Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1)=[O:2].[H][H]>C(O)C.[Pd]>[CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)=[O:2]
Reactant: O=CNNc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(NNC=O)cc1

Procedure:
1-Formyl-2-(4-nitrophenyl)hydrazine (10.2 g, 0.056 mole) and 10% palladium/charcoal (catalytic amount) were suspended in ethanol (500 ml) in a Parr shaker bottle. The reaction mixture was hydrogenated at room temperature until hydrogen uptake ceased. The reaction mixture was filtered and the solvent was evaporated from the filtrate leaving a white crystalline powder. Yield 7.1 g (84%), m.p. 122°-125° C.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:21])=O>C1C=CC=CC=1>[CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([Cl:21])=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCCCCOc1ccc(C(=O)Cl)cc1

Procedure:
4-n-Octyloxybenzoic acid in the amount of 2.0 g was reacted with 1 g of thionyl chloride in 10 ml of benzene at a temperature of 100°-110° C. for 6 hours to obtain 4-n-octyloxybenzoic chloride in the amount of 2.2 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]2[O:10][C:11]([C:13]3([O:19][CH3:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:12][C:3]=12.[CH:21](O)=O.C=O>[OH-].[Na+]>[Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]2[O:10][C:11]([C:13]3([O:19][CH3:20])[CH2:18][CH2:17][N:16]([CH3:21])[CH2:15][CH2:14]3)=[CH:12][C:3]=12
Reactant: COc1ncc(Br)c2cc(C3(OC)CCNCC3)oc12
Reactant: O=CO
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Product: COc1ncc(Br)c2cc(C3(OC)CCN(C)CC3)oc12
Temperature: 95 °C

Procedure:
4-Bromo-7-methoxy-2-(4-methoxypiperidin-4-yl)furo[2,3-c]pyridine (1.2 g), formic acid (0.76 ml) and formaldehyde (37% w/w aqueous solution) (0.66 g) were combined and heated to 95° C. for 24 hours. The reaction mixture was then diluted with 2N sodium hydroxide solution (100 ml) and extracted with ethyl acetate (3×50 ml). The combined extracts were then dried over magnesium sulphate and evaporated in vacuo to give the title compound (0.96 g) as a pale yellow oil.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:14]([NH:15][C:16]([N:18]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:33]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)(=[O:35])=[O:34])=[O:7])(C)(C)C.C(OC(C1C(NC(OCC2C=CC=CC=2)=O)CC=CCN1S(C1C=CC(OC)=CC=1)(=O)=O)=O)(C)(C)C>>[CH2:26]([N:18]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16](=[O:17])[NH:15][CH:14]1[CH2:13][CH:12]=[CH:11][CH2:10][N:9]([S:33]([C:36]2[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)(=[O:34])=[O:35])[CH:8]1[C:6]([OH:7])=[O:5])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)N(Cc3ccccc3)Cc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Agent: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)OCc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Product: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)N(Cc3ccccc3)Cc3ccccc3)C2C(=O)O)cc1

