Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]([CH3:19])([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=O)[C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].O.CCCCCC>C1(C)C=CC=CC=1>[CH:1]([C:4]1([CH3:19])[N:8]2[C:16](=[O:17])[C:15]3[C:10]([C:9]2=[N:7][C:5]1=[O:6])=[CH:11][CH:12]=[CH:13][CH:14]=3)([CH3:3])[CH3:2]
Reactant: CC(C)C(C)(C(N)=O)N1C(=O)c2ccccc2C1=O
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)C1(C)C(=O)N=C2c3ccccc3C(=O)N21
Temperature: 100 °C
Yield: 81.5 %

Procedure:
A solution of 130.1 g (0.5 mole) of α-isopropyl-α-methyl-1,3-dioxo-2-isoindolineacetamide in 650 ml toluene is heated with vigorous stirring under a Dean-Stark water separator in order to remove traces of water. The solution is cooled to 100° C. and 2.0 g sodium hydroxide in the form of pels is added and the mixture rapidly heated to reflux. Water collects in the water separator. One-half hour after the addition of the sodium hydroxide, a further 2 g is added and heating is continued for a further 11/4 hours when no further water is removed from the reaction mixture and the infrared spectrum of an aliquot indicates the reaction to be complete. The reaction mixture is cooled to room temperature, filtered and the solids washed with toluene and the toluene removed in vacuo to leave a white solid which is transferred to a filter funnel with hexane and air-dried to give 98.7 g of 3-isopropyl-3-methyl-3H-imidazo[2,1-a]isoindole-2,5-dione, melting point 93°-96° C. The product may be purified by recrystallization from hexane to give an analytically pure sample, melting point 98°-100° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[O:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][N:12]=2)=[O:7])[CH2:3]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[O:9][C:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:11][N:12]=2)=[O:7])[CH2:3]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1nnc(-c2ccccc2)o1)N1CC(O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(C(=O)c2nnc(-c3ccccc3)o2)C1
Reaction time: 8 h
Yield: 97.8 %

Procedure:
A suspension of 1B (2.00 g, 8.16 mmol) in dichloromethane (200 mL) was cooled in an ice-bath. Triethylamine (1.58 mL, 11.42 mmol) was added followed by methane-sulfonyl chloride (0.85 mL, 11.01 mmol). After the addition, the cooling bath was removed. The mixture was stirred overnight and then transferred to a separatory funnel. The mixture was washed with water and then with aqueous NaHCO3. The organic solution was dried (phase separator) and evaporated. There was obtained 2.58 g (98%) of 1C as a solid. 1H NMR (500 MHz, CDCl3): δ 3.13 (s, 3H), 4.43 (dd, 1H), 4.64 (dd, 1H), 4.87 (dd, 1H), 5.12 (dd, 1H), 5.40 (m, 1H), 7.54 (t, 2H), 7.59 (t, 1H), 8.15 (d, 2H), MS (APCI+) m/z 324 [M+H]+.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12](B(O)O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:19]1[CH:20]=[C:21]([C:26]2[N:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:29]=[C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:27]=2)[CH:22]=[C:23](Br)[CH:24]=1.C([O-])([O-])=O.[K+].[K+].[N:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[C:56]1[CH:57]=[C:58](B(O)O)[CH:59]=[CH:60][CH:61]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C.C1(C)C=CC=CC=1>[C:32]1([C:30]2[N:29]=[C:28]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:27]=[C:26]([C:21]3[CH:20]=[C:19]([C:58]4[CH:59]=[CH:60][CH:61]=[C:56]([C:51]5[CH:52]=[CH:53][CH:54]=[CH:55][N:50]=5)[CH:57]=4)[CH:24]=[C:23]([C:13]4[C:14]5[C:5]([C:6]6[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=6[CH:12]=4)=[CH:4][CH:3]=[CH:2][CH:1]=5)[CH:22]=3)[N:31]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Reactant: OB(O)c1cccc(-c2ccccn2)c1
