Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:34]([O:36][C:37](=[O:43])[CH2:38][CH2:39][CH2:40][CH2:41]Br)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:43])[CH2:38][CH2:39][CH2:40][CH2:41][O:22][C:20]1[CH:19]=[C:18]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)[CH:17]=[C:16]([C:15](=[O:32])[NH:14][CH:11]2[CH2:12][CH2:13][CH:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:33])[CH2:9][CH2:10]2)[CH:21]=1)[CH3:35]
Reactant: CCOC(=O)CCCCBr
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Product: CCOC(=O)CCCCOc1cc(Oc2ccc(C#N)cc2)cc(C(=O)NC2CCC(NC(=O)OC(C)(C)C)CC2)c1
Yield: 88.1 %

Procedure:
Using 0.63 g (1.39 mmol) of {4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino]cyclohexyl}carbamic acid tert-butyl ester and 5-bromo-pentanoic acid ethyl ester (0.29 g, 1.39 mmol) and following the procedure of Example 42(b) afforded 0.71 g of the required product. 1H NMR (DMSO-d6): δ 1.2 (4H, m), 1.25 (2H, m), 1.4 (9H, s), 1.75 (9H, m), 2.35 (2H, m) 3.2 (1H, m), 3.7 (1H, m), 4.05 (4H, m), 6.75 (1H, d), 6.9 (1H, s), 7.15 (3H, d), 7.35 (1H, s), 7.85 (2H, d), 8.25 (1H, d).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH3:10])[CH:8]=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](O)=[O:20])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[CH:8][N:7]([CH3:10])[CH3:6])[CH:19]=[O:20])=[CH:14][CH:13]=1
Reactant: CN(C)C=O
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=C(C=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a slurry of Vilsmeyer reagent, (formed from a stirred mixture of 92.0 g. of phosphorus oxychloride and 73.0 g. of N,N-dimethylformamide at a temperature below 10° C.) is added 34.12 g. of 4-chlorophenylacetic acid. This mixture is stirred at ambient temperature for 30 minutes, then is heated to 70°-80° C. during which time the mixture becomes effervescent. The mixture is kept at 70°-80° C. for 5.5 hours, then is allowed to cool. The cooled mixture is slowly poured onto cracked ice, and ice is added intermittently to maintain the temperature of the mixture below 15° C. during the portionwise addition of potassium carbonate and until pH 10 is achieved. Then 150 ml. of toluene is added and the mixture is heated on a steam bath for one hour. After cooling, the layers are separated and the aqueous layer is extracted with an additional 100 ml. of toluene. The organic layers are combined, copiously washed with water, dried over anhydrous sodium sulfate and evaporated at reduced pressure to yield a yellow solid. The solid is recrystallized from hexane to give 27.3 g. of the product of the Example as a tan solid, mp. 121°-124° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([CH2:39][CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[C:36]([OH:38])=O)=[CH:31][C:30]=1[N+:45]([O-:47])=[O:46].[NH2:48][C:49]1[S:50][CH:51]=[CH:52][N:53]=1>C(Cl)Cl>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([CH2:39][CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[C:36]([NH:48][C:49]2[S:50][CH:51]=[CH:52][N:53]=2)=[O:38])=[CH:31][C:30]=1[N+:45]([O-:47])=[O:46]
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 72.9 %

