Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][CH:6]([C:22]([OH:24])=[O:23])[N:7]([CH2:17][CH2:18][S:19][CH2:20][CH3:21])[CH:8]([O:12]C(C)(C)C)[C:9]([OH:11])=[O:10])(C)(C)C.[ClH:25]>O1CCCC1>[ClH:25].[OH:5][CH:6]([C:22]([OH:24])=[O:23])[N:7]([CH2:17][CH2:18][S:19][CH2:20][CH3:21])[CH:8]([OH:12])[C:9]([OH:11])=[O:10]
Reactant: CCSCCN(C(OC(C)(C)C)C(=O)O)C(OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: C1CCOC1
Product: CCSCCN(C(O)C(=O)O)C(O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.67 g (5 mmol) of N,N-bis-(tert-butoxycarboxy-methyl)-S-ethyl-2-mercaptoethylamine is dissolved in 12 ml of tetrahydrofuran and mixed with 6 ml of concentrated hydrochloric acid. The resulting reaction mixture is stirred for 1 hour at room temperature and concentrated by evaporation in a vacuum. The residue is pulverized with 10 ml of absolute diethyl ether. Then, the product is filtered off and dried in a medium-high vacuum.
Reaction SMILES: [N+]([C:4]1[CH:21]=[CH:20][C:7]([C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13]3)=[O:9])=[CH:6][CH:5]=1)([O-])=O.O=[N:23]C1C=CC=CC=1>CO.[Pd]>[NH2:23][C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][CH:4]=1)[C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13]2)=[O:9]
Reactant: O=C1Cc2cc(C(=O)c3ccc([N+](=O)[O-])cc3)ccc2N1
Reactant: O=Nc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(C(=O)c2ccc3c(c2)CC(=O)N3)c1
Reaction time: 0.08 h

Procedure:
5-(4-Nitro-benzoyl)-1,3-dihydro-indol-2-one (1.51 g, 5.28 mmol) was dissolved in MeOH (600 mL). 10% Pd/C (0.150 g) was added to the flask and then placed under vacuum to remove any O2(g). The reaction mixture was kept under reduced pressure for 5 min and was then charged with H2(g). This evacuation/H2(g) fill procedure was repeated twice. The reaction mixture changed from a cloudy grayish/black color to a translucent dark green/black color, signifying complete consumption of the starting material. As the desired ketone product was prone to over-reduction to the alcohol, stopping the reaction immediately upon complete consumption of the starting material limited the amount over-reduction that occurred. The reaction was allowed to run for 0.75-1.0 hours after which, the reaction mixture was filtered over celite and concentrated in vacuo resulting in a yellowish solid that contained the desired keto-aniline product plus ˜5% of the overreduced alcohol-aniline. The crude solid was purified by triturating with MeOH. The desired keto-aniline product, 5-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one was soluble in MeOH and was filtered away from the insoluble over reduced alcohol by-product. In vacuo concentration of the methanolic filtrate provided pure 5-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one in 72% (0.957 g, 3.80 mmol) yield.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[CH:21]1[CH2:25][CH2:24][CH:23]=[CH:22]1>C(O)C.[Pd]>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:15])([F:17])[F:16])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C1C=CCC1
Agent: [Pd]
Solvent: CCO
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C1CCCC1

Procedure:
5-Amino-3-cyano-4-(cyclopent-2-enyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (200 mg, 0.5 mmol, Example 7) in ethanol (10 ml) was hydrogenated at room temperature and 345 kPa (50 p.s.i.) over 10% palladium on charcoal for 9 h. The catalyst was removed by filtration, washed with ethanol and the combined filtrates concentrated in vacuo to yield an oil.
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([C:16]([F:19])([F:18])[F:17])=[C:5]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[C:7]([F:9])[CH:8]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][C:30]2[C:33]([C:36](O)=[O:37])=[N:34][NH:35][C:29]=2[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:2][C:3]1[C:4]([C:16]([F:19])([F:18])[F:17])=[C:5]([CH:10]2[CH2:11][CH2:12][N:13]([C:36]([C:33]3[C:30]4[CH2:31][CH2:32][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH2:28][C:29]=4[NH:35][N:34]=3)=[O:37])[CH2:14][CH2:15]2)[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: Fc1cc(F)c(C(F)(F)F)c(C2CCNCC2)c1
Reactant: CC(C)(C)OC(=O)N1CCc2c(C(=O)O)n[nH]c2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(C(=O)N3CCC(c4cc(F)cc(F)c4C(F)(F)F)CC3)n[nH]c2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.4 %

