.49 (s, 1H, —CH—).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[N:22]=[C:21]([NH:23][CH2:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)[CH:20]=[N:19][CH:18]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1.[N:33]1([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.CN1CCOCC1.O>CN1CCCC1=O>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][NH:23][C:21]2[N:22]=[C:17]([C:14]3[N:13]=[CH:12][C:11]4[CH:10]=[N:9][N:8]([C:6]5[N:7]=[C:2]([N:36]6[CH2:37][CH2:38][CH2:39][N:33]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:34][CH2:35]6)[CH:3]=[CH:4][CH:5]=5)[C:16]=4[CH:15]=3)[CH:18]=[N:19][CH:20]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: COc1ccc(CNc2cncc(-c3cc4c(cn3)cnn4-c3cccc(F)n3)n2)cc1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CN1CCOCC1
Product: COc1ccc(CNc2cncc(-c3cc4c(cn3)cnn4-c3cccc(N4CCCN(C(=O)OC(C)(C)C)CC4)n3)n2)cc1
Temperature: 110 °C
Yield: 100 %

Procedure:
A mixture of 6-[1-(6-fluoro-2-pyridyl)pyrazolo[4,3-c]pyridin-6-yl]-N-[(4-methoxyphenyl)methyl]pyrazin-2-amine (0.479 mmol; 316.3 mg), tert-butyl 1,4-diazepane-1-carboxylate (0.958 mmol; 192 mg), and N-Methylmorpholine (1.20 mmol; 122 mg; 0.133 mL) in 1-methyl-2-pyrrolidinone (5 mL) in a sealed pressure vial was heated at 110° C. overnight. The mixture was poured into water, and extracted with EtOAc. The organic layer was concentrated. The residue was purified on silica eluted with 0 to 100% EtOAc in DCM to afford tert-butyl 4-[6-[6-[6-[(4-methoxyphenyl)methylamino]pyrazin-2-yl]pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-1,4-diazepane-1-carboxylate (˜291 mg, 100%).
Reaction SMILES: [CH3:1][N:2]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9].C(N(CC)CC)C.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.CCCCCC.C(OC(=O)C)C>C(Cl)Cl>[CH3:1][N:2]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][S:30]([C:27]1[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=1)(=[O:32])=[O:31]
Reactant: CN(OCCOCCO)C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCOCCON(C)C(=O)OC(C)(C)C)cc1
Reaction time: 8 h

Procedure:
To a stirred solution of 2-[2-(N-Methyl-N-BOC-aminooxy)-ethoxy]ethanol (e) 1 g (4.25 mmol) in dry DCM (15 mL) was added triethylamine (910 mg, 1254 μL, 9 mmol) and toluene-4-sulfonyl chloride (1620 mg, 8.5 mmol) in 15 mL DCM. The reaction mixture was stirred under argon overnight. TLC revealed a complete reaction (Hexane/Ethylacetate 6:4). The reaction mixture was diluted with 50 mL DCM and the organic phase was washed with NaHCO3 5%, brine and water. The organic phase was dried over MgSO4, filtered and evaporated off under reduced pressure. The product was purified using a Companion combiflash (40 g column) with a gradient of Hexane/Ethylacetate. 10-65% ethyl acetate in Hexane over 20 minutes. Structure confirmed by NMR.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[C:14]2[S:13][C:12]([Cl:15])=[N:11][C:10]=2[C:9]([Cl:16])=[CH:8][C:7]=1[Cl:17]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:15][C:12]1[S:13][C:14]2[C:6]([N:5]=[C:1]=[O:2])=[C:7]([Cl:17])[CH:8]=[C:9]([Cl:16])[C:10]=2[N:11]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1c(Cl)cc(Cl)c2nc(Cl)sc12
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C=Nc1c(Cl)cc(Cl)c2nc(Cl)sc12
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Under a nitrogen atmosphere 25 mL of ethyl acetate was stirred and cooled in an ice bath. To this was added via syringe 9.5 mL (18 mmole) of 1.9M phosgene in toluene. During 25 minutes, a solution of 3.0 grams (11.8 mmole) of 7-amino-2,4,6-trichlorobenzothiazole in 75 mL of ethyl acetate was added dropwise. Upon completion of the addition the reaction mixture was warmed to ambient temperature and then gently heated at reflux for 2.5 hours. After this time the reaction mixture was concentrated under reduced pressure, yielding (2,4,6-trichlorobenzothiazol-7-yl)isocyanate, which was stored in a refrigerator.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[O:16])[NH:5][C:6]([CH3:15])=[CH:7][C:8]=1[CH:9]1CCC[CH2:11][CH2:10]1.CC1NC(=O)C(C#N)=C(CCC)C=1>>[NH2:1][CH2:2][C:3]1[C:4](=[O:16])[NH:5][C:6]([CH3:15])=[CH:7][C:8]=1[CH2:9][CH2:10][CH3:11]
Reactant: Cc1cc(C2CCCCC2)c(CN)c(=O)[nH]1
Agent: CCCc1cc(C)[nH]c(=O)c1C#N
Product: CCCc1cc(C)[nH]c(=O)c1CN

