Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([F:13])=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([F:8])([F:7])[F:6].[O:14]=[O+][O-].O=O>[Cl-].[Na+].O>[CH3:1][O:2][C:3]1([F:13])[O:14][C:4]1([C:5]([F:7])([F:6])[F:8])[C:9]([F:12])([F:10])[F:11]
Reactant: O=[O+][O-]
Reactant: COC(F)=C(C(F)(F)F)C(F)(F)F
Agent: O=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC1(F)OC1(C(F)(F)F)C(F)(F)F
Reaction time: 0.3 h
Yield: 36.5 %

Procedure:
200 g (0.88 moles) of heptafluoroisobutenyl methyl ether (purity: 93%) was charged into a three-necked flask having a capacity of 300 ml, provided with a Dimroth condenser, a stirrer and a gas feed tube, and a brine at -20° C. was passed through the Dimroth condenser. About 340 liters of ozone-containing oxygen gas (ozone concentration: 125 mg/liter) was bubbled through the ether compound at 0° C. with stirring over 11 hours 18 minutes (total ozone amount: about 0.88 moles). After the reaction, 134.8 g of the reaction product was recovered therefrom and distilled, whereby 73.0 g of perfluoro(2-methyl-1,2-epoxypropyl) methyl ether was obtained as a fraction having a boiling point of 82° to 85° C. (yield: 36.5%).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][OH:5].[Cl:6][C:7]1[C:12](O)=[CH:11][CH:10]=[CH:9][N:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:6][C:7]1[C:12]([O:5][CH2:4][C@@H:2]2[CH2:3][O:1]2)=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: OC[C@@H]1CO1
Reactant: Oc1cccnc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ncccc1OC[C@@H]1CO1
Temperature: 0 °C
Yield: 43.6 %

Procedure:
Combine (R)-oxiranemethanol (32.85 g, 443.5 mmol) with 2-chloro-3-hydroxypyridine (52.23 g, 403.18 mmol) in THF (1.34 L). Stir the mixture until the solids dissolve. Cool it to 0° C. and slowly add triphenylphosphine (116.33 g, 443.5 mmol). After all the solids dissolve, add diisopropyl azodicarboxylate (87.92 mL, 443.5 mmol) drop-wise over 25 minutes at a sufficiently slow rate to maintain the internal temperature of the reaction below 10° C. Stir the mixture while cooling for 30 minutes then allow the mixture to warm to ambient temperature and continue stirring overnight. Add EtOAc, and wash with NaOH (2×1.0 N). Dry the organic layer over Na2SO4; filter; and concentrate the filtrate under reduced pressure. Triturate the residue with a mixture of 2:1 Et2O: hexanes and stir for 5 minutes. Filter and concentrate the filtrate under reduced pressure to provide a residue. Purify the residue via flash column chromatography (2×330 g SiO2), eluting with a gradient of 0-66% THF/Hexane. Combine the desired fractions, and concentrate under reduced pressure to provide the title compound (32.6 g, 43.6%) as a white solid. MS (m/z): 186 (M+1).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])[N:21]=1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>ClCCl>[F:34][C:19]([F:18])([F:35])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([C:28]([N:12]3[CH2:13][CH2:14][CH2:15][N:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][N:7]=4)[CH2:10][CH2:11]3)=[O:29])[CH:31]=[CH:32][CH:33]=2)[N:21]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: FC(F)(F)c1ccc(N2CCCNCC2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cccc(-c2noc(C(F)(F)F)n2)c1)N1CCCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.5 %