Procedure:
3-(3,3-Dibenzylureido)-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester (200 mg, 0.33 mMol) is reacted in the same manner as 3-Benzyloxycarbonylamino-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester and purified by flash-chromatography, Dichloromethane/Methanol (9:1) to afford the free acid: Cal 550.6 found (M)+=550.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][C:3](=O)[CH2:2]1.C(N(CC)CC)C.[C:14](#[N:22])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[NH2:17]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[S:1]1[C:2]2[C:3](=[N:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[C:14]=2[NH2:22])[CH2:4][CH2:5]1
Reactant: O=C1CCSC1
Reactant: N#Cc1ccccc1N
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1c2c(nc3ccccc13)CCS2
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
To a stirred solution of tetrahydrothiophen-3-one (1.1 g, 11 mmole) in methylene chloride (10 ml) at -78° C., a 1M solution of titanium (IV) chloride in methylene chloride (11 ml) was added. A mixture of triethylamine (2.2 g, 22 mmole) and anthranilonitrile (1.2 gms, 10.0 mmole) in methylene chloride (30 ml) was then added to the reaction mixture over a period of 5 minutes. The reaction mixture was then slowly warmed to room temperature and stirred for 2 hours. Tetrahydrothiophen-3-one (1 ml) and titanium(IV) chloride (1.0 ml) was then added to the reaction mixture and the mixture was stirred at 25° C. for 16 hours. Thereafter, the reaction mixture was quenched with 12% aqueous NaOH (100 ml) and the reaction mixture was then stirred vigorously with additional methylene chloride (300 ml). The reaction mixture was then filtered through diatomaceous earth (Celite (trademark)) and the organic phase was separated. The organic solvents were removed under vacuum to afford a residue which was loaded on a flash chromatography column. Elution with 5% methanol in methylene chloride containing 1% triethylamine, afforded the title compound (1.3 gms, 64%) which was crystallized from chloroform (560 mg, 32%, m.p. 208°-210° C.). 1H-NMR (CDCl3, 300 MHz, δ): 4H, m, 3.4-3.56 ppm; 2H, bs, 4.51 ppm; 1H, dt, 7.37 ppm (J=7.0, 1.0 Hz); 1H, dt, 7.52 ppm (J=7.0, 1.10 ppm); 1H, dd, 7.61 ppm (J=7.0, 1.0 ppm); 1H, dd, 7.61 ppm (J=7.0, 1.0 ppm), 1H, dd, 7.86 ppm (J=7.0, 1.0 ppm). HRMS: Calculated--202.0575; Found--202.0545.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:15])([CH3:14])[CH2:12][OH:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:15])([CH3:14])[CH2:12][O:13][S:17]([CH3:16])(=[O:19])=[O:18])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@](O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: C[C@](O)(COS(C)(=O)=O)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 5 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
(R)-2-Chloro-1-(2,3-dihydroxy-2-methylpropyl)-4-nitroimidazole prepared in Example 10 (879 g, 3.73 mol) was dissolved in pyridine (1778 ml) and cooled to 5° C. To this solution, methanesulfonyl chloride (432.7 ml, 5.59 mol) was added dropwise below 15° C., and the resulting mixture was stirred at the same temperature for 1 hour. To the mixture, 6N hydrochloric acid (5500 ml) was added below 30° C., and the resulting mixture was stirred for 40 minutes with cooling on ice-bath. The precipitates were filtered off and washed with water and toluene in this order to afford primary crystals. In addition, the filtrate was extracted with ethyl acetate (5 liters) twice. The organic phase was washed with water, dried over magnesium sulfate, and filtered to afford a solid. The filtrate was concentrated under reduced pressure. To the residue, toluene was added and the precipitates were filtered off to afford a solid. The solids were combined and dried at 60° C. to afford (R)-2-chloro-1-(2-hydroxy-3-methanesulfonyloxy-2-methylpropyl)-4-nitroimidazole (942.6 g, yield 81%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][C:20]([C@:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=3)[C@@H:13]([C:30]#[C:31][CH3:32])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.NC1N=CC(S(N2CCN(C3N=CC([C@@](O)(C)C(F)(F)F)=CN=3)[C@H](C#CC)C2)(=O)=O)=CC=1.NC1N=CC(S(N2CCN(C3N=CC([C@](O)(C)C(F)(F)F)=CN=3)[C@H](C#CC)C2)(=O)=O)=CC=1>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][C:20]([C@@:23]([OH:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=3)[C@@H:13]([C:30]#[C:31][CH3:32])[CH2:12]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC#C[C@H]1CN(S(=O)(=O)c2ccc(N)nc2)CCN1c1ncc([C@@](C)(O)C(F)(F)F)cn1
Agent: CC#C[C@@H]1CN(S(=O)(=O)c2ccc(N)nc2)CCN1c1ncc([C@@](C)(O)C(F)(F)F)cn1
Agent: CC#C[C@@H]1CN(S(=O)(=O)c2ccc(N)nc2)CCN1c1ncc([C@](C)(O)C(F)(F)F)cn1
Product: CC#C[C@H]1CN(S(=O)(=O)c2ccc(N)nc2)CCN1c1ncc([C@](C)(O)C(F)(F)F)cn1

Procedure:
(2R)-2-(2-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol; (2S)-2-(2-((2R)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol; and (2R)-2-(2-((2R)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][C:19]#[N:20]>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[C:18](/[C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)\[C:19]#[N:20])=[CH:3][CH:2]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: N#CCc1cccs1
Product: N#C/C(=C\c1ccnc2ccccc12)c1cccs1
Yield: 66.8 %

