Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][CH:8]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])C(OCC)=O)=[CH:5][CH:4]=1.Br.O>C(O)(=O)C>[F:16][C:15]([F:17])([F:18])[C:14](=[O:19])[CH2:8][CH2:7][C:6]1[CH:20]=[CH:21][C:3]([OH:2])=[CH:4][CH:5]=1
Reactant: CCOC(=O)C(Cc1ccc(OC)cc1)C(=O)C(F)(F)F
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C(CCc1ccc(O)cc1)C(F)(F)F
Temperature: 120 °C

Procedure:
A 100 mL round bottom flask, fitted with reflux condenser, magnetic stirrer and argon inlet was charged with 2.05 g (6.7 mmol) of ethyl 2-(4-methoxybenzyl)-3-oxo-4,4,4-trifluorobutanoate (I), 20 mL of 31% (w/v) hydrogen bromide in acetic acid, and 10 mL of water. This mixture was heated overnight at 120° C., cooled, concentrated under reduced pressure and partitioned between dichloromethane and water. The organic layer was extracted sequentially with aqueous bisulfite, and saturated sodium bicarbonate, and then dried over anhydrous magnesium sulfate. Solvent was removed under reduced pressure. The crude reaction mixture was chromatographed on a 50 mm×300 mm silica gel column with ethyl acetate/hexane (50/50). Similar fractions were combined and the solvent was removed under reduced pressure to yield 600 mg (41%) as a clear oil. NMR(CDC13): 2.95(m,4H), 5.40(bs, 1H), 6.93(dd,4H) J=4, 60 Hz.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:8][C:9]=1[N:10]([S:19]([C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([Cl:29])=[CH:24][C:23]=1[CH3:30])(=[O:21])=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([I:18])[CH:13]=1)=[O:4].O[Li].O>C1COCC1.CO.O>[Cl:29][C:25]1[C:26]([CH3:28])=[CH:27][C:22]([S:19]([N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([I:18])[CH:13]=2)[C:9]2[CH:8]=[C:7]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[S:6][C:5]=2[C:3]([OH:4])=[O:2])(=[O:20])=[O:21])=[C:23]([CH3:30])[CH:24]=1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(Cc1cccc(I)c1)S(=O)(=O)c1cc(C)c(Cl)cc1C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(S(=O)(=O)N(Cc2cccc(I)c2)c2cc(-c3ccccc3)sc2C(=O)O)c(C)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.8 %

Procedure:
3-[(4-Chloro-2,5-dimethyl-benzenesulfonyl)-(3-iodo-benzyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (25 mg, 0.038 mmol) was taken in a mixture of THF:MeOH:H2O (3:2:1, 3 mL) and then added 1N aqueous solution of LiOH.H2O (0.24 mL, 0.228 mmol). The reaction mixture was stirred at room temperature for 12 h. Solvents were removed and the residue was partitioned between water and ethyl acetate. The aqueous layer was acidified using 10% KHSO4 solution. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using dichloromethane and methanol (9:1) to obtain 3-[(4-Chloro-2,5-dimethyl-benzene-sulfonyl)-(3-iodo-benzyl)-amino]-5-phenyl-thiophene-2-carboxylic acid (22 mg, 88%) as a white solid. 1H NMR (CDCl3, 400 MHz): 7.69 (m, 3H), 7.57 (m, 3H), 7.42 (m, 3H), 7.33 (d, 1H), 7.16 (s, 1H), 6.04 (dd, 1H), 4.90 (bs, 2H), 2.36 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26]([OH:28])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[O:38][N:37]=[C:36]([C:39]2([NH2:42])[CH2:41][CH2:40]2)[CH:35]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:28])[NH:42][C:39]5([C:36]6[CH:35]=[C:34]([CH3:33])[O:38][N:37]=6)[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1cc(C2(N)CC2)no1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cc(C)on5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.2 g, 0.46 mmol, 1 eq), 1-(5-methylisoxazol-3-yl)cyclopropanamine (0.074 g, 0.5 mmol, 1.1 eq), HOBT (0.094 g, 0.69 mmol, 1.5 eq), EDC.HCl (0.0.13 g, 0.69 mmol, 1.5 eq), in DCM at ambient temperature and under a nitrogen atmosphere was added diisopropylehtylamine (0.19 ml, 1.3 mmol, 3.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by Preparative TLC (Eluent Hexane:Ethyl acetate 1:1, 300 ml). Yield: 0.1 g (39.22%). 1H NMR (400 MHz, CD3OD): δ 1.39-1.48 (m, 4H), 2.36 (s, 3H), 2.380-2.382 (d, 3H, J=0.8 Hz), 2.96 (s, 3H,), 4.05, (s, 3H), 6.05 (d, 1H, J=0.8 Hz), 7.12 (s, 1H), 7.26-7.34 (m, 3H), 7.58-7.59 (d, 1H, J=1.2 Hz), 7.62-7.64 (d, 1H, J=8.8 Hz), 7.81 (s, 1H), 7.96-7.98 (m, 2H). LCMS: (ES+) m/z=554.2 (M+H)+ Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[OH-].[Na+].[CH3:19]O>>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: CO
Reactant: O=C(O)c1cc(F)cnc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1cc(F)cnc1Cl
Temperature: 0 °C
Yield: 25 %

