Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C:15]2[CH:19]=[C:18]([CH3:20])[N:17]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:16]=2[CH3:28])=[O:14])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].C(=O)([O-])[O-].[K+].[K+].Cl[C:36]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[O:37]>O.O1CCCC1>[NH2:4]/[C:2](=[N:3]\[C:36](=[O:37])[O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])/[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C:15]2[CH:19]=[C:18]([CH3:20])[N:17]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[C:16]=2[CH3:28])=[O:14])=[CH:7][CH:6]=1
Reactant: Cc1cc(C(=O)NCc2ccc(C(=N)N)cc2)c(C)n1-c1ccc(F)cc1
Reactant: CCCCCCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCOC(=O)/N=C(\N)c1ccc(CNC(=O)c2cc(C)n(-c3ccc(F)cc3)c2C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
48 mg of N-[(4-carbamimidoylphenyl)methyl]-1-(4-fluorophenyl)-2,5-dimethyl-pyrrole-3-carboxamide hydrochloride and 50 mg of potassium carbonate were dissolved in 0.6 ml of water and 3 ml of tetrahydrofuran. The mixture was stirred at room temperature, and 0.019 ml of n-hexyl chloroformate (Sigma-Aldrich) added. Stirring was continued for 1 h, following which the organic layer is removed, and dried in vacuo to obtain the synthetic target (>90% yield). The mass of the compound was verified using LC/MS/MS.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:10](OS(OCC)(=O)=O)[CH3:11].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][CH3:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOS(=O)(=O)OCC
Reactant: Oc1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(F)c(Cl)c1

Procedure:
A mixture of 3-chloro-4-fluorophenol (2.0 g, 13.7 mmol), diethylsulfate (1.58 mL, 17.8 mmol) and K2CO3 (9.4 g, 68.5 mmol) in acetone (20 mL) was heated under refluxed for 3 h. The reaction mixture was filtered and concentrated. The residue was diluted with ethyl acetate (50 mL), washed with water (30 mL) and brine. The organic layer was dried (Na2SO4) and concentrated to give the title compound as a liquid. 1H NMR (CDCl3, 400 MHz): δ=1.39 (t, 3H, J=7.2 Hz), 3.97 (q, 2H, J=7.2 Hz), 6.71-6.74 (m, 1H), 6.89-6.91 (m, 1H), 7.02 (t, 1H, J=8.8 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(C)C=CC=CC=1.[OH-].[K+]>O>[C:1]([O:5][C:6](=[O:9])[C@H:7]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Reaction time: 1 h
Yield: 26.2 %

Procedure:
The benzaldehyde Schiff base of glycine tert-butyl ester (compound 9) (0.44 g; 2 mmol), benzyl bromide (0.32 g; 1.9 mmol), and N-(9-anthracenylmethyl)cinchonidium chloride (compound 10) (107 mg; 0.2 mmol) were added to toluene (4 mL), and the mixture was stirred vigorously (1400 rpm) with ice-salt cooling. When the internal temperature thereof had dropped to −5° C. or less, 48% KOH aqueous solution (0.46 g; 4 mmol, 2 equivalents) was added thereto. The mixture was stirred for one hour while maintaining the internal temperature between −5° C. and −2° C. Distilled water (10 mL) was added thereto and the toluene layer was collected, and then the alkylated Schiff base (compound 11) was extracted with toluene (10 mL×2). Thus obtained toluene layers were combined with the toluene layer collected previously, 1 N hydrochloric acid (10 mL) was added thereto, and the mixture was stirred at room temperature for one hour. The aqueous layer was collected by separation, and then the aqueous layer was washed with toluene (10 mL), and sodium carbonate was added thereto carefully to avoid too vigorous bubbling until pH of the solution reached not lower than 11 (confirmed by universal pH test paper). The mixture was extracted with ethyl acetate (10 mL×3) to collect the ethyl acetate layer. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure to give (S)-phenylalanine tert-butyl ester (compound (S)-12) (0.11 g; yield 25%, optical purity 80% ee). The optical purity of the compound 12 was measured by HPLC under the following conditions:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[CH3:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:15][C:16]([S:19]([NH2:21])=[O:20])([CH3:18])[CH3:17].O>C1COCC1.C(O[Ti](OCC)(OCC)OCC)C>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9](/[C:12](=[N:21]\[S:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20])/[CH3:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C(C)=O)cc1
Reactant: CC(C)(C)S(N)=O
Agent: CCO[Ti](OCC)(OCC)OCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCOc1ccc(/C(C)=N\S(=O)C(C)(C)C)cc1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 86.8 %

