Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:4]([CH3:18])=[N:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28].C(Cl)Cl>C(C(C)=O)C>[CH3:1][N:2]1[C:6]([O:7][CH2:26][C:27](=[O:28])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:4]([CH3:18])=[N:3]1
Reactant: Cc1nn(C)c(O)c1C(=O)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: Cc1nn(C)c(OCC(=O)C(C)(C)C)c1C(=O)c1ccc(Cl)cc1Cl
Yield: 82.7 %

Procedure:
Into a four necked flask was charged 0.45 g of 1,3-dimethyl-4-(2,4-dichlorobenzoyl)-5-hydroxypyrazole, and the contents were dissolved in 15 ml of methyl ethyl ketone. To the solution were added 0.5 g of anhydrous potassium carbonate and then 0.3 g of tert-butyl bromomethyl ketone while stirring, and the mixture was reacted for 2 hours under the reflux condition (80° C.). After completion of the reaction, the reaction product was collected by filtration, and the solvent (methyl ethyl ketone) was distilled off to obtain a crude product. The crude product was passed through a silica gel column (eluent: methylene chloride), and the eluent was distilled off to obtain 0.5 g of the titled compound having a melting point of 104° to 105° C.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[S:7]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CCC>O>[S:4]1[CH:5]=[CH:6][C:2]([C:9]2[CH:10]=[CH:11][S:7][CH:8]=2)=[CH:3]1
Reactant: Brc1ccsc1
Reactant: OB(O)c1ccsc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: c1cc(-c2ccsc2)cs1
Temperature: 100 °C
Yield: 98 %

Procedure:
Into a glass reaction vessel equipped with a cooling apparatus were added 0.015 mmol of bis(dicyclopentyl(2-methoxyphenyl)phosphine)dichloropalladium(II), 1.5 mmol of 3-bromothiophene, 2.25 mmol of 3-thiopheneboronic acid, 3.0 mmol of potassium phosphate and 4 mL of n-butanol. The resultant mixture was stirred with heating at 100° C. for 4 hours. The resultant reaction mixture was cooled down to room temperature, 20 mL of water was added, and the mixture was extracted with 20 mL of diethyl ether twice. The resultant organic layers were mixed, and dried over anhydrous magnesium sulfate, then, filtrated, to obtain a solution. This solution was concentrated, and purified by silica gel column chromatography, to obtain 3-(3-thienyl)-thiophene with a yield of 98%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:24])[C:9]([C:11]2[C:12]([F:23])=[CH:13][C:14]3[O:19][CH2:18][C:17](=[O:20])[N:16]([CH3:21])[C:15]=3[CH:22]=2)=[O:10])=[C:4]([Cl:25])[CH:3]=1.[F:26][C:27]([Si](C)(C)C)([F:29])[F:28].[F-].C[N+](C)(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:24])[C:9]([C:11]2[C:12]([F:23])=[CH:13][C:14]3[O:19][CH2:18][C:17](=[O:20])[N:16]([CH3:21])[C:15]=3[CH:22]=2)([OH:10])[C:27]([F:29])([F:28])[F:26])=[C:4]([Cl:25])[CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C(=O)c1cc2c(cc1F)OCC(=O)N2C)c1ccc(Br)cc1Cl
Agent: C[N+](C)(C)C
Agent: [F-]
Product: CC(c1ccc(Br)cc1Cl)C(O)(c1cc2c(cc1F)OCC(=O)N2C)C(F)(F)F

Procedure:
In analogy to Example 1, step 3, 6-[2-(4-bromo-2-chloro-phenyl)-propionyl]-7-fluoro-4-methyl-4H-benzo[1,4]oxazin-3-one was reacted with (trifluoromethyl)trimethylsilane and tetramethylammonium fluoride to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=496.0 [M−H+].
Reaction SMILES: C[S:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].O.S(Cl)(Cl)(=O)=[O:13]>ClC1C=CC=CC=1>[S:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[C:5](=[O:13])[NH:6]1
Reactant: O=S(=O)(Cl)Cl
Reactant: CSc1ccccc1C#N
Solvent: O
Solvent: Clc1ccccc1
Product: O=c1[nH]sc2ccccc12
Temperature: 25 °C
Yield: 95.9 %

