Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].C(OC([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[N:38][C:37]([NH2:40])=[CH:36][N:35]=2)[CH2:30][CH2:29]1)=O)(C)(C)C>>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10]([NH:40][C:37]3[N:38]=[CH:39][C:34]([N:31]4[CH2:30][CH2:29][NH:28][CH2:33][CH2:32]4)=[N:35][CH:36]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc(N)cn2)CC1
Product: CN(C)C(=O)c1cc2cnc(Nc3cnc(N4CCNCC4)cn3)nc2n1C1CCCC1
Yield: 55.1 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.342 mmol) and 5′-amino-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (114 mg, 0.408 mmol), followed by deprotection using General Procedure A to give 7-cyclopentyl-2-(3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (82 mg, 45%). MS(ESI) m/z 436.3 (M+H)+
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]1(=[O:19])[C:13]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:12][CH2:11][CH2:10][NH:9]1.Cl[C:21]1[CH:30]=[N:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(O)C>[N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:29]=[CH:30][C:21]=1[N:16]1[CH2:17][CH2:18][C:13]2([C:8](=[O:19])[NH:9][CH2:10][CH2:11][CH2:12]2)[CH2:14][CH2:15]1
Reactant: Clc1cnc2ccccc2n1
Reactant: O=C1NCCCC12CCNCC2
Agent: CN(C)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NCCCC12CCN(c1cnc3ccccc3n1)CC2
Temperature: 160 °C
Yield: 78.1 %

Procedure:
The mixture of 2,9-diazaspiro[5.5]undecan-1-one TFA salt ([1190586-22-1], 1.0 g, 3.5 mmol), 2-chloroquinoxaline ([1448-87-9], 0.77 g, 4.6 mmol), DIPEA (3.7 ml, 21 mmol) and DMAP (22 mg, 0.18 mmol) in ethanol (10 ml) was placed in a microwave tube. The tube was sealed and the suspension was heated at 160° C. for 2 h under microwave conditions. The mixture was filtered and the residue washed with ethanol. The filtrate was concentrated and the precipitate filtered and washed with ethanol. The combined solid material was dissolved in ethyl acetate, washed with water and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 0.81 g (77%) of the title compound as a pale yellow solid which was not further purified. [1H NMR (400 MHz, DMSO-d6) ♀ ppm 8.79 (s, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.53-7.58 (m, 2H), 7.31-7.39 (m, 2H), 4.22 (dt, J=13.5, 4.4 Hz, 2H), 3.37-3.49 (m, 2H), 3.06-3.15 (m, 2H), 1.91-2.05 (m, 2H), 1.75-1.83 (m, 2H), 1.65-1.75 (m, 2H), 1.44-1.55 (m, 2H); LCMS RtB=2.80 min, [M+H]+=297.2].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH3:13])[CH3:12].[N+:14]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)([O-:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>C(COC)OC.O.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.CCOC(C)=O>[CH3:12][C:5]1([CH3:13])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:14]([O-:16])=[O:15])[CH:22]=3)[CH:3]=2)[NH:7][C:6]1=[O:11]
Reactant: CC1(C)C(=O)Nc2ccc(Br)cc21
Reactant: O=[N+]([O-])c1cccc(B(O)O)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: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CC1(C)C(=O)Nc2ccc(-c3cccc([N+](=O)[O-])c3)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 119 %