Procedure:
To a solution of 2-chloro-5-fluoronicotinic acid (5.2 g, 30 mmol) in methanol (20 ml) was added cone, sulfuric acid (0.5 ml) and the reaction mixture was stirred at reflux for 30 hours. The reaction mixture was cooled to 0° C. and 0.5 N sodium hydroxide solution was added to the mixture. The whole was extracted with diethylether. The organic phase was washed with brine, dried (sodium sulfate), and concentrated to afford 3.2 g (25%) of the title compound:
Reaction SMILES: [Li+].CCC[CH2-].C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[F:20].[C:21](=[O:23])=[O:22]>C1COCC1>[Cl:13][C:14]1[C:19]([C:21]([OH:23])=[O:22])=[CH:18][N:17]=[CH:16][C:15]=1[F:20]
Reactant: O=C=O
Reactant: Fc1cnccc1Cl
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cncc(F)c1Cl
Temperature: -78 °C
Reaction time: 6 h
Yield: 64 %

Procedure:
N-Butyllithium, 1.6 M in hexanes (9.50 mL, 15.21 mmol) was added to THF (20 mL) and cooled to −78° C. To this solution was added diisopropylamine (2.167 mL, 15.21 mmol) followed by 4-chloro-3-fluoropyridine (2 g, 15.21 mmol) and the solution stirred for 6 h at −78° C. The reaction mixture was then poured on to crushed dry ice and stirred until the reaction mixture warmed to room temperature. The reaction was quenched by addition of aqueous ammonium chloride solution and acidified to pH=2 using conc. HCl and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulphate and concentrated under reduced pressure to afford the 4-chloro-5-fluoronicotinic acid (1.7 g, 9.68 mmol, 64% yield) as a pale yellow solid. LCMS (ESI) m/e 175.9 [(M+H)+, calcd for C6H4ClFNO2 176.0]; LC/MS retention time (Method F): tR=0.57 min.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([O:7]CC(O)=O)=[CH:5][CH:4]=1.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1O.C1(N=C=NC2CCCCC2)CCCCC1.[C:38]([O:41]CC)(=[O:40])[CH3:39]>>[C:38]([O:41][O:7][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][Br:1])=[CH:13][C:12]=1[C:18]1[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][C:19]=1[Cl:21])(=[O:40])[CH3:39]
Reactant: CCOC(C)=O
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: O=C(O)COc1ccc(CBr)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(=O)OOc1ccc(CBr)cc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To 4-bromomethylphenoxyacetic acid (20 g, 81.6 mole) and 2,4-dichlorophenol (14 g, 85.7 mole) suspended in 100 ml ethyl acetate at 0° C. was added solid dicyclohexylcarbodiimide (17.7 g, 85.8 mole) in portions with stirring. After two hours at 0° C., 200 ml of ethyl acetate was added to the thick suspension that resulted, and stirring was allowed to proceed for 30 minutes as the mixture was allowed to warm to room temperature. Insoluble dicyclohexylurea was removed by filtration and was washed with ethyl acetate (3×30 ml). The combined filtrate and washes were concentrated in vacuo and the residue was dissolved in 35 ml boiling ethyl acetate. Upon cooling to room temperature, crystalline product had formed. After addition of 155 ml hexanes in portions with mixing, the product was collected by vacuum filtration, washed with hexanes/ethyl acetate (9:1), and dried in vacuo to yield 26.8 g (85%) of crystalline product (mp 114°-6° C.). The product was homogeneous by TLC (silica gel 60) and had an Rf =0.50 when developed with hexanes:ethyl acetate (8:2).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][NH:16][C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.C(N(CC)C(C)C)(C)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[C:34]([N:16]1[C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[CH2:19][N:20]2[C:11]([C:9]([NH:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:10])=[CH:12][CH:13]=[C:14]2[CH2:15]1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1NC2
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 21 h
Yield: 80.2 %