Procedure:
To a 500 ml four-necked flask equipped with a stirrer, a thermometer, and a condenser, 29.8 g (0.2 mol) of 2-(methylthio)benzonitrile, 100 g of monochlorobenzene, and 4.32 g (0.24 mol) of water were added. To the flask, 29.7 g (0.22 mol) of sulfuryl chloride was added with stirring at a temperature of from 5° to 15° C., heated to a temperature of from 70° to 80° C., and allowed to react for 1 hour. After the completion of the reaction, the reaction mixture was cooled to room temperature to precipitate white crystals. The white crystals were washed with monochlorobenzene, and dried to give 29.0 g of 1,2-benzisothiazol-3-one (melting point: 157° to 158° C.). The yield of the product was 96% against the starting 2-(methylthio)benzonitrile.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C@H:7]([C:15]([OH:17])=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:18](=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:18][O:16][C:15](=[O:17])[C@H:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:6]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H](N)Cc1ccccc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a mixture of 10.2 liters of methanol and 335 ml of conc. sulfuric acid was added 1050 g of L-phenylalanine. The mixture was stirred at 90° C. for 5 hours to effect esterification. The reaction solution was adjusted with 15% sodium carbonate aqueous solution to a Ph of 7. L-Phenylalanine methyl ester was extracted with toluene to give 10.7 liters of toluene solution of L-phenylalanine methyl ester.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[N:12]=[C:11]([NH2:13])[NH:10][N:9]=2)[CH:2]=1.[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.C(Cl)Cl>[C:14]1([NH:20][C:21]([N:10]2[C:11]([NH2:13])=[N:12][C:8]([NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[N:9]2)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1nc(Nc2cccnc2)n[nH]1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Nc1nc(Nc2cccnc2)nn1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.3 %

Procedure:
To a solution of N3-(3-pyridyl)-1H-[1,2,4]triazole-3,5-diamine (0.43 mmol) in dry THF (3 mL) and dry DCM (3 mL) was added phenylisocyanate (0.43 mmol) dropwise over 1 minute, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography [Merck silica, eluted with EtOAc and Hexanes (4:1)] to afford compound the title compound (22.0 mg, 17%). 1H NMR (400 MHz, DMSO-d6) 7.17 (1H, t), 7.28 (1H, m), 7.39 (4H, m), 7.65 (2H, d), 8.09 (1H, m), 8.23 (1H, m), 8.79 (1H, d), 9.44 (1H, s), 9.64 (1H, s); MS (ES+): m/e=296.3 (100%).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].O>C(OC(=O)CCC)(=O)CCC>[CH2:1]([C:6]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1)[CH2:2][CH3:3]
Reactant: Nc1ccccc1N
Agent: CCCC(=O)OC(=O)CCC
Solvent: O
Product: CCCc1nc2ccccc2[nH]1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A mixture of o-phenylenediamine (2.2 g) in butyric anhydride (4.7 g) was stirred for 4 hours at 110° C. To the reaction mixture was added water, which was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium bicarbonate, dilute hydrochloric acid and water and then dried. The solvent was evaporated to dryness, and the residue was refluxed for 1.5 hour in 3N-HCl (35 ml). The reaction mixture was made basic with a 6N NaOH. The crystals were recrystallized from ethyl acetate-hexane to give colorless plates (0.9 g, 38%), m.p. 160°-162° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:41])[CH2:11][C:12](=[O:40])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:39])[C@@H:23]([NH:31]C(OC(C)(C)C)=O)[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.C(OC(NC1C=CC(/C=C/C(=O)CC(=O)/C=C/C2C=CC(O)=CC=2)=CC=1)=O)(C)(C)C>C(Cl)(Cl)Cl.CO>[NH2:31][C@@H:23]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:22]([NH:21][C:18]1[CH:19]=[CH:20][C:15](/[CH:14]=[CH:13]/[C:12](=[O:40])[CH2:11][C:10](=[O:41])/[CH:9]=[CH:8]/[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)=[CH:16][CH:17]=1)=[O:39]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1ccc(C=CC(=O)CC(=O)C=Cc2ccc(O)cc2)cc1
Agent: CC(C)(C)OC(=O)Nc1ccc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)cc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: N[C@@H](Cc1ccccc1)C(=O)Nc1ccc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)cc2)cc1