Reactant: Brc1cc(Br)cc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc(-c2nc(-c3ccccc3)nc(-c3cc(-c4cccc(-c5ccccn5)c4)cc(-c4cc5ccccc5c5ccccc45)c3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
In a stream of argon, 5.00 g (10.7 mmol) of 9-phenanthreneboronic acid, 2.38 g (10.7 mmol) of 2-(3,5-dibromophenyl)-4,6-diphenyl-1,3,5-triazine and 124 mg (0.107 mmol) of tetrakis(triphenylphosphine)palladium were suspended in a mixed solvent composed of 400 mL of toluene and 50 mL of ethanol, and the resultant suspension was heated to 50° C. To the suspension, 32.1 mL (32.1 mmol) of an aqueous 1M K2CO3 solution was gradually added dropwise, and the mixture was stirred for 3 hours. The resultant reaction mixture was cooled to room temperature, and then, 3.19 g (10.7 mmol) of 3-(2-pyridyl)phenylboronic acid and 32.1 mL (32.1 mmol) of an aqueous 1M K2CO3 solution were added to the reaction mixture. The resultant mixture was heated to 60° C., and maintained at that temperature for 15 hours while being stirred. The obtained reaction mixture was cooled to room temperature, and then distilled under a reduced pressure to remove all volatile materials. Methanol was added to the concentrate, and the thus-deposited solid was collected by filtration. The obtained crude product was purified by silica gel chromatography using a hexane/chloroform (1:2) mixed solvent as an eluent to give 2.50 g of the target 4,6-diphenyl-2-[5-(9-phenanthryl)-3′-(2-pyridyl)biphenyl-3-yl]-1,3,5-triazine as a white solid (yield: 37%).
Reaction SMILES: [CH3:1][C@H:2]1[C@:7]2([CH3:15])[CH2:8][C@H:9]([C:12]([CH3:14])=[CH2:13])[CH2:10][CH2:11][C:6]2=[CH:5][CH2:4][CH2:3]1.O=O.C([O:22]O)(C)(C)C.O>C1(C)C=CC=CC=1.C(O)(C)(C)C>[CH3:1][CH:2]1[C:7]2([CH3:15])[CH2:8][CH:9]([C:12]([CH3:14])=[CH2:13])[CH2:10][CH2:11][C:6]2=[CH:5][C:4](=[O:22])[CH2:3]1
Reactant: CC(C)(C)OO
Reactant: C=C(C)[C@@H]1CCC2=CCC[C@@H](C)[C@]2(C)C1
Agent: O=O
Solvent: CC(C)(C)O
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C)C1CCC2=CC(=O)CC(C)C2(C)C1
Temperature: 45 °C
Yield: 34 %

Procedure:
Silica phosphonate chromium (III) resin (48.9 g, PhosphonicS, Ltd.) was placed in a 5 L round bottom flask equipped with a condenser, thermowell, overhead stirrer, and sparge tube. Two (2) L of t-butanol and valencene distillate (68%, 500 g, 1.67 moles, 1 eq) were added, the contents were heated to 45° C., and the heterogeneous suspension was allowed to stir as oxygen was sparged through the solution (ca 1.5 L/min) and nitrogen flushed over the head-space. 70% t-butyl hydroperoxide in water (TBHP, 315 g, 2.45 moles, 1.47 eq) was added to the solution over 2 hrs while the temperature of the reaction was heated and maintained at 60±5° C. The reaction was allowed to stir until >90% of the valencene was consumed, as determined by gas chromatography. The reaction was then allowed to cool to room temperature and the silica catalyst removed by filtration. The flask and resin were washed with 500 mL isopropanol. One (1) L of deionized water was added to the combined organic solution (t-butanol and isopropanol), and the mixture was concentrated under reduced pressure by evaporation to afford an amber colored oil. The oil was dissolved in 3 L of toluene and washed with 3.125 L of 15% sulfuric acid for 15 minutes with vigorous agitation. The aqueous layer was removed and re-extracted with 1 L of toluene. The combined toluene layers were then washed three times with 2.5 L of 1 M sodium hydroxide, twice with 500 mL saturated sodium chloride, and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed under reduced pressure by evaporation to afford 378 g of viscous amber oil (33% nootkatone by weight, 0.57 moles, 34% yield).