Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:13]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[N:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[Li]CCCC.CN([CH:30]=[O:31])C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:13]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:19])[CH3:21])[C:12]([CH:30]=[O:31])=[N:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2cncn2COCC[Si](C)(C)C)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: COc1cccc(-c2cnc(C=O)n2COCC[Si](C)(C)C)c1
Yield: 21.5 %

Procedure:
Reaction of 5-(3-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (470 mg, 1.55 mmol), 2.5 M n-BuLi (800 uL, 2.00 mmol), and DMF (479 uL, 6.18 mmol) for 2 h at −40° C. followed by column chromatography on silica gel (EtOAc/hexane 9:1) gave the title compound (111 mg, 22%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 0.95 (t, 2H, J=9.0 Hz), 3.61 (t, 2H, J=9.0 Hz), 3.89 (s, 3H), 5.8 s (s, 2H), 6.90 (d, 2H, J=9.0 Hz), 7.34–7.42 (m, 3H), 9.89 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[CH:8][C:9]=1[OH:10])=O.Cl.[OH:13][NH2:14].C([O-])(=O)C.[Na+].C(O)C>O>[CH3:1]/[C:2](/[NH:14][OH:13])=[C:4]1/[CH:5]=[CH:6][C:7]([CH:8]=[C:9]/1[OH:10])=[O:11]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C/C(NO)=C1/C=CC(=O)C=C1O
Yield: 93.4 %

Procedure:
A mixture of 306 g of 2,4-dihydroxyacetophenone, 164 g of hydroxyamine hydrochloride, 328 g of sodium acetate, 1,000 ml of ethanol and 500 ml of water was refluxed by heating for 4 hours. The reaction solution was poured into 10 l of water to precipitate crystals and these crystals were collected by filtration. 314 g of 2,4-dihydroxyacetophenoneoxime was obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:16])[C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1.[H-].[Na+].[CH3:19]I.O>CN(C=O)C>[CH3:19][O:1][CH2:2][CH2:3][N:4]([CH3:16])[C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1ccc(N(C)CCO)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N(C)CCOC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a solution of ethyl 4-[(2-hydroxyethyl) (methyl)amino]benzoate (611 mg, 2.74 mmol) in DMF (10 ml) were added sodium hydride (60% in oil, 143 mg, 3.56 mmol) and methyl iodide (0.222 ml, 3.56 mmol), and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous MgSO4, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (1:0-7:3, v/v) to give the title compound (467 mg, 72%) as a colorless oil.
Reaction SMILES: C([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:19][C@H:18]([CH3:20])[O:17][CH2:16][C@:14]2([C:21]2[S:22][CH:23]=[C:24]([NH:26][C:27]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH:36]([F:38])[F:37])=[CH:31][N:30]=3)=[O:28])[N:25]=2)[N:15]=1)(=O)C1C=CC=CC=1.[ClH:39]>C1(C)C=CC=CC=1.ClCCl>[ClH:39].[NH2:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:19][C@H:18]([CH3:20])[O:17][CH2:16][C@:14]2([C:21]2[S:22][CH:23]=[C:24]([NH:26][C:27]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH:36]([F:37])[F:38])=[CH:31][N:30]=3)=[O:28])[N:25]=2)[N:15]=1
Reactant: C[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2nc(NC(=O)c3ccc(OC(F)F)cn3)cs2)CO1
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[C@H]1C[C@H]2CSC(N)=N[C@@]2(c2nc(NC(=O)c3ccc(OC(F)F)cn3)cs2)CO1
Temperature: 35 °C
Reaction time: 0.17 h