Procedure:
To a stirred solution of 1-(4-butoxyphenyl)ethanone (3 g, 15.60 mmol) and 2-methylpropane-2-sulfinamide (2.84 g, 23.41 mmol) in THF (50 mL) was added tetraethoxytitanium (8.90 g, 39.0 mmol). The reaction was heated to 70° C. for 3 d. Cold water was added and the reaction was stirred vigorously for 20 min. The mixture was filtered through Celite® and the filtrated was diluted with EtOAc. The organic solution was washed with H2O, brine, dried over MgSO4, filtered and concentrated. The crude product was by silica gel chromatography (220 g silica gel, eluted with EtOAc in hexanes) to yield the desired product (4 g, 87%) as a yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.88 (d, J=8.80 Hz, 2H), 6.91 (d, J=8.80 Hz, 2H), 4.02 (t, J=6.46 Hz, 2H), 2.73 (s, 3H), 1.75-1.83 (m, 2H), 1.46-1.56 (m, 2H), 1.32 (s, 9H), 0.99 (t, J=7.43 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9](C(OC(C)(C)C)=O)[CH:8](C(OC)=O)[C:7]2=[O:23].[ClH:24].O>O1CCOCC1>[ClH:24].[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][NH:9][CH2:8][C:7]2=[O:23]
Reactant: COC(=O)C1C(=O)c2cccc(Br)c2CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C1CNCc2c(Br)cccc21
Temperature: 25 °C

Procedure:
To a flask containing 2-tert-butyl 3-methyl 8-bromo-4-oxo-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate (24-1) (3.44 g, 8.95 mmol) (mixed with impurities) was added was added Dioxane (20 ml), then 5N HCl in H2O (20 ml, 100 mmol). The reaction mixture was then heated to 90 C in the hood overnight. Followed by LC/MS. The next morning another 20 mL of 5N HCl was added and the reaction mixture was heated to 110 C for 3 hours, then was concentrated. The resulting residue was triturated with DCM (hot, then cooled to room temperature) & filtered to yield 8-bromo-2,3-dihydroisoquinolin-4(1H)-one hydrochloride (24-2). HRMS [M+H]: calculated; 225.9862, observed; 225.9860.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[C:3]=1[Cl:9].C1COCC1.C([Mg]Cl)(C)C.[CH:20]1[CH2:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[Cl:9][C:3]1[CH:2]=[CH:7][CH:6]=[C:5]2[C:4]=1[CH:24]1[CH2:23][CH:22]2[CH:21]=[CH:20]1
Reactant: C1=CCC=C1
Reactant: Clc1cccc(Br)c1Cl
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Clc1cccc2c1C1C=CC2C1
Temperature: -10 °C
Reaction time: 1 h
Yield: 117.9 %

Procedure:
115 g of 1-Bromo-2,3-dichlorobenzene was dissolved in 470 g of toluene and the solution was cooled down to −10° C. Then a 20% THF solution of isopropylmagnesium chloride (309 g) was added over 30 min and the reaction mixture was stirred 1 hour at −10° C. Freshly distilled cyclopentadiene (44.5 g, 1.3 eq) was added over 10 min. After one hour stirring at ambient temperature, the mixture was heated to reflux. When the conversion was completed, the reaction mixture was filtered off and washed twice with toluene. The mother liquor was evaporated and 106 g of brown crude oil was obtained (yield: 91.5%. The material can be purified by distillation or by CC (silica gel, eluant: Hept/TBME 19/1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([F:8])=[N:6][CH:7]=1.[H][H]>C(O)C.[Ni]>[NH2:9][C:4]1[C:5]([F:8])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Cl)cnc1F
Agent: [Ni]
Solvent: CCO
Product: Nc1cc(Cl)cnc1F
Yield: 76.4 %