Procedure:
The title compound was synthesized using the same procedure employed for Example 281, but with (1E,6E)-1-(4-hydroxyphenyl-7-[4-((S)-2-tert-butoxycarbonylamino-3-phenylpropionylamino)phenyl]hepta-1,6-diene-3,5-dione (30 mg, 54 μmol, synthesized in Example 269) as the starting material instead of (1E,6E)-1-[4-(tert-butoxycarbonylamino)phenyl]-7-(4-hydroxyphenyl)hepta-1,6-diene-3,5-dione, and was purified by silica gel chromatography (chloroform/methanol=97/3 to 85/15). The product was obtained as a solid (7.4 mg, 30%) having the following characteristics.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:20])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:4].Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:22]2[N:30]=[CH:29][N:28]=[C:27]3[C:23]=2[N:24]=[CH:25][NH:26]3)[CH3:20])=[C:7]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:8]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)C(=O)Nc1ccc(F)cc1Nc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)C(=O)Nc1ccc(F)cc1Nc1ccccn1
Temperature: 90 °C
Yield: 97.1 %

Procedure:
A mixture of (S)-2-amino-N-[4-fluoro-2-(pyridin-2-ylamino)phenyl]propionamide (190 mg, 0.69 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (186 mg, 0.78 mmol) and DIPEA (380 μL, 2.22 mmol) in n-butanol (1.5 mL) was heated at 90° C. in a sealed vial for 65 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue loaded into an Isolute® SCX-2 cartridge then washed with MeOH followed by 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo to afford the title compound as an orange/brown oil (263 mg, 97%). LCMS (Method C): RT 1.67 min [M+H]+ 393.3.
Reaction SMILES: [OH-].[Na+].Cl.[SH:4][CH2:5][CH2:6][NH2:7].Cl.N1C=CC=CC=1.Cl[CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>C(O)C>[N:20]1[CH:21]=[CH:22][C:17]([CH2:16][S:4][CH2:5][CH2:6][NH2:7])=[CH:18][CH:19]=1
Reactant: ClCc1ccncc1
Reactant: NCCS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCO
Product: NCCSCc1ccncc1
Temperature: 25 °C