Procedure:
5-bromo-1,3-dihydro-3,3-dimethyl-2H-indol-2-one (1.02 g, 4.26 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.244 g) were stirred under an atmosphere of nitrogen in dimethoxyethane (35 cm3). After 15 minutes, 3-nitrophenylboronic acid (1.43 g, 2.56 mmol) was added, followed by potassium carbonate (3.54 g, 2.56 mmol) in water (15 cm3). The reaction was heated to reflux for 2 hours and then stirred at room temperature overnight. Saturated ammonium chloride and EtOAc were added and the mixture was filtered. The aqueous layer was extracted with ethyl acetate (×2), and then the combined organic layers were dried (Na2SO4), filtered, and evaporated. The residue was purified by column chromatography (SiO2, EtOAc:hexane, gradient elution) to afford the title compound (0.86 g, 67%) mp 234-235° C.; 1H NMR (DMSO-d6) δ 3.33 (s, 6H), 6.98 (d, 1H, J=8.06 Hz), 7.61 (dd, 1H, J=1.85, 8.03 Hz), 7.73 (t, 1H, J=7.98 Hz), 7.81 (d, 1H, J=1.63 Hz), 8.11-8.18 (m, 2H), 8.42-8.43 (m, 1H), 10.5 (s, 1H); MS (EI) m/z 281; Anal. Calc. for C16H14N2O3.0.2H2O: C, 67.51; H, 4.92; N, 9.37; Found: C, 67.48; H, 5.17; N, 9.48.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].Br[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.ClCCl.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][N:18]1[CH2:19][CH2:20][N:15]([C:13]2[CH:12]=[CH:11][C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[C:2]([NH:1][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:14]=2)[CH2:16][CH2:17]1
Reactant: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c(N)c2)CC1
Reactant: Brc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c(Nc3ccccc3)c2)CC1
Temperature: 100 °C
Reaction time: 21 h
Yield: 112 %

Procedure:
In a dry Schlenk tube under argon atmosphere tert-butyl 2-amino-4-(4-methylpiperazin-1-yl)benzoate (800 mg, 2.745 mmol) was dissolved in dry toluene (14 mL). Argon was bubbled through the mixture for a few minutes before adding bromobenzene (0.32 mL, 3.02 mmol, 1.1 eq), Cs2CO2 (1.34 g, 4.118 mmol, 1.5 eq), Pd(OAc)2 (16 mg, 0.069 mmol, 2.5 mol %) and Rac-BINAP (88 mg, 0.137 mmol, 5 mol %). The mixture was then stirred at 100° C. for 21 hours. The mixture was allowed to cool to room temperature and diluted with dichloromethane. Salts were filtered over a Celite pad and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography over silica gel (DCM/EtOH/NH3 7% in methanol 95:5:0.5) to give 1.13 g of title compound (quant. yield) as off-white solid
Reaction SMILES: [CH3:1][CH:2]([CH3:28])[CH2:3][CH:4]=[CH:5][C@@H:6]1[CH2:10][C@@H:9]([O:11]C2CCCCO2)[CH2:8][N:7]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].Cl.C(Cl)(Cl)Cl.O>O1CCCC1>[OH:11][C@H:9]1[CH2:8][N:7]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:6]([CH:5]=[CH:4][CH2:3][CH:2]([CH3:28])[CH3:1])[CH2:10]1
Reactant: CC(C)CC=C[C@@H]1C[C@@H](OC2CCCCO2)CN1C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)CC=C[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
In 12 ml of tetrahydrofuran is dissolved 0.60 g of benzyl (2S,4R)-2-(4-methyl-1-pentenyl)-4-(tetrahydro-2H-pyran-2-yloxy)-1-pyrrolidinecarboxylate, to which is added 12 ml of 6 mol/L hydrochloric acid. The mixture thus obtained is stirred at ambient temperature for 2 hours. A mixture of chloroform and water is added to the reaction mixture, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=2:1) to obtain 0.43 g of benzyl (2S,4R)-4-hydroxy-2-(4-methyl-1-pentenyl)-1-pyrrolidinecarboxylate as a light yellow oily product.
Reaction SMILES: [OH:1]C(CCCC[C@H]1[C@@H]2[C@@H](NC(N2)=O)CS1)=O.OO.[OH:19][C:20]([CH2:22][CH2:23][CH2:24][CH2:25][C@H:26]1[C@@H:35]2[C@@H:30]([NH:31][C:32]([NH:34]2)=[O:33])[CH2:29][S:27]1=[O:28])=[O:21]>CC(O)=O>[O:33]=[C:32]1[NH:34][C@H:35]2[C@H:30]([CH2:29][S:27](=[O:1])(=[O:28])[C@H:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:20]([OH:19])=[O:21])[NH:31]1
Reactant: O=C(O)CCCC[C@H]1[C@H]2NC(=O)N[C@H]2CS1=O
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: OO
Solvent: CC(=O)O
Product: O=C(O)CCCC[C@H]1[C@H]2NC(=O)N[C@H]2CS1(=O)=O
Temperature: 25 °C
Reaction time: 65 h
Yield: 87 %

