Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16](C)(C)[O:17][SiH2]C(C)(C)C)[CH:9]=2)[CH2:7][CH2:6]1)=[O:4].O[Li].O>CO.O>[OH:17][CH2:16][C:10]1[CH:9]=[C:8]([C:5]2([C:3]([OH:4])=[O:2])[CH2:7][CH2:6]2)[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: COC(=O)C1(c2ccc(OC)c(C(C)(C)O[SiH2]C(C)(C)C)c2)CC1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: COc1ccc(C2(C(=O)O)CC2)cc1CO
Temperature: 40 °C
Reaction time: 8 h
Yield: 132.5 %

Procedure:
To a solution of 1-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-methoxy-phenyl]-cyclopropanecarboxylic acid methyl ester (6.2 g, 18 mmol) in MeOH (75 mL) was added a solution of LiOH.H2O (1.50 g, 35.7 mmol) in water (10 mL) at 0° C. The reaction mixture was stirred overnight at 40° C. MeOH was removed by evaporation under vacuum. AcOH (1 mol/L, 40 mL) and EtOAc (200 mL) were added. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and evaporated under vacuum to provide 1-(3-hydroxymethyl-4-methoxy-phenyl)-cyclopropanecarboxylic acid (5.3 g).
Reaction SMILES: [K+:1].[C:2]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][C:11](=[CH2:15])[C:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)C>[K+:1].[C:2]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:10][C@@H:11]([CH3:15])[C:12]([O-:14])=[O:13])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)[O-]
Agent: [Pd]
Agent: [K+]
Solvent: CCO
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)[O-]
Temperature: 25 °C

Procedure:
100 mg (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid potassium salt (2-a, R1=Boc, R2=H, R3=CO2K) (prepared according to procedure in Example 42) is added to ethanol (1 ml). 10% Palladium on carbon (10 mg, 50% water wet, Degussa type E101 NE/W) is then added. Hydrogen gas at ambient pressure is applied to the mixture. The mixture is stirred at ambient temperature and pressure overnight. The mixture is then filtered over Celite and washed with ethanol (2×1 ml). The mixture is then concentrated in vacuo to give (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid potassium salt (1-a, R1=Boc, R2=H, R3=CO2K) and (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid potassium salt (1-b, R1=Boc, R2=H, R3=CO2K). 1H NMR (CDCl3): 1.06-1.12, 1.31-1.36, 1.80-193, 2.25-2.49, 2.62-2.92, 3.74-4.08, 4.81 and 5.27, 6.20 and 6.54, 7.24-7.57.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[NH2:5].C(OCC)(=O)C.[Br:18]N1C(=O)CCC1=O>CS(C)=O>[Br:18][C:6]1[CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]([F:1])=[CH:3][C:4]=1[NH2:5]
Reactant: Nc1ccc([N+](=O)[O-])c(F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Nc1cc(F)c([N+](=O)[O-])cc1Br
Temperature: 22 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A flask was charged with 3-fluoro-4-nitroaniline (1.0 equiv) followed by ethyl acetate (10 vol) and stirred to dissolve all solids. N-Bromosuccinimide (1.0 equiv) was added as a portion-wise as to maintain internal temperature of 22° C. At the end of the reaction, the reaction mixture was concentrated in vacuo on a rotavap. The residue was slurried in distilled water (5 vol) to dissolve and remove succinimide. (The succinimide can also be removed by water workup procedure.) The water was decanted and the solid was slurried in 2-propanol (5 vol) overnight. The resulting slurry was filtered and the wetcake was washed with 2-propanol, dried in vacuum oven at 50° C. overnight with N2 bleed until constant weight was achieved. A yellowish tan solid was isolated (50% yield, 97.5% AUC). Other impurities were a bromo-regioisomer (1.4% AUC) and a di-bromo adduct (1.1% AUC). 1H NMR (500 MHz, DMSO)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([OH:13])(=[O:12])=[O:11].[C:14]([O:18][C:19](=[O:39])[NH:20][CH2:21][CH2:22][N:23]1[CH2:30][CH:29]2[O:31][CH:25]([CH2:26][N:27](CC3C=CC=CC=3)[CH2:28]2)[CH2:24]1)([CH3:17])([CH3:16])[CH3:15].C(O)(C)C.[H][H]>[Pd].O>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[S:10]([OH:13])(=[O:12])=[O:11].[C:14]([O:18][C:19](=[O:39])[NH:20][CH2:21][CH2:22][N:23]1[CH2:24][CH:25]2[O:31][CH:29]([CH2:28][NH:27][CH2:26]2)[CH2:30]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCN1CC2CN(Cc3ccccc3)CC(C1)O2
Reactant: [H][H]
Agent: [Pd]
Agent: Cc1cc(C)c(S(=O)(=O)O)c(C)c1
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)OC(=O)NCCN1CC2CNCC(C1)O2
Temperature: 73 °C
Reaction time: 1 h

