Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9]C)=O.[O-:19][C:20]#[N:21].[K+]>S1(CCCC1)(=O)=O>[Cl:2][C:3]1[CH:4]=[C:5]2[C:6]([C:7](=[O:9])[NH:21][C:20](=[O:19])[N:13]2[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:12]=1
Reactant: COC(=O)CNc1cc(Cl)ccc1C(=O)OC
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: COC(=O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Yield: 56.6 %

Procedure:
Hydrogen chloride is passed into 1 g of methyl 4-chloro-N-(methoxycarbonylmethyl)anthranilate and 1.6 g of potassium cyanate in 20 ml of sulfolane at 50° C. until analysis by HPLC indicates complete conversion. The product is precipitated by addition of water, filtered off, washed with water and dried. 0.59 g (57%) of methyl 1,2,3,4-tetrahydro-7-chloro-2,4-dioxoquinazolin-1-ylacetate is obtained.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:20](=[O:35])[N:21]([CH3:34])[C@@H:22]([C:30](=[O:33])[NH:31][CH3:32])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:10][C:11]1[C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[S:14][CH:15]=1)C)(C)(C)C.FC(F)(F)C(O)=O.O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[S:14]1[CH:15]=[C:11]([CH2:10][C@@H:9]([NH:7][CH3:6])[C:20]([N:21]([CH3:34])[C@@H:22]([C:30](=[O:33])[NH:31][CH3:32])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:35])[C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]1=2
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1csc2ccccc12)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1csc2ccccc12)NC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 94.8 %

Procedure:
((1R)-2-(Benzo[b]thiophen-3-yl)-1-(methyl-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)ethyl)-methylcarbamic acid tert-butylester (0.89 g; 1.70 mmol) was dissolved in methylene chloride (3 mL) and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred for 45 min at room temperature. Water (5 mL) was added. Methylene chloride (5 mL), an aqueous solution of sodium hydrogen carbonate (saturated) and sodium hydrogen carbonate (solid) was added until pH 8. The aqueous phase was extracted with methylene chloride (3×10 mL). The combined organic phases were dried (magnesium sulfate) and evaporated in vacuo to afford 0.66 g of (2R)-3-(Benzo[b]thiophen-3-yl)-N-methyl-2-methylamino-N-((1R)-1-methylcarbamoyl-2-phenylethyl)propionamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.B.O1CCCC1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][CH2:12][N:14]([CH3:16])[CH3:15])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)cc1CCC(=O)N(C)C
Agent: B
Solvent: C1CCOC1
Product: COc1ncc(Br)cc1CCCN(C)C
Temperature: 50 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
To a solution of 3-(5-bromo-2-methoxypyridin-3-yl)-N,N-dimethylpropanamide (1.0 g, 3.0 mmol) in THF (40 mL) was added borane-tetrahydrofuran (1.0 M in THF, 8.71 mL) slowly. The reaction mixture was allowed to stir for 3 h at 50° C. The mixture was allowed to cool to rt and then concentrated to dryness. To the residue, a solution of HCl (3.0 M in water, 40 mL) was added. The resulting mixture was allowed to stir for 2 h at 80° C. The mixture was allowed to cool to rt and then was basified to pH>10 with a potassium hydroxide solution. The aqueous solution was extracted with DCM. The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 3-(5-bromo-2-methoxypyridin-3-yl)-N,N-dimethylpropan-1-amine (0.377 g, 40%) as an oil. LCMS (FA): Rt=1.03 min, m/z=273.1 (M+H).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:9][CH2:8][NH:7][CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[F:17][C:18]1[C:31]([F:32])=[C:30](F)[C:29]([F:34])=[C:28]([F:35])[C:19]=1[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:21]>N1C=CC=CC=1>[C:1]([NH:4][CH:5]1[CH2:9][CH2:8][N:7]([C:30]2[C:29]([F:34])=[C:28]([F:35])[C:19]([C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:21])=[C:18]([F:17])[C:31]=2[F:32])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CC(=O)c1c(F)c(F)c(F)c(F)c1F
Reactant: CC(=O)NC1CCNC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)c1c(F)c(F)c(N2CCC(NC(C)=O)C2)c(F)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To 2.62 g (20.4 mmol) of 3-acetamidopyrrolidine dissolved in 50 mL of pyridine and cooled to 0° C. was added 2.06 g (20.4 mmol) of triethylamine and 5.24 g (18.6 mmol) of ethyl 2,3,4,5,6-pentafluorobenzoylacetate, from step 2 above. The solution was stirred at 0° C. for 1 hour, then at room temperature overnight. The solvent was removed by evaporation under vacuum and the residue was dissolved in chlorform, which was washed with 0.5N HCl and 5% potassium carbonate solution. The organic layer was dried over magnesium sulfate, filtered, and evaporated. The residue was further dried by adding and distilling off ethylene dichloride, chloroform and methylene, followed by further drying under vacuum. The crystalline residue was washed with hexane and dried to afford 6.8 g of the title compound as a tan solid, mp 90°-92° C. MS M/Z: 391 (M+H). IR (CDCl3): 1635, 1680, 1740 cm-1. NMR (CDCl3) d: 1.26 (m, 3H), 2.00 (m, 5H), 2.22 (m, 2H), 3.54 (m,1H), 3.77 (m, 2H), 3.85 (m, 1H), 3.98 (m, 1H), 4.22 (m, 2H), 5.75 (m, 1H). Analysis calculated for C17H18F4N2O4 : C, 52.31; H, 4.65; N, 7.18. Found: C, 52.47; H, 4.67; N, 7.33.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[C:14]([C:18]#[N:19])=[C:15]([NH2:17])[S:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])[CH3:3].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[C:14]([C:18]#[N:19])=[C:15]([NH:17][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:16][C:10]=2[CH2:9]1)=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc(N)c2C#N)C1
Reactant: O=C(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2c(sc(NC(=O)c3ccccc3)c2C#N)C1

