Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:16][N:17]1C(=O)C2=CC=CC=C2C1=O)[CH2:3][PH:4]([CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([O-:8])[O:5][CH2:6][CH3:7].O.[BH4-].[Na+].C(O)(=O)C>C(O)(C)C>[NH2:17][CH2:16][CH:2]([OH:1])[CH2:3][P:4]([CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])(=[O:8])[O:5][CH2:6][CH3:7]
Reactant: CCOC(OCC)[PH]([O-])(CC(O)CN1C(=O)c2ccccc2C1=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CCOC(OCC)P(=O)(CC(O)CN)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1.0 g of ethyl 2-hydroxy-3-phthalimido-propyl(diethoxymethyl)phosphonite in 23 ml of isopropanol is added 4 ml of water. To this mixture is added 0.47 g of sodium borohydride and this is stirred for a period of 24 hours at room temperature. After this time 2.6 ml of glacial acetic acid are carefully added and the reaction heated to 80° for a period of 2 hours. After this time, the reaction is cooled to room temperature, the solvent evaporated under reduced pressure and the residue passed down a silica column using a mixture of one part ethyl acetate to one part ethanol as eluant. Ethyl 3-amino-2-hydroxy-propyl(diethoxymethyl)phosphinate is obtained as colourless oil, 31P=+45.8 and +45.2 ppm (CDCl3).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:14]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[O:22][C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=3[Cl:30])=[O:15])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[Cl:31]C1C=CC=C(C(OO)=O)C=1.C[Si](C)(C)N[Si](C)(C)C.ClC(OC)=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:31][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:14]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[O:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[Cl:30])=[O:15])[CH2:6][CH2:5][N:4]2[CH:1]1[CH2:2][CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCN(C2CC2)c2ccccc21
Agent: COC(=O)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C([O-])O
Solvent: ClCCl
Product: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCN(C2CC2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 9.8 %

Procedure:
To an ice-cold suspension of 0.61 g (1.39 mmol) (4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-methanone (Example 8) in 3 mL dichloromethane were added 0.388 g (1.73 mmol) m-chloroperbenzoic acid (Aldrich, CAS RN 937-14-4). The cooling bath was removed, the reaction stirred at room temperature for 45 min., poured on a saturated solution of aqueous sodium bicarbonate and extracted three times with dichloromethane. The organic layers were washed with a saturated solution of aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The resulting powder was purified by silica gel chromatography using a MPLC system (20 g silica gel column, CombiFlash Companion, Isco Inc.) with a gradient of n-heptane:ethyl acetate:methanol (100:0:0 to 0:100:0 to 0:0:100). From the resulting light brown foam (0.51 g; MS (ESI): m/z=456.087 [M+H]+), 0.20 g (0.44 mmol) were dissolved in 8 mL tetrahydrofuran and 0.09 mL (0.44 mmol) hexamethyldisilazane and 0.08 mL (1.1 mmol) methyl chloroformate were added. The resulting brown, turbid solution was stirred for 1.5 hours at room temperature, poured on saturated aqueous sodium bicarbonate solution and was extracted three times with ethyl acetate. The organic layers were washed with brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The resulting powder was purified by silica gel chromatography using a MPLC system (10 g silica gel column, CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 25:75). The resulting orange solid (0.13 g) was dissolved in acetonitrile and a few drops N,N-dimethylformamide, filtered using a syringe micro filter and purified two times on a preparative HPLC system (Phenomenex Gemini column) using a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) to give 65 mg (31%) of the title compound as a light brown foam. MS (ESI): m/z=474.054 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=1.[CH:21](=[O:23])[CH3:22]>O1CCCC1.COC(C)(C)C.[Cl-].[NH4+].O>[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[C:19]=1[CH:21]([OH:23])[CH3:22]