Procedure:
To a suspension of N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Step C (300 mg, 0.942 mmol) in dry tetrahydrofuran (15 mL) at room temperature under nitrogen was added N,N-diisopropylethylamine (0.26 mL, 1.508 mmol) followed by benzoyl chloride (0.165 mL, 1.41 mmol) and the reaction mixture stirred at room temperature for 21 hours. The reaction was quenched by the addition of 2 M sodium hydroxide (5 mL) and then the mixture partitioned between ethyl acetate (50 mL) and 2 M sodium hydroxide (50 mL). The organic phase was washed with 2 M sodium hydroxide (50 mL), water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to afford a yellow syrup. Purification by flash chromatography using a solvent gradient of 0 to 4% methanol in dichloromethane gave a white foam that was crystallized from diethyl ether/hexane to give the title compound (0.319 g, 80%) as a white crystalline solid, m.p. 197° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][N:10]1[CH2:14][CH:13]([CH2:15][CH2:16][CH3:17])[CH2:12][C:11]1=[O:18].[CH:19](=O)[CH2:20][CH3:21].[C:23](O)(=O)C>O1CCOCC1>[CH2:20]([C:21]1[N:8]([CH2:9][N:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH3:17])[CH2:12][C:11]2=[O:18])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1)[CH2:19][CH3:23]
Reactant: CCCC1CC(=O)N(CNc2ccccc2N)C1
Reactant: CCC=O
Reactant: CC(=O)O
Solvent: C1COCCO1
Product: CCCc1nc2ccccc2n1CN1CC(CCC)CC1=O
Temperature: 25 °C
Yield: 33 %

Procedure:
In a 50 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, a solution of (2-aminophenyl){(2-oxo-4-propyl-pyrrolidin-1-yl)methyl}amine a29 (1 eq, 0.69 mmol, 170 mg), propionaldehyde (1.4 eq, 0.966 mmol, 56 mg, 71 μl), acetic acid (0.3 ml) and dioxane (4 ml) was heated at 65° C. during 40 h. After cooling to room temperature, the solvent was removed under vacuum and the crude product was purified by preparative thin layer chromatography (CH2Cl2/MeOH/NH4OH: 96/3.6/0.4) to give of 1-[(2-propyl)-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one 94 (65 mg, 33%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[C:32]([CH2:40]Br)[CH:31]=1.[OH-].[Na+]>O1CCCC1>[CH2:1]([O:8][CH2:9][C:10]1[N:14]([CH2:40][C:32]2[CH:31]=[N:30][C:39]3[C:34]([CH:33]=2)=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:13]([CH:15]([CH3:17])[CH3:16])=[C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)[N:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1cnc2ccccc2c1
Reactant: CC(C)c1nc(COCc2ccccc2)[nH]c1Sc1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)c1c(Sc2cc(Cl)cc(Cl)c2)nc(COCc2ccccc2)n1Cc1cnc2ccccc2c1
Reaction time: 8 h
Yield: 2.6 %