Procedure:
Prepared according to general procedure A starting from 2-amino-3-cyano-4,7-dihydro-thieno[2,3-c]pyridine-6(5H)-carboxylic acid 1,1-dimethylethyl ester (compound A2) and benzoyl chloride.
Reaction SMILES: Br[CH:2]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[C:9](=[O:17])[C:8]2[C:7]([OH:18])=[CH:6][CH:5]=[CH:4][C:3]1=2.[SH:19][CH2:20][C:21]([OH:23])=[O:22]>ClCCl>[C:21]([CH2:20][S:19][CH:2]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[C:9](=[O:17])[C:8]2[C:7]([OH:18])=[CH:6][CH:5]=[CH:4][C:3]1=2)([OH:23])=[O:22]
Reactant: O=C(O)CS
Reactant: O=C1c2c(O)cccc2C(Br)c2cccc(O)c21
Solvent: ClCCl
Product: O=C(O)CSC1c2cccc(O)c2C(=O)c2c(O)cccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 75 %

Procedure:
10-Bromo-1,8-dihydroxy-9-anthrone (305 mg) was dissolved in dichloromethane (10 ml) and mercaptoacetic acid (0.07 ml) was added. The solution was stirred at room temperature for 3 days, during which time a yellow precipitate was formed, which was filtered off and recrystallised from absolute ethanol to give 10-(carboxymethylthio)-1,8-dihydroxy-9-anthrone (237 mg, 75%) as yellow needles, melting point 151°-152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[CH2:4][C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][CH:11]=[C:10]([OH:16])[CH:9]=2.[I-].[N:24]1([C:34](N2C=C[N+](C)=C2)=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[CH2:4][C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][CH:11]=[C:10]([O:16][C:34]([N:24]1[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26][CH2:25]1)=[O:35])[CH:9]=2
Reactant: C[n+]1ccn(C(=O)N2CCCc3ccccc32)c1
Reactant: Cc1c(Cc2c(F)cccc2Cl)c(=O)oc2cc(O)ccc12
Agent: [I-]
Product: Cc1c(Cc2c(F)cccc2Cl)c(=O)oc2cc(OC(=O)N3CCCc4ccccc43)ccc12