Procedure:
[2-(7-Benzyl-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethyl]carbamic acid tert-butyl ester 2,4,6-trimethylbenzenesulfonic acid salt (150 g; see Preparation P above), isopropanol (IPA; 225 mL) and water (75 mL) were combined in a metal hydrogenation vessel. Solid 5% Pd/C catalyst (4.7 g, 61% water wet, Johnson Matthey type 440) was added. Hydrogen was introduced to the vessel and stirring was started. The mixture was hydrogenated under 2.5 bar of hydrogen pressure and was simultaneously heated to 55° C. (temperature overshot to 73° C.). Gas uptake measurement showed the reaction to be complete after 1 hour. After cooling to 47° C. the catalyst was removed by filtration through a glass fibre filter paper. The catalyst was washed on the filter with IPA (75 mL) and the combined filtrate and washings used in the next step.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:10](=O)([O-])[O-].[K+].[K+].IC>O1CCCC1>[CH3:10][CH:3]([C:2](=[O:1])[CH2:8][CH3:9])[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCC(=O)CC(=O)OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CCC(=O)C(C)C(=O)OC
Temperature: 0 °C
Reaction time: 6 h
Yield: 99.9 %

Procedure:
Methyl 3-oxopentanoate (6.27 ml, 50 mmol) in tetrahydrofuran (100 ml) and potassium carbonate (20.73 g, 150 mmol) was heated at reflux under argon for 3 hours, reaction mixture was cooled in an ice bath and and iodomethane (3.75 ml, 60.0 mmol) was added dropwsie. The reaction mixture was stirred at 0° C. for 6 hours, and allowed to warm to room temperature while stirring overnight. The reaction mixture was filtered through a celite and the filtrate was evaporated under reduced pressure to give the title compound as an oil (7.2 g);
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15]([CH:16]=[C:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2]>O1CCOCC1.[Pd]>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)nc1
Agent: [Pd]
Solvent: C1COCCO1
Product: CCc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Temperature: 100 °C

Procedure:
To a solution of 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzylidene}-2,4-thiazolidinedione (10 g) in dioxane (200 ml) was added 5% palladium on carbon (5 g). The mixture was heated at 100° C. under 50 kg/cm2 for 2 hours. The catalyst was filtered off, and the filtrate was concentrated to about 70 ml under reduced pressure. The resulting crystals were collected by filtration and dried at 50° C. under a reduced pressure to give 7.2 g of crude crystals. Recrystallization from acetic acid-water gave crystals of 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione. Yield: 6.42 g (63.8%).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1([Li])C=CC=CC=1.[Cl:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]([CH:40]2[CH2:42][CH2:41]2)=O)[C:33]=1[O:43][CH3:44]>CCOCC>[Cl:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]([CH:40]2[CH2:42][CH2:41]2)=[CH:2][O:3][CH3:4])[C:33]=1[O:43][CH3:44]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1c(Cl)ccnc1C(=O)C1CC1
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: CCOCC
Product: COC=C(c1nccc(Cl)c1OC)C1CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.6 %