Procedure:
To a suspension of 4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine hydrochloride (28, 500 mg, 1.66 mmol), 6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-1Hpyrazolo[3,4-c]pyridine-3-carboxylic acid (443 mg, 1.66 mmol), and diisopropylethylamine (36 μL, 2.04 mmol) in DMF (5 mL) was added HBTU (1.10 g, 2.49 mmol). The resulting mixture was stirred at ambient temperature for 18 h. the reaction was diluted in H2O (50 mL) and extracted with EtOAc (3×75 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (40 g Redisep column, 0-100% EtOAc in hexanes) to afford tert-butyl 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,5 dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (59) as a white solid (200 mg, 23%). 1H NMR (300 MHz, CDCl3) δ 7.017-6.876 (m, 1H), 6.876-6.741 (m, 1H), 5.306 (s, 1H), 4.632 (s, 2H), 3.776-3.581 (m, 2H), 2.762-2.631 (m, 2H), 1.986-1.653 (m, 4H), 1.500 (s, 9H), 1.399-1.189 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:22])[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13](Cl)=[CH:14][C:15]=3[Cl:19])[NH:10][C:9]2=[O:21])=[CH:4][CH:3]=1.[H-].[Na+].Cl.C1C[O:29][CH2:28]C1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:22])[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([O:29][CH3:28])=[CH:14][C:15]=3[Cl:19])[NH:10][C:9]2=[O:21])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: CC1(c2ccc(Br)cc2)C(=O)Nc2cc(Cl)cc(Cl)c2C1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COc1cc(Cl)c2c(c1)NC(=O)C(C)(c1ccc(Br)cc1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a solution of 3-(4-bromo-phenyl)-5,7-dichloro-3-methyl-1H-quinoline-2,4-dione (600 mg, 1.40 mmol) in dry THF (30 mL) was added NaH (140 mg, 3.50 mmol) at 0° C. and stirred for 1 hour at room temperature. The reactant was poured into a 0.5N HCl solution and extracted with ethyl acetate (100 mL×3). The organic layer was washed with brine (100 mL×2), dried over anhydrous MgSO4, and concentrated in vacuo. The pure objective compound (260 mg, 47%) was obtained as white solid by a flash column chromatography (n-hexane:EtOAc=5:1): 1H NMR (200 MHz, CDCl3) δ 1.73 (s, 3H, CH3), 3.91 (s, 3H, OCH3), 6.48 (d, J=1.6 Hz, 1H, ArH), 6.60 (d, J=1.6 Hz, 1H, ArH), 7.11-7.44 (m, 4H, ArH), 8.62 (br s, 1H, NH); m.p. 239-240° C.; MS(EI) m/e 393 [M+], 210, 183; HRMS m/e cacld. for C17H13N1O3Br1Cl1 392.9767, found 392.9760.
Reaction SMILES: [CH2:1]([O:5][CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[C:16](=[O:29])[C:17]3[CH:22]=[N:21][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]=3[N:19]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH3:4]>CCO.[Pd]>[CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:15]([C:30]3[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=3)[C:16](=[O:29])[C:17]3[CH:22]=[N:21][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]=3[N:19]=2)=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC=Cc1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCCCOCCc1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.1 %