Reactant: Clc1cncc(Cl)c1
Reactant: CC=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(O)c1c(Cl)cncc1Cl
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a 3-neck 12 L round bottom flask add tetrahydrofuran (THF, 3 L) and diisopropylamine (DIPA, 315 mL, 2.24 mol) and cool to −78° C. Add slowly n-butyllithium (1.6 M in hexanes, 1400 mL, 2.24 mol). After the addition is complete and the temperature has settled at −78° C. slowly add a solution of 3,5-dichloropyridine (296.7 g, 2.00 mol) which immediately forms a yellow solution that changes to a rust colored suspension. After the addition is complete and the temperature has settled at −78° C. slowly add acetaldehyde (230 mL, 4.05 mol) in THF (600 mL). Continue stirring at −78° C. After 3 hours, remove the dry ice bath and begin quenching the reaction by the dropwise addition of saturated aqueous ammonium chloride (1 L). Allow the reaction to warm to room temperature (RT) overnight with stirring. Dilute the mixture with methyl-tert-butylether (MTBE, 2 L), saturated aqueous ammonium chloride (1 L) and water (2 L). Partition and wash organics with saturated aqueous sodium chloride (brine). Extract the aqueous phase with MTBE (1.5 L). Combine the organic layers, dry over sodium sulfate, filter and concentrate in vacuo. Purify the residue by silica gel chromatography [25% ethylacetate (EA) in hexanes] to give the title compound as a red oil. Yield: 352 g (90%). MS (ES) m/z 192 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7].[N+](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N-]>ClCCl.CCCCCCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:18]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: COc1cccc(CO)c1
Agent: [Rh]
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)COCc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
To a solution of 3-methoxybenzyl alcohol (1.24 g, 10.0 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyl diazoacetate (0.95 mL, 9.0 mmol). The reaction mixture is stirred at RT for 30 min. The reaction mixture is diluted with heptane, filtered through Celite, and the filtrate is evaporated and the residue is vacuum distilled at 150° C. to give 2.00 g of the product 398. 1H NMR (CDCl3) δ 7.26 (t, 1H), 6.93 (m, 2H), 6.85 (m, 1H), 4.62 (s, 2H), 4.23 (q, 2H), 4.09 (s, 2H), 3.81 (s, 3H), 1.29 (t, 3H); MS: m/z 224 (M++1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH:5]=[C:4]([Cl:16])[CH:3]=1.[C:17](=[O:19])=[O:18]>O1CCCC1.Cl.C(OCC)(=O)C>[Cl:16][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH:5]=1)[C:17]([OH:19])=[O:18]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(Cl)c1
Reactant: O=C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64 %

Procedure:
To “Rieke Mg” (0.21 mol; Rieke, R. D.; Bales, S. E.; Hudnall, P. M.; Burns, T. P.; Poindexter, G. S. Org. Synth. Collective Volume VI, 1988, 845.) in tetrahydrofuran (1000 mL) was added ether 13 (27.7 g, 0.10 mol). After the reaction mixture was stirred for 20 min at ambient temperature there was an exotherm observed. The exotherm subsided within 5 min, and the reaction mixture was cooled to 20° C. with an ice bath. After 15 min, the reaction mixture was cooled to −78° C. To the cool reaction mixture was added CO2 gas for 30 min. The reaction mixture was warmed to ambient temperature, then diluted with cold (0° C.) 10% aqueous HCl (150 mL) and ethyl acetate (400 mL). The aqueous phase was extracted with ethyl acetate (400 mL). The combined organic phases were washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting solid was recrystallized from acetonitrile to provide 14 as fluffy white needles (19.3 g, 64%). 1H NMR (300 MHz, CDCl3) δ 7.70 (s, 1H), 7.43 (s, 1H), 7.08 (s, 1H), 0.99 (s, 9H), 0.23 (s, 6H). IR (KBr) 2957, 1697, 1578, 1434, 1297, 1266, 1115, 990, 871 cm−1.
