Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:34]=[CH:33][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][C:21]3[CH:32]=[CH:31][C:24]([O:25][CH2:26][C:27]([O:29]C)=[O:28])=[CH:23][CH:22]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:52][C:53]1[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH:61]2[CH2:63][O:62]2)=[CH:55][CH:54]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[OH:62][C@H:61]([CH2:60][O:59][C:56]1[CH:57]=[CH:58][C:53]([OH:52])=[CH:54][CH:55]=1)[CH2:63][NH:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:31][CH:32]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)COc1ccc(NC(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)cc1
Solvent: CO
Solvent: O=CO
Solvent: ClC(Cl)Cl
Product: O=C(O)COc1ccc(NC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 31 %

Procedure:
Methyl 2-{4-[({4-[4-(2-aminoethyl)anilino]-1-piperidinyl}carbonyl)amino] phenoxy}acetate formate (0.48 g, 1.0 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.25 g, 0.62 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.16 g, 0.192 mmol).
Reaction SMILES: Cl.[C:2]12([CH2:12][CH2:13][N:14]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:15]([C@H:17]3[CH2:21][CH2:20][CH2:19][NH:18]3)=[O:16])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.C(=O)([O-])[O-].[K+].[K+].CI.Cl.[Cl:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1.[OH-].[Na+]>CN(C)C=O.C(OCC)C>[ClH:36].[C:2]12([CH2:12][CH2:13][N:14]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:15]([C@H:17]3[CH2:21][CH2:20][CH2:19][N:18]3[CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=3)=[O:16])[CH2:9][CH:8]3[CH2:10][CH:4]([CH2:5][CH:6]([CH2:7]3)[CH2:11]1)[CH2:3]2
Reactant: ClCCc1ccncc1
Reactant: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)[C@H]1CCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)[C@H]1CCCN1CCc1ccncc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 44.3 %

Procedure:
Next, (R)-2-pyrrolidinecarboxylic acid N-[2-(1-adamantyl)ethyl]-N-pentylamide hydrochloride (1.4 g, 3.7 mmol) was dissolved in anhydrous N,N-dimethylformamide (40 ml), potassium carbonate (2.6 g, 19 mmol), methyl iodide (1.7 g, 11 mmol) and 4-(2-chloroethyl)pyridine hydrochloride (0.70 g, 3.7 mmol) were added to the solution, and the mixture was stirred at an external temperature of 80° C. overnight. A 2 N aqueous sodium hydroxide solution (70 ml) and diethyl ether (70 ml) were added to the reaction mixture, the reaction mixture was distributed, and the diethyl ether layer was washed with water (70 ml) and a saturated aqueous sodium chloride solution (70 ml) successively and dried over anhydrous magnesium sulfate. The diethyl ether layer was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography to give 0.80 g (47%) of the titled compound as an oily matter.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[N:9]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:16])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH2:13])=[N:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1ccc([N+](=O)[O-])n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Cn1ccc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
To a solution containing (3-nitro-pyrazol-1-yl)-acetic acid tert-butyl ester (104 mg, 0.46 mmol) in methanol (3 mL), palladium, 10 wt. % on activated carbon, wet (˜50 mg) was added to the solution. The vial was charged with hydrogen gas (via balloon) and the mixture was stirred for 16 h at 25° C. The mixture was passed through a plug of celite and concentrated in vacuo to give the desired (3-amino-pyrazol-1-yl)-acetic acid tert-butyl ester (80 mg, 89%) as a light blue oil: ESI-LRMS m/e calcd for C9H15N3O2 [M+] 197.1, found 395.2 [2M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13][C:14]#[N:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:13][C:14]#[N:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(=CC#N)c2ccccc2)ccc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOc1cc(C(CC#N)c2ccccc2)ccc1OC
Yield: 16.7 %