Procedure:
To a solution of 6-[4-(2-butoxy-vinyl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (5 mg, 0.01 mmol) in EtOH (1 mL) is added Pd/C (2 mg). The system is degassed by alternately applying vacuum and H2 for 3 times. The mixture is then stirred at room temperature under H2 for 24 h. After removing the catalyst by filtration, the filtrate is concentrated and purified by flash column chromatography (silica gel, 0˜30% EtOAc/hexane) to provide the title compound as white solid (3.5 mg, 69%). HPLC-MS calculated C29H25ClN4O2 (M+1+): 497.2. Found: 497.2
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:11])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([Li])CCC.CN(C)[C:19](=[O:21])[CH3:20].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:1][O:2][C:3]1[C:4]([CH2:11][C:19](=[O:21])[CH3:20])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(=O)N(C)C
Reactant: COc1ccnc(C)c1OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccnc(CC(C)=O)c1OC
Temperature: 0 °C

Procedure:
To a stirred solution of 3,4-dimethoxy-2-methylpyridine (1.53 g) in tetrahydrofuran (15 ml) was added a solution of n-butyllithium in n-hexane (1.63M, 7.36 ml) dropwise at −50° C. under a nitrogen atmosphere, and the mixture was warmed to 0° C. The mixture was cooled to −50° C., and N,N-dimethylacetamide (1.21 ml) was added dropwise. Then the mixture was warmed to room temperature, poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (100 ml×2). The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 50 g, 25% ethyl acetate in n-hexane) to give 1-(3,4-dimethoxypyridin-2-yl)propan-2-one (1.85 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([Cl:12])=[C:4]([C:7]([Cl:11])=[CH:8][C:9]=1[Cl:10])[C:5]#[N:6].[Na].Br[CH2:15][C:16]([O:18][CH2:19]C)=[O:17]>CO>[CH3:19][O:18][C:16](=[O:17])[CH2:15][O:1][C:2]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[C:4]([C:5]#[N:6])[C:3]=1[Cl:12]
Reactant: N#Cc1c(Cl)cc(Cl)c(O)c1Cl
Reactant: CCOC(=O)CBr
Agent: [Na]
Solvent: CO
Product: COC(=O)COc1c(Cl)cc(Cl)c(C#N)c1Cl
Yield: 64.5 %

Procedure:
22.5 g (0.1 mol) of 3-hydroxy-2,4,6-trichlorobenzonitrile are dissolved in 240 ml of methanol with the addition of 2.3 g (0.1 mol) of metallic sodium. To the resultant suspension of the sodium salt is added 12.15 ml (0.11 mol) of ethyl bromoacetate, and the reaction mixture is heated to reflux until solution is complete. After filtration over active carbon, the solution is cooled and stirred for several hours in an ice bath. The resultant crystalline precipitate is vacuum-filtered, washed with a little ice-cold methanol and dried at 50° C., to produce 19 g (64.5% of theory) of 3-cyano-2,4,6-trichlorophenoxyacetic acid methyl ester as a white powder, mp 110°-112° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6](=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:2]1.[H-].[Na+].[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.O>COCCOC>[O:1]1[CH:5]=[CH:4][C:3]([C:6](=[O:13])[CH:7]([CH2:22][C:21]2[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:26])[F:27])=[CH:25][CH:24]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:2]1
Reactant: CCOC(=O)CC(=O)c1ccoc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccoc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
To a solution of ethyl 3-(3-furanyl)-3-oxopropionate (20 g, 110 mmol) in 1,2-dimethoxyethane (100 ml) was added sodium hydride (60% in oil, 4.4 g, 110 mmol) under ice-cooling and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 4-trifluoromethylbenzyl bromide (26.2 g, 110 mmol) in 1,2-dimethoxyethane (50 ml) and the reaction solution was stirred at room temperature for 3 hrs. The reaction solution was poured into water (300 ml) and extracted with ethyl acetate (500 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give ethyl 3-(3-furanyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (28.8 g, 77%).
Reaction SMILES: CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[F-].[K+].[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:27]=1B(O)O.Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O1CCCC1>[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:27]=1[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: Cc1cccc(C)c1B(O)O
Reactant: CCOC(=O)CBr
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1c(C)cccc1C
Temperature: 50 °C
Reaction time: 24 h
Yield: 46.8 %