Procedure:
The title compound was prepared in the same manner as described for 3-(aminomethyl)-4-cyclohexyl-6-methyl-2(1H)-pyridinone (Intermediate 3) using 6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinecarbonitrile (2 g, 11.2 mmol). Obtained: 1.2 g (60%). LCMS E-S(M+H)=181.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.85-7.95 (br s, 3H), 5.99 (s, 1H), 3.80-3.85 (m, 2H), 2.42 (t, 2H), 2.14 (s, 3H), 1.43-1.49 (m, 2H), 0.86 (t, 3H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[C:11]([C:14]([O:16]C)=[O:15])[CH:10]=[C:9]3[O:18][CH3:19])[CH2:3][CH2:2]1.C1COCC1.[OH-].[Na+]>CO>[CH:1]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=[C:9]3[O:18][CH3:19])[CH2:2][CH2:3]1
Reactant: COC(=O)c1cc(OC)c2cccc(C3CC3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(=O)O)nc2c(C3CC3)cccc12
Reaction time: 1 h

Procedure:
30.0 g of methyl 8-cyclopropyl-4-methoxyquinoline-2-carboxylate, 250 ml of THF and 400 ml of MeOH was placed in 2 L-flask, and 46 ml of 5N NaOH aq. was added, and stirred for 1 h. The mixture was concentrated in vacuo and diluted with water. 46 ml of 5N HCl aq. was added with cooling in ice bath, extracted with 500 ml of CHCl3-MeOH (4-1), dried over Na2SO4 and filtered. The filtrate was concentrated to afford a yellow solid. The solid was washed with hexane-CHCl3, filtered and dried under vacuum to afford 8-cyclopropyl-4-methoxyquinoline-2-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][O:7][CH2:8][C:9]1([CH2:18][CH2:19]O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][O:10]1.[C:30]1(=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[O:39])[NH:31]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:26][C:24]([F:25])([F:27])[C:22]1[CH:21]=[C:5]([CH:4]=[C:3]([C:2]([F:29])([F:28])[F:1])[CH:23]=1)[CH2:6][O:7][CH2:8][C:9]1([CH2:18][CH2:19][N:31]2[C:32](=[O:39])[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:30]2=[O:40])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][O:10]1
Reactant: OCCC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCc2ccccc21
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCc2ccccc21
Reaction time: 1 h

Procedure:
To a solution of 2-(1-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-1,3-dihydroisobenzofuran-1-yl)ethanol (200 mg, 0.48 mmol), isoindoline-1,3-dione (105 mg, 0.71 mmol), and triphenylphosphine (187 mg, 0.71 mmol) in tetrahydrofuran (5 mL) at 0° C. was added diethyl azodicarboxylate (0.112 mL, 0.71 mmol). The ice bath was removed and stirring continued for 1 h. Clean, complete conversion to product was observed. The reaction was quenched by addition of saturated ammonium chloride, and extracted with ethyl acetate (2×). The organics were washed with water, then saturated sodium bicarbonate, then brine, dried over magnesium sulfate, and concentrated. Column chromatography (8% EtOAc/Hex-->12% EtOAc/Hex) gave 255 mg (98%) as a colorless oil. 1H-NMR (CDCl3, 300 MHz) δ 7.73 (s, 1H), 7.67 (m, 2H), 7.63 (s, 2H), 7.61 (m, 2H), 7.00-7.15 (m, 4H), 5.16 (qAB, JAB=12.2 Hz, 2H), 4.60 (s, 2H), 3.77 (m, 1H), 3.68 (m, 1H), 3.63 (s, 2H), 2.47 (m, 1H), 2.30 (ddd, J=14.4, 7.3, 4.9 Hz, 1H); 13C-NMR (CDCl3, 126 MHz) δ 168.1, 141.2, 140.6, 140.0, 133.7, 132.2, 131.7 (q, J=33.6 Hz), 128.0, 127.4, 127.2, 123.4 (q, J=273 Hz), 122.9, 121.5, 121.4, 121.2, 88.9, 76.8, 73.0, 72.0, 33.6, 33.5. Mass spec.: 550.20 (MH)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16](Br)=[CH2:17])[C:11](=[O:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)=[O:21].C([O-])([O-])=O.[Na+].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:25]2[CH:26]=[CH:27][C:22]([CH:20]=[O:21])=[CH:23][CH:24]=2)=[CH2:17])[C:11](=[O:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: C=C(Br)Cn1ccc(OCc2ccccc2)cc1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: C=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(C=O)cc1