Procedure:
A solution of triphenylphosphine (105 mg, 0.403 mmol) in methylene chloride (1 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (72 mg, 0.403 mmol). The reaction mixture was stirred at 0° C. for 20 min and then treated with 2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-propionic acid (100 mg, 0.336 mmol). The resulting reaction mixture was stirred at 0° C. for 10 min and then allowed to warm to 25° C. where it was stirred for 20 min. The reaction mixture was then treated with 2-aminothiazole (74 mg, 0.739 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was treated with a solution of hexanes/ethyl acetate (2 mL, 3:1) and then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate). The pure 2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (93 mg, 73%) was obtained as a pale yellow foam: mp 68-72° C. (foam to gel); EI-HRMS m/e calcd for C17H18ClN3O3S (M+) 379.0757, found 379.0760.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[CH2:10][CH:11]([N:15]1[CH:19]=[CH:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:16]1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]1[CH2:40][C@H:39]([NH2:41])[C:37](=[O:38])[NH:36][CH2:35][CH2:34]1>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:32])[CH2:10][CH:11]([N:15]1[CH:19]=[CH:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:16]1)[C:12]([NH:41][C@H:39]1[CH2:40][CH2:33][CH2:34][CH2:35][NH:36][C:37]1=[O:38])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CCCCNC1=O
Reactant: O=C(CC(C(=O)O)N1C=CN(c2ccc(-c3ccccc3)cc2)C1)OCc1ccccc1
Solvent: CN(C)C=O
Product: O=C(CC(C(=O)N[C@H]1CCCCNC1=O)N1C=CN(c2ccc(-c3ccccc3)cc2)C1)OCc1ccccc1
Yield: 67.2 %

Procedure:
According to the procedure described in Example 8(a), 2(RS)-(3-biphenyl-4-yl-1H-imidazol-1-yl)-succinic acid 4-benzyl ester (1.20 g, 2.82 mmol) and L-α-amino-ε-caprolactam (469 mg, 3.67 mmol) was coupled in DMF with pyBOP to furnish 1.02 g (67%) of 3(RS)-(3-biphenyl-4-yl-1H-imidazol-1-yl)-N-(hexahydroazepin-2-on-3(S)-yl)succinamic acid benzyl ester. FABMS: 537.5 (C32H33N4O4; M+H+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:56])[CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[CH2:16][N:17]([CH2:30][C:31]2[N:32]([CH2:36][C:37]([N:39]([CH2:48][C:49]([O:51]C(C)(C)C)=[O:50])[CH2:40][C:41]([O:43]C(C)(C)C)=[O:42])=[O:38])[CH:33]=[CH:34][N:35]=2)[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([S:26](=[O:29])(=[O:28])[NH2:27])=[CH:22][CH:21]=2)[CH:5]=[CH:6][CH:7]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[I:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:56])[CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[CH2:16][N:17]([CH2:30][C:31]2[N:32]([CH2:36][C:37]([N:39]([CH2:48][C:49]([OH:51])=[O:50])[CH2:40][C:41]([OH:43])=[O:42])=[O:38])[CH:33]=[CH:34][N:35]=2)[CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([S:26](=[O:28])(=[O:29])[NH2:27])=[CH:24][CH:25]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)Cn1ccnc1CN(CCc1ccc(S(N)(=O)=O)cc1)Cc1nccn1CC(=O)Nc1cccc(I)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(CCN(Cc2nccn2CC(=O)Nc2cccc(I)c2)Cc2nccn2CC(=O)N(CC(=O)O)CC(=O)O)cc1
Yield: 73.6 %

Procedure:
A solution of di-tert-butyl 2,2′-((2-(2-((((1-(2-((3-iodophenyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)(4-sulfamoylphenethyl)amino)methyl)-1H-imidazo 1-yl)acetyl)azanediyl)diacetate (45 mg, 0.0497 mmol) in DCM (1.0 mL) and TFA (1.0 mL) was stirred at room temperature for 5 hrs. Solvent was removed under a stream of nitrogen to give a residue, which was purified by HPLC to give compound (18) as a white solid (29 mg, 74%). 1H NMR (400 MHz, DMSO-d6) 10.69 (s, 0.66H), 10.61 (s, 0.34; H), 8.10 (s, 0.66; H), 8.07 (s, 0.34; H), 7.69-7.62 (m, 3H), 7.54 (s, 1H), 7.48-7.44 (m, 2H), 7.27 (s, 2H), 7.30-7.26 (m, 3H), 7.13 (t, J=8.0 Hz, 1H), 5.31 (s, 1.32; H), 5.15 (s, 1.32; H), 5.12 (s, 0.68; H), 4.75 (s, 0.68; H), 4.33 (s, 2H), 4.16 (s, 2H), 4.05 (s, 4H), 2.72-2.68 (m, 4H); MS (ESI), 793.1 (M+H)−.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([S:19][CH3:20])[C:3]=1[C:21]#[N:22].[OH:23]O.[OH-].[NH4+].CO>O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([S:19][CH3:20])[C:3]=1[C:21]([NH2:22])=[O:23]
Reactant: OO
Reactant: CSc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C#N
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C(N)=O
Reaction time: 10 h