Procedure:
1-(5-(Trifluoromethyl)pyridin-2-yl)-1,4-diazepane (60 mg, 0.23 mmol), 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid (68 mg, 0.28 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCl) (89 mg, 0.46 mmol) were dissolved in dichloromethane (3 mL) at room temperature. Diisopropylethylamine (DIEA) (0.085 mL, 0.93 mmol) was then introduced at room temperature and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with dichloromethane (60 mL) and washed with water (1×20 mL) and brine (1×20 mL). The organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was then purified on Prep TLC (30% Ethyl Acetate:Hexanes) to give (3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)(4-(5-(trifluoromethyl)pyridin-2-yl)-1,4-diazepan-1-yl)methanone (14 mg, 14% yield). 1H NMR (300 MHz, CDCl3) δ 8.41 (s, 1H), 8.19-8.06 (m, 2H), 7.88 (s, 1H), 7.66-7.44 (m, 2H), 6.55 (bs, 1H), 3.98-3.64 (m, 8H), 1.74 (m, 2H). MS (ESI) m/z: Calculated for C21H17F6N5O2S: 485.13. found: 486.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:38]1[N:42]=[CH:41][S:40][N:39]=1)[C:12]([NH:14][CH:15]1[C:36](=[O:37])[N:17]2[C:18]([C:23]([O:25]CC3C=CC([N+]([O-])=O)=CC=3)=[O:24])=[C:19]([Cl:22])[CH2:20][S:21][C@H:16]12)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.O1CCCC1.C(O)(=O)C.[Pd]>[C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:38]1[N:42]=[CH:41][S:40][N:39]=1)[C:12]([NH:14][CH:15]1[C:36](=[O:37])[N:17]2[C:18]([C:23]([OH:25])=[O:24])=[C:19]([Cl:22])[CH2:20][S:21][C@H:16]12)=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)c1ncsn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1ncsn1
Yield: 36.2 %

Procedure:
p-Nitrobenzyl 7-[2-tert-butoxycarbonylmethoxyimino-2-(1,2,4-thiadiazol-3-yl)acetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer) (4.9 g) dissolved in a mixed solvent of methanol (30 ml), tetrahydrofuran (30 ml) and acetic acid (1 ml). After adding 10% palladium on carbon (2.5 g) thereto, the mixture was subjected to catalytic reduction at ambient temperature under atmospheric pressure. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue were added water and ethyl acetate, and the mixture was adjusted to pH 7.5 with 20% aqueous sodium carbonate. The separated aqueous layer was adjusted to pH 2.0 with 10% hydrochloric acid and then extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was removed by evaporation to give 7-[2-tert-butoxycarbonylmethoxyimino-2-(1,2,4-thiadiazol-3-yl)acetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer) (1.4 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18](O)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45][CH2:46][NH2:47])[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45][CH2:46][NH:47][C:18]([C:14]2[CH2:15][CH2:16][O:17][C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=4)=[CH:21][C:12]=3[CH:13]=2)=[O:19])[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NCCC2CCN(C(=O)OC(C)(C)C)CC2)CCO3)cc1
Yield: 66.8 %

Procedure:
To 7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxylic acid (1402 mg, 5.00 mmol) dissolved in DMF (30 ml) were added at 0° C. 1-hydroxybenzotriazole (743 mg, 5.50 mmol), 2-[1-(tert-butoxycarbonyl)piperidin-4-yl]ethylamine (1256 mg, 5.50 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1438 mg, 7.50 mmol), and the resulting mixture was stirred at room temperature for 8 hours. The reaction mixture was concentrated, ethyl acetate (120 ml) was added to the residue and the resulting mixture was washed successively with water (30 ml), an aqueous saturated solution of sodium bicarbonate (20 ml×3) and an aqueous saturated solution of sodium chloride (20 ml). The organic layer was dried with anhydrous magnesium sulfate and was then concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel, ethyl acetate/hexane=1/2→1/1). The objective fractions were concentrated under reduced pressure and were mixed with diisopropyl ether to collect an insoluble material by filtration. The insoluble material was washed with diisopropyl ether and was dried under reduced pressure to obtain N-[2-[1-(tert-butoxycarbonyl)piperidin-4-yl]ethyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (1.64 g, 3.34 mmol, 67%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])=[O:4].S(Cl)(Cl)=O.O.[NH2:22][NH2:23]>>[N+:14]([C:6]1[CH:7]=[C:8]([C:9]([NH:22][NH2:23])=[O:10])[CH:12]=[CH:13][C:5]=1[C:3]([O:2][CH3:1])=[O:4])([O-:16])=[O:15]
Reactant: NN
Reactant: COC(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(C(=O)NN)cc1[N+](=O)[O-]