Procedure:
The title compound was prepared from 3-(2-chloro-6-fluoro-benzyl)-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. HPLC-MS m/z=478 (M+1), Rt: 5.58 min.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:27])[C:4]([C:6]1[C:7]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=2[O:23][CH2:24][O:25][CH3:26])=[CH:8][CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=1)=[O:5]>CO.[Pd]>[CH3:1][O:2][N:3]([CH3:27])[C:4]([C:6]1[C:7]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=2[O:23][CH2:24][O:25][CH3:26])=[CH:8][CH:9]=[C:10]([NH2:12])[CH:11]=1)=[O:5]
Reactant: COCOc1cccc(OC)c1-c1ccc([N+](=O)[O-])cc1C(=O)N(C)OC
Agent: [Pd]
Solvent: CO
Product: COCOc1cccc(OC)c1-c1ccc(N)cc1C(=O)N(C)OC
Yield: 104.2 %

Procedure:
A solution of Example 5B (5.67 g.) was dissolved in methanol (120 mL) and hydrogenated at 4 atm with 10% Pd/C (0.60 g) for 1 hour. The catalyst was removed by filtration and the solution concentrated to give the titled compound (5.44 g).
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[N:5]([C:13](=[O:15])[CH3:14])[C@@H:4]([CH3:16])[CH2:3]1.Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1.CN1C(=O)CCC1.CCN(C(C)C)C(C)C>O>[Br:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([C:13](=[O:15])[CH3:14])[C@@H:4]([CH3:16])[CH2:3][C@H:2]2[NH:1][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](N)C[C@@H]1C
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(Br)cc2[C@H](Nc2ccc([N+](=O)[O-])cn2)C[C@@H]1C
Temperature: 200 °C
Reaction time: 2 h
Yield: 161 %

Procedure:
To a flask charged with 1-((2S,4R)-4-amino-6-bromo-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation see Intermediate 1)(2 g, 7.06 mmol) and 2-chloro-5-nitropyridine (2.240 g, 14.13 mmol) was added NMP (10 mL) and the resulting mixture treated with DIPEA (3.70 mL, 21.19 mmol). The mixture was divided between 2 flasks, each flask flushed with nitrogen, sealed and the mixture stirred under microwave irradiation at 200° C. for 2 h. The 2 reaction mixtures were combined, diluted with water and extracted with EtOAc (×4). Combined EtOAc layers were washed with water (×3) then brine, dried over MgSO4 and concentrated in vacuo. The residual brown solid was purified by chromatography eluting with an EtOAc/hexanes gradient, which gave 1-((2S,4R)-6-bromo-2-methyl-4-((5-nitropyridin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone (4.6 g, 11.35 mmol, 161% yield) as a pale brown foam. LCMS (HpH, 2 min), Rt=1.08 min, MH+=405/407 (doublet).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[C:38]([O:41][CH2:42][CH3:43])(=O)C>CN(C)C=O>[O:41]1[C:42]2[CH:43]=[CH:3][CH:2]=[CH:1][C:7]=2[N:8]=[C:38]1[N:24]([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][S:18][C:9]1[NH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCNCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCN(CCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)c1nc2ccccc2o1

