Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1cccc(N)c1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1cccc(NC(=O)C(C)(C)C)c1
Temperature: 15 °C
Reaction time: 1 h

Procedure:
To an ice cooled solution of 20 g (162 mmol) 3-methoxy-phenylamine in 400 ml diethylether is added 24.9 ml (178 mmol) triethylamine and slowly within 30 minutes 23.9 ml (195 mmol) pivaloyl chloride. Due to the exothermic reaction the temperature rises despite cooling to 15° C. The temperature is left rising to room temperature, after 1 hour the reaction mixture is poured on ice and extracted with ethyl acetate, washed 2× with water and 1× with brine, dried with Na2SO4 and evaporated to give a crude product which is purified by two crystallizations from CH2Cl2/hexane to yield N-(3-methoxy-phenyl)-2,2-dimethyl-propionamide.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(#N)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:3]([CH:6]=1)[C:4]#[N:5])([O-:12])=[O:11]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: C1CCNCC1
Solvent: CC#N
Product: N#Cc1cc([N+](=O)[O-])ccc1N1CCCCC1
Reaction time: 1 h
Yield: 67.1 %

Procedure:
2-Chloro-5-nitrobenzonitrile (20 g) and piperidine (9.34 g) were added to acetonitrile (100 ml) and the mixture was stirred at the refluxing temperature for 1 hr. The solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization and the crystals were recrystallized from methanol to give 5-nitro-2-piperidinobenzonitrile (17 g). Subsequently, ammonium chloride (1.6 g) and iron powder (8.4 g) were added to a mixed solvent of water (40 ml) and ethanol (120 ml) and the mixture was heated to 65° C. 5-Nitro-2-piperidinobenzonitrile (10 g) was added by portions over 20 min and the mixture was stirred at the refluxing temperature for 30 min. The reaction mixture was ice-cooled and the reaction solution was filtrated. The solvent was evaporated under reduced pressure. An aqueous sodium hydroxide solution was added and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization and the crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (8.3 g). melting point: 148-149° C.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C@@H:11]([CH3:12])[CH2:10][N:9]([C:13]3[S:14][C:15]([C:19]([O:21]CC)=[O:20])=[C:16]([CH3:18])[N:17]=3)[C:8]2=[O:24])=[CH:4][CH:3]=1.[OH-].[Li+].Cl>O1CCCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C@@H:11]([CH3:12])[CH2:10][N:9]([C:13]3[S:14][C:15]([C:19]([OH:21])=[O:20])=[C:16]([CH3:18])[N:17]=3)[C:8]2=[O:24])=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1sc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Yield: 69.4 %

Procedure:
To a solution of (S)-ethyl 2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate (0.50 g, 1.32 mmol) in tetrahydrofuran (20.0 mL) was added a solution of lithium hydroxide (0.16 g, 6.62 mmol) in water (15 mL). The reaction mixture was refluxed for 16 h and followed by the addition of 1 N aqueous hydrochloric acid solution to adjust pH to 2. The mixture was extracted with ethyl acetate (3×40 mL). The organic layer was washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated in vacuo and the residue was purified by crystallized in ethyl acetate to afford the title compound as a colorless solid (0.32 g, 69%): mp 208-210° C. (ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.31-7.26 (m, 2H), 7.04 (dd, J=8.6, 8.6 Hz, 2H), 4.83 (d, J=15.3 Hz, 1H), 4.29-4.14 (m, 2H), 3.78-3.65 (m, 2H), 2.65 (s, 3H), 1.31 (d, J=5.9 Hz, 3H); MS (ES−) m/z 347.9 (M−1).
Reaction SMILES: [Br:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:13]([F:12])[CH:14]=1
Reactant: Clc1ccc2[nH]ncc2c1Br
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Fc1cc(-n2ncc3c(Br)c(Cl)ccc32)ccc1OCc1ccccc1
Reaction time: 120 h

Procedure:
A mixture of 4-bromo-5-chloro-1H-indazole (D22) (0.361 g, 1.56 mmol), {3-fluoro-4-[(phenylmethyl)oxy]phenyl}boronic acid (0.57 g, 2.32 mmol), copper (II) acetate (0.42 g, 2.31 mmol) and pyridine (0.25 mL, 3.10 mmol) in dichloromethane (50 mL) were stirred together vigorously under an air atmosphere with powdered 4A molecular sieves (1.5 g). After 5 days, the mixture was filtered through celite and the solvent evaporated. The concentrate was chromatographed (silica, dichloromethane/hexane) to give the title compound (D23) as an off white solid (0.32 g)
Reaction SMILES: [CH3:1]I.[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[C:9](=[O:14])[NH:10][CH2:11][CH2:12][N:13]=1.O.Cl>C(OCC)C.O1CCCC1>[CH3:1][C:8]1([C:4]2[S:3][CH:7]=[CH:6][CH:5]=2)[NH:13][CH2:12][CH2:11][NH:10][C:9]1=[O:14]
Reactant: O=C1NCCN=C1c1cccs1
Reactant: CI
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC1(c2cccs2)NCCNC1=O
Reaction time: 15 h