Procedure:
A 25 ml three-neck flask with magnetic stirrer, reflux condenser and dropping funnel is initially charged with 20 ml of tetrahydrofuran (THF) which has been dried over molecular sieve, and 0.36 ml of water. The mixture is heated to 50° C. while passing argon through for a few minutes, and then cooled again to room temperature. Still under argon, the following are now added: 17.2 mg [0.03 mmol=0.3 mol %] of bis(dibenzylideneacetone)palladium, 27.4 mg of P(o-tolyl)3 [0.09 mmol], 2.91 g of potassium fluoride (dried over P2O5 at 140° C.), 1.5 g [10 mmol] of 2,6-dimethylphenylboronic acid and 2.56 g [15 mmol] of ethyl bromoacetate. This mixture is stirred under reflux in a gentle argon stream for 24 hours. Then it is filtered through a little Celite, and the filtercake is washed three times with 20 ml each time of ethyl acetate. The combined filtrates are extracted by shaking with 20 ml of 1 N hydrochloric acid. The aqueous phase is re-extracted twice with 20 ml of ethyl acetate each time. The combined organic phases are then washed with 20 ml of saturated aqueous NaCl solution, dried and concentrated. This gives 1.59 g of an oil which, according to GC-MS, as well as 10.7 area % of m-xylene, contains 56.6 area % of ethyl 2,6-dimethylphenylacetate. This corresponds to a yield of 46.8% of theory.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C1COCC1.[F:12][C:13]([F:54])([F:53])[C:14]1[CH:15]=[C:16]([C@H:24]2[O:28][C:27](=[O:29])[N:26]([CH2:30][C:31]3[C:36]([C:37]4[C:38]([O:46][CH3:47])=[N:39][CH:40]=[C:41]([CH:43]([CH3:45])[CH3:44])[CH:42]=4)=[CH:35][N:34]=[C:33](S(C)(=O)=O)[N:32]=3)[C@H:25]2[CH3:52])[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C(#N)C.O>CC#N>[F:22][C:20]([F:21])([F:23])[C:18]1[CH:17]=[C:16]([C@H:24]2[O:28][C:27](=[O:29])[N:26]([CH2:30][C:31]3[C:36]([C:37]4[C:38]([O:46][CH3:47])=[N:39][CH:40]=[C:41]([CH:43]([CH3:45])[CH3:44])[CH:42]=4)=[CH:35][N:34]=[C:33]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[N:32]=3)[C@H:25]2[CH3:52])[CH:15]=[C:14]([C:13]([F:12])([F:54])[F:53])[CH:19]=1
Reactant: COc1ncc(C(C)C)cc1-c1cnc(S(C)(=O)=O)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O
Product: COc1ncc(C(C)C)cc1-c1cnc(N2CCOCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 90 °C