Procedure:
SiliCycle, SiliaMetS® Diamine (4.72 g, 5.36 mmol) was added to a solution of C9 (1.00 g, 1.79 mmol) in toluene (10 mL), and the reaction mixture was heated at reflux overnight. After being cooled to 35° C., the reaction mixture was diluted with dichloromethane (10 mL), stirred for 10 minutes at 35° C., and filtered through diatomaceous earth to remove the SiliCycle reagent. The filter pad was rinsed with dichloromethane and the combined filtrates were heated to reflux and displaced with isopropyl acetate (4×10 mL) to a final volume of 15 mL. This mixture was heated to 50° C., treated with concentrated hydrochloric acid (0.17 mL, 2.0 mmol), and subsequently cooled to 0° C. to 5° C. and allowed to granulate for 1 hour. The solid was collected via filtration and washed with cold propan-2-yl acetate to afford the product as a solid. This material was crystalline by powder X-ray diffraction analysis. Yield: 0.67 g, 1.4 mmol, 78%. 1H NMR (400 MHz, DMSO-d6) δ 11.30 (br s, 1H), 10.73 (s, 1H), 9.6-9.9 (v br s, 1H), 8.6-8.9 (v br s, 1H), 8.63 (d, J=2.7 Hz, 1H), 8.24 (d, J=8.6 Hz, 1H), 7.93 (dd, J=8.7, 2.8 Hz, 1H), 7.84 (s, 1H), 7.51 (t, JHF=72.8 Hz, 1H), 3.96 (AB quartet, JAB=12.2 Hz, ΔνAB=62.6 Hz, 2H), 3.75-3.85 (m, 1H), 3.02-3.11 (m, 3H), 1.73-1.82 (m, 1H), 1.39-1.52 (m, 1H), 1.21 (d, J=6.2 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:13][CH2:12]1.C(N(CC)CC)C>CS(C)=O>[N+:8]([C:5]1[CH:4]=[CH:3][C:2]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:7][N:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2CCC(N3CCCCC3)CC2)cn1
Yield: 26.7 %

Procedure:
To 5-bromo-2-nitropyridine (1.2 g, 5.9 mmol) in DMSO (4 mL) was added 1-(4-piperidyl)piperidine (1.0 g, 5.9 mmole) and triethyl amine (0.99 mL, 7.1 mmole). The contents were heated to 120 degrees in a CEM Discovery microwave system for 3 hours. The crude reaction was then loaded over a silica gel column and eluted with DCM/methanol (0-20%) to afford 2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine as an oil (457 mg). 1H NMR (600 MHz, DMSO-d6) δ ppm 1.26-1.36 (m, 2H) 1.43 (m, 6H) 1.76 (m, 2H) 2.37 (m, 5H) 2.94 (t, J=12.74 Hz, 2H) 4.06 (d, J=13.47 Hz, 2H) 7.41 (dd, J=9.37, 2.64 Hz, 1H) 8.08 (d, J=9.37 Hz, 1H) 8.20 (d, J=2.64 Hz, 1H).
Reaction SMILES: [CH2:1]([S:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:16]=O)[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:18]#[N:19])[CH2:2][CH2:3][CH3:4].COC1C=CC(/C=[C:35]2/[C:36]([NH:38][C:39]([S:41]/2)=[NH:40])=[O:37])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:40][C:39]1[S:41]/[C:35](=[CH:16]\[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:18]#[N:19])=[C:6]3[S:5][CH2:1][CH2:2][CH2:3][CH3:4])/[C:36](=[O:37])[N:38]=1
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Reactant: CCCCSc1c(C#N)cnc2ccc(C=O)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCSc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 38 was used, starting from 4-butylsulfanyl-6-formyl-quinoline-3-carbonitrile (example 53b), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-butylsulfanyl-quinoline-3-carbonitrile. LC-MS m/e 367 (MH+).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][OH:11])/[CH3:8])[CH3:3].[OH:12][CH2:13]/[CH:14]=[C:15](/[CH3:22])\[CH2:16][CH2:17][CH:18]=[C:19](C)C.C(N(CC)CC)C.C1(CC(Cl)=O)C=CC=CC=1>ClCCl>[C:15]1([CH2:14][C:13]([O:11][CH2:10]/[CH:9]=[C:7](/[CH2:6][CH2:5][CH:4]=[C:2]([CH3:1])[CH3:3])\[CH3:8])=[O:12])[CH:16]=[CH:17][CH:18]=[CH:19][CH:22]=1
Reactant: CC(C)=CCC/C(C)=C\CO
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)=CCC/C(C)=C/COC(=O)Cc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of geraniol and nerol (approximately 70:30 by weight) in the amount of 51.02 g (0.324 mol) and triethylamine in the amount of 33.13 g (0.324 mol) are combined with 275 mL of dichloromethane. The reaction mixture is treated with a solution of phenylacetyl chloride in the amount 51.14 g (0.324 mol) dissolved in 100 ml of dichloromethane over 1 h. After heating to reflux for 1 h, the product mixture is cooled to room temperature, washed with 100 mL of brine twice, 100 mL of saturated NaHCO3 solution twice, 100 mL of water, and dried over MgSO4. The filtrate is concentrated by rotary evaporation followed by Kugelrohr distallation. Purification of the product by column chromatography provides a colorless oil. Purity of the product is determined by thin layer chromatography and the structure confirmed by 13C and 1H NMR.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH:4]=[O:5].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)[CH:7]=[C:6]([CH3:11])[C:3]=1[CH:4]=[O:5]
Reactant: Cc1cc(O)cc(O)c1C=O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1cc(OC2CCCCO2)cc(O)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask were placed a solution of 2,4-dihydroxy-6-methylbenzaldehyde (2.0 g, 13.16 mmol, 1.00 equiv) in dichloromethane (50 mL), 3,4-dihydro-2H-pyran (1.65 g, 19.64 mmol, 1.49 equiv) and pyridinium p-toluenesulfonate (330 mg, 1.31 mmol, 0.10 equiv). The resulting solution was stirred overnight at room temperature. Then it was diluted with 100 mL of dichloromethane and washed with 3×20 mL of 1 M sodium carbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.8 g (52%) of 2-hydroxy-6-methyl-4-(tetrahydro-2H-pyran-2-yloxy)benzaldehyde as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.O1CCOCC1>Cl[Pd]Cl.O>[N:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]3)=[CH:24][CH:23]=1
Reactant: O=C(O)c1cc2cc(Br)ccc2[nH]1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc2cc(-c3ccncc3)ccc2[nH]1