Procedure:
Following the procedure of Sachon et al.,42 D-biotin (83, 0.304 g, 1.24 mmol) was suspended in AcOH (3.0 mL) and then H2O2 (35% in H2O, 1.0 mL) was added at room temperature. The suspension became a colorless, clear solution after 10 min at room temperature, and biotin sulfoxide began to precipitate after 5 hours. The reaction was stirred at room temperature for 65 hours, then filtered. The white filter cake was then washed with 20 mL of ether and dried under reduced pressure to provide 89 as a white solid (0.298 g, 1.08 mmol, 87%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:17]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+]>>[CH2:20]([N:14]1[CH2:13][CH:12]=[C:11]([C:9]2[S:10][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:18])([F:1])[F:19])=[CH:17][C:7]=3[N:8]=2)[CH2:16][CH2:15]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: FC(F)(F)c1ccc2sc(-c3ccncc3)nc2c1
Agent: [BH4-]
Agent: [Na+]
Product: FC(F)(F)c1ccc2sc(C3=CCN(Cc4ccccc4)CC3)nc2c1
Yield: 46.7 %

Procedure:
4-(5-Trifluoromethylbenzothiazol-2-yl)pyridine (10 g, 0.04 mol) was reacted with benzyl bromide (6.4 ml, 0.06 mol) followed by sodium borohydride (1.76 g, 0.052 mol) as exemplified in Example 7 step 2. The crude product was purified by flash chromatography eluting with 15% ethyl acetate in petroleum ether to give a yellow solid. Recrystallisation from ethyl acetate afforded the title compound as a pale yellow solid (7 g, 47%); mp. 124°-125° C.; (Found: C, 63.85; H, 4.48; N, 7.48. C20 H17F3N2S requires C, 64.16; H, 4.58; N, 7.48%). δH (CDCl3), 2.75 (2H, m, NCH2CH2), 2.81 (2H, m, NCH2CH2), 3.24 (2H, m, NCH2CH2), 3.67 (2H, s, NCH2Ar), 6.71 (1H, m, NCH2CH), 7.28 (5H, m, ArH), 7.55 (1H, d of d, J 8.4Hz, J 1.4Hz, ArH), 7.89 (1H, d, J 8.4Hz, ArH), 8.23 (1H, s, ArH); m/z (ES+) 375 (M+1)+.
Reaction SMILES: [Cl:1][Pt-2:2](Cl)([Cl:4])[Cl:3].[K+].[K+].[CH:8]1([C:14]#[N:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>O>[Cl:1][Pt-:2]([Cl:4])[Cl:3].[CH:8]1([C:14]#[N:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Cl[Pt-2](Cl)(Cl)Cl
Agent: N#CC1CCCCC1
Agent: [K+]
Solvent: O
Product: Cl[Pt-](Cl)Cl
Reaction time: 240 h

Procedure:
To a solution of (N(CH3)4)2[PtCl4] or K2[PtCl4] in 5 mL of deionized water will be added the cyclohexanecarbonitrile (1 mmol). The reaction mixture will then be stirred for approximately 10 days. Solid will be filtered, and the filtrate evaporated to dryness. A small amount of acetone will be added to the residue, and solid filtered. The filtrate will then be evaporated to obtain the desired product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[CH3:14].Cl.[O:17]([CH2:24][CH2:25][O:26][NH2:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.CON>>[CH3:14][C:13]1[N:27]([O:26][CH2:25][CH2:24][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=1
Reactant: NOCCOc1ccccc1
Reactant: CC(=O)Nc1cnc2ccccc2c1Cl
Agent: CON
Agent: Cl
Product: Cc1nc2cnc3ccccc3c2n1OCCOc1ccccc1
Yield: 65 %