Reaction SMILES: [CH:1]1([CH:6]([N:10]2[CH:14]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:12]=[N:11]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:25]1[C:26]2[CH:33]=[CH:32][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:27]=2[N:28]=[CH:29][N:30]=1.O1CCOCC1.C(=O)(O)[O-].[Na+]>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(OCC)(=O)C.O>[CH:1]1([CH:6]([N:10]2[CH:14]=[C:13]([C:25]3[C:26]4[CH:33]=[CH:32][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:27]=4[N:28]=[CH:29][N:30]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[N:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OB(c2cnn(C(CC#N)C3CCCC3)c2)OC1(C)C
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
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: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C4CCCC4)c3)ncnc21
Temperature: 90 °C
Yield: 83.6 %

Procedure:
Into a 25 ml round bottom flask equipped with a stir bar, condenser, thermocouple and 3-way valve was charged 3-cyclopentyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile (23, 0.697 g, 2.21 mmol, 1.3 equiv), 4-chloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (3a, 0.506 g, 1.69 mmol), 1,4-dioxane (4.44 mL), water (4.44 mL), and sodium bicarbonate (NaHCO3, 0.666 g, 7.93 mmol, 4.7 equiv) at room temperature. The resulting mixture was degassed four times backfilling with nitrogen each time before tetrakis(triphenylphosphine)palladium(0) (91.6 mg, 0.079 mmol, 0.047 equiv) was added. The resulting reaction mixture was degassed four times backfilling with nitrogen each time. The reaction was then warmed to 90° C. for 2-6 h. When TLC and HPLC showed that the coupling reaction was deemed complete, the reaction mixture was allowed to cool to room temperature followed by dilution with water (5 mL) and ethyl acetate (10 mL). The two layers were separated, and the aqueous layer was back extracted with ethyl acetate (10 mL). The combined organic fractions were washed with water (10 mL) and saturated aqueous NaCl solution (10 mL), dried over magnesium sulfate (MgSO4), and concentrated under reduced pressure to give the crude product (9) as an amber oil. The crude product was purified by flash column chromatography (SiO2, 0% to 40% ethyl acetate/hexane gradient elution) to afford racemic 3-cyclopentyl-3-{4-[7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrazol-1-yl}propionitrile (9, racemic SEM-protected compound, 617 mg, 737.9 mg theoretical, 83.6% yield) as a yellow oil. For 9: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.83 (s, 1H), 8.75 (s, 1H), 8.39 (s, 1H), 7.77 (d, 1H, J=3.7 Hz), 7.09 (d, 1H, J=3.7 Hz), 5.63 (s, 2H), 4.53 (td, 1H, J=19.4, 4.0 Hz), 3.51 (t, 2H, J=8.1 Hz), 3.23 (dq, 2H, J=9.3, 4.3 Hz), 2.41 (m, 1H), 1.79 (m, 1H), 1.66-1.13 (m, 7H), 0.81 (t, 2H, J=8.2 Hz), 0.124 (s, 9H); C23H32N6OSi (MW, 436.63), LCMS (EI) m/e 437 (M++H) and m/e 459 (M++Na).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[C:15]([O:19]C)(=[O:18])[CH:16]=[CH2:17].[OH-].[K+]>CO.O>[CH:4]1[C:5]2[CH:6]3[CH2:17][CH:16]([C:15]([OH:19])=[O:18])[CH:13]([C:12]4[C:7]3=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:14]=2[CH:1]=[CH:2][CH:3]=1
Reactant: c1ccc2cc3ccccc3cc2c1