Procedure:
A solution of 5-bromo-1H-indole-2-carboxylic acid (25 mg), PdCl2 HPNor2 (5 mg), K3PO4 (45 mg), 4-pyridylboronic acid (26 mg), dioxane (1 mL) and H2O (1 mL) was heated to 170° C. in a microwave for 2 h. The solution was passed thru a C18-SPE cartridge eluting with 3, 20, 60, and finally 95% CH3CN in H2O to yield the crude product. LCMS (m/z): 239.1 (M+H).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21].C(O)CO>[Cu]I.C(O)CCC>[CH2:9]([NH:16][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)c1ccccc1Cl
Reactant: NCc1ccccc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CCCCO
Product: O=C(O)c1ccccc1NCc1ccccc1
Temperature: 100 °C
Yield: 48 %

Procedure:
Copper(I) iodide (19 mg, 0.10 mmol), K3PO4 (636 mg, 3.00 mmol), benzylamine (131 μL, 1.20 mmol), 2-chlorobenzoic acid (157 mg, 1.00 mmol), ethylene glycol (111 μL, 2.00 mmol) and 1-butanol (1.0 mL) were used and heated to 100° C. for 72 hours. The above workup procedure was followed and gave 2-(N-benzyl)aminobenzoic acid (109 mg, 48% isolated yield) as a light yellow solid.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](Cl)=[O:12]>>[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:12]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: NC1CCCC1
Product: O=C(NC1CCCC1)c1cccc(Cl)c1
Yield: 92 %