Procedure:
A mixture of 5-amino-3-methylsulfanyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole-4-carbonitrile (2.7 g, 7.35 mmol), 30% hydrogen peroxide (10 ml), ammonium hydroxide (90 ml), methanol (70 ml) and water (15 ml) was stirred in a pressure reactor for 10 hours. The mixture was filtered and washed with water to give an off-white solid. The filtrate was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated to recover more product as an off-white solid. Both portions of off-white solid were combined to give 1.400 g of the desired title compound which was identical to the first title compound of Preparation B.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[CH3:22][NH:23][CH3:24]>>[CH3:22][N:23]([CH3:24])[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21]
Reactant: CNC
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CN(C)c1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Temperature: 150 °C

Procedure:
A mixture of 100 mg (0.314 mmol) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide and 0.185 ml (0.925 mmol) of dimethylamine (33% in ethanol) in a closed vial is heated in a microwave reactor at 150° C. for 15 minutes. After cooling, the reaction mixture is concentrated to dryness and the residue crystallized from tetrahydrofuran/water yielding 90 mg of the title compound as an orange powder, m.p. 245-260° C. (decomp.).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O[N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]1=[O:16].C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[C:1]([O:8][N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]1=[O:16])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CCCCCC(=O)ON1C(=O)CCC1=O
Reaction time: 5 h
Yield: 87.1 %

Procedure:
To a solution of 55.2 g (0.475 mol) of hexanoic acid and 60.161 g (0.523 mol) of N-hydroxy succinimide in 600 mL THF, 107.855 g (0.523 mol) of DCCI was added. The mixture was cooled with an ice-water bath and stirred for 5 h. The dicyclohexyl urea (DCU) precipitate was removed by filtration, and the THF solvent was removed by vacuum rotary evaporation. The yellow oil residue was dissolved again in 600 mL hexane followed by another vacuum filtration to remove the excess dicyclohexyl urea (DCU). The filtrate was then concentrated under vacuum evaporation yield a white solid, which was vacuum dried at ambient temperature to give 88.187 g (87.07%) of N-hexanoyloxy succinimide. IR (KBr): 1816 cm−1 (ν(C═O) of ester), 1745-1786 cm−1 (ν(C═O) of imide). 1H-NMR (DMSO-d6, ppm): 0.86 (3H, —CH3), 1.31 (4H, —(CH2)2CH3), 1.62 (2H, CH2CH2COO—), 2.64 (2H, —CH2COO—), 2.80 (4H, —COCH2CH2CO—).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][N:12]=[C:13]=[S:14])=[CH:5][CH:4]=1.[N-:15]=[N+:16]=[N-:17].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][N:12]2[C:13]([SH:14])=[N:17][N:16]=[N:15]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCCN=C=S)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: COc1ccc(CCCn2nnnc2S)cc1
Yield: 55.1 %

Procedure:
3-(4-Methoxyphenyl)propylisothiocyanate (0.0174 mol) and sodium azide (0.0261 mol) were reacted substantially as described in Example 7H to give 2.4 g (55%) of an orange oil.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:14][O:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[N:6][CH:5]=1.[CH2:29]([NH2:31])[CH3:30]>>[CH2:29]([NH:31][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:14][O:15][C:16]=2[C:17]([F:20])([F:18])[F:19])=[N:6][CH:5]=1)[CH3:30]
Reactant: CCN
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1
Product: CCNC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1
Yield: 72 %

