Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:31][CH2:30][C:18]3([CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1>C(Cl)Cl>[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:16][CH2:17][C:18]3([CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:30][CH2:31]2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccc(F)cc3)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(N2CCC3(CCNC3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (0.6 ml) was added to a cooled (0° C.) solution of tert-butyl 8-(4-fluorophenyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (0.31 mmol, 1.0 eq.) in methylene chloride (2 ml) and the reaction mixture was stirred at 25° C. for 1 h. When the reaction was complete, the solvent was removed in vacuo in order to obtain the desired amine (AMN-22).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:27][CH2:26][C:21]4([O:25][CH2:24][CH2:23][O:22]4)[CH2:20][CH2:19]3)=[C:14]([CH3:28])[CH:13]=2)[C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=1.[NH2:29][C@@H:30]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]1.CN1CCCC1=O.C(=O)([O-])O.[Na+]>O>[C:8]([C:5]1[N:6]=[CH:7][C:2]([NH:29][C@@H:30]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]2)=[N:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:27][CH2:26][C:21]3([O:25][CH2:24][CH2:23][O:22]3)[CH2:20][CH2:19]2)=[C:14]([CH3:28])[CH:13]=1)(=[O:9])[NH2:10]
Reactant: Cc1cc(Nc2nc(Cl)cnc2C(N)=O)ccc1N1CCC2(CC1)OCCO2
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(Nc2nc(N[C@@H]3CCN(C(=O)OC(C)(C)C)C3)cnc2C(N)=O)ccc1N1CCC2(CC1)OCCO2

Procedure:
A mixture of 5-chloro-3-{[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-3-methylphenyl]amino}pyrazine-2-carboxamide (1.7 g), tert-butyl (3R)-3-aminopyrrolidine-1-carboxylate (3.57 mL), and N-methylpyrrolidone (10.8 mL) was reacted in a microwave reaction device at 190° C. for 60 minutes. The reactant was left to be cooled, and then water and a saturated aqueous sodium hydrogen carbonate solution were added thereto, followed by extraction with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-500:10:1) to obtain tert-butyl (3R)-3-[(5-carbamoyl-6-{[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-3-methylphenyl]amino}pyrazin-2-yl)amino]pyrrolidine-1-carboxylate (1.71 g) as a yellow amorphous substance.
Reaction SMILES: [C:1]1([CH3:32])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=[C:13]3[C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:33]([N:37]([CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[NH:38][C:39]1[C:44]([F:45])=[CH:43][N:42]=[C:41](Cl)[N:40]=1)([CH3:36])([CH3:35])[CH3:34].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[C:33]([N:37]([CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[NH:38][C:39]1[C:44]([F:45])=[CH:43][N:42]=[C:41]([C:12]2[C:13]3[C:14](=[N:15][CH:16]=[C:17]([C:19]([F:20])([F:22])[F:21])[CH:18]=3)[N:10]([S:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:32])=[CH:6][CH:5]=3)(=[O:8])=[O:9])[CH:11]=2)[N:40]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CCOC(=O)CN(Nc1nc(Cl)ncc1F)C(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(C(F)(F)F)cnc32)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CCOC(=O)CN(Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(C(F)(F)F)cc23)ncc1F)C(C)(C)C
Temperature: 120 °C

Procedure:
A solution of 1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyrrolo[2,3-b]pyridine, 153a, (0.551 g, 1.181 mmol), ethyl 2-(1-tert-butyl-2-(2-chloro-5-fluoropyrimidin-4-yl)hydrazinyl)ethanoate, 152a, (0.300 g, 0.984 mmol) and K3PO4 (0.627 g, 2.953 mmol) in 2-MethylTHF (26 mL) and H2O (5 mL) was degassed under a stream of nitrogen for 45 minutes. To the reaction mixture was added X-phos (0.056 g, 0.118 mmol) and Pd2(dba)3 (0.022 g, 0.025 mmol). The reaction mixture was heated at 120° C. for 75 minutes. The aqueous phase was removed and the organic phase was filtered through a pad of celite, concentrated in vacuo and purified by silica gel chromatography (30% EtOAc/Hexanes) to afford 540 mg of the desired product: 1H NMR (400 MHz, CDCl3) δ 9.49 (s, 1H), 8.71 (t, J=7.0 Hz, 1H), 8.63 (d, J=11.1 Hz, 1H), 8.16-8.11 (m, 3H), 7.31 (d, J=8.2 Hz, 2H), 7.11 (d, J=21.4 Hz, 1H), 4.10 (dd, J=13.4, 6.3 Hz, 2H), 3.79 (s, 2H), 2.39 (s, 3H), 1.24 (s, 9H), 1.17 (t, J=7.1 Hz, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=4.18 minutes (M+H) 609.37.