Procedure:
The method of Part B of Example 25 was used to treat N-(4-chloroquinolin-3-yl)acetamide (2.9 g, 13 mmol) with O-(2-phenoxyethyl)hydroxylamine hydrochloride (2.5 g, 13 mmol) in lieu of O-methylhydroxylamine hydrochloride with the modification that the reaction was heated at reflux overnight. 2-Methyl-1-(2-phenoxyethoxy)-1H-imidazo[4,5-c]quinoline (2.7 g) was obtained as a dark oil.
Reaction SMILES: [C:1]([C:4]1[O:8][CH:7]=[N:6][C:5]=1[CH3:9])(=[O:3])[CH3:2].[C:10]1([Li])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.[Cl-].[Na+]>C(OCC)C>[CH3:9][C:5]1[N:6]=[CH:7][O:8][C:4]=1[C:1]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:3])[CH3:2]
Reactant: [Li]c1ccccc1
Reactant: CC(=O)c1ocnc1C
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1ncoc1C(C)(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
5-Acetyl-4-methyloxazole (5g) in dry diethylether (25ml) at -70° C. under a nitrogen atmosphere was treated dropwise with phenyllithium (1.8M solution in cyclohexane-diethylether, 27ml). After 45 minutes the mixture was allowed to warm to room temperature and water (10 ml) was added. The mixture was poured into saturated aqueous sodium chloride and extracted with dichloromethane. The product thus obtained was crystallised from diethylether to give 1-(4-methyl-5-oxazolyl)-1-phenylethanol, m.p. 102-104° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2C2CCCCO2)=[C:4]([NH:17][CH:18]([C:20]2[N:21]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:22](=[O:31])[C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:30])[CH3:19])[N:3]=1.C([O-])(O)=O.[Na+].[Cl:43][C:44]1[N:52]=[C:51]2[C:47]([N:48]=[CH:49][NH:50]2)=[C:46]([NH:53][CH:54]([C:56]2[N:57]([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[C:58](=[O:67])[C:59]3[C:64]([CH:65]=2)=[CH:63][CH:62]=[CH:61][C:60]=3[CH3:66])[CH3:55])[N:45]=1>Cl.CCO>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:17][C@H:18]([C:20]2[N:21]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:22](=[O:31])[C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:30])[CH3:19])[N:3]=1.[Cl:43][C:44]1[N:52]=[C:51]2[C:47]([N:48]=[CH:49][NH:50]2)=[C:46]([NH:53][CH:54]([C:56]2[N:57]([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[C:58](=[O:67])[C:59]3[C:64]([CH:65]=2)=[CH:63][CH:62]=[CH:61][C:60]=3[CH3:66])[CH3:55])[N:45]=1
Reactant: Cc1cccc2cc(C(C)Nc3nc(Cl)nc4c3ncn4C3CCCCO3)n(-c3ccccc3)c(=O)c12
Agent: Cc1cccc2cc(C(C)Nc3nc(Cl)nc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Product: Cc1cccc2cc([C@H](C)Nc3nc(Cl)nc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-(1-(2-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (compound 5303) (172 mg, 0.33 mmol) was dissolved in HCl/EtOH (3 M, 5 mL) and the resulting mixture was stirred at room temperature for 1 h. The mixture was neutralized with saturated NaHCO3 aqueous solution to pH=7-8, and then extracted with CH2Cl2 (50 mL×3). The combined organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and recrystallized from ethyl acetate and hexanes. The solid was collected by filtration and dried in vacuo to afford the desired product, 3-(1-(2-chloro-9H-purin-6-ylamino)ethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (compound 5304) (128 mg, 90% yield) as a white solid.
Reaction SMILES: C([O:5][C:6]([C:8]1[S:9][C:10]([C:24]2[CH:28]=[CH:27][N:26](S(=O)(=O)N(C)C)[N:25]=2)=[CH:11][C:12]=1[NH:13][S:14]([C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15])=[O:7])(C)(C)C.Cl>O1CCOCC1.CO.O>[NH:26]1[CH:27]=[CH:28][C:24]([C:10]2[S:9][C:8]([C:6]([OH:7])=[O:5])=[C:12]([NH:13][S:14]([C:17]3[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:15])[CH:11]=2)=[N:25]1
Reactant: Cc1ccccc1S(=O)(=O)Nc1cc(-c2ccn(S(=O)(=O)N(C)C)n2)sc1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccccc1S(=O)(=O)Nc1cc(-c2cc[nH]n2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 26 h
Yield: 65.2 %