Procedure:
30.78 g of (methoxymethyl) triphenyl phosphonium chloride is suspended in 300 ml of anhydrous ether and 102 ml of phenyllithium (0.88 M) was dropped thereto and the resulting mixture was stirred at a room temperature for 15 minutes. 210 ml of ether solution of 18.10 g of (4-chloro-3-methoxy-2-pyridyl)cyclopropylketone (X) was dropped thereto and was stirred at a room temperature for 12 hours. The resulting residue was separated by filtering and washed with ether, and thereafter, the ether filtrate and ether used for washing were collected together and the collected solution was washed with water, and thereafter, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=4:1) to obtain 8.94 g of 2-(4-chloro-3-methoxy-2-pyridyl)-2-cyclopropyl-1-methoxyethene (XI).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].S(Cl)([Cl:15])=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([Cl:15])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)cc1F
Product: COc1ccc(C(=O)Cl)cc1F

Procedure:
3-Fluoro-4-methoxybenzoic acid (830 mg, 4.88 mmol) and thionyl chloride (10 mL) were refluxed for 2 h. The excess thionyl chloride was removed by repeated evaporation with dry toluene in vacuo, giving the subtitle compound as a brown solid, which would be used for the next step directly.
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[N+:20]([O-])([OH:22])=[O:21]>C(O)(=O)C>[CH2:1]([C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=[N+]([O-])O
Reactant: CCCCCCCCCCCCc1ccc(O)cc1
Solvent: CC(=O)O
Product: CCCCCCCCCCCCc1ccc(O)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
7.5 g of the 4-dodecylphenol obtained in (1) above was dissolved in 25 ml of acetic acid and 12.6 ml of 30% aqueous nitric acid solution was dropwise added slowly to the resulting solution, and then the resulting mixture was subjected to reaction at about 10° C. for one hour. The reaction mixture was added to 35 g of ice water and the extraction with 35 ml of diethyl ether was conducted three times. The diethyl ether layer thus obtained was washed with 35 ml of 5% aqueous NaHCO3 solution, and then dried with MgSO4. Subsequently, the solvent was distilled off to obtain 5.93 g of 4-dodecyl-2-nitrophenol.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.[Si:22]([O:29][C:30]1[CH:31]=[C:32]([CH:61]=[CH:62][C:63]=1[F:64])[C:33]([NH:35][NH:36][C:37](=[O:60])[C@H:38]([NH:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]#[N:57])=[C:52](Cl)[C:51]=1C)[C@@H:39]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[CH3:40])=O)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].[CH2:65]([Cl:67])Cl>>[Si:42]([O:41][C@@H:39]([CH3:40])[C@@H:38]([NH:49][C:50]1[CH:51]=[CH:52][C:53]([C:56]#[N:57])=[C:65]([Cl:67])[C:55]=1[CH3:54])[C:37]1[O:60][C:33]([C:32]2[CH:61]=[CH:62][C:63]([F:64])=[C:30]([O:29][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24])[CH:31]=2)=[N:35][N:36]=1)([C:45]([CH3:48])([CH3:46])[CH3:47])([CH3:44])[CH3:43]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(F)c(O[Si](C)(C)C(C)(C)C)c2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Reactant: ClCCl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(F)c(O[Si](C)(C)C(C)(C)C)c3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl

Procedure:
Triphenylphosphine (331 mg, 1.26 mmol) was dissolved in 25 mL of DCM followed by addition of I2 (321 mg, 1.26 mmol) and TEA (256 mg, 2.53 mmol) at 0° C. 3-(tert-butyldimethylsilyloxy)-N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-4-fluorobenzohydrazide (410 mg, 0.631 mmol) in 15 mL DCM was added to the pre-cooled solution mixture of PPh3/I2/TEA system and stirred. The temperature was allowed to rise to room temperature and stirred for additional 10 min. The reaction was quenched with 50 mL saturated sodium thiosulfate and extracted with EtOAc. The crude mixture was chromatographed to give the product (400 mg). 1H NMR(500 MHz, CDCl3, δ in ppm): 7.69 (m, 3H), 7.54 (d, J=9 Hz, 1H), 7.35 (t, J=9 Hz, 1H), 6.65 (d, J=9 Hz, 1H), 5.56 (d, J=9 Hz, 1H), 4.99 (m, 1H), 4.74 (m, 1H), 2.37 (s, 3H), 1.62 (d, J=6 Hz, 3H), 1.20 (s, 9H), 1.06 (s, 9H), 0.40 (s, 6H), 0.27 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-])=O)[CH:3]=1>[Pt].C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:6])=[CH:7][CH:8]=1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: C1CCOC1
Product: Nc1ccc(Br)cc1N
Yield: 103 %