Procedure:
In tetrahydrofuran (10 ml)was dissolved 245 mg (2 mmol) of 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1H-imidazole (101a). To this solution, a methylene chloride solution of quinolin-3-ylmethylbromide was added at room temperature with stirring, followed by addition of 200 mg (5 mmol)of sodium hydroxide and 39 mg (0.12 mmol)of n-tetrabutylammonium bromide. After stirring for 2 hours, the mixture was left overnight and worked up. The reaction mixture was distilled off under reduced pressure. The residue was extracted with methylene chloride, and the extract was washed with water and dried. The solvent was distilled off, and the residual oil was purified by silica gel column chromatography (methylene chloride-ethyl acetate). As the first eluate, 26 g (2.6%)of 2-benzyloxymethyl-4-(3,5-dichlorophenylthio)-5-isopropyl-1-(quinolin-3-ylmethyl)-1H-imidazole (100a)was obtained. From the subsequent eluate, 730 mg of 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(quinolin-3-ylmethyl)-1H-imidazole (100b)suited to the next step of the reaction was obtained (yield 73%). mp 95-98° C.
Reaction SMILES: [H-].[Na+].C(O[C:6](=O)[CH:7](C)[C:8]([CH3:10])=[O:9])C.[CH2:13]1[CH2:19][S:16](=[O:18])(=[O:17])[O:15][CH2:14]1>C1COCC1>[CH3:6][CH:7]([C:8](=[O:9])[CH3:10])[CH2:14][CH2:13][CH2:19][S:16]([OH:15])(=[O:18])=[O:17]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: O=S1(=O)CCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)C(C)CCCS(=O)(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium hydride (2.1 g, 80 wt %=69 mmol) was slurried in 10 ml dry THF. The suspension was cooled to 0° C. and a solution of ethyl-2-methylacetoacetate (10 g, 69 mmol) in 10 ml dry THF was added dropwise. The solution was stirred at room temperature for one h. A solution of 1,3-propanesultone (8.42 g, 69 mmol) in 10 ml dry THF was added dropwise. Once the addition was complete, the solution was stirred for two h at 40° C. The solution was evaporated to dryness. The residue was dissolved in 100 ml water. The aqueous solution was extracted twice with ethylacetate, then 100 ml concentrated HCl was added and the solution was refluxed for two hours. The solvent was evaporated in vacuum. The residue was purified by column chromatography (silica, methanol/dichloromethane) to give 4-methyl-5-oxohexane sulfonic acid. Yield 10 g; MS (ESI−): 193.2 [M]−
Reaction SMILES: C([O:8][C:9](=[O:42])[CH:10]([CH2:30][N:31]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]1=[O:41])[CH:11]([C:16](=[O:29])[NH:17][CH:18]([C:23](=[O:28])[NH:24][CH:25]1[CH2:27][CH2:26]1)[C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH:13]([CH3:15])[CH3:14])C1C=CC=CC=1.C1CCCCC=1>C(OCC)(=O)C.[Pd]>[CH:25]1([NH:24][C:23]([CH:18]([NH:17][C:16]([CH:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH:10]([CH2:30][N:31]2[C:39](=[O:40])[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]2=[O:41])[C:9]([OH:42])=[O:8])=[O:29])[C:19]([CH3:20])([CH3:21])[CH3:22])=[O:28])[CH2:26][CH2:27]1
Reactant: CC(C)CC(C(=O)NC(C(=O)NC1CC1)C(C)(C)C)C(CN1C(=O)c2ccccc2C1=O)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)CC(C(=O)NC(C(=O)NC1CC1)C(C)(C)C)C(CN1C(=O)c2ccccc2C1=O)C(=O)O
Yield: 41.1 %