Procedure:
Morpholine (0.062 mL, 0.711 mmol) was added to a THF (1 mL) solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-(5-isopropyl-2-methoxypyridin-3-yl)-2-(methylsulfonyl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 17, 90 mg, 0.142 mmol) in a microwave vial. The vial was capped, then heated for 15 minutes at 90° C. in a BIOTAGE microwave reactor. LCMS showed complete conversion to product. The reaction was diluted with 2 mL CH3CN and loaded directly onto an X-Bridge 21.2×150 mm RP column. Using a 10-100% acetonitrile/water (0.1% NH4OH) linear gradient at 15 mL/minutes over 20 minutes, the product of interest was recovered and lyophilized to give the titled compound as a white solid. LCMS (M+H)+: 640.5. 1H NMR (CDCl3, 500 MHz): δ 8.17 (s, 1H), 8.10 (d, J=2.2 Hz, 1H), 7.91 (s, 1H), 7.75 (s, 2H), 7.35 (d, J=2.2 Hz, 1H), 5.64 (d, J=8.5 Hz, 1H), 4.72 (d, J=17.1 Hz, 1H), 4.32 (m, 1H), 4.00 (d, J=17.2 Hz, 1H), 3.94 (s, 3H), 3.88 (m, 4H), 3.83 (m, 4H), 2.96 (m, 1H), 1.29 (d, J=7.0 Hz, 6H), 0.71 (d, J=6.5 Hz, 3H). SPA IC50: 229 nM.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][C:9]([NH2:12])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.O=O>[Cu].C(O)C>[C:1]1([N:7]2[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC1=NN(c2ccccc2)CC1
Agent: [Cu]
Agent: O=O
Solvent: CCO
Solvent: c1ccncc1
Product: Nc1ccn(-c2ccccc2)n1
Reaction time: 2 h

Procedure:
1-phenyl-3-amino-2-pyrazoline, copper salt (CuCl) and metallic copper, if any, and/or pyridine, in the form of a suspension or of a solution in the solvent (e.g., ethyl alcohol) are introduced, in the desired amounts (between 5 and 6%), into a reactor equipped with feeding systems for reagents and with an effective stirrer. Stirring is started in an oxygen atmosphere. After about 2 hours, oxidation is concluded and the whole solid is dissolved. The catalyst is filtered, the solvent is distilled under vacuum, and the 1-phenyl-3-aminopyrazole is isolated by extraction with, e.g., n-heptane. Additional 1-phenyl-3-aminopyrazole is recovered by treating the n-heptane extraction residue with diluted hydrochloric acid, followed by neutralization with aqueous NaOH to precipitate the 1-phenyl-3-aminopyrazole. Optionally, the heptane extraction residue diluted with hydrochloric acid can be clarified with animal charcoal, prior to neutralization thereof. As is known, the 1-phenyl-3-aminopyrazoles are an important class of products which are valuable for various industrial uses, such as active intermediates in the preparation of dyestuffs, of sensitive agents for use in photography, and of other fine chemicals.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[CH3:10][N:11]1[C:15]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[O:22][C:23]3([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:14]=2[CH:13]=[N:12]1.[CH:29]([S:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][C:36]=1[CH3:44])(=[O:34])=[O:33])([CH3:31])[CH3:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH:29]([S:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39]([N:26]2[CH2:27][CH2:28][C:23]3([C:14]4[CH:13]=[N:12][N:11]([CH3:10])[C:15]=4[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[O:22]3)[CH2:24][CH2:25]2)=[O:40])=[CH:37][C:36]=1[CH3:44])(=[O:34])=[O:33])([CH3:31])[CH3:30]
Reactant: Cn1ncc2c1-c1ccccc1OC21CCNCC1
Reactant: Cc1cc(C(=O)O)ccc1S(=O)(=O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)ccc1S(=O)(=O)C(C)C
Temperature: 40 °C
Yield: 67.6 %