Procedure:
4-Bromo-2-nitroaniline (12 g, 55 mmol), 1% Pt/C (1.2 g) and THF (120 mL) were added to a 250 mL bottle. The reaction mixture was hydrogenated at a pressure of approximately 40 psig H2. The hydrogenation reaction mixture was monitored by HPLC until the Area % of 4-bromo-2-nitroaniliine was less than 1%. The reaction mixture was filtered and then concentrated to yield 10.6 g of 4-bromo-benzene-1,2-diamine (as a black oil that solidifies). 4-Bromo-benzene-1,2-diamine was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 3.28 (br, 4H), 6.54 (d, 1H), 6.77-6.81 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-])=O)[CH:3]=1.C(O)C.O.O.[Sn](Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([NH2:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(Br)cc1N
Temperature: 25 °C
Reaction time: 72 h
Yield: 88.2 %

Procedure:
In a round bottom flask were combined 4-Bromo-2-nitroaniline (4.03 g, 18.6 mMol), ethanol (190 proof, 93 mL), and tin chloride dihydrate (8.38 g, 37.1 mMol) and a water-cooled condenser attached. The reaction was heated to reflux in an oil bath and stirred for three days. The mixture was then cooled to room temperature and diluted with ethyl acetate (250 mL). Saturated sodium bicarbonate solution was added until the pH was basic. The slurry was then filtered thru Celite and the filtrate transferred to a separatory funnel. The aqueous layer was discarded and the organics washed with saturated sodium bicarbonate (2×50 mL), brine (50 mL), and then dried with magnesium sulfate, filtered, and concentrated to dryness to yield 3.07 g (88% yield) of 4-Bromo-1,2-phenylenediamine as an orange-brown solid. 1H NMR (DMSO-d6): δ=6.63 (d,1H,J=2.3Hz), 6.5-6.3 (m,2H), 4.71 (br s,2H), 4.56 (br s,2H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3](=[O:11])[O:2]1.[BrH:12]>C(O)(=O)C>[Br:12][CH2:1][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:4][C:3]([OH:2])=[O:11]
Reactant: Br
Reactant: O=C1Cc2ccccc2CO1
Solvent: CC(=O)O
Product: O=C(O)Cc1ccccc1CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A solution of isochroman-3-one (1.5 g, 10 mmol) in 30% HBr in acetic acid (13 mL) was stirred at room temperature for 2 h, and 70° C. for 1 h. The reaction mixture was cooled to room temperature, and poured into ice-water. The precipitate was collected to afford (2-bromomethylphenyl)acetic acid as an off-white solid (2-15 g, 93%): 1H NMR (300 MHz, DMSO-d6) δ 7.45-7.23 (m, 4H), 4.73 (s, 2H), 3.73 (s, 2H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:16][CH2:17][C:18](Cl)=[O:19]>C1COCC1>[CH2:1]([NH:8][C:18](=[O:19])[CH2:17][Cl:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCl)NCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of benzylamine (60.3 mL) and triethylamine (96.3 mL) in THF (800 mL) was added chloroacetyl chloride (45.8 mL) at 0° C. The reaction mixture was allowed to warm to room temperature over night. Additional chloroacetyl chloride (4.6 mL) was added and stirring was continued until no starting material could be detected. The reaction mixture was filtered, washed with ethyl acetate and concentrated. The crude product was crystallized from dichloromethane to yield N-benzyl-2-chloro-acetamide (71.6 g) as off-white solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:11][C:4]1[CH:3]=[C:2]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-n2cncn2)ccc1[N+](=O)[O-]

