Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)=[O:4].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)C(C)C)C>C1COCC1>[Cl:13][C:8]1[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=[CH:10][C:9]=1[Cl:12]
Reactant: O=C(CBr)Nc1ccc(Cl)c(Cl)c1
Reactant: Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNc1ccccc1)Nc1ccc(Cl)c(Cl)c1
Yield: 1000.4 %

Procedure:
To 2-bromo-N-(3,4-dichloro-phenyl)-acetamide (2 g) in THF (80 mL) was added aniline (41 mg) and N-ethyldiisopropylamine and the reaction mixture was stirred over night at reflux. The precipitated salt was then filtered off and the filtrate was then concentrated in vacuo. The residue was then purified by column chromatography to give the title compound as a light brown solid (1.3 g, mp=110-112° C.).
Reaction SMILES: ClC[SiH2][C:4]1[CH2:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.C1C[O:16][CH2:15][CH2:14]1>>[CH2:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[C:4]1[CH2:14][CH2:15][OH:16]
Reactant: C1CCOC1
Reactant: ClC[SiH2]C1=Cc2ccccc2C1
Product: OCCC1=Cc2ccccc2C1
Temperature: -78 °C
Reaction time: 15 h
Yield: 33.4 %

Procedure:
Under nitrogen flow, a 1 L three-necked flask receives 400 mL of THF and 8 g of 2-chloromethylsilylindene and the mixture is cooled to −78° C. To this, 38.5 mL (38.5 mmol) of a solution (1.0M) of LiN(trimethylsilylene)2 in THF is added dropwise. After stirring at room temperature for 15 hours, the solvent is distilled off and the residue is extracted with 300 mL of hexane. The solvent was distilled off to obtain 2.2 g (6.4 mmol) of (1,2′-dimethylsilylene)(2,1′-dimethylsilylene) (indene) 2 (yield:33.4%). The results of 1H-NMR analysis (90 MHz, CDCl3) are as follows: δ-0.69, 0.73 (12H, dimethylsilylene), 3.66 (4H, —CH2—), 7.17 (8H, Ar—H).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@@:9]2([OH:23])[CH2:14][CH2:13][N:12]([C:15](=[O:20])[C@H:16]([NH3+:19])[CH2:17][CH3:18])[CH2:11][C:10]2([CH3:22])[CH3:21])=[CH:5][CH:4]=1.[CH:24]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C@@:9]2([OH:23])[CH2:14][CH2:13][N:12]([C:15](=[O:20])[C@H:16]([NH:19][C:29]([CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:30])[CH2:17][CH3:18])[CH2:11][C:10]2([CH3:22])[CH3:21])=[CH:7][CH:8]=1
Reactant: CC[C@@H]([NH3+])C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Reactant: O=C(Cl)C1CCCC1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC[C@@H](NC(=O)C1CCCC1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Yield: 52.3 %

Procedure:
(R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-1-oxobutan-2-aminium chloride (52.4 mg, 0.14 mmol), cyclopentane carbonylchloride (20 mg, 0.17 mmol), THF (5 mL), and DIPEA (135 mg, 1.1 mmol) were stirred overnight at rt. The reaction was concentrated, and Example 627 was isolated as a white solid using preparative reverse-phase HPLC (30.75 mg, 52.3% yield), M+H=421.31.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:5]([C:6]#[N:7])=[C:4]([F:12])[CH:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.CCOC(C)=O>[F:12][C:4]1[CH:3]=[C:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[C:8]([O:10][CH3:11])[C:5]=1[C:6]#[N:7]
Reactant: OB(O)c1ccccc1
Reactant: COc1cc(Br)cc(F)c1C#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(-c2ccccc2)cc(F)c1C#N
Temperature: 80 °C
Yield: 97.9 %