Procedure:
34.1 g of sodium hydroxide was dissolved in 500 ml of ethanol under an argon atmosphere and 48.6 g of 2-mercaptoethanamine hydrochloride and 35 g of 4-chloromethylpyridine pyridine hydrochloride were added with ice bath cooling. The reaction mixture was allowed to warm to room temperature over 2 hours, was concentrated, diluted with 300 ml of water and was extracted with 3×150 ml of dichloromethane. The combined organic layers were washed with 100 ml of saturated brine, dried over potassium carbonate and were evaporated to a dark oil which was distilled. The fractions bp 120°-130° C./0.1 mm amounted to 30.68 g (85%) of 2-[[(4-pyridyl)methyl]thio]ethanamine.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]=1[CH2:20][C:21]([O:23]CC)=O.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]#[N:34]>C1COCC1>[NH2:34][C:33]1[C:28]2[C:27](=[CH:32][CH:31]=[CH:30][CH:29]=2)[NH:26][C:21](=[O:23])[C:20]=1[C:12]1[NH:13][C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:19]2[N:11]=1
Reactant: N#Cc1ccccc1N
Reactant: CCOC(=O)Cc1nc2cccnc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1c(-c2nc3cccnc3[nH]2)c(=O)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
LiHMDS (3.0 eq) was added to ethyl 3H-imidazo[4,5-b]pyridin-2-ylacetate (1.0 eq) in THF at −78° C. After 20 minutes, a solution of 2-aminobenzenecarbonitrile (1.1 eq) in THF was added. The resulting mixture was allowed to warm to room temperature, stirred for 3 hours, and then refluxed overnight. The mixture was cooled to 0° C. and quenched with an aqueous saturated NH4Cl solution. A precipitate formed, was filtered off, and was washed repeatedly with ether to yield the desired compound as a light brown solid. LC/MS m/z 278.2 (MH+), Rt 1.82 minutes.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si](C(C)(C)C)(C)C)[CH2:9][C@H:8]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[O:6])[CH:2]=[CH2:3].Cl.C(=O)(O)[O-].[Na+]>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1Cc1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1Cc1ccccn1
Reaction time: 5 h
Yield: 72.4 %

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-(2-pyridylmethyl)pyrrolidine (4.88 g) in acetonitrile (50 ml) was added dropwise conc. hydrochloric acid (3.3 ml) at room temperature. The reaction mixture was stirred for 5 hours, then neutralized with saturated aqueous sodium bicarbonate and diluted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give (2R,4R)-1-allyloxycarbonyl-4-hydroxy-2-(2-pyridylmethyl) pyrrolidine (2.46 g). On the other hand the aqueous layer was extracted five times with chloroform. The combined chloroform layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give (2R,4R)-1-allyloxycarbonyl-4-hydroxy-2-(2-pyridylmethyl) pyrrolidine (0.23 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11]C(=O)/C=C\C(O)=O)=[O:10])[CH:6]=[CH:5][N:4]=1.O=P(Cl)(Cl)Cl.[NH2:24][NH:25][C:26]([C:35]1[CH:40]=[CH:39][N:38]=[CH:37][N:36]=1)=[N:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34]>C1(C)C=CC=CC=1>[Cl:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[N:27]1[C:6](/[CH:7]=[CH:8]/[C:3]2[O:10][C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=3)=[N:11][N:4]=2)=[N:24][N:25]=[C:26]1[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][N:36]=1
Reactant: NNC(=Nc1ccccc1Cl)c1ccncn1
Reactant: COc1cc(C(=O)NC(=O)/C=C\C(=O)O)ccn1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(-c2nnc(/C=C/c3nnc(-c4ccncn4)n3-c3ccccc3Cl)o2)ccn1

Procedure:
To a suspension of (Z)-4-(2-methoxypyridine-4-carboamido)-4-oxobut-2-enoic acid 9 (200 mg, 0.75 mmol) in 20 mL of PhMe was added 0.5 mL of POCl3. The mixture was stirred at reflux for 2 h. After removal of solvent, the residue was dissolved in 20 mL of dichloromethane and added to 150 mg (0.6 mmol) of N-amino-N′-(2-chlorophenyl)pyrimidine-4-carboxamidine 5. The mixture was stirred at ambient temperature for 2 h. After removal of solvent, the residue was suspended in 20 mL of PhMe and refluxed for 3 h. After removal of solvent, the residue was purified by column (0-5% of methanol in dichloromethane) to give 4-(4-(2-chlorophenyl)-5-((E)-2-(5-(2-methoxypyridin-4-yl)-1,3,4-oxadiazol-2-yl)vinyl)-4H-1,2,4-triazol-3-yl)pyrimidine as a solid. Yield: 30 mg.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O1CCCC1.[N:29]1([CH2:34][CH2:35][CH2:36][NH2:37])[CH:33]=[CH:32][N:31]=[CH:30]1>O>[N:29]1([CH2:34][CH2:35][CH2:36][NH:37][C:9](=[O:11])[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: NCCCn1ccnc1
Reactant: O=C(O)CCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCc1ccccc1)NCCCn1ccnc1
Reaction time: 18 h