Procedure:
From 4-methoxycarbonyl-3-nitrobenzoic acid, thionyl chloride and hydrazine monohydrate, 758 mg of the desired product was obtained in the same manner as in Reference Synthetic Example 39 as a white solid (yield 79%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[CH2:11]([OH:14])[CH2:12]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:27]N1C(=O)CCC1=O.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>C1C=CC=CC=1.CCOCC>[Br:27][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH3:9])[O:14][CH2:11][CH2:12][O:10]1
Reactant: OCCO
Reactant: CC(=O)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: CCOCC
Solvent: O
Solvent: c1ccccc1
Product: CC1(c2ccccc2CBr)OCCO1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
To a solution of 2′-methyl-acetophenone (2.68 g, 20.0 mmol) in benzene (100 mL)was added ethylene glycol (2.0 mL, 35.9 mmol) followed by p-toluenesulfonic acid monohydrate (0.39 g, 2.10 mmol). The reaction flask was topped with a Dean-Stark trap, and the mixture was heated to reflux overnight. The mixture was cooled to room temperature, diluted with Et2O (100 mL), washed with saturated aqueous NaHCO3 (5×20 mL) and brine (3×25 mL), dried (MgSO4), and concentrated. The resultant colorless oil (3.6 g) was dissolved in CCl4 (50 mL) and to this solution was added N-bromosuccinimide (3.76 g, 21.1 mmol) followed by 1,1′-azobis(cyclo-hexanecarbonitrile) (0.98 g, 3.99 mmol). The resultant mixture was refluxed for 5 hours then cooled to room temperature, filtered through filter paper, and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:hexanes-EtOAc) provided 4.09 g (80%) of 2-(2-bromomethyl-phenyl)-2-methyl-[1,3]dioxolane as a colorless oil. 1H NMR (CDCl3) δ 1.74 (s, 3H), 3.75-3.81 (m, 2H), 4.04-4.08 (m, 2H), 4.89 (s, 2H), 7.24-7.31 (m, 2H), 7.44-7.57 (m, 2H).
Reaction SMILES: [C:1]([CH:3]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:4](Cl)=[O:5])#[N:2].Cl.[CH2:12]([C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[O:16][CH:17](N)[CH2:18][CH3:19])[CH3:13].C([N:27](CC)CC)C>C(Cl)Cl>[C:1]([CH:3]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:4]([NH:27][CH:18]([CH3:19])[CH2:17][O:16][C:15]1[CH:21]=[CH:22][CH:23]=[CH:24][C:14]=1[CH2:12][CH3:13])=[O:5])#[N:2]
Reactant: CCN(CC)CC
Reactant: CCc1ccccc1OC(N)CC
Reactant: CC(C)(C)C(C#N)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CCc1ccccc1OCC(C)NC(=O)C(C#N)C(C)(C)C
Reaction time: 2 h
Yield: 42.1 %

Procedure:
A solution of 2-cyano-3,3-dimethylbutanoyl chloride (E. Schaumann, H. Mrotzek; J. Org. Chem., 1979, 35, 1965) (0.364 g, 2.28 mmol) in 10 mL methylene chloride was added dropwise to a solution of 1-(2-ethylphenoxy)propanamine hydrochloride (0.56 g, 2.6 mmol), triethyl amine (1.0 mL, 7.2 mmol) in 30 mL methylene chloride. The reaction mixture was stirred for 2 h then concentrated in vacuo. The residue was purified by flash chromatography using 20% ethyl acetate/hexanes as eluent to give 0.290 g (42%) of the title compound as a white solid: mp 94-97° C., 1H NMR (CDCl3) δ 1.20 (m, 12H), 1.40 (m, 3H), 2.65 (q, 2H), 3.16 (dd, 1H), 3.98 (m, 1H), 4.05 (m, 1H), 4.40 (m, 1H), 6.00 (d, 1H), 6.25 (dd, 1H), 6.95 (t, 1H), 7.18 (t, 2H).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]1([CH:18]([NH2:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)C1C(=CC=CC=1)C(N)=O.C(C(O)C1C=CC=C(OC2C=CC=CC=2)C=1)#C>>[C:12]1([CH:18]([NH:20][C:4](=[O:5])[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1]([OH:6])=[O:11])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(N)c1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: C#CC(O)c1cccc(Oc2ccccc2)c1
Agent: NC(=O)c1ccccc1C(=O)O
Product: CC(NC(=O)c1ccccc1C(=O)O)c1ccccc1