Procedure:
Method A, Part B. A solution of N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-heptanamine (prepared according to the procedure of U.S. patent application Ser. No. 07/416,606, Billheimer et al. ) (8.57 g, 19.7 mmol), the sulfone prepared in Method A, Part A above (3.52 g, 17.9 mmol) and potassium carbonate (3.00 g, 21.7 mmol) in dimethylformamide (30 mL) was heated to 90° C. for 18 hours. The mixture was allowed to cool and poured into ethyl acetate (200 mL). This solution was washed with water (4×200 mL), and the water washings were back-extracted in sequence with ethyl acetate (200 mL). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The residual oil was separated by flash chromatography (1:4 ethyl acetate-hexane), and the title product was obtained as a foam from evaporation from heptane solution, m.p. 58°-60° C. (7.00 g, 12.7 mmol, 71%). 1H NMR (CDCl3): 10.77 (1H, br s); 7.61-6.84 (14H, m); 3.52-3.40 (4H, m); 3.04 (2H, t, J=7.2 Hz); 1.79-1.58 (6H, m); 1.53-1.40 (2H, m); 1.37-1.21 (8H, m); 0.87 (3H, t, J=6.6 Hz). High-resolution mass spectrum: for C34H40N4OS, calc. 552.2923, obs. 552.2925, diff. 0.4 ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[N:14][N:13]([CH2:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=3)=[O:18])[C:12](=[O:27])[CH:11]=2)=[N:6][CH:7]=1.S(Cl)([Cl:30])=O>C(Cl)Cl.C(OC)(C)(C)C>[Cl:30][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:17](=[O:18])[CH2:16][N:13]2[C:12](=[O:27])[CH:11]=[C:10]([O:9][CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)[CH:15]=[N:14]2)=[CH:20][CH:21]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(Cn1ncc(OCc2ccc(F)cn2)cc1=O)c1ccc(CO)cc1
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: O=C(Cn1ncc(OCc2ccc(F)cn2)cc1=O)c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 400 mg (1.08 mmol) 5-(5-fluoro-pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one (preparation 19c) in 10 mL DCM is added 0.12 mL (1.62 mmol) thionylchloride at 0° C. The reaction mixture is stirred 2 h at RT and diluted with tert-butylmethylether. The precipitate is collected and dried.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([C:11](=[O:19])[CH2:12][NH:13][C:14]([CH2:17][CH3:18])([CH3:16])[CH3:15])=[CH:5][C:4]=1[Br:20]>>[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([CH:11]([OH:19])[CH2:12][NH:13][C:14]([CH2:17][CH3:18])([CH3:16])[CH3:15])=[CH:5][C:4]=1[Br:20]
Reactant: CCC(C)(C)NCC(=O)c1cc(Br)c(N)c(C#N)c1
Agent: Cl
Product: CCC(C)(C)NCC(O)c1cc(Br)c(N)c(C#N)c1

Procedure:
m.p. of the hydrochloride: 202°-204° C. (decomp.), was prepared from 4'-amino-3'-bromo-5'-cyano-2-tert.pentylaminoacetophenone analogous to Example 48.
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH2:10][OH:11])[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[S:20](Cl)(=[O:23])(=[O:22])[NH2:21]>C(COC)OC>[C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH2:8][O:9][S:20](=[O:23])(=[O:22])[NH2:21])[CH2:10][O:11][S:20](=[O:23])(=[O:22])[NH2:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)Cl
Reactant: OCC(CO)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: NS(=O)(=O)OCC(COS(N)(=O)=O)(c1ccccc1)c1ccccc1
Temperature: 4 °C
Reaction time: 8 h