Reactant: C=CC(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1CC2c3ccccc3C1c1ccccc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Anthracene (40 gm) was combined with methyl acrylate (30 gm) in a Parr bomb and heated to 150°-175° C. for 6 hours. The mixture was allowed to remain in the bomb at room temperature for 72 hours. The mixture was dissolved in methanol (225 ml), treated with a solution of potassium hydroxide (40 gm) in water (40 ml) and heated to reflux for 4 hours. The solution was cooled to room temperature and most of the solvent was removed on a rotary evaporator. The residue was dissolved in water (200 ml), filtered through charcoal and acidified with concentrated hydrochloric acid. The resulting mixture was allowed to stand overnight and the precipitate was filtered. The white solid was dried at 80° and recrystallized from benzene to provide the product (mp=188°-189° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:26][S:27]([N:30]1[CH2:35][CH2:34][CH:33]([C:36](Cl)=[O:37])[CH2:32][CH2:31]1)(=[O:29])=[O:28].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:22]([N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:19])[F:20])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:36]([CH:33]2[CH2:34][CH2:35][N:30]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:31][CH2:32]2)=[O:37])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH:23]([CH3:25])[CH3:24]
Reactant: CS(=O)(=O)N1CCC(C(=O)Cl)CC1
Reactant: CC(C)CN(c1ccccc1C(F)(F)F)S(=O)(=O)c1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CN(c1ccccc1C(F)(F)F)S(=O)(=O)c1ccc(NC(=O)C2CCN(S(C)(=O)=O)CC2)cc1
Yield: 65.1 %

Procedure:
A solution of 4-amino-N-isobutyl-N-(2-trifluoromethyl-phenyl)-benzenesulfonamide (100 mg, 0.268 mmol), 1-(methylsulfonyl)-4-piperidinecarbonyl chloride (108 mg, 0.48 mmol) and DIPEA (138 μL, 0.804 mmol) in DCM (8 mL) was stirred at room temperature for 3 hours. The mixture was diluted with DCM, washed with 1 N aqueous HCl, saturated aqueous NaHCO3, water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-100% EtOAc in cyclohexane) and triturating with Et2O/pentane gave the title compound (98 mg, 65%). 1H NMR (400 MHz, DMSO δ 10.42 (s, 1H), 7.85 (d, J=8.8 Hz, 2H), 7.82 (dd, J=7.7, 1.9 Hz, 1H), 7.62-7.63 (m, 1H), 7.58 (d, J=8.8 Hz, 2H), 6.99 (d, J=7.8 Hz, 1H), 3.63 (d, J=11.8 Hz, 2H), 3.38-3.39 (m, 1H), 3.11 (dd, J=13.4, 4.7 Hz, 1H), 2.90 (s, 3H), 2.76-2.78 (m, 2H), 1.95 (d, J=13.5 Hz, 2H), 1.63-1.68 (m, 2H), 1.44-1.48 (m, 1H), 1.09 (t, J=7.0 Hz, 1H), 0.88 (d, J=6.5 Hz, 3H), 0.71 (d, J=6.7 Hz, 3H). LCMS (m/z, Method B) ES+ 562.0 [M+1]+.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:32])[C:9]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:10]([C:19]3[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=3)[C:11]=2[C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:39]1([CH3:45])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]1([C:7]2[C:8](=[O:32])[C:9]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([C:41]4[CH:42]=[CH:43][C:44]5[C:16]6[C:15](=[CH:14][CH:13]=[CH:12][CH:17]=6)[C:45]([CH2:21][CH2:22][CH3:23])([CH2:10][CH2:9][CH3:26])[C:39]=5[CH:40]=4)=[CH:21][CH:20]=3)[C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([C:41]3[CH:42]=[CH:43][C:44]4[C:6]5[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=5)[C:45]([CH2:8][CH2:7][CH3:11])([CH2:24][CH2:19][CH3:20])[C:39]=4[CH:40]=3)=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1
Reactant: O=C1C(c2ccccc2)=C(c2ccc(Br)cc2)C(c2ccc(Br)cc2)=C1c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCC1(CCC)c2ccccc2-c2ccc(-c3ccc(C4=C(c5ccccc5)C(=O)C(c5ccccc5)=C4c4ccc(-c5ccc6c(c5)C(CCC)(CCC)c5ccccc5-6)cc4)cc3)cc21
Yield: 99 %

Procedure:
Tetrakis(triphenylphosphine)-palladium (0) (1.48 g, 1.3 mmol) was added to a solution of (9) (13.8 g, 26 mmol) and (8) (22.6 g, 77 mmol) in a mixture of ethanol (100 mL), 2M aqueous sodium carbonate (100 mL) and toluene (300 mL) that had been deoxygenated with argon. The solution was deoxygenated and heated at reflux for 16 hours, then poured into methanol. The resulting brown precipitate was filtered, dissolved in chloroform, washed with brine, and dried over magnesium sulfate. The solution was poured into methanol, and the brown precipitate filtered to give (10) (22.4 g, 99%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[C:7]3[C:16](=[CH:17][CH:18]=[C:5]2[CH:4]=[N:3]1)[N:15]=[C:14]1[C:9]([C:10]([C:19](O)=[O:20])=[CH:11][CH:12]=[CH:13]1)=[N:8]3.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH:26][C:19]([C:10]1[C:9]2[C:14](=[N:15][C:16]3[C:7]([N:8]=2)=[C:6]2[N:2]([CH3:1])[N:3]=[CH:4][C:5]2=[CH:18][CH:17]=3)[CH:13]=[CH:12][CH:11]=1)=[O:20]
Reactant: Cn1ncc2ccc3nc4cccc(C(=O)O)c4nc3c21
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)c1cccc2nc3ccc4cnn(C)c4c3nc12

Procedure:
1-Methyl-1H-pyrazolo[3,4-α]phenazine-10-carboxylic acid (2-dimethylamino-ethyl)-amide was prepared from 1-methyl-1H-pyrazolo[3,4-α]phenazine-10-carboxylic acid (II.8) and N,N-dimethylethylenediamine
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C(OC(C1CCCCC1=O)=O)C.[C:19]([O:23][C:24]([C@@H:26]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].Br[C:33]1[CH:34]=[CH:35][C:36]([C:39]([F:42])([F:41])[F:40])=[N:37][CH:38]=1>CS(C)=O.[Cu](Br)Br>[C:19]([O:23][C:24]([C@@H:26]1[CH2:30][CH2:29][C:28](=[O:31])[N:27]1[C:33]1[CH:38]=[N:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1
Reactant: FC(F)(F)c1ccc(Br)cn1
Agent: Br[Cu]Br
Agent: CCOC(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1c1ccc(C(F)(F)F)nc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A solution of cesium carbonate (1.539 g; 4.725 mmol), copper bromide (0.032 g; 0.225 mmol) and ethyl-2-oxocyclohexanecarboxylate (0.072; 0.45 mmol) in anhydrous dimethyl sulfoxide (1.25 mL) is degassed with argon and stirred 30 minutes. To this solution is added (S)-5-oxo-pyrrolidine-2-carboxylic acid tert-butyl ester (0.5 g; 2.699 mmol) and 5-bromo-2-trifluoromethylpyridine (0.508 g; 2.25 mmol) in 1 mL anhydrous dimethyl sulfoxide. The mixture is heated in a sealed tube to 60° C. in an oil bath and stirred overnight. The reaction mixture is cooled to room temperature, filtered through Celite® and washed with ethyl acetate. The combined organics are washed with brine, dried over sodium sulfate and concentrated under reduced pressure. ESI m/z 331 [M+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:31][Si:32]([C:35]#[CH:36])([CH3:34])[CH3:33]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I.C(N(CC)CC)C>[CH3:31][Si:32]([C:35]#[C:36][C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1)([CH3:34])[CH3:33]
Reactant: NS(=O)(=O)c1cccc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccc(S(N)(=O)=O)c1

Procedure:
Into a sealable tube was weighed 1.24 g of 3-bromophenylsulfonamide, 112 mg of triphenylphosphine, 40 mg of palladium acetate, 32 mg of copper (I) iodide, and 5 mL of triethylamine. To this suspension was added 2.0 mL of trimethylsilylacetylene and the vessel was sealed, was set in an oil bath, and was rapidly stirred at 90-950C. After 1 h the reaction was cooled, unsealed, and was filtered with added ethyl acetate to remove solids. The filtrate was concentrated in vacuo and the residue was purified by silica gel flash chromatography (Jones Flashmaster, 50 g silica gel, gradient elution from 100% hexanes to 20% ethyl acetate over 30 minutes). Appropriate fractions were combined and concentrated in vacuo affording 3-trimethylsilanylethynyl-benzenesulfonamide as a faintly yellow semi-crystalline solid, yield: 908.3 mg (68%). 1H NMR (CDCl3): δ 8.02 (s, 1H), 7.85 (d, J=8 Hz, 1H), 7.64 (d, J=8 Hz, 1H), 7.48 (t, J=8 Hz, 1H), 5.02 (br s, 2H), 0.26 (s, 9H). Into a 50 mL flask was weighed 423.7 mg of trifluoromethanesulfonic acid 2-(2-chlorophenyl)-5-trifluoromethyl-2H-pyrazol-3-yl ester (1.07 mmol), 325.6 mg (1.28 mmol) of alkyne, 26.5 mg of copper (I) chloride, and 69.3 mg (600 μmol) of triphenylphosphine, followed by 5 mL of DMF. The reaction was heated at 80-850C for 5 h then was quenched by addition of 3 M HCl. The reaction mixture was washed into a separatory funnel with ethyl acetate and 3.0 M HCl. The ethyl acetate was separated, washed with brine, was dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel flash chromatography (Jones Flashmaster, 50 g silica gel, gradient elution from 100% hexanes to 40% ethyl acetate over 30 minutes). Appropriate fractions were combined and concentrated in vacuo affording the product as a grayish powder, yield: 78.4 mg (17%); 1H NMR (CDCl3): δ 7.89 (m, 1H), 7.84 (s, 1H), 7.60 (d, J=8 Hz, 1H), 7.35-7.6 (m, 5H), 6.94 (s, 1H), 4.82 (s, 2H); MS (ES): 426 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19])[CH2:4][CH2:5][OH:6])[CH3:2].[F:20][C:21]1[C:26](O)=[CH:25][CH:24]=[CH:23][N:22]=1.C1[C@@H](COC2C=CC=NC=2[18F])NC1.C(OCC[N+](C)(C)C)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:1]([N:3]([CH2:7][CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19])[CH2:4][CH2:5][O:6][C:26]1[C:21]([F:20])=[N:22][CH:23]=[CH:24][CH:25]=1)[CH3:2]
Reactant: Oc1cccnc1F
Reactant: CCN(CCO)CCN1C(=O)c2ccccc2C1=O
Agent: CC(=O)OCC[N+](C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: [18F]c1ncccc1OC[C@@H]1CCN1
Solvent: C1CCOC1
Product: CCN(CCOc1cccnc1F)CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.7 %

Procedure:
To a solution of compound 3 (1.65 g, 6.29 mmol) in anhydrous tetrahydrofuran (THF, 80 mL) were successively added, under argon, 2-fluoro-3-hydroxypyridine (0.72 g, 6.37 mmol) (Dollé, F.; Valette, H.; Bottlaender, M.; Hinnen, F.; Vaufrey, F.; Guenther, I.; Crouzel, C. Synthesis of 2-[18F]fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine, a highly potent radioligand for in vivo imaging central nicotinic acetylcholine receptors. J. Label. Compds. Radiopharm. 1998, 41, 451-463), triphenylphosphine (1.65 g, 6.29 mmol) and dropwise diisopropyl azodicarboxylate (DIAD, 1.71 mL, 8.68 mmol). The mixture was stirred at room temperature for 24 h. The solvent was evaporated under reduced pressure and the residue was chromatographed (Al2O3, AcOEt) to give compound 4 (1.77 g, 4.95 mmol) as a yellow solid. Yield 79%; Rf (Al2O3, AcOEt) 0.84; mp 58-60° C.; IR (KBr) ν 1192, 1240, 1290, 1395, 1452, 1712, 2847, 2943 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.29 (t, 3H, J=7.1 Hz), 2.97 (q, 2H, J=7.1 Hz), 3.14 (t, 2H, J=6.5 Hz), 3.24 (t, 2H, J=5.9 Hz), 4.08 (t, 2H, J=6.5 Hz), 4.31 (t, 2H, J=5.9 Hz), 7.35 (ddd, 1H, 5JH-F=0.9 Hz, J=4.8, 7.8 Hz), 7.52 (ddd, 1H, 4JH-F=10.0 Hz, J=1.6, 7.8 Hz), 7.97 (m, 3H), 8.07 (m, 2H); MS m/z 357 (M+, 1), 231 (15), 197 (100), 174 (23), 130 (10), 85 (17), 76 (10), 57 (45).