Reaction SMILES: C([O:5][C:6](=[O:51])[CH2:7][C@H:8]([NH:24][C:25](=[O:50])[CH2:26][N:27]([C:35](=[O:49])[C@@H:36]([NH:40][C:41](=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH:37]([CH3:39])[CH3:38])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:9]([C:11]1[O:12][CH:13]=[C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[N:15]=1)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:41]([NH:40][C@@H:36]([CH:37]([CH3:39])[CH3:38])[C:35]([N:27]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:26][C:25]([NH:24][C@H:8]([C:9]([C:11]1[O:12][CH:13]=[C:14]([C:16]2[C:17]([Cl:23])=[CH:18][CH:19]=[CH:20][C:21]=2[Cl:22])[N:15]=1)=[O:10])[CH2:7][C:6]([OH:51])=[O:5])=[O:50])=[O:49])(=[O:48])[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)c1nc(-c2c(Cl)cccc2Cl)co1)Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@@H](CC(=O)O)C(=O)c1nc(-c2c(Cl)cccc2Cl)co1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound 709 in CH2Cl2 (4.0 mL) was added TFA (2.0 mL) and the reaction stirred at rt for 1 hr. The reaction was concentrated in vacuo and the residue co-concentrated with toluene. Prep-HPLC provided 35 mg of compound 710: 1H NMR (500 MHz, CD3 OD) δ 8.90 (m), 8.52 (m), 8.35 (m), 7.83 (m), 7.62-7.39 (m), 7.38-7.16 (m), 5.52 (m), 5.01 (m), 5.01 (m), 4.99-4.53 (m), 4.42 (m), 4.33-3.82 (m), 3.16-2.93 (m), 2.91-2.48 (m), 2.24 (m), 1.09-0.85 (m). ##STR89##
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:36])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:34][CH3:35])=[C:16]([O:19][C@H:20]4[CH2:25][CH2:24][C@@H:23]([NH:26]C(OC(C)(C)C)=O)[CH2:22][CH2:21]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[ClH:37]>ClCCl>[ClH:1].[ClH:37].[Cl:1][C:2]1[C:3]([F:36])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:34][CH3:35])=[C:16]([O:19][C@H:20]4[CH2:21][CH2:22][C@@H:23]([NH2:26])[CH2:24][CH2:25]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CC[C@@H](N)CC1

Procedure:
Prepared by treating 843 mg of the compound of Example 3 with 3.3 ml isopropanolic hydrochloric acid (5-6 M) in 8 ml dichloromethane at ambient temperature.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=[C:10]3[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[CH:19][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:28](OCC)(OCC)[O:29]CC>>[CH:1]1([NH:7][C:8]2[C:13]([C:14]([NH:16][CH:28]=[O:29])=[O:15])=[CH:12][N:11]=[C:10]3[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[CH:19][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(OCC)OCC
Reactant: C[Si](C)(C)CCOCn1ccc2c(NC3CCCCC3)c(C(N)=O)cnc21
Product: C[Si](C)(C)CCOCn1ccc2c(NC3CCCCC3)c(C(=O)NC=O)cnc21
Temperature: 25 °C
Yield: 27 %

Procedure:
4-(Cyclohexylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (45 mg, 0.12 mmol) in triethyl orthoformate (2 mL) was stirred at 120° C. for one day. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1→0/1 (v/v)) to give the title compound as a pale yellow amorphous (12.4 mg, yield 27%).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1.C(O)CO>[Cu]I.CCCCCC.C(OCC)(=O)C.CC(O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: Clc1ccc(I)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Clc1ccc(NCc2ccccc2)cc1
Yield: 83.6 %

Procedure:
The general procedure under argon was followed using copper(I) iodide (10 mg, 0.05 mmol), K3PO4 (425 mg, 2.00 mmol), benzylamine (131 μL, 1.20 mmol), 4-chloroiodobenzene (239 mg, 1.00 mmol), ethylene glycol (111 μL, 2.00 mmol) and 2-propanol (1.0 mL). Column chromatography using a solvent mixture (hexane/ethyl acetate=10/1, Rf=0.4) afforded N-(4-chlorophenyl)benzylamine (182 mg, 84% isolated yield) as light yellow liquid. The spectral data (1H NMR) matched with the literature references and GC analysis indicated >95% purity. See Burton, R. D.; Bartberger, M. D.; Zhang, Y.; Eyler, J. R.; Schanze, K. S. J. Am. Chem. Soc. 1996, 118, 5655–5664.