Procedure:
A mixture of 4-bromo-2-fluoro-6-methoxybenzonitrile (2, 5.22 g, 22.7 mmol), phenylboronic acid (4.15 g, 34 mmol) and 2 M Na2CO3 (23 mL) in toluene (100 mL) was purged with N2 for 10 min. Pd(PPh4)3 (2.62 g, 27.7 mmol) and EtOH (5 drops) were added. The mixture was then heated under N2 in a sealed tube at 80° C. for 18 h. The mixture was cooled to room temperature, diluted with EtOAc (300 mL), filtered through celite, concentrated and purified by silica gel chromatography eluting with ethyl acetate in hexane (0-100%) to afford the title compound (5.05 g, 97%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 7.57-7.55 (m, 2H), 7.50-7.23 (m, 3H), 7.01-6.99 (m, 1H), 6.93 (s, 1H), 3.95 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[O:8].[CH2:9](O)[CH2:10][OH:11].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[O:8]1[CH2:9][CH2:10][O:11][CH:7]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: O=Cc1ccccn1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(C2OCCO2)nc1
Yield: 29 %

Procedure:
A mixture of 2-pyridinecarboxaldehyde (267 g, 2.5 mol), ethylene glycol (310.35 g, 5 mol), and 118.8 g (0.62 mol) of p-toluenesulfonic acid in 1.5 L of toluene placed in a 3 L flask fitted with a Dean Stark trap was allowed to reflux until the removal of water was complete. The mixture was concentrated in vacuo and the residue was poured into 800 mL of ice/10% potassium carbonate solution. The above mixture was extracted with ether (2×500 mL), and the organic layer was dried over sodium sulfate, filtered through an active charcoal/supercel and concentrated in vacuo to yield an oil. The oil was distilled (0.15 mm/90° C.) to afford 109.7 g (29.3%) of 2-(1,3-dioxolan-2-yl)-pyridine, as a pale yellow liquid.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[O-]S(C(F)(F)[F:20])(=O)=O.F[N+]1C(Cl)=CC=CC=1Cl>C(#N)C.O1CCCC1.C(=O)([O-])O.[Na+]>[F:20][C:9]1[C:10]([CH:13]=[O:14])=[CH:11][NH:12][C:8]=1[C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: O=Cc1c[nH]c(-c2cccnc2F)c1
Agent: F[n+]1c(Cl)cccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: O=Cc1c[nH]c(-c2cccnc2F)c1F
Reaction time: 2 h
Yield: 15.2 %

Procedure:
5-(2-Fluoropyridin-3-yl)-1H-pyrrole-3-carbaldehyde (660 mg) was dissolved in acetonitrile (30 mL) and tetrahydrofuran (30 mL), 1-fluoro-2,6-dichloropyridinium triflate (1.32 g) was added, and the mixture was stirred for 2 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=3:2→3:7) to give the title compound as pale-yellow crystals (yield 110 mg, 15%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:13])[C:5](=[O:12])[NH:6]2.[H-].[Na+].Br[Mg][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[O:25][CH3:26].[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([OH:13])([C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[O:25][CH3:26])[C:5](=[O:12])[NH:6]2
Reactant: O=C1Nc2ccc(Cl)c(Cl)c2C1=O
Reactant: COc1ccc(C)cc1[Mg]Br
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C)cc1C1(O)C(=O)Nc2ccc(Cl)c(Cl)c21
Reaction time: 4.5 h