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[N:10][C:9]([Br:24])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N([O-])=O.[Na+].[N-:29]=[N+:30]=[N-].[Na+].CCOCC>C(O)(C(F)(F)F)=O.O>[N:1]([C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[N:10][C:9]([Br:24])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(N3CCOCC3)cc2)c1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Br)nc(-c2ccc(N3CCOCC3)cc2)c1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
Methyl 3-amino-6-bromo-2-(4-morpholinophenyl)isonicotinate (2.0 g, 5.1 mmol) was quickly dissolved in TFA (25 mL) and the light brown solution was cooled in an ice-bath. Solid sodium nitrite (0.405 g, 5.86 mmol) was added in small portions over 5 min with stirring to give a dark red mixture. After 30 min, solid sodium azide (1.24 g, 19.1 mmol) was added over 1 min followed by Et2O (25 mL). The mixture was stirred in the ice-bath for 30 min. Water was added and the mixture was extracted with EtOAc. The combined organic phases were washed with water (3×), brine, sat. aq. NaHCO3 solution (until aq. phases were basic), and brine (1×). After drying with sodium sulfate, the solvent was removed and silica gel chromatography (step gradient elution with hexane containing 5, 10, 15, 20% EtOAc) to afford methyl 3-azido-6-bromo-2-(4-morpholinophenyl)isonicotinate (1.27 g, 3.04 mmol, 60% yield) as a solid. 1H NMR (500 MHz, chloroform-d) δ ppm 7.77 (2H, d, J=9.16 Hz), 7.70 (1H, s), 6.99 (2H, d, J=9.16 Hz), 4.02 (3H, s), 3.87-3.92 (4H, m), 3.26-3.31 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:10]3[CH:9]([OH:18])[N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:25]=1.N1C=CC=CC=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>O>[C:32]([O:18][CH:9]1[N:8]=[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]2[CH:25]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:11]2[N:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:10]12)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1nc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OC1N=C(c2ccccc2)c2cc(Cl)ccc2-n2nc(C(N)=O)nc21
Reaction time: 2 h

Procedure:
To a solution of 0.38 g. of 8-chloro-4-hydroxy-6-phenyl-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxamide (3/2 hydrate) in 5 ml. of pyridine is added 0.2 ml. of acetic anhydride and the mixture is left to stand at room temperature for 2 hours, followed by addition of water. The precipitated crystals are collected by filtration to yield 4-acetoxy-8-chloro-6-phenyl-4H-s-triazolo[1,5-a][1,4]-benzodiazepine-2-carboxamide as crystals. This product is identical with the product in Example 1 with respect to melting point and infrared absorption spectrum.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9](=[CH2:11])[CH3:10]>[O-]C1C=CC=CC=1.[Al+3].[O-]C1C=CC=CC=1.[O-]C1C=CC=CC=1>[C:9]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:9]([CH3:11])([CH3:10])[CH3:8])[C:1]=1[OH:7])([CH3:10])([CH3:8])[CH3:11]
Reactant: Oc1ccccc1
Reactant: C=C(C)C
Agent: [Al+3]
Agent: [O-]c1ccccc1
Product: CC(C)(C)c1cccc(C(C)(C)C)c1O

Procedure:
Phenol was reacted with isobutylene in the presence of an aluminum phenoxide catalyst by the customary procedure. Thereafter, the aluminum phenoxide catalyst was removed, thereby obtaining crude 2,6-di-t-butylphenol.