Procedure:
The Grignard solution prepared from 7.3 g of Mg and 42.6 g of methyl iodide in 150 ml of diethyl ether is added dropwise slowly at room temperature to a solution of 18 g of 3-(thien-2-yl)-5,6-dihydropyrazin-2-one in 150 ml of tetrahydrofuran. Stirring is continued for 15 hours at room temperature and the mixture is then hydrolyzed with 100 ml of water. The pH of the mixture is adjusted to 2 with concentrated HCl, the organic phase is separated off and the aqueous phase is extracted twice by shaking with diethyl ether and its pH is adjusted to 8 with potassium carbonate. The compound is then extracted with methylene chloride. The methylene chloride phase is dried and concentrated. The residual oil is purified by column chromatography over silica gel made by Merck, Darmstadt, type "0.04-0.06", the mobile phase being methylene chloride/methanol in a ratio by volume of 95:5. The fractions containing the compound are concentrated on a rotary evaporator and the residue is recrystallized from isopropanol.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:8]=3[CH:9](Cl)[CH2:10][C:4]=2[CH:3]=1.[C:19]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:21][CH2:22][CH3:23])=[O:20]>C(Cl)(Cl)Cl>[C:19]([N:24]1[CH2:29][CH2:28][N:27]([CH:9]2[C:8]3[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:7]=3[S:6][C:5]3[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][C:4]=3[CH2:10]2)[CH2:26][CH2:25]1)([O:21][CH2:22][CH3:23])=[O:20]
Reactant: Fc1ccc2c(c1)C(Cl)Cc1cc(Cl)ccc1S2
Reactant: CCOC(=O)N1CCNCC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCN(C2Cc3cc(Cl)ccc3Sc3ccc(F)cc32)CC1
Temperature: 0 °C

Procedure:
24 G. of 2,10-dichloro-8-fluoro-10,11-dihydro-dibenzo[b,f]thiepin in 80 ml. of chloroform are heated together with 38.4 g. of 1-carbethoxy-piperazine under reflux conditions for 20 hours. The reaction mixture is poured over ice water and extracted with chloforom. The organic phase is dried over magnesium sulfate and evaporated under reduced pressure, whereby there is obtained oily 1-carbethoxy-4-(2-chloro-8-fluoro-10,11-dihydro-dibenzo [b,f]thiepin-10-yl)-piperazine. 24.5 G. of 1-carbethoxy-4-(2-chloro-8-fluoro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-piperazine, 350 ml. of ethyleneglycol, 19 g. of potassium hydroxide and 1.5 ml. of water are heated together at 160° for 1 hours. The reaction mixture is poured over water and extracted with chloroform. The organic phase is washed with water, dried over magneisum sulfate and evaporated under reduced pressure, whereby there is obtained 1-(2-chloro-8-fluoro-10,11-dihydro-dibenzo[b,f]-thiepin-10-yl)-piperazine as a thick oil.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19]C1C=CC=CC=1)[N:14]=[CH:13][NH:12][C:11]2=O.S(Cl)([Cl:29])=O>>[Cl:29][C:11]1[C:10]2[C:15](=[CH:16][C:17]([O:18][CH3:19])=[C:8]([O:7][CH3:6])[CH:9]=2)[N:14]=[CH:13][N:12]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Cl)c2cc1OC
Yield: 90 %