Procedure:
1.50 g of 4,5-dichloro-1H-indol-2,3-dione was added under ice cooling and a nitrogen atmosphere to a 40 mL tetrahydrofuran solution of 310 mg of sodium hydride, and the reaction mixture was stirred for 1 hour. After this, 20 mL of a previously prepared tetrahydrofuran solution of bromo(2-methoxy-5-methylphenyl)magnesium was added dropwise over a period of 20 minutes, and the reaction mixture was stirred for 4.5 hours at the same temperature, after which 50 mL of a saturated ammonium chloride aqueous solution was added, and the reaction mixture was stirred for 30 minutes at room temperature. After liquid separation, the aqueous layer was extracted with ethyl acetate (30 mL×3), the combined organic layer was washed with saturated brine and dried with sodium sulfate, and the drying agent was then filtered off and the solvent was distilled off under reduced pressure. The residue thus obtained was stirred and washed with isopropyl ether and the solids were filtered off to obtain 1.23 g of the titled compound (yellow solid).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:25](O)([CH3:28])([CH3:27])[CH3:26].N>O1CCCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: CC(C)(C)O
Agent: N
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)OC(=O)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
76.5 g (0.5 mols) of p-hydroxyphenylacetic acid was dissolved in 500 ml of tetrahydrofuran (THF). The resulting reaction solution was then cooled to a temperature of from −20° C. to −15° C. To the reaction solution was then added dropwise 231 g (1.1 mols) of trifluoroacetic anhydride. After the termination of dropwise addition, the reaction mixture was stirred at room temperature for 12 hours. The reaction solution was then again cooled to a temperature of from −20° C. to −15° C. To the reaction solution was then added dropwise 37 g (0.5 mols) of t-butanol. The reaction mixture was then stirred at room temperature for 3 hours. To the reaction solution was then added dropwise 100 ml of aqueous ammonia. The reaction mixture was then extracted with water to obtain t-butyl p-hydroxyphenylacetate.
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].[Li+].CC([N-]C(C)C)C.CN1C(=O)N(C)CCC1.I[CH2:25][C:26]1[S:30][C:29]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)=[N:28][C:27]=1[CH3:41]>O1CCCC1>[CH2:5]([O:4][C:1](=[O:3])[CH2:2][CH2:25][C:26]1[S:30][C:29]([C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:35][CH:36]=2)=[N:28][C:27]=1[CH3:41])[CH3:6]
Reactant: CCOC(C)=O
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)CCc1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 21.5 %

Procedure:
A solution of ethyl acetate (2.24 ml, 22.8 mmol) in tetrahydrofuran (6 ml) was added to a −78° C. cold solution of LDA (2 M solution in tetrahydrofuran/n-heptane; 9.8 ml, 19.6 mmol) in tetrahydrofuran (15 ml) within 30 min under an argon atmosphere. The solution was stirred for 30 min at −78° C. and DMPU (3.9 ml, 32.6 mmol) was added within 20 min. A solution of 5-iodomethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (2.5 g, 6.5 mmol) in tetrahydrofuran (15 ml) was added within 30 min and stirring was continued for additional 30 min. The mixture was naturally warmed to ambient temperature, stirred for one hour and poured onto aqueous ammonium chloride/ice water 1/1. Twofold extraction with ethyl acetate was followed by washing of the combined extracts with ice water/brine 1/1 (two times), drying over sodium sulfate and removal of the solvent under reduced pressure. The residue was purified by column chromatography (silica gel, heptane/AcOEt) and crystallized from heptane/dichloro-methane to yield 480 mg (1.4 mmol, 21%) of the title compound as light yellow solid.
Reaction SMILES: [CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][C@H:6]1[CH:7]=[C:8]([CH2:23][CH2:24][O:25][Si](C(C)(C)C)(C)C)[C@H:9]2[CH2:14][O:15][Si](C(C)(C)C)(C)C)[CH:2]=[CH2:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][C@H:6]1[CH:7]=[C:8]([CH2:23][CH2:24][OH:25])[C@H:9]2[CH2:14][OH:15])[CH:2]=[CH2:3]
Reactant: C=CCON1C(=O)N2C[C@H]1C=C(CCO[Si](C)(C)C(C)(C)C)[C@H]2CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCON1C(=O)N2C[C@H]1C=C(CCO)[C@H]2CO
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a solution of (2S,5R)-6-(allyloxy)-3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1,6-diazabicyclo[3.2.1]oct-3-en-7-one (Intermediate 285, 0.96 g, 1.99 mmol) in THF (6 mL) at 0° C. was added tetrabutylammonium fluoride (1M in THF) (5.97 mL, 5.97 mmol). The reaction mixture was stirred for ˜1 hour and then concentrated onto silica gel. Silica gel chromatography (0%-10% methanol/dichloromethane) afforded the title compound (0.446 g, 88%) as a cloudy yellow oil.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].C[Al](C)C.[C:10]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]([O:26]CC)=O)[CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>C(Cl)Cl>[CH3:2][O:3][N:4]([CH3:5])[C:24](=[O:26])[CH2:23][N:20]1[CH2:19][CH2:18][N:17]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:22][CH2:21]1
Reactant: CNOC
Reactant: CCOC(=O)CN1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
N-Methoxy-N-methylamine hydrochloride (4.3 g, 44.1 mmol) was dissolved in methylene chloride (25 mL). The solution was cooled to −78° C., and a solution of trimethylaluminum (44.1 mL, 44.1 mmol, 1 M in heptane) was slowly added. The mixture was stirred at 0° C. for 30 min and was allowed to warm to room temperature and stirred for 30 min. The mixture was then cooled to 0° C., and a solution of ethyl 4-Boc-piperazin-1-ylacetate (10 g, 36.8 mmol) was added dropwise. After 15 min, the cold bath was removed and stirring continued overnight. The mixture was diluted with ethyl acetate and water. The layers were separated, and the water layer extracted with ethyl acetate. The organic layers were combined, washed with brine, dried (Na2SO4), filtered, and concentrated to provide N-methoxy-N-methyl-4-Boc-piperazin-1-ylacetamide as a light yellow oil (6.02 g, 57%) that solidified upon standing. The product was used without further purification.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1>C(O)C>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][CH:2]2[CH2:3][C:4](=[O:6])[NH:5][C:1]2=[O:7])=[CH:12][CH:11]=1
Reactant: COc1ccc(S)cc1
Reactant: O=C1C=CC(=O)N1
Solvent: CCO
Product: COc1ccc(SC2CC(=O)NC2=O)cc1