Procedure:
As described for example 137, 6-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.25 mmol) was converted, using ethylamine instead of methylamine, to the title compound (75 mg, 72%) which was obtained as a white solid. MS: m/e=410.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[C:23]([Cl:30])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:21]C)=[C:9]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:10]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[C:23]([Cl:30])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([OH:21])=[C:9]([S:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)(=[O:13])=[O:12])[CH:10]=1
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1S(=O)(=O)c1ccc(F)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Cl)c(Oc2ccc(O)c(S(=O)(=O)c3ccc(F)cc3)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a solution of 5-(2,6-dichloro-4-nitro-phenoxy)-2-methoxy-(4-fluoro-benzenesulfonyl)-benzene (468 mg, 0.99 mmol) in CH2Cl2 (8 mL) was added boron tribromide (1M in CH2Cl2, 2.0 mL, 2.0 mmol). The resulting mixture was stirred at room temperature for 2 h and quenched with water (50 mL). After stirring at room temperature for 1 h, the solution was extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried and concentrated to yield the title compound of Step B (454 mg). The title product of Step B was used in the next step without purification. MS (APCl−) Calc.: 457.0, Found: 456.0 (M−1).
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].[C:5]([OH:10])(=[O:9])[C:6]([CH3:8])=[CH2:7]>>[C:1]([S:3][CH2:7][CH:6]([CH3:8])[C:5]([OH:10])=[O:9])(=[O:4])[CH3:2]
Reactant: C=C(C)C(=O)O
Reactant: CC(O)=S
Product: CC(=O)SCC(C)C(=O)O
Reaction time: 18 h

Procedure:
A mixture of thioacetic acid (50 g.) and methacrylic acid (40.7 g.) is heated on the steam bath for 1 hour and then stored at room temperature for 18 hours. After confirming by nmr spectroscopy that complete reaction of the methacrylic acid has been achieved, the reaction mixture is distilled in vacuo and the desired 3-acetylthio-2-methylpropanoic acid is separated in the fraction with boiling point 128.5°-131° (2.6 mmHg.), yield 64 g.
Reaction SMILES: [Br:1]/[C:2](/[C@@H:22]([OH:30])[C@@H:23]([CH3:29])[CH2:24][C:25]#[C:26][CH2:27][CH3:28])=[CH:3]/[C@@H:4]1[C@H:11]([O:12]C(=O)C2C=CC=CC=2)[CH2:10][C@H:9]2[C@@H:5]1[CH2:6][C:7](=[O:21])[O:8]2.C(=O)([O-])[O-].[K+].[K+].Cl>CO>[Br:1]/[C:2](/[C@@H:22]([OH:30])[C@@H:23]([CH3:29])[CH2:24][C:25]#[C:26][CH2:27][CH3:28])=[CH:3]/[C@@H:4]1[C@H:11]([OH:12])[CH2:10][C@H:9]2[C@@H:5]1[CH2:6][C:7](=[O:21])[O:8]2
Reactant: CCC#CC[C@H](C)[C@H](O)/C(Br)=C\[C@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCC#CC[C@H](C)[C@H](O)/C(Br)=C\[C@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.1 %

Procedure:
3.12 g of (1S,5R,6R,7R)-6-[(E)-(3S,4S)-2-bromo-3-hydroxy-4-methyl-non-1-en-6-inyl]-7-benzoyloxy-2-oxa-bicyclo[3.3.0]octan-3-one was dissolved in 18 ml of p.A. methanol, mixed with 290 mg of a finely powdered potassium carbonate and stirred for 3 h at 25° C. It was adjusted to pH 7 by addition of a 50% hydrochloric acid and concentrated by evaporation in a water-jet vacuum at 30° C. The residue was taken up in methylene chloride, filtered over magnesium sulfate and Celite, again concentrated by evaporation in a water-jet vacuum and chromatographed under pressure on about 200 ml of fine silica gel using a gradient of hexane/ethyl acetate. 2.00 g (82%) of the title compound was isolated as colorless oil.
Reaction SMILES: [CH2:1]([N:3]([CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)C(=O)OC(C)(C)C)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([NH:3][CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]([OH:33])([C:29]([F:30])([F:32])[F:31])[C:25]([F:27])([F:28])[F:26])=[CH:22][CH:23]=2)[CH2:15][CH2:16]1)[CH3:2]
Reactant: CCN(C(=O)OC(C)(C)C)C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNC1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reaction time: 20 h
Yield: 98.4 %