Reaction SMILES: [CH2:1]([N:8]([CH3:16])[C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][O:12]1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[O:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[CH2:9][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:16]
Reactant: CN(Cc1ccccc1)C(=O)[C@H]1CCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)C[C@H]1CCCO1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 24.60 g of (R)-tetrahydrofuran-2-carboxylic acid-N-benzyl-N-methylamide in 90 ml tetrahydrofuran is added dropwise to 17.00 g of lithium aluminium hydride in 150 ml of tetrahydrofuran. The reaction mixture is refluxed for two hours. For working up it is cooled to 0° C. in an ice bath, mixed with 20 ml of water and 10 ml of 15 N sodium hydroxide solution and stirred for another 20 minutes. Then it is filtered through a layer of magnesium sulfate and washed with a total of about 500 ml of tetrahydrofuran. The filtrate is evaporated down in vacuo, leaving a yellowish oil which is further reacted without any more purification. Yield: 21.10 g (92% of theory); mass spectrum (ESI+): m/z=206 [M+H]+.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH3:11][N:12]1[CH2:33][CH2:32][N:15]2[C:16]3[CH:31]=[CH:30][CH:29]=[CH:28][C:17]=3[CH2:18][N:19]3[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH:21]=[C:20]3[CH:14]2[CH2:13]1>C(Cl)Cl>[CH3:11][N:12]1[CH2:33][CH2:32][N:15]2[C:16]3[CH:31]=[CH:30][CH:29]=[CH:28][C:17]=3[CH2:18][N:19]3[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:21]([CH:3]=[O:4])=[C:20]3[CH:14]2[CH2:13]1
Reactant: CN1CCN2c3ccccc3Cn3c(cc4ccccc43)C2C1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CN1CCN2c3ccccc3Cn3c(c(C=O)c4ccccc43)C2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the reagent made from 0.56 ml of dimethylformamide in 5 ml methylene chloride and 1.03 g of phosphorous oxychloride is added a solution of 1.88 g of 1,3,4,16b-tetrahydro-2-methyl-2H,10H-indolo[2,1-c]pyrazino[1,2-a][1,4]-benzodiazepine in 5 ml methylene chloride in a dropwise manner maintaining the temperature of the reaction below 10°. The reaction is allowed to stir at room temperature for 30 minutes. The reaction mixture is quenched with 10 ml of a saturated solution of sodium acetate and heated at reflux temperature for 1 hour. On cooling to room temperature the reaction is extracted with 3×50 ml methylene chloride. The organic extracts are combined and dried over anhydrous sodium sulfate and the solvent removed by evaporation under reduced pressure to yield 1,3,4,16b-tetrahydro-2-methyl-2H,10H-indolo[2,1-c]pyrazino[1,2-a][1,4]benzodiazepine-16-carboxaldehyde which is converted to the hydrochloride salt, mp 260°-266°.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[C:4](OC)=O.CC([N:15]([C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])C)=[CH:21][CH:20]=1)[C:16](=[O:18])[O-:17])(C)C>CN(C=O)C>[CH3:21][C:22]([O:17][C:16]([NH:15][C:19]1[CH:20]=[CH:21][C:22](/[C:25](/[OH:27])=[CH:4]/[C:3]([O:9][CH3:10])=[O:8])=[CH:23][CH:24]=1)=[O:18])([CH3:25])[CH3:23]
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)c1ccc(N(C(=O)[O-])C(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C(\O)c1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 111.3 %

Procedure:
NaH (60% dispersion, 2.22 g, 55.5 mmol) was added to a solution of dimethyl oxalate (2.73 g, 23.1 mmol) and 1,1-dimethylethyl(4-acetylphenyl)carbamate (N-BOC-4-aminoacetophenone, 5.44 g, 23.1 mmol) in anhydrous DMF (50 mL) at 0° C. The reaction mixture was allowed to warm to room temperature overnight and quenched with saturated aqueous NH4Cl and neutralized with 1M HCl. The reaction was diluted with ethyl acetate (80 mL) and the organic layer washed successively with saturated aqueous NaHCO3 and brine. The organic phase was separated and dried over Na2SO4, filtered, concentrated in vacuo and triturated with chloroform to provide the condensation product (3.77 g, 53.1% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C=O)C>[Si:21]([O:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]1=[O:15])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1c2ccccc2C(=O)N1CCCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.2 %

Procedure:
To a solution of N-(3-hydroxypropyl)phthalimide (5.25 g, 24.36 mmol) in DMF (20 mL) was added imidazole (16.6 g, 240 mmol) and tert-butyldimethylsilyl chloride (19 g, 120 mmol). The reaction was stirred at room temperature for 18 hours before the volatiles were removed in vacuo and a portion of the crude product was subjected to column chromatography (SiO2, 1:1 DCM/hexanes) to give 2-[3-(tert-butyldimethylsilanyloxy)propyl]isoindole-1,3-dione as a clear oil (5 g). 2-[3-(tert-Butyldimethylsilanyloxy)propyl]isoindole-1,3-dione (5 g, 26.4 mmol) was dissolved in ethanol (50 ml) and methyl hydrazine (2.94 ml, 55.4 mmol) added. The reaction was heated to 75° C. for 8 hours before concentration in vacuo. The crude residue was triturated with a mixture of diethyl ether (150 mL) and hexanes (50 mL) and the resultant solid removed by filtration. The solvents were removed in vacuo to give the title compound as a pale yellow oil (1.8 g, 61%). δH (DMSO-d6) 4.58 (2H, br s), 3.63-3.58 (2H, m), 2.67-2.62 (2H, m), 1.60-1.55 (2H, m), 0.83 (9H, d, J 1.1 Hz), 0.00 (6H, d, J 1.2 Hz). LCMS (ES+) RT 1.77 minutes, 190 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][CH2:14][C:15]1[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=1.C(N1C=CN=C1)([N:25]1C=CN=C1)=O.[OH-].[NH4+]>CN(C=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][CH2:14][C:15]1[S:16][C:17]([C:20]([NH2:25])=[O:22])=[CH:18][N:19]=1
Reactant: Cc1onc(-c2ccccn2)c1CCc1ncc(C(=O)O)s1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccn2)c1CCc1ncc(C(N)=O)s1
Temperature: 60 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To a solution of 2-[2-(5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (73 mg, 0.23 mmol) in DMF (3 mL) was added 1,1′-carbonyldiimidazole (45 mg, 0.28 mmol). The resulting reaction mixture was stirred for 1 h at 60° C. and then treated with an ammonium hydroxide solution (357 μL, 2.3 mmol) and stirred overnight at room temperature. The reaction mixture was then evaporated. Purification by chromatography (silica, 0 to 10% methanol in dichloromethane) afforded the title compound (51 mg, 70%) as an off white solid. MS: m/e=315.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4]([OH:6])=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>O.C(OCC)C>[CH3:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:7])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: c1ccccc1
Reactant: CC(C)=CC(=O)O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: O
Product: CC(C)(CC(=O)O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