Procedure:
A mixture of 3-fluoro-6-nitrotoluene (50.0 g), 1,2,4-triazole (22.2 g) and sodium carbonate (34.0 g) was heated with stirring in dimethylformamide (300 cm3) at 130° for 16 hours. The cooled mixture was then concentrated in vacuo, the residue was acidified to pH1 with 4M hydrochloric acid, and the resulting solution was extracted with chloroform (2×25 cm3) to remove any neutral material. The combined aqueous phases were basified to pH10 with 2.5M sodium hydroxide solution and the mixture was extracted with chloroform (3×250 cm3). The combined and dried (MgSO4) organic extracts were concentrated in vacuo to give a solid which was recrystallised from toluene to give 1-(3-methyl-4-nitrophenyl)-1,2,4-triazole, m.p. 116°-7°.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:6][CH:5]=1)([O-])=O.ClCCl.CCOCC>C(O)C.[Pd]>[N:11]1([CH2:10][CH2:9][O:8][C:7]2[CH:16]=[CH:17][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: O=[N+]([O-])c1ccc(OCCn2ccnc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOCC
Solvent: ClCCl
Product: Nc1ccc(OCCn2ccnc2)cc1
Yield: 75 %

Procedure:
Hydrogenation of the nitro compound (Step A above) in ethanol with 10% palladium on carbon at 2 atmospheres pressure gave, after filtration, evaporation, and crystallization from dichloromethane/ether, 75% yield of 4-(2-imidazol-1-yl-ethoxy)-phenylamine as a light orange solid, mp 93-94° C. Mass spectrum (LR-APCI) MH+=203.
Reaction SMILES: [CH3:1][Li].[C:3]1([CH:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH:11]=[CH:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl-].[NH4+]>C(OCC)C.O.[Cu]Br>[CH3:1][CH:10]1[CH:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:14][CH2:13][C:12](=[O:15])[CH2:11]1
Reactant: [Li]C
Reactant: O=C1C=CC(c2ccccc2)CC1
Agent: [Cu]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CC1CC(=O)CCC1c1ccccc1
Temperature: -20 °C
Yield: 37.4 %

Procedure:
Under a nitrogen atmosphere, a stirred mixture of 2.9 grams (0.020 mole) of copper(I) bromide in 10 mL of diethyl ether was cooled to -20° C., and 50 mL (0.070 mole) of 1.4M methyllithium in diethyl ether was added slowly. Upon completion of addition, a solution of 4.6 grams (0.027 mole) of 4-phenyl-2-cyclohexenone in 5 mL of diethyl ether was added dropwise at a rate to maintain the reaction mixture temperature below -20° C. Upon completion of addition, a solution of 4.2 grams (0.080 mole) of ammonium chloride in 20 mL of water was added. Upon completion of addition, the reaction mixture was stirred as it warmed to ambient temperature. The reaction mixture was then diluted with 200 mL of diethyl ether and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished commencing with 10% diethyl ether in petroleum ether and finishing with 15% diethyl ether in petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 1.9 grams of 3-methyl-4-phenylcyclohexanone as a liquid. The NMR spectrum was consistent with the proposed structure, and it indicated that the product was predominantly the trans isomer. The reaction was repeated on a larger scale. The 3-methyl-4-phenylcyclohexanone isolated from the larger reaction was a solid, mp 71.5°-72.5° C. The NMR spectrum of a sample from the larger reaction was also consistent with the proposed structure.
Reaction SMILES: C([Li])CCC.[N:6]#N.[CH:8]([NH:11][CH:12](C)C)([CH3:10])C.N1C=CN=[C:16]1[CH2:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1.CI>O1CCCC1>[N:11]1([CH:20]([C:21]2[CH:22]=[CH:23][C:24]([C:25]#[N:26])=[CH:27][CH:28]=2)[CH3:16])[CH:8]=[CH:10][N:6]=[CH:12]1
Reactant: N#N
Reactant: N#Cc1ccc(Cc2ncc[nH]2)cc1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC(c1ccc(C#N)cc1)n1ccnc1
Reaction time: 0.5 h