Procedure:
A mixture of 1.50 g. of 3-phenylpropionic acid, 1.62 g. of 1,1'-carbonyldiimidazole, and 40 ml. of tetrahydrofuran was stirred for 3 hours and 2.0 g. of 1H-imidazole-1-propanamine was added. The mixture was stirred for 18 hours, 5 ml. of water was added, and the reaction mixture was heated at reflux temperature for 30 minutes. The mixture was concentrated and 10 ml. 1N sodium hydroxide and 100 ml. of methylene chloride were added. The layers were separated and the organic layer was washed with water, dried over magnesium sulfate, and concentrated. The desired product was obtained as an oil, which was converted to the fumarate salt, m.p. 90°-92° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[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:14]2=[O:24])[CH2:6]1.N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>CN(C)C=O>[Si:30]([O:1][CH2:2][CH2:3][O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[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:14]2=[O:24])[CH2:6]1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: C[C@]12CC[C@H](OCCO)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCO[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Yield: 93 %

Procedure:
To a solution of 2.0 g of 3β-(2-hydroxyethoxy)-androst-5-en-17-one (Julia S. et al., Bull. Soc. Chim. France, 1960, 297) in 20 ml of dimethylformamide, 3.5 g of imidazole and 4.0 g of t-butyldimethylsilyl chloride were added at 0° C. After 12 hrs the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give 2.5 g of crude 3β-(2-tert-butyldimethylsilyloxyethoxy)-androst-5-en-17-one.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:16]#[C:17][CH3:18])[CH2:13][C:14]#[N:15])=[CH:8][CH:7]=1.[N-:23]=[N+:24]=[N-:25].[Na+].[Cl-].[NH4+].O>CN(C=O)C>[CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:16]#[C:17][CH3:18])[CH2:13][C:14]2[NH:25][N:24]=[N:23][N:15]=2)=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC#CC(CC#N)c1ccc(OCc2ccccc2C)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CC(Cc1nnn[nH]1)c1ccc(OCc2ccccc2C)cc1
Temperature: 110 °C
Reaction time: 48 h
Yield: 2.9 %

Procedure:
To a solution of 23.3 (200 mg, 0.51 mmol) in DMF (5 mL) was added sodium azide (35 mg, 0.54 mmol) and ammonium chloride (29 mg, 0.54 mmol). The solution was stirred at 110° C. for 48 hours. The reaction mixture was poured into 50 mL of water and extracted with ethyl acetate (2×25 mL). The combined organic layers were concentrated under reduce pressure, and the resulting residue was purified via HPLC to yield 5 mg (3%) of 5-{2-[4-(2-Methyl-benzyloxy)-phenyl]-pent-3-ynyl}-1H-tetrazole (23) as a film. LC/MSD m/e: 333.1 (M+H). 1H NMR (400 MHz) (acetone-d6) δ 7.45 (1H, m), 7.34 (2H, m), 7.25 (3H, m), 7.00 (2H, m), 5.11 (2H, s), 4.17 (1H, m), 3.37 (2H, d, J=7 Hz), 2.39 (3H, s), 1.79 (3H, s).
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:8]=[C:7]([CH3:9])[S:6][C:5]=1[C:10]([O:12][CH3:13])=[O:11]>C(O)(=O)C>[Br:1][C:8]1[C:4]([OH:3])=[C:5]([C:10]([O:12][CH3:13])=[O:11])[S:6][C:7]=1[CH3:9]
Reactant: BrBr
Reactant: COC(=O)c1sc(C)cc1O
Solvent: CC(=O)O
Product: COC(=O)c1sc(C)c(Br)c1O
Temperature: 0 °C
Yield: 56.3 %