3-Methyl-2-butenoic acid (1, 5.10 g, 50.9 mmol) and AlCl3 (20.4 g, 153 mmol) were placed in a one-neck round-bottomed flask. Benzene (50 mL) was added, which produced vigorous bubbling. Upon completion of the bubbling, a capped condenser (i.e. closed system) was attached, the reaction mixture was stirred and placed in an oil bath at 65° C. The pressure in the system was occasionally released. The progress of the reaction was followed by following the loss of starting material by GC. If the reaction was not complete within 1 h, a small quantity of AlCl3 was added and stirring was continued. To the solution was added diethyl ether and the mixture was cooled to 0° C. Slowly conc. HCl and some water were added until all the solid dissolved and the pH was less than 2. The aqueous layer was extracted with diethyl ether three times. The organic layer was concentrated to 150 mL and then was extracted with a saturated sodium hydrogen carbonate solution six times. The combined aqueous layer were acidified with conc. HCl until the pH was less than 2. The acidic aqueous layer was extracted with diethyl ether three times and the accumulated organic layer was dried with magnesium sulfate. The solution was filtered and the diethyl ether was removed in vacuo producing a white solid (8.51 g, 47.7 mmol) in 94% yield, which did not need further purification. mp 55-56° C. 1H-NMR (400 MHz, CDCl3) 10.45 (bs, 1H, CO2H), 7.38 (d, 2H, J=7.2 Hz, H-11 and H-7), 7.32 (t, 2H, J=7.2 Hz, H-10 and H-8), 7.21 (t, 2H, J=7.2 Hz, H-9), 2.65 (s, 2H, H-2), 1.47 (s, 6H, H-5 and H-4); Mass spectrum (EI) 178 (23, M.+), 119 (100, [C9H11]+). For pioneering work to form 2 see: F. J. Eijkman (1908) Chem. Kentr. II, p. 110; or A. Hoffman (1929) J. Am. Chem. Soc. 51:2542.
Reaction SMILES: Cl.[NH2:2]O.C(=O)(O)[O-].[Na+].O.[N:10]1[C:18]2[CH:17]=[C:16]([C:19]#[N:20])[N:15]=[CH:14][C:13]=2[NH:12][CH:11]=1>C(O)C>[N:10]1[C:18]2[CH:17]=[C:16]([C:19](=[NH:2])[NH2:20])[N:15]=[CH:14][C:13]=2[NH:12][CH:11]=1
Reactant: NO
Reactant: N#Cc1cc2nc[nH]c2cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(N)c1cc2nc[nH]c2cn1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Hydroxylamine hydrochloride (27.2 mg, 0.39 mmol), sodium bicarbonate (49.4 mg, 0.59 mmol), and water (0.392 mL) were combined in a vial and stirred for 15 minutes. This solution was added to a vial containing 4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(1R or S)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (99 mg, 0.196 mmol), dissolved in ethanol (0.915 mL). The mixture was sealed and heated at 100° C. for 1 hour. The reaction was cooled to room temperature, quenched with water, and extracted with ethyl acetate (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford 4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-N-hydroxy-3-[(1R or S)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide. MS ESI calc'd. for C28H36ClN7O2 [M+H]+ 538. found 538.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:12]([C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:13])[O:8][N:7]=1)([CH3:5])[CH:3]=O.Cl.[NH2:26][OH:27].N1C=CC=CC=1>CO>[OH:27][N:26]=[CH:3][C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:12]([C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:13])[O:8][N:7]=1)([CH3:1])[CH3:5]
Reactant: CC(C)(C=O)c1cc(NC(=O)[C@@H]2CCCN2C2CCOCC2)on1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)(C=NO)c1cc(NC(=O)[C@@H]2CCCN2C2CCOCC2)on1
Temperature: 60 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