Procedure:
7.5 g (0.042 mol) of 5-chloro-2-fluoro-3-nitropyridine are dissolved in 80 ml of ethanol. This solution is hydrogenated with hydrogen, in the presence of 1 g of Raney nickel catalyst, under normal pressure and at a temperature in the range from 20° to 25° C. After a hydrogenation period of 20 hours, the catalyst is removed and the solvent is evaporated off. The residue is taken up in ethyl acetate and the resultant solution is filtered through a layer of silica gel. The solvent is evaporated off and the residue is triturated in hexane. The precipitate is subsequently filtered and dried, affording 4.7 g (76%) of 3-amino-5-chloro-2-fluoropyridine, m.p. 74° C.
Reaction SMILES: [Br:1][C:2]1[C:3](O[C:6](=[O:8])[CH:7]=1)=[O:4].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(=O)C.C(Cl)Cl>[CH2:9]([N:16]1[C:6](=[O:8])[CH:7]=[C:2]([Br:1])[C:3]1=[O:4])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCc1ccccc1
Reactant: O=C1C=C(Br)C(=O)O1
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1C=C(Br)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of bromomaleic anhydride (1 g, 5.7 mmol) and benzyl amine (0.7 mL, 6.8 mmol) in acetic acid (15 mL) was warmed to 50° C. and stirred overnight. The reaction was then cooled to room temperature, diluted with CH2Cl2 (50 mL) and washed with NaHCO3 (3×25 mL) and brine (25 mL). The organic layer was then dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was purified using gradient flash chromatography (0-100% ethyl acetate in pet ether) to provide 1-benzyl-3-bromo-1H-pyrrole-2,5-dione (18). 1H NMR (400 MHz, CDCl3) δ 4.71 (s, 2H), 6.87 (s, 2H), 7.26-7.37 (m, 5H). A stirred solution of 1-benzyl-3-bromo-1H-pyrrole-2,5-dione (0.26 g, 1.0 mmol) and p-tolylboronic acid (0.16 g, 1.2 mmol) in dioxane (10 mL) was degassed with a stream of nitrogen for 10 minutes before being treated with CsF (0.39 g, 2.6 mmol) and C12Pd(dppf).CH2Cl2 (0.05 g, 0.06 mmol). The reaction was stirred at room temperature for 1 h then warmed to 40° C. for 1 h. The mixture was then cooled, diluted with CH2Cl2 (30 mL) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure and purified using gradient flash chromatography (0-10% ethyl acetate in pet ether) to provide the title compound 15.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(N(CC)CC)C.Cl[C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>C1COCC1>[NH2:6][C:4]([C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[NH:1][C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:5]
Reactant: CCOC(=O)C(=O)Cl
Reactant: NC(=O)c1cc([N+](=O)[O-])ccc1N
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1ccc([N+](=O)[O-])cc1C(N)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 28.8 %