Procedure:
To a solution of 3-(3-ethoxy-4-methoxyphenyl)-3-phenylacrylonitrile (0.9 g, 3.2 mmol) in a mixture of ethanol and ethyl acetate (20 mL/ 30 mL) was added 0.5 g of 10% palladium on carbon catalyst in portions. The mixture was hydrogenated in a Parr-Shaker apparatus at 55-60 psi of hydrogen for 12 days. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford the crude product. The crude product was purified by flash column chromatography (silica gel, 4% hexane/methylene chloride) to afford 0.15 g (15%) of the product as an oil: 1H NMR (CDCl3) δ 7.40-7.16 (m, 5 H); 6.88-6.78 (m, 3 H), 4.32 (t, J=7.5 Hz, 1 H), 4.03 (q, J=7 Hz, 2 H), 3.85 (s, 3 H), 3.00 (d, J=7.5 Hz, 2 H), 1.42 (t, J=7 Hz, 3 H); 13C NMR (CDCl3) δ 148.7, 148.5, 141.5, 133.7, 128.8, 127.4, 127.3, 119.5, 118.5, 112.7, 111.6, 64.4, 55.9, 46.7, 24.5, 14.7; Anal. Calcd for C18H17NO2. Theoretical: C, 76.84; H, 6.81; N, 4.98. Found: C, 76.53; H, 6.92; N, 4.95.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.CN(C)CCN(C)CCN(C)C.C([Li])CCC.B(OC)(OC)[O:28]C.OO.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C.O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:28]
Reactant: COc1ccc(F)cc1
Reactant: COB(OC)OC
Agent: CN(C)CCN(C)CCN(C)C
Agent: O=S([O-])[O-]
Agent: OO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(F)c(O)c1
Temperature: -70 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a flask, 4-fluoroanisole (20.00 g, 159 mmol), N,N,N′,N″,N″-pentamethyldiethylenetriamine (27.75 g, 160 mmol), and tetrahydrofuran (100 mL) were added, and the resulting mixture was cooled to −70° C. under nitrogen atmosphere. To the solution, n-butyllithium (59.2 mL, 163 mmol, 2.76 M, in hexane) was added dropwise, and trimethyl borate (39.8 mL, 357 mmol) was added three hours later. One hour later, the reaction mixture was warmed to −10° C., and acetic acid (28.0 mL) was added thereto. The reaction temperature was then changed to 5° C., and 30% aqueous hydrogen peroxide solution (30 mL) was added dropwise to the reaction mixture, after which the resulting mixture was stirred overnight at room temperature. To the reaction mixture, 10% aqueous sodium sulfite solution was added, and the resulting mixture was extracted with tert-butyl methyl ether. To the organic layer, a 2 N aqueous sodium hydroxide solution was added, and the resulting mixture was extracted. After adding 5 N hydrochloric acid to the aqueous layer to adjust the pH to 6, the resulting mixture was extracted with tert-butyl methyl ether. The organic layer was sequentially washed with water and 5% saline, dried over anhydrous magnesium sulfate, and then filtered. The filtrate obtained was concentrated under reduced pressure to obtain the captioned compound (21.7 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[C:19](Cl)(=[O:21])[CH3:20]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH:12][C:19](=[O:21])[CH3:20])=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: CC(=O)Cl
Reactant: Cc1nc(-c2sc(N)nc2-c2ccccc2)no1
Product: CC(=O)Nc1nc(-c2ccccc2)c(-c2noc(C)n2)s1

Procedure:
Prepared from 5-(5-methyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-thiazol-2-ylamine and acetyl chloride.
Reaction SMILES: Cl[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2N=C(N)NC(=O)C=2N=C1.P(N)([O-])[O-].[I:25][CH2:26][C:27]([NH2:29])=[O:28].ICC(OC(=O)CI)=O.IC#N.N[C:43]1[CH:51]=[CH:50][C:46]([C:47]([OH:49])=[O:48])=[CH:45][CH:44]=1>O1CCOCC1>[I:25][CH2:26][C:27]([NH:29][C:43]1[CH:51]=[CH:50][C:46]([C:47]([OH:49])=[O:48])=[CH:45][CH:44]=1)=[O:28]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: NC(=O)CI
Agent: N#CI
Agent: NP([O-])[O-]
Agent: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2Cl)c(=O)[nH]1
Solvent: C1COCCO1
Product: O=C(CI)Nc1ccc(C(=O)O)cc1