Procedure:
Triethylamine (152 μL, 1.1 mmol) was added to a mixture of 1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]dihydrochloride (108 mg, 0.33 mmol), 4-(isopropylsulfonyl)-3-methylbenzoic acid (80 mg, 0.33 mmol), HATU (126 mg, 0.33 mmol), and dichloromethane (2 mL) at 25° C. The mixture was heated at 40° C. for 3 h. The mixture was concentrated and the residue was purified by column chromatography (0-100% ethyl acetate/hexanes) to give (4-(isopropylsulfonyl)-3-methylphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone (107 mg, 65%) as a fluffy white solid. ESI-MS m/z calc. 479.6. found 480.3 (M+1)+. Retention time: 2.24 minutes (3 min run).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Si:11]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:14]([Si:11]([CH3:13])([CH3:12])[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([CH3:29])([CH3:28])[CH:26]=[O:27])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(CO)CCCCCCO[Si](C)(C)C(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C=O)CCCCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl Chloride (5.9 mL) was added at −70° C. to a solution of dimethylsulfoxide (4.98 mL) in dry dichloromethane (60 mL) and the mixture stirred for 1 hour. 8-(tert-Butyldimethylsilyloxy)-2,2-dimethyloctan-1-ol (example 279, step b) (10.11 g), dissolved in dichloromethane (20 mL), was added dropwise and the mixture allowed to stir for 1 hour. Triethylamine (19.4 mL) was then added and stirring continued for 1 hour. The cooling bath was removed and the mixture allowed to warm to room temperature, at which point DCM (15 mL) was added. 1N HCl was added dropwise to dissolve the salts present in the reaction mixture and the layers separated. The aqueous layer was extracted with DCM (2×250 mL) then the combined organic layers were washed with saturated aqueous sodium carbonate (250 mL), dried over magnesium sulfate, filtered and concentrated under vacuum to give an orange liquid. The residue was filtered through a short plug of silica using diethyl ether as the eluent to afford 8-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-octanal as a yellow liquid which was used without further purification.
Reaction SMILES: C(O[C@H](CCCCCCCCCC(C)C)CC(O)=O)C1C=CC=CC=1.BrC1C=CC([C@:33](CC=O)([CH:37]([O:52][C:53](=[O:69])[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH:49]([CH3:51])[CH3:50])[C:34]([O-:36])=[O:35])=CC=1>[Zn]>[C:53]([O:52][C@H:37]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH:49]([CH3:50])[CH3:51])[CH2:33][C:34]([OH:36])=[O:35])(=[O:69])[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCC(C)C)[C@](CC=O)(C(=O)[O-])c1ccc(Br)cc1
Agent: CC(C)CCCCCCCCC[C@H](CC(=O)O)OCc1ccccc1
Agent: [Zn]
Product: CCCCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCCC(C)C)CC(=O)O
Yield: 95.8 %

Procedure:
In a manner similar to the synthesis of 107, compound 120 (500 mg, 0.666 mmol) was treated with zinc (<10 micron, 430 mg, 6.66 mmol) to afford 109 as an amorphous solid (335 mg, 96%). Rf=0.35 (toluene/ethyl acetate, 4/1, v/v); [α]25D=−0.6° (c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3): δ 5.19 (m, 1H, H-3), 2.58 (m, 2H, H-2), 2.25 (t, 2H, J=7.5 Hz, H-2′), 1.60-1.43 (m, 5H, H-4, H-15, H-3′), 1.23-1.14 [m, 44H, H-(5-14), H-(4′-15′)], 0.85-0.83 (m, 9H, H-16, H-16′); 13C NMR (75 MHz, CDCl3): δ 176.24 (C═O), 173.27 (C═O), 69.95 (C-3). HR MS (m/z) calculated for C33H64O4 [M+Na]+, 547.4697. found, 547.5009.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2)[CH:2]=1.[BH4-].[Na+].Cl.C([O-])(O)=O.[Na+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@H:7]2[CH2:8][CH2:9][C@H:10]([OH:13])[CH2:11][CH2:12]2)[CH:2]=1
Reactant: O=C1CCC(c2cccnc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: O[C@H]1CC[C@H](c2cccnc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(3-pyridyl)cyclohexanone (3.22 g, 18.4 mmol) in MeOH (25 ml) was added portionwise NaBH4 (348 mg. 9.30 mmol) at 0° C., and stirred for 30 min at room temperature. The reaction mixture was poured into 0.5M HCl and basified with sat. NaHCO3 aq. and then extracted with CH2Cl2. The organic layer was dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (Hexane/EtOAc=5/1) to yield trans-4-(3-pyridyl)cyclohexanol (2.48 g, 76%) as a colorless powder.