Procedure:
To a solution of 17.3 g. (0.076 mol.) of 2,2-diphenyl-1,3-propanediol in 200 ml. of dimethoxyethane is added 12.7 g. (0.3 mol.) of 57% sodium hydride followed by an additional 400 ml. of dimethoxyethane. After stirring overnight the suspension is cooled to 4° C. A solution of 31.2 g. (0.27 mol.) of sulfamoyl chloride in 600 ml. of dimethoxyethane is then added dropwise. The suspension is stirred overnight at room temperature. After filtering the mixture the filtrate is concentrated and the residue washed with heptane. Chromatography on SilicAR, CC-7, followed by crystallization affords 2,2-diphenyl-1,3-bis-O-sulfamyl-1,3-propanediol.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[C:18]1([CH2:17][O:9][C:8]([CH:5]2[CH2:6][CH2:7][C:2](=[O:1])[CH2:3][CH2:4]2)=[O:10])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCC(C(=O)O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1CCC(C(=O)OCc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
To an acetone solution containing 12.0 g (84.4 mmol) of 4-ketocyclohexane carboxylic acid and 4.7 g (33.8 mmol) of potassium carbonate, 17.3 g (101.3 mmol) of benzyl bromide was added at room temperature. Next, this was agitated at 60° C. for 3 hours. After the reaction ended, crude product was obtained, and after potassium carbonate was removed by filtration and acetone was evaporated, the crude product was purified by silica gel column chromatography, and 16.5 g of 4-ketocyclohexane carboxylic acid phenylmethyl ester was obtained.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][CH2:9][C:10]#[N:11])=[CH:3][CH:2]=1.[OH-].[Na+].[N:15](OC)=[O:16].OS(O)(=O)=O.N([O-])=O.[Na+]>CO.CO.O.O>[OH:16][N:15]=[C:9]([CH:8]=[CH:7][C:4]1[CH:3]=[CH:2][C:1]([CH3:12])=[CH:6][CH:5]=1)[C:10]#[N:11]
Reactant: Cc1ccc(C=CCC#N)cc1
Reactant: CON=O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc(C=CC(C#N)=NO)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
In a 3-necked 50 ml flask fitted with a sintered glass gas inlet tube, 2.13 g (0.0135 mol) of 4-p-tolyl-but-3-enenitrile are dissolved in 30 ml of methanol, and cooled to 0° C. Sodium hydroxide (0.54 g; 0.0135 mol) is added. The turbid, slightly brownish mixture is then treated with ca. 0.025 mol of gaseous methyl nitrite bubbled below the surface of the mixture through the gas inlet tube (methyl nitrite is generated by dropwise addition of [0.8 ml of H2SO4 conc+1.6 ml H2O] to a suspension of sodium nitrite (1.72 g; 0.025 mol) in 3 ml of methanol:water 1:1 (v:v); see M. Itoh et al. Org. Synth. Coll vol. VI, 1988, 199). The mixture is then stirred overnight, allowing the temperature to rise to 25° C. The solvent is evaporated in vacuo, the residue is redissolved in water and extracted with toluene. The aqueous phase is then acidified with conc. HCl to pH ca 2, the beige precipitate is filtered, rinsed neutral with water, and dried under vacuum. The crude product is redissolved in ethyl acetate, filtered through a short pad of SiO2, and evaporated. 2-Hydroxyimino-4-p-tolyl-but-3-enenitrile (1.9 g; 76%), mp 135-137° C. is obtained and used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:11]([CH3:12])[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:18][CH3:19])=[C:7]([O:16][CH3:17])[C:8]=2[CH:13]([CH3:15])[CH3:14])[CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([C:8]([CH:13]([CH3:14])[CH3:15])=[C:7]([O:16][CH3:17])[C:6]([O:18][CH3:19])=[CH:5]2)=[CH:10][C:11]=1[CH3:12]
Reactant: COc1cc2c(c(C(C)C)c1OC)CC(C)C(Br)=C2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: COc1cc2cc(Br)c(C)cc2c(C(C)C)c1OC
Reaction time: 2 h
Yield: 91.9 %