Procedure:
4-Quinolinecarboxaldehyde (157 mg) was condensed with 2-thiopheneacetonitrile (123 mg) through Method B (production step 3), to thereby yield the target product (yield: 175 mg, 67%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:39]1[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=1>>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:45][C:42]3[CH:43]=[CH:44][N:39]=[CH:40][CH:41]=3)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccncc1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Cl)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccncc4)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1

Procedure:
A solution of the product from Example 43D and Pyridin-4-ylamine was reacted to provide 4-(4-Benzyloxy-phenoxy)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-N-pyridin-4-yl-benzamide using the procedure from Example 43E. The material was then deprotected using the procedure from Example 43F to provide the crude title compound which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (30 mg, 61%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.62 Hz, 6 H) 3.27 (m, 1 H) 6.78 (m, 2 H) 6.94 (m, 3 H) 7.81 (d, J=8.46 Hz, 1 H) 8.01 (dd, J=8.64, 2.02 Hz, 1 H) 8.22 (m, 3 H) 8.72 (d, J=6.99 Hz, 2 H) 8.83 (s, 1 H) 8.96 (d, J=8.46 Hz, 1 H) 9.50 (s, 1 H) 11.10 (s, 1 H) 11.35 (s, 1 H); MS (ESI+) m/z 493 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[CH:9]1([C:15](Cl)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.Cl>O>[CH:9]1([C:15]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: NCCC(=O)O
Reactant: O=C(Cl)C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCNC(=O)C1CCCCC1
Reaction time: 5 h
Yield: 84.9 %

Procedure:
Ten grams of β-alanine and 9 g of sodium hydroxide were dissolved in 100 mL of purified water, and 14.9 g of cyclohexanecarbonyl chloride were added dropwise under freezing conditions. After stirring for five hours, hydrochloric acid was added and the pH was adjusted to 2 or less. After extraction with 500 mL of ethyl acetate, the product was desiccated over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was recrystallized with aqueous ethanol, and 17.2 g of the desired product was obtained (yield of 85%).
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=1.[OH-].[Na+]>C(O)C>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(OCc2nc3ccccc3s2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(OCc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
15 ml of concentrated hydrochloric acid were carefully added to 4.99 g of O-(benzothiazol-2-ylmethyl)-4-nitrophenol [prepared as described in step (a) above] suspended in 100 ml of ethanol, with ice cooling, after which 8.26 g of stannous chloride were added in small portions to the resulting mixture at the same temperature. The temperature of the reaction mixture was then elevated to room temperature and the mixture stirred for 30 minutes at this temperature, before elevating the temperature further to 50° C. and stirring at this new temperature for a further 1.5 hours. At the end of this time 15 ml of concentrated hydrochloric acid and 8.26 g of stannous chloride were added to the reaction mixture and the resulting mixture was then stirred at 50° C. for 4 hours. The reaction mixture was then allowed to cool to room temperature, after which a saturated aqueous sodium hydroxide solution was added to the reaction mixture to adjust it to pH 10 and the resulting mixture was extracted with ethyl acetate. The resulting extract was washed with water, dried over anhydrous sodium sulfate and the solvent was removed by evaporation under reduced pressure to give a crude crystalline solid which was washed with a 10:1 by volume mixture of hexane and ethyl acetate to give 1.92 g (yield 43%) of the title compound as a solid having a melting point of 87° to 90° C.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[SH:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl>O.C(O)(C)C>[CH2:1]([S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(O)CCS
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCCCCSCCC(=O)O
Temperature: 80 °C