Procedure:
To a solution of 2-amino-5-nitrobenzamide (18.1 g) and triethylamine (15 mL) in THF (100 mL) was added dropwise a solution of ethyl chloroglyoxylate (14.4 g) in THF (20 mL) under ice-cooling, and the mixture was stirred at 0° C. for 1 hr. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogencarbonate and saturated brine, dried, and concentrated. The obtained crude crystals were washed with diisopropyl ether to give ethyl {[2-(aminocarbonyl)-4-nitrophenyl]amino}(oxo)acetate (8.1 g).
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH2:8][CH2:9][CH3:10])[C:5](O)=O)[CH3:3].S(Cl)(Cl)=O.[C:15]1([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24]([NH2:26])=[O:25])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClC(Cl)Cl>[CH3:1][N:2]([CH3:3])[CH:4]([CH3:5])[CH2:8][CH2:9][C:10]1[N:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:22]2[C:23]([C:24](=[O:25])[N:26]=1)=[CH:27][CH:28]=[CH:29][CH:30]=2
Reactant: CCCC(C(=O)O)N(C)C
Reactant: NC(=O)c1ccccc1Nc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CC(CCc1nc(=O)c2ccccc2n1-c1ccccc1)N(C)C
Temperature: 57.5 °C
Reaction time: 1.5 h

Procedure:
3.80 g (20.9 mmol) dimethylamino-pentanoic acid were added to 25 ml thionyl chloride and stirred for 90 min. at 55-60° C. The remaining thionyl chloride was distilled in vacuum and the residue was added to a solution of 2.00 g (9.42 mmol) 2-phenylamino-benzamide (see above) in 30 ml trichloromethane at 0° C. The reaction mixture was boiled for 4 h and stirred overnight at room temperature. The residue was filtrated and dissolved in dichloromethane and saturated sodium bicarbonate solution. The organic solvent was dried over magnesium sulfate and evaporated. The yellow oil slowly crystallized.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>ClCCl>[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=4)[NH:9]3)=[CH:6][CH:7]=2)=[O:39])=[CH:36][CH:35]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(N)cc1)N2
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)c3ccc(F)cc3)cc1)N2
Yield: 37 %

Procedure:
To a solution of methyl 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (70 mg, 0.23 mmol) and N,N-diisopropylethylamine (0.09 mL, 0.52 mmol,) in dichloro methane (5 mL) was added 4-fluorobenzoyl chloride (54 mg, 0.34 mmol). The resultant mixture was stirred at room temperature for 16 hrs under nitrogen. The solvent was removed in vacuo and the residue was washed with dichloromethane/petroleum ether, the precipitate was collected to afford methyl 2-(4-(4-fluorobenzamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow solid, 43 mg, yield: 37%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](O)=[O:22])=[CH:15][CH:16]=2)[NH:11][N:10]=1.[CH3:28][C:29](=[CH2:32])[CH2:30][NH2:31].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:32][C:29](=[CH2:28])[CH2:30][NH:31][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[NH:18][C:14]1[CH:13]=[C:12]2[C:17]([C:9](/[CH:8]=[CH:7]/[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:10][NH:11]2)=[CH:16][CH:15]=1
Reactant: C=C(C)CN
Reactant: O=C(O)c1ccccc1Nc1ccc2c(C=Cc3ccccn3)n[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=C(C)CNC(=O)c1ccccc1Nc1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Reaction time: 8 h
Yield: 130.8 %

Procedure:
A solution of 2-[3-(2-Pyridin-2-yl-vinyl)-1H-indazol-6-ylamino]-benzoic acid (50.0 mg, 0.084 mmol), 2-methyl-allylamine (16.4 μL, 0.17 mmol), triethylamine (58 μl, 0.42 mmol), dissolved in DMF (0.8 mL), was treated with HATU (48 mg, 0.13 mmol). The mixture was stirred overnight, then purified by reverse phase HPLC yielding 45 mg (91%) of the title compound as a TFA salt (1.6 H2O, 1.3 TFA, effective MW=586.53). 1H NMR (DMSO-d6): δ 9.78 (1H, s), 8.72 (2H, m), 8.13 (4H, m), 7.70 (1H, d, J=7.1), 7.58 (2H, m), 7.41 (2H, m), 7.27 (1H, s), 7.06 (1H, d, J=7.1), 6.91 (1H, t, J=7.5), 4.42 (1H, m), 2.22 (2H, m), 2.08 (2H, m), 1.68 (2H, m). ESIMS (M+H+): 410.1.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH:19]=[C:20]([C:25]([O:27][CH3:28])=[O:26])[C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=1.[H][H]>CO.O1CCOCC1.[Pd]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][CH:20]([C:25]([O:27][CH3:28])=[O:26])[C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=1
Reactant: [H][H]
Reactant: COC(=O)C(=Cc1ccc(OCCOc2ccc3ccccc3c2)cc1)C(=O)OC
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)C(Cc1ccc(OCCOc2ccc3ccccc3c2)cc1)C(=O)OC
Yield: 94 %