To 90.0 mg (0.27 mmol) of (S)-1-(tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acid [3-(1,1-dimethyl-2-oxo-ethyl)-isoxazol-5-yl]-amide in MeOH (3.00 mL) are added 22.4 mg (0.32 mmol) hydroxylamine hydrochloride and 58.5 μL (0.72 mmol) pyridine. The reaction is stirred at 60° C. for 3 h. The solvent is removed under reduced pressure and the residue is purified by HPLC-MS to afford 79.0 mg of (S)-1-(tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acid [3-(2-hydroxyimino-1,1-dimethyl-ethyl)-isoxazol-5-yl]-amide. Yield: 84%; ESI-MS: 351 [M+H]+; HPLC (Rt): 1.04 min (method E)
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:14][C@@:8]2([C:15]([O:17][CH3:18])=[O:16])[O:9][C:10]([CH3:13])([CH3:12])[O:11][CH:7]2[C@@H:6]1[OH:19])=[N+]=[N-]>CO>[NH2:1][CH2:4][C@@H:5]1[O:14][C@:8]2([C:15]([O:17][CH3:18])=[O:16])[C@@H:7]([O:11][C:10]([CH3:12])([CH3:13])[O:9]2)[C@@H:6]1[OH:19]
Reactant: COC(=O)[C@@]12O[C@@H](CN=[N+]=[N-])[C@@H](O)C1OC(C)(C)O2
Solvent: CO
Product: COC(=O)[C@@]12O[C@@H](CN)[C@@H](O)[C@@H]1OC(C)(C)O2
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of 15 (1.0 g, 3.7 mmol) in MeOH (30 mL) were added aqueous HCl (conc., 0.32 mL) and palladium, 10 wt. % (dry basis) on activated carbon (wet, Degussa type E101 NE/W, 307 mg, Aldrich). It was hydrogenated at 22 psi for 0.5 h. The mixture was filtered through a Celite cake and the solvent evaporated to dryness. Product 16 was obtained as an off white solid (1.0 g; yield 91.0%).
Reaction SMILES: [NH2:1][OH:2].[CH:3]1([NH:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15]/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][C:21]([C:24](=[O:36])[N:25]([CH:27]([C:32]([NH:34][CH3:35])=[O:33])[C:28](OC)=[O:29])[CH3:26])=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:4]1.S([O-])([O-])(=O)=O.[Na+].[Na+]>CO.C(Cl)(Cl)Cl.O.C(OCC)(=O)C>[CH:3]1([NH:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15]/[CH:16]=[CH:17]/[C:18]3[CH:19]=[CH:20][C:21]([C:24]([N:25]([CH3:26])[CH:27]([C:32]([NH:34][CH3:35])=[O:33])[C:28]([NH:1][OH:2])=[O:29])=[O:36])=[CH:22][CH:23]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:4]1
Reactant: NO
Reactant: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(/C=C/C#Cc2ccc(CNC3CC3)cc2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CNC(=O)C(C(=O)NO)N(C)C(=O)c1ccc(/C=C/C#Cc2ccc(CNC3CC3)cc2)cc1
Reaction time: 0.5 h
Yield: 25 %

Procedure:
A 50% aqueous solution (2.0 mL) of hydroxylamine was added, under ice cooling, to a methanol (4.0 mL) solution of 1-[(cyclopropylamino)methyl]-4-[(3E)-4-(4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}phenyl)but-3-en-1-yn-1-yl]benzene (0.20 g) as obtained in Example 22-(4), and the mixture was stirred for 30 minutes under ice cooling and then stirred for 2 hours under water cooling. Ethyl acetate and water were added to the reaction mixture to isolate the organic layer, and the extract was washed sequentially with water and brine. The precipitate was dissolved with methanol and water, and the organic layer was isolated. Chloroform, methanol and anhydrous sodium sulfate were added to the extract, and the desiccant was filtered out, whereafter the solvents were distilled off under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (gradient elution with chloroform/methanol=20/1→10/1), and further purified by preparative silica gel thin-layer chromatography (chloroform/methanol=10/1) to obtain 2-[({4-[(1E)-4-{4-[(cyclopropylamino)methyl]phenyl}but-1-en-3-yn-1-yl]phenyl}carbonyl)(methyl)amino]-N-hydroxy-N′-methylpropanediamide (Compound 477, light yellow solid) (51 mg, 25%).