Procedure:
An oligonucleotide, 20 bases in length, comprised of 2′-chloro-deoxyguanosine bases, acts as the sequence-specific component of the first reagent. This oligonucleotide is prepared on an automated oligonucleotide synthesizer using phosphoramidite chemistry. A primary amino group is introduced at the 3′-terminus of the oligonucleotide during its synthesis using the reagent 3'Amine O CPG (Clontech Laboratories, Inc., Palo Alto, Calif.). The primary amine at the 3′-terminus of the oligonucleotide is then reacted with SIAB (succinimydl 4-iodoacetyl aminobenzoate, Pierce, Rockford, Ill.) to introduce an iodoacetamide residue, according to Weltman, et al. (Weltman, J. K., et al., “N-Succinimidyl(4-lodoacetyl)Aminobenzoate: A New Heterobifunctional Crosslinker,” Biotechniques 1:148-152 (1983)). Weltman et al. disclose in their “MATERIALS AND METHODS” section the preparation of N-succinimidyl(4-iodoacetyl)amino-benzoate (SIAB). SIAB is prepared as outlined in FIG. 1 of Weltman et al. (figure not shown below). Iodoacetic anhydride, 354 mg (1 mmole) purchased from ICN Pharmaceuticals-K and K Laboratories, is reacted with 68.6 mg (0.5 mmoles) of p-aminobenzoic acid in 7.5 ml of dioxane, for 5 hours at room temperature in the dark, and then for 2 days at 4 degrees. A white flocculent intermediate (4-iodoacetylaminobenzoic acid) is isolated by centrifugation and triturated with 0.5 ml of diethyl ether three times. The resulting white intermediate is dried with hot air with a yield of 160 mg. Dicyclohexycarboiimide (86.2 mg; 0.4 mmoles) is added to a solution of the intermediate (128 mg; 0.4 mmoles) and N-hydroxysuccinimide (48.5 mg; 0.4 mmoles) in 3.35 ml of tetrahydrofuran (THF) and placed at 4 degrees for 20 hours. A precipitate is removed and the supernatant liquid is recovered and evaporated to dryness and triturated with diethyl ether. Pale yellow crystals of SIAB are recovered, yield 135 mg (80%), melting point 172-175 degrees. The yellow crystals of SIAB are recrystallized from methanol and washed twice with diethyl ether, yielding white crystals of SIAB, melting point 194-196 degrees with decomposition. The calculated molecular weight of SIAB is 402 daltons. The iodoacetamide-derivatized oligo(dG) is then reacted with the thiol group on the derivatized Fab′ fragment, thereby forming the first reagent of the invention.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:33])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Br:32])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:32][C:28]1[CH:27]=[C:26]([C:24]2[CH2:23][C:22](=[O:33])[NH:21][C:9]3[CH:10]=[C:11]([C:17]([F:20])([F:19])[F:18])[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]=3[N:7]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(Br)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(Br)c1)=N2

Procedure:
) The title compound was prepared from the above described {2-[3-(3-bromo-phenyl)-3-oxo-propionylamino]-5-dimethylamino-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (2.2 g, 4.04 mmol) and TFA (15 mL) in DCM (45 mL) according to general procedure I step 2. Obtained as an off-white solid (1.61 g, 93%). MS (ISP) 426.0 [(M+H)+]; mp 193° C. (dec).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.[F-].[K+]>C1COCC1>[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8]
Reactant: Cc1ccccc1B(O)O
Reactant: Cc1ccccc1Br
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccccc1C
Yield: 97.9 %