Procedure:
To a solution of 86.8 gm (0.25 mole) octadecyl bromide, 29.2 gm (0.275 mole) 3-mercaptopropionic acid and 90.0 gm isopropanol at 80° C. was added 95.0 gm (0.275 mole) 40% aqueous potassium carbonate solution dropwise. The mixture was heated at 80° C. for 8 hours and then cooled to 60° C. After adding 125.0 gm water and 36.8 gm of 30% hydrochloric acid solution, the mixture was slowly heated to 94° C. while distilling aqueous isopropyl alcohol from the reaction. The product separated as an oil from the aqueous phase. It was isolated using a separatory funnel and washed with hot water. Upon cooling, the product solidified as a light tan waxy solid. It was dried in a vacuum oven at 50° C. to yield 91.35 gm (98%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[O:23]1[CH:27]=[CH:26][C:25]([NH2:28])=[N:24]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([NH:28][C:25]2[CH:26]=[CH:27][O:23][N:24]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Nc1ccon1
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)Nc2ccon2)cc1Cl
Reaction time: 2 h
Yield: 33.3 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 93 mg, 0.27 mmol), isoxazol-3-ylamine (29 □L, 0.30 mmol) and N,N-diisopropylethylamine (141 μL, 0.81 mmol) were combined in acetonitrile (1.25 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (103 mg, 0.27 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 25% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-N-isoxazol-3-yl-acetamide (37 mg, 33%) as a slightly yellow solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C17H18ClN3O5S [M+] 411.07, found 412 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.67 (m, 4 H, 2×CH2), 1.88 (m, 4 H, 2×CH2), 3.31 (s, 3 H, SO2CH3), 4.94 (m, 1 H, OCH), 7.07 (d, J=1.7 Hz, 1 H, Ar), 7.56 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.66 (d, Jm=1.5 Hz, 1 H, Ar), 8.20 (d, Jo=8.2 Hz, 1 H, Ar), 8.33 (d, J=1.7 Hz, 1 H, Ar), 9.40 (s, 1 H, NH).
Reaction SMILES: Br[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH2:10])[CH:5]=[C:4]([NH2:11])[N:3]=1.CC([O-])=O.[K+].[OH-].[Na+].C1C=CC=CC=1>C1COCC1.CO.Cl.O.[Pd]>[C:8]([C:7]1[CH:2]=[N:3][C:4]([NH2:11])=[CH:5][C:6]=1[NH2:10])#[N:9]
Reactant: N#Cc1c(N)cc(N)nc1Br
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CO
Solvent: c1ccccc1
Product: N#Cc1cnc(N)cc1N
Reaction time: 168 h
Yield: 69 %

Procedure:
Crude 2-bromo-3-cyano-4,6-diaminopyridine [(W. J. Middleton, U.S. Pat. No. 2,790,806 (Apr. 30, 1957), Du Pont; Chem. Abst. 51:P14829 (1957), see also next experimental] (15.1 g, 0.071 mole) is hydrogenated in THF/MeOH (200 mL, 2:1) containing KOAc (7.0 g, 0.071 mole) and 5% Pd/C (4 g) at 55 p.s.i. and 20° C. for 7 days. Filtration over celite, washing with THF/MeOH and removal of the solvent gives a solid, which is dissolved in dilute HCl and water. Adjustment of the solution pH to 10 (conc. NaOH) and cooling gives 3-cyano-4,6-diaminopyridine (6.58 g, 69%) as a yellow solid, mp 197-198° C. [Metzger, R.; Oberdorfer, J.; Schwager, C.; Thielecke, W.; Boldt, P. Liebigs Ann. Chem. 1980, 946-953 record mp (benzene) 205° C.]. Extraction of the remaining liquor with EtOAc (4×200 mL) gives further product (2.12 g, 22%). 1H NMR (DMSO) δ 7.91 (1H, s), 6.26, 6.24 (2H, 2H, brs), 5.63 (1H, s)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:17])[NH:12]2.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[C:22]([CH3:33])[NH:21][C:20]=1[CH:34]=O>C(O)C.N1CCCCC1>[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]2)=[O:25])=[C:22]([CH3:33])[NH:21][C:20]=1[CH:34]=[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[NH:12][C:11]1=[O:17]
Reactant: O=C1Cc2c(cccc2-c2ccccc2F)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccccc4F)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 51.9 %

Procedure:
To a solution of 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The solvent was evaporated and the solid was washed by ether for three times to provide pure product 3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one (59.5 mg, 52%)
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[C@H:14]([CH:18]([CH3:20])[CH3:19])[C:15](O)=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1.Cl.[CH2:29]([O:36][NH2:37])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl.C(ON)(C)(C)C>>[CH2:29]([O:36][NH:37][C:15](=[O:16])[C@H:14]([N:13]([S:10]([C:7]1[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=1)(=[O:11])=[O:12])[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[CH:18]([CH3:20])[CH3:19])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)O)C(C)C)cc1
Reactant: NOCc1ccccc1
Agent: CC(C)(C)ON
Agent: Cl
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)NOCc2ccccc2)C(C)C)cc1