Procedure:
A mixture of 2-amino-4-benzyloxy-5-methoxybenzamide (10 g, 0.04 mol—prepared according to J. Med. Chem. 1977, 20, 146-149), and Gold's reagent (7.4 g, 0.05 mol) in dioxane (100 ml) was stirred and heated at reflux for 24 hours. Sodium acetate (3.02 g, 0.037 mol) and acetic acid (1.65 ml, 0.029 mol) were added to the reaction mixture and it was heated for a further 3 hours. The volatiles were removed by evaporation, water was added to the residue, the solid was collected by filtration, washed with water and dried. Recrystallisation from acetic acid yielded 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (8.7 g, 84% yield) as a white solid. b) Dimethylformamide (0.2 ml) was added dropwise to a solution of 6-methoxy-7-benzyloxy-3,4-dihydroquinazolin-4-one (5.00 g, 17.9 mmol) in thionyl chloride (100 ml) and the reaction was heated at reflux for 1 hour. The reaction was cooled, excess thionyl chloride was removed in vacuo and the residue was azeotroped with toluene (3×50 ml) to remove the last of the thionyl chloride. The residue was taken up in dichloromethane (550 ml), the solution was washed with saturated aqueous sodium hydrogen carbonate solution (100 ml) and water (100 ml) and the organic phase was dried over magnesium sulphate. Solvent evaporation in vacuo yielded 4-chloro-6,7-dimethoxyquinazoline (4.80 g, 90% yield) as a pale brown solid:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[O:11])[CH:6]=[CH:7][C:8]=1[OH:9].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:12]([O:9][C:8]1[CH:7]=[CH:6][C:5]([CH:10]=[O:11])=[CH:4][C:3]=1[O:2][CH3:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1cc(C=O)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
15.2 g (0.1 mol) of vanilline, 20.5 g (0.12 mol) of benzyl bromide, 17.9 g (0.13 mol) of potassium carbonate and 150 ml of N,N-dimethylformamide were mixed and stirred at 50° C. for 2 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochloric acid and then saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was washed with hexane and dried to give 23.1 g of 4-benzyloxy-3-methoxybenzaldehyde.
Reaction SMILES: [CH3:1][Si:2]([CH3:8])([CH3:7])[CH2:3][CH2:4][CH2:5]Br.[Mg].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22]C1CCCCO1.[Cl-].[Li+].[Cl-]>O1CCCC1>[CH3:1][Si:2]([CH3:8])([CH3:7])[CH2:3][CH2:4][CH2:5][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22]
Reactant: BrCCCCCCCCCCCOC1CCCCO1
Reactant: C[Si](C)(C)CCCBr
Agent: [Cl-]
Agent: [Li+]
Agent: [Mg]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCCCCCCCCCCCCCO

Procedure:
The Grignard reagent prepared from 31.6 g. 3-(trimethylsilyl)propyl bromide and 4.0 g. magnesium turnings in 100 ml. dry tetrahydrofuran was dropwise added under argon to a cold (-20°) stirred solution of 33 g. 11-bromoundecyltetrahydropyranyl ether, 82 mg. lithium chloride and 125 mg. cuprus chloride in 250 mg. dry tetrahydrofuran. After the reagents had been combined, the solution was left to stir at room temperature for 17 hr. The reaction was diluted with 400 ml. 10% hydrochloric acid solution, the layers were separated, and the aqueous layer was extracted three times with 150 ml. portions of ether. The combined organic solutions were washed with brine, dried with anhydrous magnesium sulfate, and evaporated to 36.7 g. milky liquid. This intermediate tetrahydropyranyl ether was dissolved into 250 ml. ethanol and 15 ml. concentrated hydrochloric acid and stirred at reflux for 40 hr. The solvents were evaporated, the residue was re-dissolved into 300 ml. methylene chloride, and this solution was passed through a pad of hydrous magnesium silicate. The methylene chloride was evaporated and the residue was distilled in vacuo to yield a colorless liquid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[CH2:25]([Mg]Cl)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>C1COCC1>[C:14]([C:11]1[CH:10]=[C:7]([CH:8]([OH:9])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:12]=1[OH:13])([CH3:17])([CH3:16])[CH3:15]
Reactant: Cl[Mg]CCc1ccccc1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)c1cc(C(O)CCc2ccccc2)cc(C(C)(C)C)c1O
Temperature: 80 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To a 5-liter, 4-neck round-bottom flask fitted with a mechanical stirrer, reflux condenser, thermometer, and addition funnel were charged 238.5 grams (1.02 moles) of 3,5-di-t-butyl-4-hydroxybenzaldehyde and 979 grams of toluene. To this suspension, a one molar solution of phenethylmagnesium chloride in THF was slowly added such that the pot temperature slowly rose to 40° C. After the addition of several hundred milliliters of Grignard reagent solution a green sticky solid formed. The addition was halted, an additional 859 mL of toluene was added, and the solution was warmed to 80° C. The remaining Grignard reagent was slowly added while maintaining the pot temperature between 50° C. and 70° C. After the addition was complete, the reaction mixture was stirred at 70° C. for one hour. During this time, the green solids dissolved and the reaction mixture formed two liquid phases. After this time, the reaction was cooled and then quenched by slowly adding 80 mL of deionized water. The quenched reaction mixture was then poured into six liters of water. The organic phase was separated and the solvent removed in vacuo. The resulting crude product was then dissolved in warm hexane and filtered. The filtrate was washed with hexane (2×100 mL). The hexane portions were combined and solvent removed producing 242 grams (69.8 percent) of a viscous amber oil.
Reaction SMILES: FC1C=CC(OC)=C(C2C(C(O)=O)=CC([N+]([O-])=O)=CC=2)C=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[C:31]1[C:32]([C:40]([O:42]C)=[O:41])=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=1>>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[C:31]1[C:32]([C:40]([OH:42])=[O:41])=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(C)ccc1OC
Agent: COc1ccc(F)cc1-c1ccc([N+](=O)[O-])cc1C(=O)O
Product: COc1ccc(C)cc1-c1ccc([N+](=O)[O-])cc1C(=O)O
Yield: 100.2 %