Procedure:
A solution of n-butyl lithium (25 mL of 2.1M reagent in hexane, 0.0525 mole) is added dropwise in an N2 atmosphere to a solution of di-isopropylamine (5.6 g) in tetrahydrofuran (100 mL) which is maintained at -20°. This cold solution is then added dropwise to a solution of 4-(1-imidazolylmethyl)benzonitrile (9.15 g) in tetrahydrofuran (250 mL) which is maintained at -50° during addition and for 30 minutes subsequently. The reaction mixture is then cooled to -70° and methyl iodide (10.7 g) is added, all at once. The reaction is stirred at -70° for 30 minutes and then without external cooling for 10 hours. The reaction is quenched by addition of water (300 mL) and extracted with diethyl ether (3×100 mL). The combined ether extracts are extracted with 3N hydrochloric acid (3×60 mL) and the acid extracts are made basic (pH 9) with 6N sodium hydroxide. The crude product is extracted into ether (3×60 mL), and after drying (MgSO4) and solvent evaporation, 4-[1-(1-imidazolyl)ethyl]benzonitrile is obtained. The crude material is dissolved in acetone and treated with ethereal HCl to afford the hydrochloride salt, m.p. 184°-186°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][C:10]#[N:11].O.[NH2:14][NH2:15]>C(O)C>[NH2:11][C:10]1[NH:15][N:14]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:9]=1
Reactant: NN
Reactant: N#CCC(=O)c1ccccc1Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2ccccc2Cl)n[nH]1
Temperature: 80 °C
Reaction time: 15 h
Yield: 88.4 %

Procedure:
To a solution of 3-(chlorophenyl)-3-oxo-propionitrile (4.0 g, 22.2 mmol) in absolute ethanol (21 mL) was added hydrazine hydrate (6.5 mL, 134 mmol). The reaction mixture was stirred at 80° C. for 15 hours, then it was concentrated in vacuo and purified on silica gel with 0-10% MeOH in CH2Cl2 as eluent to give 3.8 g (87% yield) of 5-amino-3-(2-chlorophenyl)pyrazole as a yellow solid. 1H NMR (d6-DMSO) δ: 11.7 (broad s, 1H), 7.66 (d, 1H), 7.48 (d, 1H), 7.35 (t, 1H), 7.30 (t, 1H), 5.83 (s, 1H), 4.84 (broad s, 2H); HPLC/MS m/z: 194.1 [MH]+.
Reaction SMILES: C(O[C:5]1([C:26](=[O:29])[CH2:27]O)[C@:21]2([CH3:22])[CH:8]([CH:9]3[C:18](=[CH:19][CH2:20]2)[C@:17]2([CH3:23])[C:12](=[CH:13][C:14](=[O:24])[CH:15]=[CH:16]2)[C@@H:11]([CH3:25])[CH2:10]3)[CH2:7][CH2:6]1)(=O)C.[C:30](=[O:33])([O-])[O-:31].[K+].[K+].[CH3:36]N(C)C=O>>[C:30]([O:31][CH2:27][C:26](=[O:29])[C:5]1[C@:21]2([CH3:22])[CH:8]([CH:9]3[C:18](=[CH:19][CH2:20]2)[C@:17]2([CH3:23])[C:12](=[CH:13][C:14](=[O:24])[CH:15]=[CH:16]2)[C@@H:11]([CH3:25])[CH2:10]3)[CH2:7][CH:6]=1)(=[O:33])[CH3:36]
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Reactant: CC(=O)OC1(C(=O)CO)CCC2C3C[C@H](C)C4=CC(=O)C=C[C@]4(C)C3=CC[C@@]21C
Agent: [K+]
Product: CC(=O)OCC(=O)C1=CCC2C3C[C@H](C)C4=CC(=O)C=C[C@]4(C)C3=CC[C@]12C

Procedure:
(6S,10R,13S)-17-(2-hydroxyacetyl)-6,10,13-trimethyl-3-oxo-6,7,8,10,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-17-yl acetate is heated with 2 equivalents of potassium carbonate in dimethyl formamide. Standard aqueous workup yields the title compound.