Procedure:
Bromine (4.6 g, 29 mmoles) is added dropwise at room temperature to a stirred solution of methyl 3-hydroxy-5-methyl-2-thiophenecarboxylate (5.0 g, 29 mmoles) in acetic acid (25 mL). After 16 hours the mixture is stirred into ice water (200 mL), and the precipitate is filtered off, rinsed with water, with aqueous sodium thiosulfate, again with water and dried. Recrystallization from methyl t-butyl ether gave the pure product (4.1 g); mp 96°-97° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].S([O-])(=O)(=O)C.[CH2:22]([N:24]([CH:27](O)[CH2:28][CH3:29])[CH2:25][CH3:26])[CH3:23]>CN(C=O)C.O>[CH2:22]([N:24]([CH2:25][CH3:26])[CH2:27][CH2:28][CH2:29][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:23]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CCC(O)N(CC)CC
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCCOc1cccc([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
To a stirred solution of 3-nitrophenol (2 mmol) in DMF (6 mL) at rt, solid potassium carbonate (4 mmol) was added. A solution of the mesylate of N,N-diethylaminopropanol (2.2 mmol) in DMF (2 mL) was then added to the reaction mixture and heated to 80° C. until completion, according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was then treated with cold H2O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired N,N-diethyl-N-[3-(3-nitrophenoxy)propyl]amine. The crude product was used directly for further transformation.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[NH4+].[CH2:6]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[CH3:7]>S(=O)(=O)(O)O>[CH2:6]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=1[N+:1]([O-:4])=[O:2])[CH3:7]
Reactant: O=[N+]([O-])[O-]
Reactant: CCc1ccc(N)cc1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: CCc1ccc(N)cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 75.2 %

Procedure:
Ammonium nitrate (39.6 g, 0.49 mol) is added portionwise to a chilled (ice-bath) solution of 4-ethylaniline (20 g, 0.16 mol) in concentrated sulfuric acid (100 ml, maintaining the temperature −10° to 0° C. by external cooling. The reaction mixture is stirred for two hours, then poured onto crushed ice, and the precipitate is collected by filtration. The solid is taken up in water, the solution made neutral by addition of dilute aqueous sodium hydroxide solution and the extracted with ethyl acetate. The organic extracts are combined, dried over anhydrous sodium sulfate, filtered and the filtrate evaporated in vacuo to give 4-ethyl-3-nitroaniline (20 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][S:17][CH2:18][C@H:19]([O:35][C:36](=[O:48])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:20][O:21][C:22](=[O:34])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:82][CH2:83][CH2:84][O:85][CH2:86][CH2:87][O:88][CH2:89][CH2:90][O:91][CH2:92][CH2:93][C:94]([O:96][C:97]([CH3:100])([CH3:99])[CH3:98])=[O:95]>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][S:17][CH2:18][C@H:19]([O:35][C:36](=[O:48])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:20][O:21][C:22](=[O:34])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:13](=[O:14])[NH:82][CH2:83][CH2:84][O:85][CH2:86][CH2:87][O:88][CH2:89][CH2:90][O:91][CH2:92][CH2:93][C:94]([O:96][C:97]([CH3:100])([CH3:99])[CH3:98])=[O:95])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCN
Reactant: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OC(=O)NCCCCCCCCCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCOCCOCCOCCC(=O)OC(C)(C)C)OC(=O)NCCCCCCCCCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-2-(benzyloxycarbonylamino)-3-((R)-2,3-bis(decylcarbamoyloxy)propylthio)propanoic acid (15, 1 eq) and HBTU (1.2 eq) in DCM (0.06 M) was added DIEA (2.4 eq), followed by tert-butyl 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoate (1.2 eq). The reaction was stirred at room temperature for 4 hours. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-100% EtOAc/Hex to afford the title compound as an off-white solid.