Procedure:
To 6.17 g (19.3 mmol) 4-benzyloxy-1-(2-bromo-allyl)-1H-pyridin-2-one (preparation 9a), 3.76 g (25.1 mmol) 4-formylphenylboronic acid and 1.56 g (1.35 mmol) tetrakis-triphenyl-phosphanepalladium in 150 ml 1,4-1,4-dioxanee and 45 mL MeOH is added 19.3 mL (38.5 mmol) 2M aqueous Na2CO3-solution under a nitrogen atmosphere. The reaction mixture is evacuated three times and flushed with nitrogen. The mixture is refluxed overnight under a nitrogen atmosphere and is diluted with water. The phases are separated and the aqueous phase is extracted with DCM. The combined organic phase is dried over MgSO4, filtered and the solvent is evaporated. To the residue is added MeOH/acetonitrile, the mixture is filtered and purified via reverse HPLC chromatography (Waters symmetry, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH:27]=[C:28]1[C:34]2[CH:35]=[CH:36][CH:37]=[N:38][C:33]=2[CH2:32][O:31][C:30]2[CH:39]=[CH:40][C:41]([C:43]([OH:46])([CH3:45])[CH3:44])=[CH:42][C:29]1=2>C(#N)C.O>[CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[CH2:6][CH2:7][N:8]([CH2:25][CH2:26][CH:27]=[C:28]2[C:34]3[CH:35]=[CH:36][CH:37]=[N:38][C:33]=3[CH2:32][O:31][C:30]3[CH:39]=[CH:40][C:41]([C:43]([OH:46])([CH3:45])[CH3:44])=[CH:42][C:29]2=3)[CH2:9][CH2:10]1)=[O:4]
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: COC(=O)C1(c2ccc(Cl)cc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C1(c2ccc(Cl)cc2)CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4-(4-chloro-phenyl)-piperidine-4-carboxylic acid methyl ester in acetonitrile/water (4/1) was added potassium carbonate (221 mg, 1.6 mmol), followed by 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (150 mg, 0.4 mmol). The reaction mixture was stirred at room temperature for 48 hours and then concentrated in vacuo. The resulting residue was treated with water and extracted with ethyl acetate. Solvent was evaporate from the combined dried (MgSO4) organic extracts. Purification on silica gel chromatography using dichloromethane-methanol (9.6:0.4) afforded the title compound.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[O:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[C:13](#N)[CH3:14].OO.S([O-])([O-])=O.[Na+].[Na+]>O.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C1CCCCC1>[CH:14]1([O:1][N:2]2[C:7]([CH3:8])([CH3:9])[CH2:6][C:5](=[O:10])[CH2:4][C:3]2([CH3:12])[CH3:11])[CH2:13][CH2:5][CH2:4][CH2:3][CH2:11]1
Reactant: CC1(C)CC(=O)CC(C)(C)N1O
Reactant: CC#N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=S([O-])[O-]
Agent: OO
Solvent: C1CCCCC1
Solvent: O
Product: CC1(C)CC(=O)CC(C)(C)N1OC1CCCCC1
Yield: 64 %

Procedure:
A solution of 0.104 g (0.523 mmol) of ferrous chloride tetrahydrate and 0.168 g (0.799 mmol) of citric acid monohydrate in 1.5 ml of water is added to a mixture of 3.14 g (18.4 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidin-4-one, 30 ml of acetonitrile, and 20 ml of cyclohexane that has been heated to the reflux temperature of 60°. A solution of 5.27 g (77 mmol) of 50% aqueous hydrogen peroxide is added dropwise over 2 hours to the reaction mixture while the temperature is maintained at reflux. A solution of 0.047 g of ferrous chloride tetrahydrate and 0.055 g of citric acid monohydrate in 0.5 ml of water is added to the reaction mixture 1.6 hours after the peroxide addition is started. After the peroxide is added, the reaction mixture is heated at reflux for 30 minutes, then allowed to cool slowly. Aqueous sodium sulfite solution is added to the reaction mixture to decompose excess peroxide. The aqueous layer is extracted with a 2:1 mixture of acetonitrile-cyclohexane and then with ethyl acetate. The combined organic layers are concentrated. Purification by flash chromatography with 20:1 heptane-ethyl acetate affords 3.01 g (64% yield) of the title compound as a colorless liquid. GC assay is 99%.
Reaction SMILES: O=[C:2]1[C:11]2[CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]1[CH2:12][C:13]([O-:15])=O.N1C2C(=O)CCCC=2C=CC=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][NH2:35])=[CH:30][CH:29]=1>>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[C:13](=[O:15])[CH2:12][CH:3]3[C:2]([C:11]4[CH:10]=[N:9][CH:8]=[CH:7][C:6]=4[CH2:5][CH2:4]3)=[N:35]2)=[CH:30][CH:29]=1
Reactant: O=C([O-])CC1C=CC2=C(CNCC2)C1=O
Reactant: NNc1ccc(Cl)cc1
Agent: O=C1CCCc2cccnc21
Product: O=C1CC2CCc3ccncc3C2=NN1c1ccc(Cl)cc1