Procedure:
Employing 0.16 g (1.9 mmol) of cyclopentylamine and 0.51 g, (2.9 mmol) of 3-chloro-benzoyl chloride in the procedure described above and elution with CHCl3/MeOH/Et3N (9.8:0.1:0.1) gave white crystals in 92% yield).
Reaction SMILES: [CH3:1][C@:2]12[CH2:10][CH2:9][C:8]3[C:11]4[CH:12]=[CH:13][C:14]([OH:19])=[CH:15][C:16]=4[CH2:17][CH2:18][C:7]=3[C:6]1=[CH:5][CH2:4][C:3]2=[O:20]>C1C=CC=CC=1.[H][H].C>[CH3:1][C@:2]12[CH2:10][CH2:9][C:8]3[C:11]4[CH:12]=[CH:13][C:14]([OH:19])=[CH:15][C:16]=4[CH2:17][CH2:18][C:7]=3[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:20]
Reactant: C[C@]12CCC3=C(CCc4cc(O)ccc43)C1=CCC2=O
Reactant: [H][H]
Solvent: c1ccccc1
Product: C[C@]12CCC3=C(CCc4cc(O)ccc43)[C@@H]1CCC2=O
Yield: 69.5 %

Procedure:
Shake 13β-methyl-3-hydroxygona-1,3,5(10), 8,14-pentaen-17-one (0.05 g) in benzene (25 cc) in hydrogen at atmospheric pressure using a 10% palladized charcoal catalyst (0.025 g). Hydrogenation becomes very slow when 1.1 moles hydrogen has been absorbed. Filter and evaporate to obtain the title product (0.035 g), recrystallize from methanol to get pale blue crystals, m.p. 225°-228°, melting to a red liquid; ultraviolet absorption peak at 280 mμ (ε12,000).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]=[N+:13]=[N-:14])=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:15][N:16]1[CH:20]=[CH:19][N:18]=[C:17]1[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[F:28])[CH3:2].[C:29]([O:33][CH2:34][CH3:35])(=[O:32])[C:30]#[CH:31]>C(O)C>[CH2:34]([O:33][C:29]([C:30]1[N:14]=[N:13][N:12]([C:10]2[CH:9]=[CH:8][C:7]3[N:3]([CH2:1][CH3:2])[C:4]([CH2:15][N:16]4[CH:20]=[CH:19][N:18]=[C:17]4[C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[F:28])=[N:5][C:6]=3[CH:11]=2)[CH:31]=1)=[O:32])[CH3:35]
Reactant: C#CC(=O)OCC
Reactant: CCn1c(Cn2ccnc2-c2cc(F)ccc2F)nc2cc(N=[N+]=[N-])ccc21
Solvent: CCO
Product: CCOC(=O)c1cn(-c2ccc3c(c2)nc(Cn2ccnc2-c2cc(F)ccc2F)n3CC)nn1

Procedure:
A mixture of crude 1-ethyl-2-{[2-(2,5-difluorophenyl)-1H-imidazol-1-yl]methyl}-5-azido-1H-benzimidazole (143 mg) and ethyl propiolate (1 eq.) in ethanol (10 mL) is heated at reflux for 6 h. The mixture is cooled, concentrated, and the residue purified by preparative silica gel chromatography to give 1-{2-[2-(2,5-Difluoro-phenyl)-imidazol-1-ylmethyl]-1-ethyl-1H-benzoimidazol-5-yl}-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester. 1H NMR (CDCl3): δ 8.51s, (1H), 8.05(s, 1H), 7.74(m,1H), 7.50-7.39(m,4H), 7.21-7.17(m,2H), 7.06(s,1H), 5.54(s,2H), 4.47(q,2H), 3.86(q,2H), 1.43(t,3H), 1.04(t,3H), LCMS MH+ 460.6.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[Li+].[CH3:16][CH:17]([N-]C(C)C)C.C(I)C>C1COCC1>[CH3:7][C:4]1[N:3]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:16][CH3:17])[N:9]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: CC(C)[N-]C(C)C
Reactant: Cc1cccc(-n2c(C)ccc2C)n1
Agent: [Li+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCCc1cccc(-n2c(C)ccc2C)n1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
A solution of the product from Example 2a (7.53 g, 40.0 mmol) in 30 mL of dry THF was added dropwise with stirring to a solution of LDA (42.4 mmol) in 30 mL of dry THF at −30° C. Stirred at −30° C. for 30 min. Added EtI (3.42 mL, 42.0 mmol) in 20 mL of dry THF dropwise with stirring for 30 min then warmed to room temperature. After 2 h quenched by pouring into saturated NaCl solution and extracted with ether. Dried over MgSO4, filtered and concentrated under vacuum giving the title compound. The product was purified by silica gel column chromatography eluting with EtOAc/hexane to give the title compound (5.21 g, 60%).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:19][C:20]1[N:24]([CH2:25][CH2:26][CH3:27])[CH:23]=[N:22][CH:21]=1.O>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:19][C:20]2[N:24]([CH2:25][CH2:26][CH3:27])[CH:23]=[N:22][CH:21]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(S)nc1
Reactant: CCCn1cncc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1cncc1CSc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 40 h
Yield: 70.7 %