Procedure:
A reaction mixture of 5-(1-Dimethylsulfamoyl-1H-pyrazol-3-yl)-3-(toluene-2-sulfonylamino)-thiophene-2-carboxylic acid tert-butyl ester (10 mg, 0.019 mmol) and 4N HCl (0.3 mL) solution in dioxane in MeOH (0.3 mL) was stirred at room temperature 26 h. Reaction mixture was then diluted with water and extracted with EtOAc, concentrated and purified on preparative TLC using MeOH/CH2Cl2/AcOH (5:95:1) furnished the 5-(1H-Pyrazol-3-yl)-3-(toluene-2-sulfonylamino)-thiophene-2-carboxylic acid (4.5 mg, 65.2% yield). 1H NMR (CD3OD, 400 MHz) 7.99 (d, J=7.9 Hz, 1H), 7.81 (s, 1H), 7.43 (t, J=7.5, 1.3 Hz, 1H), 7.42-7.26 (m, 2H), 7.19 (s, 1H), 2.69 (s, 3H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:6]1[CH:7]=[C:8]2[C:14](=[O:15])[N:13]([C:16]([CH:21]([CH3:23])[CH3:22])([CH3:20])[C:17]([NH2:19])=[O:18])[C:12](=O)[C:9]2=[N:10][CH:11]=1)[CH2:4][CH3:5].O>C1(C)C=CC=CC=1>[CH:21]([C:16]1([CH3:20])[N:13]2[C:14](=[O:15])[C:8]3[C:9](=[N:10][CH:11]=[C:6]([CH2:3][CH2:4][CH3:5])[CH:7]=3)[C:12]2=[N:19][C:17]1=[O:18])([CH3:23])[CH3:22]
Reactant: CCCc1cnc2c(c1)C(=O)N(C(C)(C(N)=O)C(C)C)C2=O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1cnc2c(c1)C(=O)N1C2=NC(=O)C1(C)C(C)C

Procedure:
With the simultaneous addition of 0.5 g of powdered sodium hydroxide, a solution of α-[3-n-propyl-6H-pyrrolo[3,4-b]pyridine-5,7-dione-6-yl]-α-isopropyl-α-methyl-acetamide (m.p.: 82° C.) in 100 ml of toluene is heated under reflux for 2 hours in a water separator. After the reaction solution has cooled, it is filtered through silica gel and the filtrate is washed with ethyl acetate and then concentrated by evaporation. The residue is recrystallised from ethyl acetate/petroleum ether, affording 13.1 g of the title compound which melts at 116° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[NH2:11][C:12]1[CH:25]=[CH:24][C:23]([N+]([O-])=O)=[CH:22][C:13]=1[C:14](C1C=CC=CC=1)=[O:15]>C([O-])(=O)C.[Na+]>[NH2:11][C:12]1[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=1[CH:14]=[O:15].[NH2:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: NCC(=O)c1ccccc1
Agent: [Na+]
Product: Nc1ccccc1C=O