Procedure:
Prepared according to the method described in Example 1 from methyl 5,6,7,8, -tetrahydro-8-oxoisoquinoline-7-acetate (prepared from 5,6-dihydroquinoline-8(7H)-one (Boyd et al, J. Chem. Soc., Perkin Trans. I (1992)31) according to the method of Wu et al supra) and 4-chlorophenylhydrazine.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:5]=[C:6]([CH:12]2[CH:17]([N+:18]([O-:20])=[O:19])[CH2:16][CH:15]=[CH:14][CH2:13]2)[CH:7]=[C:8]([F:11])[C:9]=1[F:10].[Br:21]N1C(=O)CCC1=O>CO.CO.C(OC(=O)C)C>[F:3][C:4]1[CH:5]=[C:6]([CH:12]2[C:17]([Br:21])([N+:18]([O-:20])=[O:19])[CH2:16][CH:15]=[CH:14][CH2:13]2)[CH:7]=[C:8]([F:11])[C:9]=1[F:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])C1CC=CCC1c1cc(F)c(F)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=[N+]([O-])C1(Br)CC=CCC1c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 56 mg (1 mmol) of KOH in 6 ml of methanol was added dropwise a solution of 257 mg (1 mmol) of 3,4,5-trifluoro-1-(6-nitrocyclohex-3-en-1-yl)-benzene from example 2.3 in 4 ml of methanol/ethylacetate (3:1) and the resulting mixture was stirred for 20 min at room temperature. 178 mg (1 mmol) of NBS (N-bromosuccinimide) were added and the mixture was stirred for another 30 min. The solvents were evaporated in vacuo. Column chromatography (SiO2, cyclohexane/ethylacetate 10:1) yielded 312 mg (0.93 mmol, 93% of theory) of the title compound as yellowish crystals.
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[C:3]=1[O:15][CH2:16][O:17][CH3:18].[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[CH3:12][C:11]1[C:2]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:3]([O:15][CH2:16][O:17][CH3:18])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([O:13][CH3:14])=[CH:6][CH:5]=2
Reactant: COCOc1c(Br)c(C)cc2cc(OC)ccc12
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COCOc1c(-c2ccccc2)c(C)cc2cc(OC)ccc12
Temperature: 160 °C
Reaction time: 0.42 h
Yield: 182.6 %