Procedure:
2-Bromotoluene (87 mg, 0.51 mmol) reacted with 2-methylphenylboronic acid (88 mg, 0.65 mmol) using 1 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (87 mg, 1.50 mmol) in THF solvent at room temperature to give the title compound (91 mg, 98%) as a colorless oil: 1H-NMR (300 MHz, CDCl3): δ 7.29-7.35 (m, 6H), 7.20 (d, 2H, J=6.3 Hz), 2.15 (s, 6H).). 13C{1H}-NMR (100 MHz, CDCl3): δ 141.56, 135.76, 129.77, 129.25, 127.12, 125.51, 19.81. GC/MS(EI): m/z 182 (M+).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([CH2:14][C:15]([OH:17])=[O:16])[C:10]([CH3:18])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O-])(O)=O.[Na+]>Cl>[CH3:19][O:16][C:15](=[O:17])[CH2:14][C:11]1[C:10]([CH3:18])=[N:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:12]=1[CH3:13]
Reactant: Cc1nn(Cc2ccccc2)c(C)c1CC(=O)O
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: COC(=O)Cc1c(C)nn(Cc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(1-Benzyl-3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid (1.00 g, 4.1 mmol) was dissolved in 3N methanolic HCl (7.5 mL) and stirred at room temperature for 18 h. The reaction mixture was neutralized with aqueous NaHCO3 solution and extracted with dichloromethane. The organic layer was dried over MgSO4 and concentrated under reduced pressure.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:42][CH3:43])=[C:10]([CH2:19][NH:20][C:21](=[O:41])[CH2:22][C:23]([NH:25][CH2:26][C:27]3[CH:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]=O)[CH:34]=4)[CH:30]=[CH:31][CH:32]=3)=[O:24])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:42][CH3:43])=[C:10]([CH2:19][NH:20][C:21](=[O:41])[CH2:22][C:23]([NH:25][CH2:26][C:27]3[CH:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][N:44]5[CH2:49][CH2:48][O:47][CH2:46][CH2:45]5)[CH:34]=4)[CH:30]=[CH:31][CH:32]=3)=[O:24])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1cccc(-c2cccc(C=O)c2)c1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1cccc(-c2cccc(CN3CCOCC3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
To N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-3-biphenylyl)methyl]propanediamide (30 mg, 0.051 mmol) was added morpholine (4.49 mg, 0.051 mmol) followed by NaB(OAc)3H (36.4 mg, 0.172 mmol) and AcOH (4.91 μL, 0.086 mmol) in dimethyl sulfoxide (DMSO) (0.5 mL). The mixture was stirred overnight at room temperature. The reaction was quenched with saturated NaHCO3 and extracted with EtOAc (3×1 mL). Combined organic layers were washed with saturated NaCl, dried (Na2SO4) and concentrated. The crude products were redissolved in MeOH/DMSO (1/1) and purified using a Gilson HPLC (acidic conditions) and basified with an amine cartridge to afford 11.9 mg (34%) of the title compound. LC-MS m/z 654 (M+H)+.
Reaction SMILES: C(OC1C=C(C=C(OCC)C=1F)CN1CCC([NH:14][C:15](=O)[C:16]2[CH:21]=[C:20]([CH3:22])[C:19]([NH:23][CH3:24])=[N:18][CH:17]=2)CC1)C.[CH3:33][Si](C)(C)[N-][Si](C)(C)C.[Na+].CI>C1COCC1>[CH3:33][N:23]([CH3:24])[C:19]1[C:20]([CH3:22])=[CH:21][C:16]([C:15]#[N:14])=[CH:17][N:18]=1
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cnc(NC)c(C)c3)CC2)cc(OCC)c1F
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc(C#N)cnc1N(C)C