Procedure:
To a solution of maleimide (5.92 g, 61 mmol) in 200 ml of ethanol was added 4methoxybenzenethiol (7.5 ml, 61 mmol), and after 18 hours at room temperature the solvent was removed to give 3-(4-methoxy-phenylsulfanyl)pyrrolidine-2,5-dione, mp 93-94° C. This compound (5.0 g, 21 mmol) was oxidized with hydrogen peroxide, 30% in acetic acid, 220 ml to give 3-(4-methoxybenzenesulfonyl)pyrrolidine-2,5-dione as a white solid, mp 144-146° C. This compound was reacted with 1-chloro-4-(5-iodopent-1-ynyl)benzene in DMF using two equivalents of sodium bishexamethyldisilazide to give the title compound as colorless crystals, mp 160-162° C.; mass spectrum,(M−H) 444.2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[Si]([O:29][CH2:30][C:31]1[C:39]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:38][C:37]2[N:36]3[CH2:44][CH2:45][NH:46][CH:47]([CH:48]([CH3:50])[CH3:49])[C:35]3=[CH:34][C:33]=2[CH:32]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCN(C(C)C)C(C)C>CC(O)C.C(Cl)Cl>[CH:48]([CH:47]1[C:35]2=[CH:34][C:33]3[CH:32]=[C:31]([CH2:30][OH:29])[C:39]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:38][C:37]=3[N:36]2[CH2:44][CH2:45][N:46]1[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1)([CH3:50])[CH3:49]
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: CC(C)C1NCCn2c1cc1cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(S(C)(=O)=O)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)C1c2cc3cc(CO)c(S(C)(=O)=O)cc3n2CCN1c1nccc(C(F)(F)F)n1
Temperature: 110 °C
Reaction time: 30 h
Yield: 72 %

Procedure:
A mixture of 2-chloro-4-(trifluoromethyl)pyrimidine (80 mg, 0.44 mmol), 8-(((tert-butyldiphenylsilyl)oxy)methyl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole (crude, from step 9), and DIEA (115 μL, 0.66 mmol) in i-PrOH/CH2Cl2 (2 mL/1 mL) was stirred at 110° C. for 30 h. The solvent was removed under reduced pressure and the crude residue was purified by silica chromatography and SFC separation on a chiral column to give isomers of (1-isopropyl-7-(methylsulfonyl)-2-(4-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydropyrazino[1,2-a]indol-8-yl)methanol (75 mg, 72% yield for two steps).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH:16]([CH3:18])[O:15][CH:14]([CH3:19])[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30](O)=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1>>[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:13][CH:14]([CH3:19])[O:15][CH:16]([CH3:18])[CH2:17]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:20])=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: CC1CN(c2nn(N)c(=O)c3ccccc23)CC(C)O1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: CC1CN(c2nn(NC(=O)Cc3cc(F)cc(F)c3)c(=O)c3ccccc23)CC(C)O1