Reaction SMILES: [CH:1]1([O:6][C:7]2[N:12]=[C:11]([CH:13]([CH3:16])[CH2:14][NH2:15])[CH:10]=[CH:9][C:8]=2[O:17][CH3:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:19]1[CH:24]=[CH:23][C:22]([O:25][C:26](OC2C=CC=CC=2)=[N:27][C:28]#[N:29])=[CH:21][CH:20]=1>C(O)C>[C:28]([N:27]=[C:26]([O:25][C:22]1[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1)[NH:15][CH2:14][CH:13]([C:11]1[CH:10]=[CH:9][C:8]([O:17][CH3:18])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[N:12]=1)[CH3:16])#[N:29]
Reactant: COc1ccc(C(C)CN)nc1OC1CCCC1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CCO
Product: COc1ccc(C(C)CNC(=NC#N)Oc2ccccc2)nc1OC1CCCC1
Yield: 61.7 %

Procedure:
A solution of (±)-6-(cyclopentyloxy)-5-methoxy-β-methyl-2-pyridineethanamine (0.037 mol) and diphenyl N-cyanocarbonimidate (0.037 mol) in ethanol (100 ml) was stirred for one day at RT. The precipitate was filtered off, washed with ethanol, DIPE, then dried, yielding 9 g (61.7%) of (±)-phenyl N′-cyano-N-[2-[6-(cyclopentyloxy)-5-methoxy-2-pyridinyl]propyl]carbamimidate(interm. 9). The filtrate was evaporated under reduced pressure. The residue was dissolved in CH2Cl2. The organic solution was washed three times with 2 N NaOH. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 4.1 g of intermediate (9). Total yield is 89%.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:14][CH2:15]O)[C:10]([O:12][CH3:13])=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>ClCCl.CN(C1C=CN=CC=1)C>[Si:1]([O:8][C@@H:9]([CH2:14][CH2:15][S:24]([CH3:27])(=[O:26])=[O:25])[C:10]([O:12][CH3:13])=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@H](CCO)O[Si](C)(C)C(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCS(C)(=O)=O)O[Si](C)(C)C(C)(C)C
Reaction time: 1.5 h

Procedure:
To a solution of (S)-methyl 2-(tert-butyldimethylsilyloxy)-4-hydroxybutanoate (91c, 3.9 g, 15.7 mmol) in anhydrous dichloromethane was added triethylamine, DMAP, and mesyl chloride. The reaction was allowed to stir for 1.5 h. The reaction was quenched with saturated aqueous NH4Cl. The aqueous phase was extracted with dichlormethane and the combine organic phases were washed with brine. The organic layer was dried over anhydrous sodium sulfate and the solvent removed in vacuo to yield (S)-methyl 2-(tert-butyldimethylsilyloxy)-4-mesylbutanoate (91d, 4.9 g, 15 mmol) as a yellow oil. [M+H] calc'd for C12H26O6SSi, 327. found, 327.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1[C:8]([F:13])=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2([CH2:25][C:26](OC(C)(C)C)=[O:27])[NH:18][S:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20].[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1[C:8]([F:13])=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2([NH:18][S:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])[CH2:25][CH2:26][OH:27]
Reactant: CC(C)(C)OC(=O)CC1(NS(=O)C(C)(C)C)c2cc(Br)ccc2Oc2c1cc(Cl)nc2F
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC1(CCO)c2cc(Br)ccc2Oc2c1cc(Cl)nc2F
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
A solution of tert-butyl 2-(7-bromo-3-chloro-5-(1,1-dimethylethylsulfinamido)-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)acetate (7.5 g, 13.69 mmol) in dry THF (25 mL) was cooled to −78° C. and diisobutylaluminum hydride (54.8 mL, 54.8 mmol) was added drop wise. The mixture was warmed to 0° C. and kept at this temperature for 1 h. The reaction mixture was quenched with a aqueous, saturated solution of Rochelle's salt and vigorously stirred for 15 h. The organic layer was separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. The solution was concentrated under reduced pressure. The residue was purified by chromatography (0-30% EtOAc/hexanes) to afford N-(7-bromo-3-chloro-1-fluoro-5-(2-hydroxyethyl)-5H-chromeno [2,3-c]pyridin-5-yl)-2-methylpropane-2-sulfinamide (5.8 g, 89% yield) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=1.[CH3:30][S:31][CH2:32][CH2:33][CH2:34][NH2:35].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:35][CH2:34][CH2:33][CH2:32][S:31][CH3:30])=[O:17])=[N:14][CH:15]=1