Procedure:
This compound was prepared in a manner similar to that of 5'-fluoro-2'-methoxy-4-nitro-2-biphenylcarboxylic acid (EXAMPLE 107) from methyl 2'-methoxy-5'-methyl-4-nitro-2-biphenylcarboxylate (2.02 g) to afford 1.93 g (99%) of 2'-methoxy-5'-methyl-4-nitro-2-biphenylcarboxylic acid as a white solid. Data for 2'-methoxy-5'-methyl-4-nitro-2-biphenylcarboxylic acid: 1H NMR (400 MHz, acetone-d6) 8.63 (d, J=2.5, 1H), 8.42 (dd, J=8.5, 2.5, 1H), 7.63 (d, J=8.5, 1H), 7.19 (m, 1H), 7.14 (d, J=2.2, 1H), 6.93 (d, J=8.4, 1H), 3.70 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH:18]=[C:19]2[S:23][CH2:24][CH3:25])[C@H:15]2[C@@:6]1([F:28])[C@:7]1([CH3:27])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:26])[CH:9]=[CH:8]1)(=[O:3])[CH3:2].[CH2:29]([SH:33])[CH2:30][CH2:31][CH3:32]>>[C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C:19]2([S:33][CH2:29][CH2:30][CH2:31][CH3:32])[S:23][CH2:24][CH3:25])[C@H:15]2[C@@:6]1([F:28])[C@:7]1([CH3:27])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:26])[CH:9]=[CH:8]1)(=[O:3])[CH3:2]
Reactant: CCCCS
Reactant: CCSC1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@]12C
Product: CCCCSC1(SCC)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@@]21C
Temperature: 10 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
A solution of 11β-acetyloxy-17-(ethylthio)-9-fluoroandrosta-1,4,16-triene-3-one (700 mg; see example 11c) and n-butanethiol (271 mg) is cooled and stirred in a bath at -40° to -45° C. and distilled boron trifluoride etherate (0.3 ml) is added. After 2.0 hours at -40° to -45° C., the solution is gradually warmed to 10° C. in the course of 1.5 hours. The mixture is then diluted with dichloromethane, washed successively with a saturated sodium bicarbonate solution and brine, dried (MgSO4 anh.) and is evaporated to afford the crude title compound. This material is chromatographed over a column of silica gel (20 g), eluting the column with chloroform-hexane mixtures (1:1, 1:4), chloroform and chloroform-ethyl acetate (95:5) to afford the title compound (700 mg). Examination of the nmr spectrum and tlc behavior shows that this material is contaminated with a significant amount of the starting steriod which is not readily separable from the more polar isomer of the product under the tlc systems examined. Partial separation of the two 17-isomers is achieved under these tlc conditions.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1O.[OH-:11].[Na+].O.[Cl:14][CH2:15][CH2:16]Cl>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1>[Br:1][CH:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[CH:6][C:7]1([O:11][CH2:16][CH2:15][Cl:14])[CH3:8]
Reactant: [OH-]
Reactant: ClCCCl
Reactant: Cc1cc(C)c(Br)c(O)c1
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC1=CC(C)(OCCCl)C(Br)C=C1
Yield: 90 %

Procedure:
A mixed solution of 2-bromo-3,5-dimethylphenol obtained in Reference Example 149 (16.3 g, 74.6 mmol) and benzyl-tri-n-butylammonium chloride (23.3 g, 7.46 mmol) in 1,2-dichloroethane (150 mL)—a 8 N aqueous sodium hydroxide solution (26 mL)—water (110 mL), was heated under reflux for 5 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The combined organic layer was washed with water, a saturated sodium hydrogen carbonate solution, and a saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 16.6 g (yield 90%) of the title compound. Oily matter.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:17](I)[CH3:18]>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:17][CH3:18])[C@@H:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(C(=O)OC(C)(C)C)[C@@H](C)C(=O)OC
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 38.7 %