Procedure:
The product from Example 60A and 2-(3,5-difluorophenyl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54-11.55 (m, 1H), 8.30-8.34 (m, 1H), 8.01-8.04 (m, 1H), 7.96-8.01 (m, 1H), 7.87-7.92 (m, 1H), 7.11-7.19 (m, 3H), 3.84-3.93 (m, 2H), 3.73 (s, 2H), 3.32-3.36 (buried m, 2H), 2.40-2.47 (m, 2H), 1.12 (d, J=6.2 Hz, 6H); MS (APCI+) M/Z 429 (M+H)+.
Reaction SMILES: [Si]([O:18][C@@H:19]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C@@H:21]([CH2:22][CH2:23][C@@H:24]3[C@@H:33]2[CH2:32][CH2:31][C@@:29]2([CH3:30])[C@H:25]3[CH2:26][CH2:27][C@@H:28]2[C:38]#[C:39][CH:40]([OH:42])[CH3:41])[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[NH4+].[Cl-]>O1CCCC1>[OH:42][CH:40]([CH3:41])[C:39]#[C:38][C@H:28]1[CH2:27][CH2:26][C@H:25]2[C@H:24]3[C@H:33]([CH2:32][CH2:31][C@:29]12[CH3:30])[C@:34]1([CH3:37])[C@H:21]([CH2:20][C@H:19]([OH:18])[CH2:36][CH2:35]1)[CH2:22][CH2:23]3
Reactant: CC(O)C#C[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)C#C[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 4[3α-(t-butyidiphenylsilyloxy)-5α-androstan-17β-yl]-3-butyn-2-ol (30 mg, 0.052 mmol) in anhydrous tetrahydrofuran (2 mL) was treated with a 1M solution of (n-Bu)4N+F− (1.04 mL, 1.04 mmol) and the resulting solution was stirred at RT for 24 h. Addition of saturated aqueous NH4Cl solution was followed by extraction with ethyl acetate. The organic layer was extracted with water, brine and was dried with Na2SO4, and the solvent was evaporated in vacuo. Subsequent purification of the residue with flash column chromatography using methylene chloride/ethyl acetate 90/10 as eluent afforded the desired compound named above.
Reaction SMILES: [CH3:1][CH:2]([CH2:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:3][CH2:4][C:5]1[CH:41]=[CH:40][C:8]([C:9]([C:11]2[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[C:17]([C:23](=O)[C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH:32]([CH3:38])[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:26][CH:25]=3)=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=O)=[CH:7][CH:6]=1.[H][H]>O1CCCC1.[Pd]>[CH3:38][CH:32]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:31][CH2:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][C:17]2[CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]([CH2:9][C:8]3[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH:2]([CH3:1])[CH2:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[CH:41][CH:40]=3)=[CH:19][C:18]=2[C:20]([OH:22])=[O:21])=[CH:25][CH:26]=1
Reactant: CC(CCc1ccc(C(=O)c2cc(C(=O)O)c(C(=O)c3ccc(CCC(C)CC(C)(C)C)cc3)cc2C(=O)O)cc1)CC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(CCc1ccc(Cc2cc(C(=O)O)c(Cc3ccc(CCC(C)CC(C)(C)C)cc3)cc2C(=O)O)cc1)CC(C)(C)C