Procedure:
(-)-N-α-phenylethylphthalamic acid was prepared from phthalic anhydride and (-)α-phenylethylamine by the method of Mann and Wastom (J. Chem. Soc., 1947, 510). The ester of this phthalamic acid with racemic α-ethynyl-3-phenoxybenzyl alcohol was prepared by the method of Human and Mills (J. Chem. Soc., 1949, S77). The individual (-)(+) and (-)(-) ester diastereoisomers were separated by chromatography (HPLC) and then hydrolysed with a slight excess of alkali to recover the resolved α-ethynyl-3'-phenoxybenzyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([I:13])[CH:8]=2)[N:3]=1.[OH-:14].[Na+]>C1COCC1.O.Cl.CCOC(C)=O>[Cl:1][C:2]1[N:11]=[C:10]([OH:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([I:13])[CH:8]=2)[N:3]=1
Reactant: [OH-]
Reactant: Clc1nc(Cl)c2cc(I)ccc2n1
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Oc1nc(Cl)nc2ccc(I)cc12
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 2,4-dichloro-6-iodoquinazoline (10 g, 30.8 mmol) in THF (8 ml) and water (8 ml) was treated with aqueous NaOH (1 N, 4 ml). The solution was stirred for 1 h, then diluted with aqueous HCl (1 N) and EtOAc. The organic phase was separated and washed with brine then dried over Na2SO4. Filtration and removal of the volatiles afforded the title compound (9.4 g, 100%) as a solid. LCMS (ES+) m/z 307 (M+H)+.
Reaction SMILES: O.CO[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([CH:12]=[O:13])=[O:11].[CH3:14][C:15]([NH2:28])([CH3:27])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1.[CH3:29]S(C)=O>>[CH3:27][C:15]([N:28]=[C:12]([O:13][CH3:29])[C:10]([C:5]1[CH:4]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:11])([CH3:14])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1
Reactant: COc1ccccc1C(=O)C=O
Reactant: CS(C)=O
Reactant: COc1ccc(CC(C)(C)N)cc1OC
Solvent: O
Product: COC(=NC(C)(C)Cc1ccc(OC)c(OC)c1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
645 mg of 2-methoxyphenylglyoxal hydrate are dissolved in one ml of dimethylsulfoxide, and a solution of 826 mg of α,α-dimethyl-3,4-dimethoxyphenethylamine in 1.5 ml of dimethylsulfoxide is added thereto. The mixture is stirred at 25° C. for one hour, whereby a solution of α-(α,α-dimethyl-3,4-dimethoxyphenethylimino)-2-methoxyacetophenone in dimethylsulfoxide is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:14]([NH:21][S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)NCc2ccccc2)cc1
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of p-Nitrobenzenesulfonylchloride (274 g, 1.2 eq) in DCM (1 l), was added to a solution of benzylamine (500 g, 1 eq) and triethylamine (469 ml, 1.5 eq) in DCM (1 l) at 4° C. in small portions and then stirred for 1 h. Afterwards the mixture was stirred at rt for 16 h. The solvent was removed in vacuo and the residue was washed with a mixture of DCM/PE (1/1) at 4° C., filtered and dried in vacuo to give N-Benzyl-4-nitrobenzenesulfonamide. Yield 90%.
Reaction SMILES: C(OP([CH2:9]/[C:10](/[CH3:17])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.CN1CCCN(C)C1=O.C([Li])CCC.[F:32]/[C:33](=[C:36](/[C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][C:47]=1[O:48][CH3:49])[O:44][C:43]([CH3:51])([CH3:50])[CH:42]=[C:41]2[CH:52]([CH3:54])[CH3:53])\[CH3:37])/[CH:34]=O>C1COCC1>[F:32]/[C:33](=[C:36](/[C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][C:47]=1[O:48][CH3:49])[O:44][C:43]([CH3:51])([CH3:50])[CH:42]=[C:41]2[CH:52]([CH3:54])[CH3:53])\[CH3:37])/[CH:34]=[CH:9]/[C:10](/[CH3:17])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Reactant: COc1cc2c(cc1/C(C)=C(/F)C=O)C(C(C)C)=CC(C)(C)O2
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(C)/C=C/C(F)=C(/C)c1cc2c(cc1OC)OC(C)(C)C=C2C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 4-(diethoxyphosphoryl)-3-methyl-but-2E-enoate (240 mg, 0.91 mmol) in THF (10 mL), and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 0.13 mL) under argon at −78° C. was slowly added n-butyl lithium (1.6 M in hexanes, 0.60 mL, 0.96 mmol). The resulting mixture was stirred at −78° C. for 15 min before a solution of (2E)-2-fluoro-3-(4-isopropyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-but-2-enal (Compound 95, 100 mg, 0.31 mmol) and THF (3 mL) was added via cannula. The resulting mixture was stirred at 0° C. for 1 h. The reaction was quenched with saturated NH4Cl, and the product was extracted with diethyl ether. The combined ethereal layers were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 5% ethyl acetate in hexane) to yield the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=O.CC(C)=O.Cl.[CH2:24]([N+:28]([O-:30])=[O:29])/[CH:25]=N\O>O>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]1[C:3]2[C:2](=[C:16]([CH3:17])[CH:15]=[C:14]([CH3:18])[CH:13]=2)[N:1]=[CH:25][C:24]=1[N+:28]([O-:30])=[O:29]
Reactant: O=[N+]([O-])C/C=N\O
Reactant: Cc1cc(C)c(N)c(C(=O)c2ccccc2Cl)c1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(C)c2ncc([N+](=O)[O-])c(-c3ccccc3Cl)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-amino-2'-chloro-3,5-dimethylbenzophenone (1 g), acetone (50 ml), 20 % hydrochloric acid (20 ml) and methazonic acid (4.5 g, wet) was stirred for 2 hrs. at room temperature and refluxed for 4 hrs. The mixture was diluted with water, and extracted with chloroform. The organic layer was washed with water, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by a column chromatography on silica gel to give 4-(2-chlorophenyl)-6,8-dimethyl-3-nitroquinoline as crystals, which was recrystallized from a mixture of methanol and chloroform. m.p. 130°-131° C. Yield 1.95 g (54.2 %).
Reaction SMILES: [F:1][C:2]1([F:17])[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][C:12]([N+:14]([O-])=O)=[CH:13][C:4]=2[O:3]1.[Cl-].[NH4+].C(Cl)Cl>CCO.O.[Fe]>[F:17][C:2]1([F:1])[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][C:12]([NH2:14])=[CH:13][C:4]=2[O:3]1
Reactant: CN1C(=O)C(F)(F)Oc2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CN1C(=O)C(F)(F)Oc2cc(N)ccc21
Temperature: 80 °C
Yield: 92.2 %