Procedure:
2-mercapto-5-nitropyridine (2.3 g) was dissolved in DMF (47 ml), potassium carbonate (6.2 g) and 5-chloromethyl-1-propylimidazole hydrochloride (3.5 g) was added to the mixture, and the mixture was stirred for 40 hours at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 5-nitro-2-[[(1-propylimidazol-5-yl)methyl]sulfanyl]pyridine (2.9 g).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].Cl[C:22]1[C:23]2[C:30]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])=[CH:29][NH:28][C:24]=2[N:25]=[CH:26][N:27]=1.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[CH3:20][C:17]1[CH:18]=[CH:19][N:6]2[C:7]=1[C:8](=[O:16])[N:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([C@@H:2]([NH:1][C:22]1[C:23]3[C:30]([C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:32])=[CH:29][NH:28][C:24]=3[N:25]=[CH:26][N:27]=1)[CH3:3])=[N:5]2
Reactant: O=C(OCc1ccccc1)c1c[nH]c2ncnc(Cl)c12
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(C(=O)OCc5ccccc5)c34)n(-c3ccccc3)c(=O)c12
Temperature: 80 °C
Reaction time: 12 h
Yield: 69.1 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (418 mg, 1.56 mmol) and benzyl 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (500 mg, 1.74 mmol) were dissolved in tert-butanol (8 ml) and DIEA (2 ml, 11.45 mmol) was added. After stirring the mixture at 80° C. for 12 h, the solvent was evaporated under reduced pressure and the residue was suspended in water, basified with sodium carbonate and extracted with AcOEt (×3). The organic phase was successively washed with water and brine, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. The residue was purified using SP1® Purification System (0% to 50%, hexane-ethyl acetate) to obtain 560 mg (66% yield) of the title compound as a white solid. Purity 96%.
Reaction SMILES: [CH:1]1([C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])=[CH:15][CH:14]=1>CS(C)=O.[Cl-].[Na+].O>[CH:1]1([C:4](=[O:8])[CH:5]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N+:25]([O-:27])=[O:26])=[CH:17][CH:18]=2)[C:6]#[N:7])[CH2:3][CH2:2]1
Reactant: N#CCC(=O)C1CC1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(CBr)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC(Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1)C(=O)C1CC1
Reaction time: 1 h
Yield: 33.6 %