Procedure:
3-(1-Cyclopropylcarbamoyl-2,2-dimethyl-propylcarbamoyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-5-methyl-hexanoic acid-1-benzyl ester (3.46 g, 6.02 mmol) was dissolved in ethyl acetate (90 ml) and cyclohexene (10 ml) and the solution was placed under a blanket of argon. 10% palladium on charcoal catalyst (0.75 g) was added and the mixture was heated at reflux for 4 hours. The mixture was cooled and the catalyst was removed by filtration and the filtrate was evaporated to leave a pale yellow foam. Column chromatography (silica gel, gradient elution, 30 to 60% ethyl acetate in hexane) afforded the desired product as a white solid (1.2 g, 41%). 1H-NMR (CD3OD); δ 8.30 (1H, m), 8.08 (1H, m), 7.81 (5H, m), 7.11 (1H, m), 4.11 (0.75H, m), 3.92 (0.25H, m), 3.76 (1 H, m), 3.13-2.85 (2H, br m), 1.72 (1H, m), 1.53 (2H, m), 1.14 (6.7H, s), 1.08 (2.3H, s) and 0.86 (6H, m).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[F:19][C:20]([F:28])([F:27])[C:21]([CH3:26])=[CH:22][C:23](Cl)=[O:24].O>C1COCC1.CCO>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:23](=[O:24])/[CH:22]=[C:21](\[CH3:26])/[C:20]([F:28])([F:27])[F:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=CC(=O)Cl)C(F)(F)F
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: C/C(=C\C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C(F)(F)F
Temperature: -45 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
(4S)-4-Benzyl-1,3-oxazolidin-2-one (828 g, 4.67 moles) was dissolved in 6.8 L THF and cool to −40 to −50° C. To the solution of (4S)-4-benzyl-1,3-oxazolidin-2-one, 2.5 M BuLi in hexanes (1302 g, 1880 mL, 4.70 mole, 1.01 equivalents) was added while keeping the temperature at <−40° C. To the cold solution of the Li salt of (4S)-4-benzyl-1,3-oxazolidin-2-one, 4,4,4-trifluoro-3-methyl-2-butenoic acid chloride (887 g, 5.14 moles, 1.1 equivalents) was added over 10-30 minutes, all-owing the temperature to rise and wash in with 0.4 L THF. The reaction was warmed to 20-25° C. and stirred for 2 h. 0.9 L water was added and stirred for 16 h. The THF was distilled off with a bath temperature of 35° C. and vacuum<40 mm Hg. Toluene (5.8 L) was added and the phases split. 4-L saturated NaHCO3 was used to wash (2×), the mixture was filtered through Celite and the phases split. 2.5-L water (2×) was used as a wash and the toluene layer was filtered through Celite. The remaining water was removed. The toluene was distilled off with a bath temperature of 40° C. and vacuum<40 mm Hg. At the end of the distillation the product started to crystallize with a pot temperature of 30° C. Distillation is continued to a pot temperature of 35° C. giving a solid mobile mass of 1456 g. The solid is dissolved in 2.9 L (2 vol) EtOH (99.5% EtOH:0.5% toluene). While stirring at 20-25° C., water (1.09 L, 0.75 vol) was added over 1 h forming crystals. Stirring is continued for 16 h at 15-25° C., followed by cooling to 0-5° C. and holding for 1 h. The crystals are filtered, washed with filtrate and dried at 50° C. for 16 h giving 1229 g, 84% of (4S)-4-benzyl-3-[(2E)-4,4,4-trifluoro-3-methyl-but-2-enoyl]-1,3-oxazolidin-2-one.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([S:12]([OH:15])(=[O:14])=[O:13])[CH:8]=[CH:7]2.[OH:16]S([O-])=O.[Na+].[OH-].[Na+].Cl>O>[OH:16][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([S:12]([OH:15])(=[O:14])=[O:13])[CH:8]=[CH:7]2
Reactant: Nc1cccc2ccc(S(=O)(=O)O)cc12
Reactant: O=S([O-])O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(O)c1ccc2cccc(O)c2c1
Yield: 99.5 %