Procedure:
To a stirred suspension of 2,2-difluoro-4-methyl-7-nitro-4H-1,4-benzoxazin-3-one (Step 1, 1.3 g, 5.32 mmol) in EtOH (20 mL) and water (10 mL) is added ammonium chloride (2.85 g, 53.32 mmol). To this mixture is added iron (892 mg, 15.09 mmol) in 3 equal portions. The resulting mixture is heated to 80° C. for 2 h at which time the reaction is cooled to room temperature followed by addition of CH2Cl2 (50 mL). The resulting mixture is filtered through celite and the filtrate is further diluted with water (50 mL). The organic layer is separated followed by further extraction of the aqueous phase with CH2Cl2 (50 mL×3). The combined organic phase is dried over Na2SO4 and concentrated under reduced pressure, and the residue is purified by passing it through a short silica gel column with EtOAc to give the title compound (1.05 g, Quant.), MS (m/z): 215.5 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@H:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:5].C(Cl)CCl.[NH:19]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:20]([C:23](O)=[O:24])[CH2:21][CH3:22].CN(C=O)C>C(Cl)Cl.N(C(OC(C)(C)C)=O)[C@H](C(O)=O)CC>[CH3:1][O:2][C:3](=[O:14])[C@H:4]([N:6]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:23](=[O:24])[C@@H:20]([NH:19][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH3:22])[CH3:5]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H](C)NCc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: ClCCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N(Cc1ccccc1)[C@H](C)C(=O)OC
Reaction time: 18 h
Yield: 87.6 %