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reactant: CSCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CSCCCNC(=O)c1cc(C)c(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 94.3 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (222 mg, 0.527 mmol) obtained in Example 12 in methylene chloride (5 ml), 3-methylthiopropylamine (66 mg, 0.632 mmol), 1-hydroxybenzotriazole (71 mg, 0.527 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (121 mg, 0.632 mmol) and 4-methylmorpholine (69 μl, 0.632 mmol) were added. The reaction solution was stirred for 3 days at room temperature, and was concentrated under reduced pressure. The concentration residue was subjected to silica gel column chromatography, and the fraction obtained from an elution with ethyl acetate:methylene chloride (=1:20) was concentrated under reduced pressure, to obtain the title compound (253 mg, 0.497 mmol, 94%) as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH:7]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:6]=2[C:5]([CH3:24])=[N:4]1)[CH3:2].CCN(C(C)C)C(C)C.[CH3:34][NH:35][C:36]([CH:38](OS(C1C=CC(C)=CC=1)(=O)=O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:37]>CC(C)C(C(C(C(C)C)C)=O)C>[CH2:1]([N:3]1[C:11]2[CH2:10][CH2:9][N:8]([CH:38]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:36]([NH:35][CH3:34])=[O:37])[CH:7]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=3)[C:6]=2[C:5]([CH3:24])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C)c2c1CCNC2CCc1ccc(C(F)(F)F)cc1
Reactant: CNC(=O)C(OS(=O)(=O)c1ccc(C)cc1)c1ccccc1
Agent: CC(C)C(C)C(=O)C(C)C(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCn1nc(C)c2c1CCN(C(C(=O)NC)c1ccccc1)C2CCc1ccc(C(F)(F)F)cc1
Temperature: 90 °C
Yield: 96.3 %

Procedure:
In an inert atmosphere, 1-ethyl-3-methyl-4-[2-(4-trifluoromethyl-phenyl)-ethyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (51 mg, 0.15 mmol) was dissolved in 3-methyl-2-butyl-ketone (MIBK) (1 ml) followed by the addition of DIPEA (21.3 mg, 0.165 mmol) and toluene-4-sulfonic acid methylcarbamoyl-phenyl-methyl ester (71.8 mg, 0.225 mmol). The reaction mixture was heated to 90° C. for 24 h, concentrated in vacuo and the crude product was purified by prep. HPLC to give 70 mg (95%) of 2-{1-ethyl-3-methyl-4-[2-(4-trifluoromethyl-phenyl)-ethyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-N-methyl-2-phenyl-acetamide. LC-MS: tR=0.84 min; [M+H]+=485.28.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][CH2:12][NH:11][C@@H:10]1[C@H:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([Cl:25])[C:18]=1[CH3:26])[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:36](Cl)(Cl)=[O:37].C1(C)C=CC=CC=1>C(Cl)Cl>[O:8]([C@@H:9]1[C@@H:10]2[N:11]([C:36](=[O:37])[N:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([Cl:25])[C:18]=3[CH3:26])[C@@H:14]2[CH3:15])[CH2:12][CH2:13]1)[Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1c(N[C@H](C)[C@H]2NCC[C@@H]2O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(N2C(=O)N3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]3[C@H]2C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of crude 80F (˜0.068 mmol) in CH2Cl2 (2 mL) was added i-Pr2NEt (36 μL, 0.20 mmol) followed by 20% phosgene in toluene (50 μL, 0.1 mmol)-dropwise. The reaction was stirred at rt for 4 days and no desired product was formed. The solvent was removed and the residue was dissolved in 1,2-dichloroethane (2 mL) and treated with i-Pr2NEt (108 μL) at 80° C. for 3 h. Reaction was concentrated and the residue was purified by preparative TLC (30% EtOAc/hexane) to provide the title compound 80G (11 mg): MS (ES) m/z 420.5 [M+H]+; HRMS calcd for C21H31N3O2ClSi 420.1874, found 420.1870.