Procedure:
A solution of 8-amino-2-naphthalenesulfonic acid (Aldrich, 2.40 g, 10.8 mmol) and 3.9M aq. NaHSO3 solution (20.0 mL, 77.0 mmol) in water (10.0 mL) was refluxed for 15 h. The reaction mixture was then basified with 30% aq. NaOH solution (430 mg, 10.8 mmol) and refluxed for 4 h. The reaction mixture was neutralized with conc. HCl and then concentrated in vacuo. The remaining solid was azeotroped with 1:1 MeOH/PhMe (3×) to give the title compound (2.41 g, 95%). 1H NMR (DMSO-d6) δ 9.43 (br s, 1H), 8.36 (s, 1H), 7.96 d, J=8.4 Hz, 1H), 7.88-7.78 (m, 2H), 7.52 (t, J=7.8 Hz, 1H), 7.43 (d, J=7.3 Hz, 1H); MS(ESI−) m/z 222.3 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[CH:11][C:10]=1[N+:18]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Ni].CO>[NH2:18][C:10]1[CH:11]=[C:12]([CH2:15][C:16]#[N:17])[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: N#CCc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CO
Product: N#CCc1ccc(OCc2ccccc2)c(N)c1
Yield: 76.7 %

Procedure:
In the presence of Raney nickel, 53.6 g of (4-benzyloxy-3-nitrophenyl)acetonitrile in 1.2 1 of methanol is hydrogenated until 12.2 1 of hydrogen has been absorbed. The crude product obtained after removing the catalyst by filtration and after evaporation is purified by chromatography on silica gel with cyclohexane/ethyl acetate (1:1), thus obtaining 36.5 g of (3-amino-4-benzyloxyphenyl)acetonitrile as an oil.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26]>C1COCC1>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:25](=[O:26])[C:14]([CH3:19])([CH3:13])[C:15]([O:17][CH3:18])=[O:16])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: COC(=O)C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(C)(C)C(=O)c1ccc(OC)c(OC)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
124 ml of diisopropylamine is dissolved in 500 ml of THF under a blanket of dry nitrogen and cooled to 0° C. and 550 ml n-BuLi (1.6M in hexane) is added dropwise. Next, the mixture is cooled to minus 40° C., using an acetone/N2 bath, and 100 ml methyl 2-methylproponate is added. The resulting mixture is stirred for an additional 15 min at minus 40° C., after which 160.5 g of 3,4-dimethoxybenzoyl chloride dissolved in 750 ml of THF is added dropwise in 60 min during which the temperature is kept below −40° C. The cooling bath is removed and stirring is continued for 60 min at RT. 150 ml of 4M hydrochloric acid is added and the THF layer is separated and washed with 100 ml of water, 200 ml 1M of sodium carbonate and 100 ml of brine, dried over MgSO4 and concentrated in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:52])[C:30]([CH3:51])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][C:48](=[O:50])[CH3:49])=[C:42]([CH:46]=2)[C:43](O)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29](=[O:52])[C:30]([CH3:51])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][C:48](=[O:50])[CH3:49])=[C:42]([CH:46]=2)[C:43]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: COc1ccc(N)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 48 %

Procedure:
p-Methoxyaniline (0.046 g, 0.374 mmol), triethylamine (0.038 g, 0.374 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.063 g, 0.374 mmol) were added to a methylene chloride solution (5 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.070 g, 0.187 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.043 g, 0.0897 mmol, 48%).