Procedure:
Compound 13 (3.50 g, 10.8 mmol) was dissolved in 25 mL of benzene and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (2.45 g, 10.8 mmol) was added slowly with stirring and stirring was continued for 2 h. The reaction mixture was filtered through a short column of silica and eluted with dichloromethane. The solvent was evaporated and the product was crystallized from petroleum ether to give 3.21 g (9.93 mmol, 92%) of 14 as colorless crystals: mp 62-63° C.; 1H NMR δ1.51 (d, J-7.2 Hz, 6H), 2.56 (s, 3H), 3.90 (s, 3H), 3.96 (s, 3H), 3.97 (m, 1H), 6.94 (s, 1H), 7.92 (s, 1H), 7.96 (s, 1H). Anal. (C16H19BrO2) C, H.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][CH:8]2[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(F)(F)F.C[CH2:25][O:26]CC>CO>[OH:13][CH:8]([C:7]([O:26][CH3:25])([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: CCOCC
Reactant: COC(=O)C1OC1(c1ccccc1)c1ccccc1
Agent: FB(F)F
Solvent: CO
Product: COC(=O)C(O)C(OC)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
5 g (19.6 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate were dissolved in 50 ml of absolute methanol and, at 0° C., 0.1 ml of boron trifluoride etherate was added. The mixture was stirred at 0° C. for 2 h and at room temperature for a further 12 h. The solvent was distilled out, the residue was taken up in ethyl acetate, washed with sodium bicarbonate solution and water and dried over magnesium sulfate. After removal of the solvent by distillation there remained 5.5 g (88%) of a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([CH3:13])[CH:6]=[N:5]2>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C@@H:7]([CH3:13])[CH2:6][NH:5]2
Reactant: Cc1cnc2cc(Cl)c(Cl)cc2n1
Solvent: Cc1ccccc1
Product: C[C@H]1CNc2cc(Cl)c(Cl)cc2N1
Temperature: 40 °C
Reaction time: 16 h
Yield: 95.1 %

Procedure:
To an argon-purged pressure-resistant glass vessel (100 mL) equipped with a magnetic stir bar, RuCl[(R)-daipena][(R)-dm-segphos] (2.9 mg, 2.5 μmol) and KO(t-Bu) (14.0 mg, 0.125 mmol) were added, and the vessel was purged with argon again. To this vessel, a toluene (1.0 mL) solution containing 6,7-dichloro-2-methylquinoxaline (105.4 mg, 0.495 mmol) and being degassed by the freeze-pump-thaw technique in advance was added by pressure transfer using a cannula. An operation in which hydrogen was introduced into the pressure-resistant vessel up to 0.8 MPa and then released was repeated 10 times to completely substitute the inside with hydrogen. Then, hydrogen was introduced up to 2.0 MPa, and the vessel was stirred in a water bath at 40° C. for 16 hours. After hydrogen was released, the solution was concentrated under reduced pressure, and the residue was purified by silica gel thin-layer chromatography (hexane:ethyl acetate=5:1) to obtain (S)-6,7-dichloro-1,2,3,4-tetrahydro-2-methylquinoxaline (102.2 mg, 95%). A result of an analysis was conducted by high performance liquid chromatography (column: CHIRALCEL OB-H, mobile phase: hexane:IPA=95:5, 1 mL/min) showed that the optical purity of this product was 98% ee.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[CH:10]=2)[CH:5]=[CH:4][C:3]=1B(O)O.C([O-])(O)=O.[Na+].Br[C:25]1[CH:30]=[CH:29][N:28]([CH2:31][CH2:32][CH2:33][CH3:34])[C:27](=[O:35])[C:26]=1[C:36]#[N:37]>O1CCOCC1.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>[CH2:31]([N:28]1[CH:29]=[CH:30][C:25]([C:3]2[CH:4]=[CH:5][C:6]([O:8][C:9]3[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[CH:10]=3)=[CH:7][C:2]=2[F:1])=[C:26]([C:36]#[N:37])[C:27]1=[O:35])[CH2:32][CH2:33][CH3:34]
Reactant: Cc1cc(Oc2ccc(B(O)O)c(F)c2)ccn1
Reactant: CCCCn1ccc(Br)c(C#N)c1=O
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: C1COCCO1
Product: CCCCn1ccc(-c2ccc(Oc3ccnc(C)c3)cc2F)c(C#N)c1=O
Yield: 67.4 %

Procedure:
To a solution of intermediate 14 (1.77 mmol) in 1,4-dioxane ml) and a saturated solution of NaHCO3 (6 ml) was added intermediate 6 (0.451 g, 1.77 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.204 mg, 0.177 mmol). The reaction was then microwaved in a sealed tube at 150° C. for 10 minutes. The resulting cooled reaction mixture was filtered through a pad of diatomaceous earth and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/MeOH up to 3% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound 4 (0.45 g, 68%).