Procedure:
5-Methyl-6-methylamino-nicotinonitrile (example 121, 0.345 g, 2.34 mmol) was dissolved in 3.2 ml of abs. THF and treated at 0° C. with sodium hexamethyldisilazide-solution (1M in THF, 7.03 ml, 3.0 eq.) and, after 5 Min., 4 eq. of methyl iodide (0.58 ml). The mixture was allowed to react for 1 h at room temperature. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (silica gel, hexane/AcOEt=7/3) yielded 0.330 g of the title compound as off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31]N3CCCC3)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[I-].[K+].[C:39]([O-:42])(=[O:41])[CH3:40].[K+]>CN(C)C=O.O.[Cl-].[Na+]>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][CH2:31][O:42][C:39](=[O:41])[CH3:40])(=[O:28])=[O:27])[CH2:24][CH2:25]2)[N:3]=1
Reactant: CC(=O)[O-]
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCN3CCCC3)CC2)nc1N
Agent: [Cl-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCOC(C)=O)CC2)nc1N
Yield: 51.5 %

Procedure:
A suspension of [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (80 mg, 0.16 mmol, Example 273), potassium iodide (100 mg, 0.61 mmol), and potassium acetate (120 mg, 1.22 mmol) in dimethylformamide (6 mL) was heated at 65–85° C. under nitrogen for 14 hours. The resulting solution was diluted with 50 mL of cold water plus 20 mL of saturated aqueous sodium chloride. Solids were filtered, collected and dissolved in methylene chloride. After washing with water, the organic layer was separated and dried (Na2SO4). The residue was purified by silica gel chromatography (ethyl acetate/hexane) and crystallized from methylene chloride/ethyl ether to give acetic acid 3-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-sulfonyl]-propyl ester as a white solid (42 mg, 51% yield). HRMS, observed: 510.1822; Calcd for (M+H)+: 510.1817
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:28])=[C:13]([C:23](OCC)=[O:24])[C:14](=[O:22])[N:15]2[CH2:18][CH:19]2[CH2:21][CH2:20]2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]1([NH2:33])[CH2:32][CH2:31][CH2:30]1>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:28])=[C:13]([C:23]([NH:33][CH:29]3[CH2:32][CH2:31][CH2:30]3)=[O:24])[C:14](=[O:22])[N:15]2[CH2:18][CH:19]2[CH2:21][CH2:20]2)=[N:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(CC2CC2)c1=O
Product: O=C(NC1CCC1)c1c(O)c2ncc(Cc3ccccc3)cc2n(CC2CC2)c1=O

Procedure:
This compound was prepared from ethyl 7-benzyl-1-(cyclopropylmethyl)-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and cyclobutylamine employing methods similar to those described in Example 5 and was obtained as an off-white solid: 1H NMR (CDCl3) δ 10.34 (1H, br d, J=7 Hz), 8.59 (1H, s), 7.46 (1H, s), 7.35 (2H, t, J=7 Hz), 7.28 (1H, t, J=7 Hz), 7.21 (2H, d, J=7 Hz), 4.53 (1H, m), 4.17 (2H, s), 4.08 (2H, d, J=7 Hz), 2.42 (2H, m), 2.09 (2H, m), 1.80 (2H, m), 1.01 (1H, m), 0.50 (2H, m), 0.40 (2H, m); HRMS calcd for C24H25N3O3+H+: 404.1974. Found: 404.1971.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:5]=[C:6]2[C:14]=1[O:13][C:9]1([CH2:12][CH2:11][CH2:10]1)[CH2:8][C@@H:7]2[NH:15][CH2:16][C@H:17]([C@@H:19]([NH:23][C:24](=[O:28])[CH2:25][O:26][CH3:27])[CH2:20][CH:21]=[CH2:22])[OH:18].C(=O)([O-])[O-].[Cs+].[Cs+].[NH:40]1[CH:44]=[CH:43][N:42]=[CH:41]1.CNCCNC>CN(C=O)C.[Cu]I.CN(C=O)C.O>[CH3:32][C:30]([CH3:31])([CH3:33])[CH2:29][C:4]1[CH:5]=[C:6]2[C:14](=[C:2]([N:40]3[CH:44]=[CH:43][N:42]=[CH:41]3)[CH:3]=1)[O:13][C:9]1([CH2:10][CH2:11][CH2:12]1)[CH2:8][C@@H:7]2[NH:15][CH2:16][C@H:17]([C@@H:19]([NH:23][C:24](=[O:28])[CH2:25][O:26][CH3:27])[CH2:20][CH:21]=[CH2:22])[OH:18]
Reactant: C=CC[C@H](NC(=O)COC)[C@H](O)CN[C@H]1CC2(CCC2)Oc2c(Br)cc(CC(C)(C)C)cc21
Reactant: c1c[nH]cn1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: C=CC[C@H](NC(=O)COC)[C@H](O)CN[C@H]1CC2(CCC2)Oc2c1cc(CC(C)(C)C)cc2-n1ccnc1
Temperature: 185 °C