Procedure:
To a solution of 2.61 g (24.0 mmol) 3-cyclopropyl-3-oxopropanenitrile in 150 mL DMSO was added 1.01 g (25.2 mmol) 60% NaH in oil. After 1 hour, 3.50 g (12.0 mmol) 4'-bromomethyl-2-nitrobiphenyl was added all at once to the solution. After 3 hours, the solution was poured into brine and extracted 3 times with ether. The combined organic material was dried over MgSO4, stripped of solvent in vacuo, and was chromatographed on silica gel under medium pressure using 3/40/57 EtOAc/CH2Cl2/hexanes to give 1.29 g (34% yield) of the title compound as a yellow glass. Rf 0.13 in 3/40/57 EtOAc/CH2Cl2/hexanes, visualized by UV and ammonium molybdate/ceric sulfate stain; Rf of the dialkylated material is 0.19 in the same solvent mixture.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][N:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([OH:11])=[O:10])[CH2:4][CH:3]=1.[O:15]([C:22]1[N:27]=[C:26]([CH2:28]Br)[CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCOCC>[CH3:1][C:2]1[CH2:7][CH2:6][N:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([O:11][CH2:28][C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:27]=2)=[O:10])[CH2:4][CH:3]=1
Reactant: CC1=CCN(C(C(=O)O)C(C)C)CC1
Reactant: BrCc1cccc(Oc2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1=CCN(C(C(=O)OCc2cccc(Oc3ccccc3)n2)C(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The resulting 2-(4-methyl-1,2,5,6-tetrahydro-1-pyridyl)-3-methylbutanoic acid (7.0 mmol) is combined with (6-phenoxy-2-pyridyl)methyl bromide (7.0 mmol) and potassium carbonate (14.0 mmol) in 15 ml dimethylformamide, and the mixture is stirred at RT, under nitrogen, for 20 hours. The solution is brought up in ether, washed with water (3X) and brine, and dried over sodium sulfate to give (6-phenoxy-2-pyridyl)methyl 2-(4-methyl-1,2,5,6-tetrahydro-1-pyridyl)-3-methylbutanoate.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1COCC1.CC(C)([O-])C.[K+].F[C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>C(OCC)(=O)C>[CH2:1]([O:9][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=1[C:31]([F:32])([F:34])[F:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCO
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 75 °C
Yield: 99.3 %

Procedure:
1-octanol (315 μL, 2.0 mmol), THF (5 mL), potassium t-butoxide (5 mL, 1M solution in THF), 4-Fluoro-3-trifluoromethylbenzoic acid (417 mg, 2.0 mmol) were mixed and heated at 75° C. for 3-4 hrs. The reaction mixture was then diluted with ethyl acetate and washed with water. The water layer was acidified and extracted with ethyl acetate. The organic layer was washed with brine and dried over Na2SO4 and concentrated to afford the title compound (632 mg, HPLC purity >95%), which was used for next reaction without further purification. HPLC retention time on a C8(2) column (30×3.00 mm, 3μ) was 3.28 min with gradient 50-98% acetonitrile-H2O (0.1% trifluoroacetic acid (TFA)) in 3.5 min as mobile phase.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[N:18]1[C:26](=[O:27])[C:25]2[C@@H:24]3[C:28]([CH3:30])([CH3:29])[C@@:21]([CH3:31])([CH2:22][CH2:23]3)[C:20]=2[NH:19]1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.ClCCl>[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[N:18]1[C:26](=[O:27])[C:25]2[C@@H:24]3[C:28]([CH3:30])([CH3:29])[C@@:21]([CH3:31])([CH2:22][CH2:23]3)[C:20]=2[N:19]1[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: BrCCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1CCc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 27.4 %

Procedure:
A mixture of (2-bromoethyl)benzene (200 μL, 1.46 mmol), (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 100 mg, 0.33 mmol) and tetra-n-butylammonium iodide (94 mg, 0.25 mmol) in N,N-dimethylformamide (1 mL) was heated in a pressure tube in an oil-bath at 100° C. for 18 h. Additional portions of (2-bromoethyl)benzene (200 μL, 2.2 mmol) and tetra-n-butylammonium iodide (100 mg, 0.27 mmol) were added and the reaction mixture was heated at 100° C. for 3 days, and then allowed to stand overnight at room temperature. The reaction mixture was diluted with dichloromethane (100 mL), washed with water (5×25 mL) and sodium thiosulfate solution (25 mL), dried (magnesium sulfate), filtered, and evaporated and the residue was purified on an Isco 40 g column, eluting with 40-100% ethyl acetate/hexanes to give (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1-phenethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (37 mg, 28%) as a pale yellow oil that solidified on standing. ES(+)-MS (M+H) 409.