Procedure:
Evaluation of the reaction efficiency as a function of the reactant to protein concentration ratio, and the reactivity with 2-ABA-like reactants is shown in FIG. 27. The mass spectra of hRBP4 with PCL incorporated at position 122 (hRBP4 Phe122PCL) after reaction with 0.1 mM 2-amino-benzaldehyde (2-ABA) is shown in FIG. 27A, while the mass spectra for hRBP4 Phe122PCL after reaction with 0.1 mM 2-amino-acetophenone (2-AAP) and 0.1 mM 2-amino-5-nitro-benzophenone (2-ANBP) are shown if FIG. 27B and FIG. 27C, respectively. All reactions were performed in 200 mM sodium acetate, pH 5.0. The protein conjugates are detected at the correct mass and with the expected mass increase as given in FIG. 23. In addition, yields of greater than 88% conversion for 2-ABA and 2-AAP were achieved, although because of low solubility a yield of about 5% was obtained for 2-ANBP. However, this demonstrates that 2-ABA analogues react efficiently at the PCL incorporation site at reactant to protein concentration ratios of 6 to 1. The extent of the reactions is only slightly lower than those performed at reactant to protein ratios of 600 to 1 (FIG. 26).
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][S:36]([NH2:39])(=[O:38])=[O:37])=[CH:31][CH:30]=1>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:39][S:36]([CH2:35][C:32]3[CH:31]=[CH:30][C:29]([F:28])=[CH:34][CH:33]=3)(=[O:37])=[O:38])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)Cc1ccc(F)cc1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)Cc2ccc(F)cc2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and [(4-fluorophenyl)methyl-sulfonamide (Synlett, 1997, 375) in accordance with Procedure 1, Method B described hereinabove. Yield (32%); 1H NMR (d6-DMSO) δ 11.63 (br s, 1H), 7.53 (d, J=15.7 Hz, 1H), 7.40-7.10 (m, 16H), 6.87 (d, J=8.1 Hz, 2H), 6.41 (d, J=15.7 Hz, 1H), 4.72 (s, 2H), 2.37 (q, J=7.4 Hz, 2H), 0.83 (t, J=7.4 Hz, 3H); APcI m/z: 526 (M+H+).
Reaction SMILES: CO.O.[OH:4][C:5]1[CH:6]=[C:7]([C:11]2([CH3:30])[CH2:16][CH2:15][N:14](CC(CC3C=CC=CC=3)C(O)=O)[CH2:13][CH:12]2[CH3:29])[CH:8]=[CH:9][CH:10]=1>O>[CH3:29][C@@H:12]1[C@@:11]([C:7]2[CH:6]=[C:5]([OH:4])[CH:10]=[CH:9][CH:8]=2)([CH3:30])[CH2:16][CH2:15][NH:14][CH2:13]1
Reactant: CC1CN(CC(Cc2ccccc2)C(=O)O)CCC1(C)c1cccc(O)c1
Solvent: O
Solvent: CO
Product: C[C@H]1CNCC[C@@]1(C)c1cccc(O)c1

Procedure:
A beaker was charged with methanol (0.4 kg), water (0.5 L), and Compound 7(100 g). The mixture was charged to the reactor and rinsed forward with a solution of water (0.3 L) and methanol (0.2 kg) to seed the reaction mixture.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH2:17][N:18]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[C:19](=[O:30])[C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=3)=[O:16])=[CH:10][CH:9]=2)[N:7]=1.[OH-].[Na+:40]>CO>[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([CH2:17][N:18]([C:31]3[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)[C:19](=[O:30])[C:20]3[CH:29]=[CH:28][C:23]([C:24]([O-:26])=[O:25])=[CH:22][CH:21]=3)=[O:16])=[CH:12][CH:13]=2)[N:7]=1.[Na+:40]
Reactant: COC(=O)c1ccc(C(=O)N(CC(=O)Nc2ccc(-c3csc(N)n3)cc2)c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(N(CC(=O)Nc2ccc(-c3csc(N)n3)cc2)C(=O)c2ccc(C(=O)[O-])cc2)cc1

Procedure:
Methanol (20 ml) solution of methyl N-({[4-(2-aminothiazol-4-yl)phenyl]carbamoyl}methyl)-N-(4-methoxyphenyl)terephthalamate monohydrochloride (800 mg) was mixed with 1 M sodium hydroxide aqueous solution (1.5 ml) and then heated under reflux for 4 hours. The reaction solution was concentrated, and ethanol (20 ml) and diisopropyl ether (10 ml) were added to the thus obtained residue to effect precipitation of crystals. After filtration, the crystals were washed with diisopropyl ether to obtain 530 mg of sodium N-({[4-(2-aminothiazol-4-yl)phenyl]carbamoyl}methyl)-N-(4-methoxyphenyl)terephthalamate (white crystals).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.C1(C2[C:27](C3N=CN(C4C=CC=CC=4)C=3)=[C:26](C(F)(F)F)[O:25]N=2)C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:26](=[O:25])[CH3:27])=[C:11]([C:13]([F:14])([F:16])[F:15])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)no1
Reactant: FC(F)(F)c1onc(-c2ccccc2)c1-c1cn(-c2ccccc2)cn1
Product: CC(=O)c1c(-c2ccc(Cl)cc2)noc1C(F)(F)F
Yield: 60 %

Procedure:
As described for Example 1e, 3-(4-chloro-phenyl)-5-trifluoromethyl-isoxazole (36 g, 145.4 mmol), instead of 3-phenyl-4-(1-phenyl-1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole, was converted to the title compound (25.2 g, 60%) which was obtained as a light orange oil. MS: m/e=287.9 [M−H]−.