Reaction SMILES: [CH2:1]=CC1C=CC=CC=1.C1C=CC=CC=1.C1(C(C2C=CC=CC=2)C)C=CC=CC=1.[C:29]1([CH:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[CH3:43])[CH3:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1(C)C(C)=CC=CC=1.C1(C)C=CC=CC=1>[C:29]1([C:35]2([CH2:36][CH3:1])[CH:41]=[CH:40][CH:39]=[C:38]([CH3:43])[CH:37]2[CH3:42])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1ccccc1C(C)c1ccccc1
Reactant: C=Cc1ccccc1
Agent: CC(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Solvent: Cc1ccccc1C
Product: CCC1(c2ccccc2)C=CC=C(C)C1C

Procedure:
When styrene is reacted with, for example, benzene, toluene or xylene according to the method of the present invention, 1,1-diaryl-ethane such as 1,1-diphenyl-ethane, 1-phenyl-1-tolyl-ethane, or 1-phenyl-1-xylyl-ethane is obtained, respectively, as an aralkylation product.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([NH2:11])=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[Cl:21][C:22]1[N:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>C1COCC1>[Cl:21][C:22]1[N:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:25]
Reactant: Nc1ccccc1NC1CC1
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccccc1NC1CC1)c1cccnc1Cl
Yield: 65.5 %

Procedure:
To a solution of title compound 381 (0.83 g, 5.84 mmol) and diisopropylethylamine (1.02 mL, 0.74 mmol) in THF (50 mL) was added a solution of 2-chloronicotinoyl chloride (1.03 g, 5.84 mmol) in THF at 0° C. The reaction mixture was stirred over night and concentrated. To the residue was added a saturated solution of bicarbonate (3 mL) and this aqueous layer was extracted with DCM (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated. The solid was triturated in DCM (3 mL) and filtered. The filtrate was evaporated and purified by flash chromatography (0% to 80% ethyl acetate in hexanes). The 2 solids were mixed to afford title compound 382 (1.1 g, 65%) as a white solid. MS (m/z): 288.0 (M+H).
Reaction SMILES: BrC([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)C.[C:14]([NH:17][CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:16])[CH3:15].[CH3:29]C[O-].[Na+]>C(O)C>[CH2:22]([O:21][C:19](=[O:20])[C:18]([NH:17][C:14](=[O:16])[CH2:15][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:23]
Reactant: CC(Br)c1ccc2ccccc2c1
Reactant: CC[O-]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)(NC(=O)Cc1ccc2ccccc2c1)C(=O)OCC
Temperature: 40 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
2-(1-Bromoethyl)-naphthalene (105 g, 446 mmol) in anhydrous ethanol (150 mL) was added to a stirred solution of diethyl acetamidomalonate (97.6 g, 450 mmol) previously reacted with sodium ethylate (sodium metal 10.3 g, 448 mmol) in anhydrous ethanol (400 mL). The reaction mixture was stirred at 40° C. overnight. After removal of two-thirds of the solvent in vacuo and keeping the mixture in the refrigerator overnight, the precipitated product and NaBr crystals were collected by filtration. The solid was washed with cold ethanol and distilled water (to eliminate NaBr), yielding 112 g (67%) of diethyl-α-methyl-2-naphthylacetamidomalonate as white crystals: mp 148-150° C.; C21H25NO5 MS: 371,44.