Procedure:
A mixture containing 20.0 grams of 2,5-bis[4-(3,5,5-trimethylhexyl)benzoyl]terephthalic acid in 1500 mL of tetrahydrofuran (THF) and 1.4 grams of 10% palladium on carbon (as a catalyst) was heated to 90° C. in an atmosphere of hydrogen at 620 kPa and 90° C. for 17 hours. The mixture was filtered through Celite™ diatomaceous earth filter agent to remove the catalyst. The filtrate was concentrated in vacuo to give 2,5-bis[4-(3,5,5-trimethylhexyl)benzyl]terephthalic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[CH3:15][S:16]([O-:18])=[O:17].[Na+].[OH-].[Na+]>CS(C)=O>[CH3:15][S:16]([C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1)(=[O:18])=[O:17]
Reactant: O=[N+]([O-])c1cc(Br)cc(C(F)(F)F)c1
Reactant: CS(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Yield: 33.5 %

Procedure:
Stir the mixture of 1-bromo-3-nitro-5-(trifluoromethyl)benzene (6 g, 22.2 mmol), sodium methanesulfinate (2.8 g, 26.7 mmol), cuprous iodide (0.5 g, 2.22 mmol), L(−)-proline (0.5 g, 4.44 mmol) and sodium hydroxide (0.088 g, 4.44 mmol) in DMSO (20 mL) at 100° C. for 15 hrs under nitrogen atmosphere. Add water, extract the mixture with ethyl acetate (200 mL×3), combine the organic layers, dry over anhydrous sodium sulfate, and concentrate the mixture under reduced pressure. Purify the residue by flash chromatography to afford the desired product (2 g, 33.3%).
Reaction SMILES: Cl[C:2]1(Cl)[CH:9]2[CH:4]([CH2:5][CH2:6][CH:7]=[CH:8]2)[C:3]1=[O:10].C(N(CC)CC)C.[Cl-].[NH4+].[CH3:21][OH:22]>[Cu].[Zn]>[CH3:21][O:22][C:4]12[C:3](=[O:10])[CH2:2][CH:9]1[CH:8]=[CH:7][CH2:6][CH2:5]2
Reactant: O=C1C2CCC=CC2C1(Cl)Cl
Reactant: CO
Agent: [Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Product: COC12CCC=CC1CC2=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of 60 g of 8,8-dichlorobicyclo[4.2.0]oct-2-en-7-one in 500 ml of methanol under nitrogen at room temperature was added 48 ml of triethylamine over a period of 1 hour. The mixture was stirred for 30 minutes, then 90 g of ammonium chloride and 60 g of zinc-copper couple (as a powder) was added. The reaction mixture was stirred at room temperature for 2.5 hours, filtered through celite and the solvent removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and the solvent was distilled under vacuum, giving 32 g of 6-methoxybicyclo[4.2.0]oct-2-en-7-one.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[NH:12]([C:19]1[C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=[C:21](SC)[N:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C.[C:39]1([C:45]2[CH:49]=[C:48]([CH2:50][N:51]3[CH2:56][CH2:55][CH:54]([CH2:57][NH2:58])[CH2:53][CH2:52]3)[O:47][N:46]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl.C(OCC)(=O)C>[NH:12]([C:19]1[C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=[C:21]([NH:58][CH2:57][CH:54]2[CH2:53][CH2:52][N:51]([CH2:50][C:48]3[O:47][N:46]=[C:45]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH:49]=3)[CH2:56][CH2:55]2)[N:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Reactant: CSc1ncc(C(N)=O)c(Nc2ccccc2)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NC(=O)c1cnc(NCC2CCN(Cc3cc(-c4ccccc4)no3)CC2)nc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.5 %

Procedure:
3-Chloroperoxybenzoic acid (195 mg) was added to a 0° C. suspension of the compound prepared in Example 93 (100 mg) in dichloromethane (4 mL). The reaction was stirred one hour at room temperature. Diisopropylethylamine (0.669 mL) and the compound prepared in Example 9 (198 mg) were added and the mixture was stirred at room temperature for 18 hours. The reaction was diluted with ethyl acetate and sequentially washed with a saturated sodium bicarbonate solution and brine. The organics were dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (concentrated aqueous ammonia:methanol:ethyl acetate=0.1:0.9:25) to obtain the title compound (51 mg) having the following physical data.