Procedure:
2-Bromo-3-methyl-6-(methyloxy)-1-{[(methyloxy)methyl]oxy}naphthalene (14) (2.32 g, 7.46 mmol), phenylboronic acid (1.83 g, 15.0 mmol, 2.0 eq), tetrakistriphenylphosphine palladium (0) (0.869 g, 0.752 mmol, 10 mol %), 2 M sodium carbonate (65 mL), and ethylene glycol dimethyl ether (65 mL) were combined in a glass pressure bottle. The bottle was sealed with a screw cap and the reaction mixture was heated at 160° C. with stirring for 25 min. The reaction mixture was allowed to cool at RT. The reaction mixture was transferred to a separatory funnel and extracted with Et2O. The organic phase was separated, dried over MgSO4, filtered, and the filtrate was concentrated to give 4.96 g of the crude product. The crude product was combined with an additional 4.43 g of crude product (from a second Suzuki coupling reaction) and purified the crude product by chromatography over SiO2 with hexanes:CH2Cl2 (2:3) to give 4.2 g (91%) of the title compound (15) as a yellow oil. 1H NMR (400 MHz; DMSO-d6): δ 2.13 (s, 3H), 2.98 (s, 3H), 3.86 (s, 3H), 4.64 (s, 2H), 7.13 (dd, J=2.4 Hz, 9.1 Hz, 1H), 7.25 (d, J=2.4 Hz, 1H), 7.29 (d, J=7.0 Hz, 2H), 7.36 (t, J=7.5 Hz, 1H), 7.45 (t, J=7.5 Hz, 2H), 7.51 (s, 1H), 7.94 (d, J=9.1 Hz, 1H).
Reaction SMILES: C1CCCCCC1.N([O:10][C:11](C)(C)[CH3:12])=O.ON1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2C1=O.C1(=NO)CCCCCC1.[N+](C1CCCCCC1)([O-])=O.C1(=O)CCCCCC1>C(O)(=O)C>[C:11]([O:21][CH:20]1[CH2:18][CH2:25][CH2:24][CH2:23][CH2:22][CH2:19]1)(=[O:10])[CH3:12]
Reactant: CC(C)(C)ON=O
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: C1CCCCCC1
Agent: O=C1CCCCCC1
Agent: O=[N+]([O-])C1CCCCCC1
Solvent: CC(=O)O
Product: CC(=O)OC1CCCCCC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Cycloheptane (1 ml), t-butyl nitrite (1 mmol), N-hydroxyphthalimide (0.2 mmol), and acetic acid (1 ml) were placed in a flask and were stirred at 80° C. in an atmosphere of argon gas (1 atm=0.101 MPa) for 20 hours. The resulting reaction mixture was analyzed to find that cycloheptanone oxime, nitrocycloheptane, cycloheptanone, and cycloheptyl acetate were formed in yields of 21%, 3%, 7%, and less than 1%, respectively.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][N:12]2[C@@H:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][CH2:16][CH2:15][C@@H:14]([NH:25]C(=O)OC(C)(C)C)[C:13]2=[O:33])[CH2:10][CH2:9]1>ClCCl>[NH2:25][C@@H:14]1[CH2:15][CH2:16][CH2:17][C@H:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:12]([CH2:11][CH:8]2[CH2:9][CH2:10]2)[C:13]1=[O:33]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H](c2ccccc2)N(CC2CC2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CCC[C@H](c2ccccc2)N(CC2CC2)C1=O
Reaction time: 1 h
Yield: 89.2 %

Procedure:
Trifluoroacetic acid (2.5 mL) was added to a solution tert-butyl (3R,7R)-1-(cyclopropylmethyl)-2-oxo-7-phenylazepan-3-ylcarbamate (82 mg, 0.23 mmol) in dichloromethane (5 mL). After 1 h, the mixture was concentrated and aqueous saturated sodium bicarbonate was added. The mixture was extracted with dichlormethane (2×), and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated to give the title compound (53 mg). 1H NMR (500 MHz, CDCl3) δ 7.40–7.37 (m, 2H), 7.34–7.31 (m, 3H), 4.97 (dd, J=9.3, 3.7 Hz, 1H), 4.05 (dd, J=9.8, 4.2 Hz, 1H), 3.24 (dd, J=14.4, 7.1 Hz, 1H), 2.69 (dd, J=14.2, 7.1 Hz, 1H), 2.16–2.10 (m, 2H), 2.03–1.97 (m, 1H), 1.92–1.85 (m, 2H), 1.65–1.56 (m, 1H), 0.69–0.63 (m, 1H), 0.34–0.23 (m, 2H), 0.09–0.04 (m, 1H), −0.10–0.15 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[N:15]=[C:16]([CH3:19])[N:17]([CH3:18])[C:13]=2[CH:12]=[C:11]([NH:20][C:21](=[O:23])[CH3:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24]I.[H-].[Na+].O>O1CCCC1>[CH2:1]([O:8][C:9]1[C:14]2[N:15]=[C:16]([CH3:19])[N:17]([CH3:18])[C:13]=2[CH:12]=[C:11]([N:20]([CH3:24])[C:21](=[O:23])[CH3:22])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC(=O)Nc1cc(OCc2ccccc2)c2nc(C)n(C)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N(C)c1cc(OCc2ccccc2)c2nc(C)n(C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a suspension of 5.8 g (18.8 mmol) N-(7-benzyloxy-2,3-dimethy-3H-benzimidazol-5-yl)-acetamide in tetrahydrofuran (200 ml) were added 1.3 ml (20.5 mmol) methyl iodide and 0.74 g (20.5 mmol) sodium hydride (60%) in portions. The reaction was stirred at room temperature for 1 h and then poured into water (100 ml) and extracted with ethyl acetate (4×50 ml). The organic layers were dried over magnesium sulphate and concentrated in vacuo. The residue afforded 6.0 g (99%) of the title compound as ochre solid. m.p. 144°-149° C.