Procedure:
A mixture of tert-butyl ethyl(1-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperidin-4-yl)carbamate (6.61 mmol, 3.2 g), dichloromethane (10 mL) and trifluoroacetic acid (10 mL) was stirred for 20 hours. Purification by SCX chromatography gave the title compound (2.5 g). MS (ESI) m/z 385.1 [M+H]+
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][C:14]2[CH:19]=[C:18]([NH:20]C(OC(C)(C)C)=O)[CH:17]=[CH:16][C:15]=2[Cl:28])[CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[NH2:20][C:18]1[CH:17]=[CH:16][C:15]([Cl:28])=[C:14]([CH:19]=1)[O:13][C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)c(O[C@@H]2CCN(C(=O)OC(C)(C)C)C2)c1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccc(Cl)c(O[C@@H]2CCNC2)c1
Reaction time: 2 h
Yield: 77.7 %

Procedure:
To solution of (R)-3-(5-tert-butoxycarbonylamino-2-chlorophenoxy)-pyrrolidine-1-carboxylic acid-tert-butyl ester (2 g, 4.9 mmol) in dioxane (30 mL) was added 6 N hydrogen chloride (20 mL). The reaction mixture was stirred for 2 hours, at which time it was concentrated. The resultant residue was triturated with ethyl acetate and dichloromethane, the diluted with 2.5 M potassium hydroxide (50 mL) and extracted with dichloromethane (3×50 mL). The combined organics were washed with brine (50 mL), dried over magnesium sulfate, and concentrated to give (R)-3-(5-amino-2-chlorophenoxy)-pyrrolidine (810 mg, 75%).
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14](B(O)O)=[CH:15][CH:16]=2)[C:11]([CH3:21])=[CH:10][C:9]1([CH3:23])[CH3:22])=O)(C)(C)C.[F:24][C:25]1[CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=[C:29](I)[CH:30]=1>>[F:24][C:25]1[CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=[C:29]([C:14]2[CH:13]=[C:12]3[C:17](=[CH:16][CH:15]=2)[NH:8][C:9]([CH3:22])([CH3:23])[CH:10]=[C:11]3[CH3:21])[CH:30]=1
Reactant: O=[N+]([O-])c1cc(F)cc(I)c1
Reactant: CC1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(B(O)O)cc21
Product: CC1=CC(C)(C)Nc2ccc(-c3cc(F)cc([N+](=O)[O-])c3)cc21
Yield: 69.1 %

Procedure:
This compound was prepared according to General Method 2 (EXAMPLE 9 ) from Compound 9 (140.2 mg, 0.44 mmol) and 5-fluoro-3-nitroiodobenzene (117.6 mg, 0.44 mmol). The crude material was purified by flash column chromatography (150 ml silica, hexane to 20% acetone/hexane) followed by a second flash column chromatography (100 mL silica, hexane to 20% acetone/hexane) to afford 95 mg (69%) of Compound 280. Data for Compound 280: 1H NMR (400 MHz, acetone-d6) 8.22 (app t, J=3.0, 1.5, 1H), 7.78 (m, 1H), 7.43 (d, J=2.2, 1H), 7.38 (dd, J=8.4, 2.3, 1H), 6.61 (d, J=8.3, 1H), 5.58 (s, 1H), 5.40 (s, 1H), 2.05 (s, 3H), 1.29 (s, 6H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.Cl[C:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:12]>C1COCC1>[C:11](=[O:12])([O:9][CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1)[O:13][C:14]1[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OC1CN2CCC1CC2
Solvent: C1CCOC1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CN2CCC1CC2
Reaction time: 4 h