Procedure:
To a microwave vial is added N-((1S)-1-((1R)-2-(((4S)-8-bromo-6-(2,2-dimethylpropyl)-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-1-hydroxyethyl)-3-buten-1-yl)-2-methoxyacetamide (100 mg, 191 μmol), cesium carbonate (311 mg, 955 μmol), 1H-imidazole (65 mg, 955 μmol), and copper(I) iodide (36 mg, 191 μmol). The vial was purged with N2 5×, then 10:1 DMF/H2O (2 mL) and N1,N2-dimethylethane-1,2-diamine (21 μl, 191 μmol) were added. The vial was sealed and heated in a microwave at 185° C. for 30 min. The crude product was dissolved in DMF, filtered through an Acrodisc filter and purified by reverse phase HPLC to afford the title compound as a white amorphous solid. MS m/z=511.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([CH2:19][N:20]4[CH:24]=[C:23]([C@:25]([OH:32])([C:28]([F:31])([F:30])[F:29])[CH2:26][CH3:27])[N:22]=[N:21]4)=[CH:16][CH:17]=3)[N:12]=[C:11]([C:33]#[N:34])[CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O-])([O-])=[O:36].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+]>CC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([CH2:19][N:20]4[CH:24]=[C:23]([C@:25]([OH:32])([C:28]([F:31])([F:29])[F:30])[CH2:26][CH3:27])[N:22]=[N:21]4)=[CH:16][CH:17]=3)[N:12]=[C:11]([C:33]([NH2:34])=[O:36])[CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC[C@](O)(c1cn(Cc2ccc3c(-c4cc(Cl)cc(Cl)c4)cc(C#N)nc3c2)nn1)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4cc(Cl)cc(Cl)c4)cc(C(N)=O)nc3c2)nn1)C(F)(F)F
Reaction time: 1.5 h

Procedure:
To a solution of (S)-4-(3,5-dichlorophenyl)-7-({4-[1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)quinoline-2-carbonitrile (30 mg, 0.059 mmol) in acetone (1.5 mL) and water (1 mL) was added sodium percarbonate (28 mg, 0.18 mmol). After 1.5 h at 50° C., the reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure. Purification on silica gel (eluting with acetone/dichloromethane, 2:8) gave the title compound. MS (+ESI): 524 (M+H)+.
Reaction SMILES: [CH:1](=[O:10])[C:2]1[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH:4]=O.[CH2:11]([O:13][C:14]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:15])[CH3:12]>ClCCl>[CH2:11]([O:13][C:14](=[O:15])/[CH:16]=[CH:4]/[C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[CH:1]=[O:10])[CH3:12]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1C=O
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1ccccc1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
To a solution of phthalaldehyde (6.7 g) in dichloromethane (30 ml) was added ethoxycarbonylmethylenetriphenylphosphorane (17.42 g) and the mixture was stirred for 30 minutes at room temperature. The solvent was evaporated and the residue was dissolved in diethyl ether. After the mixture was filtered, the filtrate was evaporated. The residue was distilled under vacuum (125° C., 0.6 mmHg) to give (E)-3-(2-formylphenyl)propenoic acid ethyl ester (6 g).