Procedure:
To a solution of (R)-2-benzylamino-propionic acid methyl ester (3.5 g, 18.1 mmol) and EDC (3.65 g, 19.0 mmol) in anhydrous DCM (30 mL) was added Boc-Abu-OH (3.68 g, 18.1 mmol). The reaction was stirred for 18 h, then additional Boc-Abu-OH (0.74 mmol, 3.62 mmol), EDC (1.35 g 7.1 mmol) and DMF (2.4 mL) were added to the reaction, followed by stirring for 18 h. The solvent was removed in vacuo and the resulting oil was dissolved in EtOAc (50 mL) and washed with 1 M hydrochloric acid (50 mL×3), 1 M aqueous NaOH (50 mL×3), brine (50 mL), dried over sodium sulfate, filtered and concentrated, to give (R)-2-[benzyl-((S)-2-tert-butoxycarbonylamino-butyryl)-amino]-propionic acid methyl ester (6.0 g, 87%) as a pale colourless oil. An aliquot (3.9 g, 10.3 mmol) was dissolved in DCM (52 mL) and HCl gas was bubbled through the reaction for 30 min at ambient temperature. The reaction was stirred for an additional hour and then solvent removed in vacuo. The resultant solid was triturated with Et2O, to give (R)-2-[((S)-2-amino-butyryl)-benzyl-amino]-propionic acid methyl ester hydrochloride (3.0 g, 93%) as a colourless solid. This material was slurried in EtOAc (47 mL) at ambient temperature and saturated aqueous sodium bicarbonate (14 mL) added. After stirring for 18 h, the organic layer was separated and washed with brine, dried over sodium sulfate, filtered and concentrated, to give the title compound (1.68 g, 72%) as a colourless oil. 1H NMR (Me-d3-OD): 7.44-7.23 (5H, m), 5.19 (1H, d), 4.28-4.08 (2H, m), 3.86 (1H, q), 2.18-1.99 (1H, m), 1.96-1.79 (1H, m), 1.46 (3H, d), 0.95 (3H, t).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]1=[O:21].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[Br-:1].[CH2:22]([N+:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[C:10]2=[O:21])=[C:2]([Br:1])[CH:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc2c(c1)CCC(Cc1ccncc1Br)C2=O
Reactant: BrCc1ccccc1
Solvent: ClCCl
Product: COc1ccc2c(c1)CCC(Cc1cc[n+](Cc3ccccc3)cc1Br)C2=O
Product: [Br-]
Yield: 158.5 %

Procedure:
Compound 99 (69.2 mg, 0.2 mmol) was dissolved in dichloromethane (2 mL). Benzyl bromide (48 μL, 0.4 mmol) was then added and the solution was heated under reflux for 12 h in a sealed tube. After concentration under reduced pressure, the solid was triturated with diethylether, filtered and washed (3×) with n-pentane to afford the title product 117 as a pale brown powder (Yield 82 mg, 80%).