Procedure:
To a stirred solution of 3-quinuclidinol (3.00 g, 23.6 mmol) in THF (100 mL) was added 4-nitrophenyl chloroformate (5.94 g, 29.5). After stirring for 4 hours, the precipitate was filtered off, rinsed with THF and air dried on the frit under house vacuum. The filtercake was dissolved in ethyl acetate (150 mL) and washed with aqueous NaHCO3 (1×150 mL) and water (2×150 mL). The organic layer was dried (Na2SO4) and concentrated to afford crude 4-nitrophenyl quinuclidin-3-yl carbonate product, which was used in the next step without purification.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH2:23][O:24]C(=O)C)[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:28][C:29](=[O:31])[CH3:30])[CH2:6]1)(=O)C>CO.C(=O)([O-])[O-].[K+].[K+].O>[C:29]([O:28][C@H:14]1[CH2:13][CH2:12][C@H:11]2[C@H:10]3[C@H:19]([CH2:18][CH2:17][C@:15]12[CH3:16])[C@:20]1([CH2:23][OH:24])[C:7]([CH2:6][C@@H:5]([OH:4])[CH2:22][CH2:21]1)=[CH:8][CH2:9]3)(=[O:31])[CH3:30]
Reactant: CC(=O)OC[C@]12CC[C@H](OC(C)=O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(CO)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-androstene-3β,17β,19-triol triacetate in methanol and potassium carbonate in water is combined and stirred at room temperature for a period of about 2 hours. The solution is poured onto water and the solid which forms is collected by filtration. Crystallization of this solid from an acetone solution yields 5-androstene-3β,17β,19-triol 17-acetate.
Reaction SMILES: [CH3:1][CH:2]([CH:8]=[CH:9][CH:10]=[C:11]([CH3:18])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[CH:3](OC)[O:4]C.O1CCCC1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O>[CH3:1][CH:2]([CH:8]=[CH:9][CH:10]=[C:11]([CH3:18])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[CH:3]=[O:4]
Reactant: COC(OC)C(C)C=CC=C(C)CCC=C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=CCCC(C)=CC=CC(C)C=O
Temperature: 22.5 °C
Reaction time: 24 h
Yield: 101.8 %

Procedure:
To a 250 mL four-neck reaction flask protected from atmospheric moisture by nitrogen gas throughout the course of the reaction a solution of 12.6 g in 2,6,10-trimethyl-1,1-dimethoxy-3,5,9-undecatriene (2C, 0.05 mol), 100 mL tetrahydrofuran and 1.2 g of PTSA was added. After stirred until homogeneous, 22 g of water was added, and further 24 h of stirring at 20-25° C. was needed until the reaction completed according to GC. Then a solution of 2 g of NaHCO3 in 20 mL water was added for neutralization. Removal of THF by vacuum distillation, 100 mL of cyclohexane was added and then stratification. The organic layer was washed with 30 mL of water, dried over anhydrous magnesium sulfate and subsequently filtered. Removal of the volatile organic solvents by evaporation at reduced pressure afforded 10.5 g of crude 2,6,10-trimethyl-3,5,9-undecatriene-1-aldehyde of formula (12).
Reaction SMILES: [S:1]1[C:5]([C:6](=[O:23])[CH2:7][O:8][C:9]([CH:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:10])=[CH:4][CH:3]2[S:24][CH:25]=[CH:26][CH:2]12.[Br:27]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[C:19]([O:18][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][CH:11]1[C:9]([O:8][CH2:7][C:6]([C:5]1[S:1][CH:2]2[CH:26]=[C:25]([Br:27])[S:24][CH:3]2[CH:4]=1)=[O:23])=[O:10])=[O:17])([CH3:20])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)OCC(=O)C1=CC2SC=CC2S1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)OCC(=O)C1=CC2SC(Br)=CC2S1
Yield: 65.6 %

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-[2-(3a,6a-dihydro-thieno[3,2-b]thiophen-2-yl)-2-oxo-ethyl]ester (595 mg, 1.5 mmol) was dissolved in DMF (7.5 mL) and treated with N-bromosuccinimide (295 mg, 1.65 mmol). The reaction mixture was stirred for 4d at RT then diluted with EtOAc and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over MgSO4, filtered and concentrated. The crude residue was purified by silica column chromatography (20% to 50% EtOAc/Hex) to afford the title compound (469 mg, 66%).