Procedure:
To a solution of dimethyl 4-[2-(2-naphthoxy)ethoxy]benzylidenemalonate (2.22 g, 5.47 mmol) in a mixture of methanol (20 ml) and 1,4-dioxane (150 ml) is added 5% palladium on charcoal (1.20 g). Then the mixture is stirred under an atmosphere of hydrogen at room temperature until hydrogen uptake ceased. The solution is filtered through Celite, and the filtrate is evaporated under a vacuum. The residue is crystallized from ethyl acetate to give the title compound (2.10 g, 94%). HRMS calcd for C24H24O6: 408.4476. Found: 408.4475. MA calcd for C24H24O6: C, 70.58%; H, 5.92%. Found: C, 70.71%; H, 5.89%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([O:19][C:20]4[CH:29]=[C:28](F)[CH:27]=[CH:26][C:21]=4[C:22]([O:24][CH3:25])=[O:23])[C:13]=3[N:12]=[CH:11]2)=[CH:5][CH:4]=1.[NH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([O:19][C:20]4[CH:29]=[C:28]([N:39]5[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]5)[CH:27]=[CH:26][C:21]=4[C:22]([O:24][CH3:25])=[O:23])[C:13]=3[N:12]=[CH:11]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(F)cc1Oc1cccc2c1ncn2C(c1ccc(OC)cc1)c1ccc(OC)cc1
Reactant: C1CNCCN1
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N2CCNCC2)cc1Oc1cccc2c1ncn2C(c1ccc(OC)cc1)c1ccc(OC)cc1

Procedure:
A solution of EXAMPLE 403D (500 mg), and piperazine (420 mg) in dimethylsulfoxide (9 mL) was heated at 100° C. for 3 hours. The crude product was isolated by concentration and, following an aqueous work up, it was purified on silica gel, and was eluted with a 5 and 10% methanol in methylene chloride step gradient to provide the title compound.
Reaction SMILES: C([Li])(CC)C.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:22])=[C:11]([CH:21]=1)[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].[F:23][CH:24]([F:35])[CH:25]=[N:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>C1COCC1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:22][CH:25]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH:24]([F:35])[F:23])=[C:11]([CH:21]=1)[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19]
Reactant: COc1ccc(N=CC(F)F)cc1
Reactant: Cc1ccc(Cl)cc1CNC(=O)OC(C)(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COc1ccc(NC(Cc2ccc(Cl)cc2CNC(=O)OC(C)(C)C)C(F)F)cc1
Temperature: 25 °C
Yield: 16.8 %