Procedure:
(S)-methyl 2-(tert-butoxycarbonylamino)propanoate (10.0 g, 49.2 mmol) was dissolved in THF (100 mL) and cooled to 0° C. under nitrogen. Sodium hydride (60% susp. in mineral oil, 3.00 g, 75.1 mmol) was added in portions over 2 min. The reaction mixture was stirred for 5 min at 0° C. and EtI (4.80 mL, 59.5 mmol) was added. It was allowed to warm to room temperature over the period of 1 h, stirred at room temperature overnight and at 70° C. for 7 d. The reaction mixture was cooled, filtered and concentrated in vacuo. The solid was triturated with hexanes (2×70 mL), the triturates were concentrated in vacuo and the residue was purified using flash column chromatography on silica gel (330 g SiO2, hexanes:ethyl acetate 19:1-9:1) to afford the title compounds as an oil (4.40 g, 39%). [M+H] calc'd for C11H21NO4, 232; found, 232.
Reaction SMILES: ClCl.C([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=O)C.[OH-:11].[Na+].[C:13]([OH:16])(=[O:15])[CH3:14]>O>[S:7]1[CH:8]=[CH:9][CH:10]=[C:6]1[CH:14]([OH:11])[C:13]([OH:16])=[O:15]
Reactant: CC(=O)c1cccs1
Reactant: CC(=O)O
Reactant: [OH-]
Agent: ClCl
Agent: [Na+]
Solvent: O
Product: O=C(O)C(O)c1cccs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Chlorine was bubbled through a solution of 6.31 g (50 mmol) of 2-acetylthiophene in glacial acetic acid (25 ml). The reaction solution which evolved heat was cooled with water and kept below 28° C. The reaction was discontinued at the stage when the reaction solution turned slight yellow by the excess chlorine, and then acetic acid was distilled off at room temperature under a reduced pressure to give crude 2-(dichloroacetyl)thiophene. This crude product was added in dropwise with vigorous stirring to a solution of 10.0 g (250 mmol) of sodium hydroxide in water (90 ml) which was kept at 50° C. The temperature of the reaction solution rose to ca. 55° C. The addition was completed after ca. 2 hr., and the mixture was stirred for another 1 hr. at the same temperature. After cooling to room temperature, the reaction mixture was washed with diethylether, then acidified (pH 1) by addition of 12 N hydrochloric acid under ice cooling. The acidic material which separated out was extracted with diethylether, and the ether layer was washed with a saturated aqueous solution of sodium chloride, and after drying with sodium sulfate, the solvent was distilled off to give 2-thiopheneglycolic acid in quantitative yield (7.9 g).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C>[N:27]1([CH2:26][CH2:25][C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: Fc1ccc2nnc(CCN3CCCC3)n2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N[C@H]1CC[C@@H](Oc2ccc3nnc(CCN4CCCC4)n3c2)c2ccccc21
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 63.8 %

Procedure:
Intermediate A (189 mg, 1.16 mmol) was added to a suspension of sodium hydride (60% in mineral oil, 139 mg, 3.48 mmol) in DMF (5 mL). The reaction was stirred for 20 mins, then Intermediate 1b (292 mg, 1.16 mmol) was added in DMF (5 mL) and the reaction heated to 60° C. for 2 h. The mixture was cooled and quenched by dropwise addition of MeOH. The solution was loaded onto an SCX-2 cartridge, which was washed with MeOH and product eluted with 2M NH3 in MeOH. The residue was purified by FCC using 0-10% [2M NH3 in MeOH] in DCM to give the title compound (270 mg, 0.74 mmol, 64%). 1H NMR (400 MHz, d4-MeOD): 1.80-1.86 (4H, m), 1.92-2.02 (1H, m), 2.05-2.18 (2H, m), 2.30-2.40 (1H, m), 2.62-2.70 (4H, m), 2.99-3.05 (2H, t, J 7.8), 3.28-3.36 (2H, t, J 7.8), 3.98-4.04 (1H, dd, J 8.6, 5.2), 5.46-5.50 (1H, t, J 4.3), 7.22-7.40 (4H, m), 7.54-7.58 (1H, d, J 7.8), 7.63-7.68 (1H, dd, J 9.8, 0.7), 7.97 (1H, s), 8.09-8.11 (1H, d, J 1.6).