Procedure:
sec-Butyl-lithium (1.3 M in cyclohexane, 10.72 mL) was added to a stirred solution of tert-butyl 5-chloro-2-methylbenzylcarbamate (1.781 g, 6.96 mmol) in THF (14 mL) at −78° C. under nitrogen to give a deep red solution. After 10 min N-(-2,2-difluoroethylidene)-N-(4-methoxyphenyl)amine (1.29 g, 6.96 mmol) was added and after a further 5 min the solution was quenched with excess saturated aqueous NH4Cl and warmed to ambient temperature. The solution was partitioned between EtOAc and brine. The organic layer was dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash column chromatography on silica (eluting with 5% methylene chloride, 5-15% ethyl acetate/hexanes gradient) to give tert-butyl 5-chloro-2-{3,3-difluoro-2-[(4-methoxyphenyl)amino]propyl}benzylcarbamate (0.516 g) as a foam; MS m/z=441.1.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:19]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27]C)=[O:26])[CH:16]=2)[N:11]=1.[OH-].[Na+].Cl>CO.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:19]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=[O:26])[CH:16]=2)[N:11]=1
Reactant: CCN(CC)c1nc2cc(C(=O)OC)ccc2nc1-c1cc2ccccc2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCN(CC)c1nc2cc(C(=O)O)ccc2nc1-c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
To a solution of methyl 2-(1-benzofuran-2-yl)-3-(diethylamino)quinoxaline-6-carboxylate (65 mg, 0.17 mmol) in methanol (10 mL) and water (1 mL) was added sodium hydroxide (13 mg, 0.33 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), adjusted the pH to 6 with 3N HCl and filtered to give 2-(1-benzofuran-2-yl)-3-(diethylamino)quinoxaline-6-carboxylic acid as a light yellow solid (32.2 mg, 51%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10](=[O:15])(=[O:14])[N:11]([CH3:13])[CH3:12])[CH2:5]O.S(Cl)([Cl:18])=O>C(Cl)Cl.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10](=[O:15])(=[O:14])[N:11]([CH3:13])[CH3:12])[CH2:5][Cl:18]
Reactant: O=S(Cl)Cl
Reactant: CN(C)S(=O)(=O)c1ccc(CO)cc1Br
Solvent: CCCCCC
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1ccc(CCl)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
To a solution of OBS02002 (5.0 g, 16.12 mmol) in anhydrous DCM (50 mL) was added thionyl chloride (1.76 mL, 24.18 mmol). The mixture was stirred at room temperature for 2 h and the volatiles removed in vacuo. The residue was re-dissolved and co-evaporated three times with DCM (3×20 mL) to give a yellow oil which solidified on standing. The solid was stirred in n-hexane, filtered and air-dried to give OBS02003 as an off-white solid (5.01 g, 95%). TLC [SiO2, EtOAc-n-hexane (1:1)] Rf=0.79; 1H-NMR (270 MHz, CDCl3)=3.05 (6H, s), 4.51 (2H, s), 7.32 (1H, dd, J=2.2, 8.4), 7.48 (1H, d, J=8.4), 7.62 (1H, d, J=2.2). Dimethylsulfamic Acid 2-bromo-4-{[(4-cyano-phenyl)-[1,2,4]triazol-4-ylamino]methyl}phenyl ester (OBS02005, STX732)
Reaction SMILES: [F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([CH3:25])[C@@H:15]3[C:16](=[O:19])[CH2:17][OH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:27])[CH:4]=[CH:5][C:6](=[O:26])[CH:7]=1.C[OH:29]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([CH3:25])[C@@H:15]3[C:16](=[O:19])[C:17]([OH:29])=[O:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:27])[CH:4]=[CH:5][C:6](=[O:26])[CH:7]=1
Reactant: CO
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@H]1C(=O)CO
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@H]1C(=O)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
One gram of 9α-fluoro-11β,21-dihydroxy-16α-methyl-1.4-pregnadiene-3,20-dione is dissolved in 125 ml. of methanol and combined with a solution of 250 mg. of copper(II) acetate in 125 ml. of methanol. The mixture is stirred for 15 minutes at room temperature while passing air therethrough, and then is combined with methylene chloride, washed with 5% ammonium chloride solution and water, and concentrated under vacuum. The thus-obtained product is dissolved in 50 ml. of methanol. The solution is mixed with 165 mg. of potassium cyanide, 1.0 ml. of acetic acid, and 5 g. of manganese(IV) oxide and agitated for 30 minutes at room temperature. Then the mixture is filtered, the filtrate diluted with methylene chloride, washed with water, dried, and concentrated under vacuum. The residue is chromatographed over a silica gel column, recrystallized from acetone/hexane, and the methyl ester of 9α-fluoro-11β-hydroxy-3,20-dioxo-16α-methyl-1,4-pregnadiene-21-oic acid is thus produced, m.p. 215° C.