Procedure:
The N-(benzyloxy) substituted prodrug derivative of the above compound is prepared as follows: 2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanoic acid hydrochloride is reacted with O-benzylhydroxylamine hydrochloride under conditions described for reaction with O-t-butylhydroxylamine hydrochloride to yield N-(benzyloxy)-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methyl-butanamide, m.p. 74.5°-76° C.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].C(OC([N:14]1[CH2:21][CH2:20][C@:19]2([CH3:24])[C@H:22]([CH3:23])[C@H:15]1[CH2:16][C:17]1[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][C:18]=12)=O)(C)(C)C.Cl[C:39]1[N:40]=[N:41][C:42]([CH3:45])=[CH:43][CH:44]=1>CN(C)C=O>[CH3:24][C@:19]12[C@H:22]([CH3:23])[C@H:15]([NH:14][CH2:21][CH2:20]1)[CH2:16][C:17]1[CH:28]=[CH:27][C:26]([C:39]3[N:40]=[N:41][C:42]([CH3:45])=[CH:43][CH:44]=3)=[CH:25][C:18]2=1
Reactant: C[C@@H]1[C@H]2Cc3ccc(B4OC(C)(C)C(C)(C)O4)cc3[C@]1(C)CCN2C(=O)OC(C)(C)C
Reactant: Cc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)[C@]2(C)CCN[C@H](C3)[C@H]2C)nn1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2 M Aqueous Na2CO3 solution (1.13 mL) is added to a mixture of (2R,6R,11S)-6,11-dimethyl-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl ester (483 mg) and 3-chloro-6-methyl-pyridazine (218 mg) in dimethylformamide (2 mL). The resulting mixture is flushed with argon and then 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane complex (73 mg) is added. The mixture is heated to 100° C. and stirred at this temperature overnight. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are washed with water and brine and dried (MgSO4). The solvent is removed under reduced pressure and the residue is taken up in CH2Cl2 (3 mL) and treated with F3CCOO2H (0.5 mL) for 1 h. Then, the solution is concentrated and the residue is purified by HPLC on reversed phase (MeCN/H2O/NH3) to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][C@H:11]([CH3:14])[CH2:12][Cl:13]>>[Cl:13][CH2:12][C@@H:11]([CH3:14])[CH2:10][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: C[C@H](CCl)CBr
Reactant: Oc1ccccc1Br
Product: C[C@H](CCl)COc1ccccc1Br

Procedure:
Prepared by Procedure U and Scheme AK using 2-bromophenol and (2R)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: IN1C(=O)CCC1=O.[CH3:9][O:10][CH2:11][CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[C:18](=O)[CH2:19][C:20]([O:22][CH3:23])=[O:21].[NH2:25][C:26]([NH2:28])=[S:27]>CCOC(C)=O>[NH2:28][C:26]1[S:27][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([C:14]2[N:13]([CH2:12][CH2:11][O:10][CH3:9])[CH:17]=[CH:16][N:15]=2)[N:25]=1
Reactant: NC(N)=S
Reactant: COCCn1ccnc1C(=O)CC(=O)OC
Agent: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Product: COCCn1ccnc1-c1nc(N)sc1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
N-Iodosuccinimide (9.3 g, 41 mmol) was added to a mixture of 7.52 g (41 mmol) methyl 3-[1-(2-methoxyethyl)-1H-imidazol-2-yl]-3-oxopropanoate (Intermediate 56) and 7.5 g Amberlyst-15 resin in 400 ml EtOAc followed by stirring for 1 hour at room temperature. The resin was filtered off and rinsed with EtOAc. Solvent was removed from the filtrate and the residue was taken up in diethyl ether. Insoluble material was filtered off and rinsed with additional ether. Solvent was removed from the filtrate and the residue was dissolved in 200 ml MeOH before added 4.7 g (62 mmol) thiourea. The mixture was heated at reflux for 1 hour. Then the solvent was removed and the residue was taken up in aqueous Na2CO3. Insoluble material was collected by filtration and rinsed well with water. The solids were dried in vacuo affording 4.51 g of the title compound: MS (ES) (M+H)+: 283 for C11H14N4O3S; NMR: 3.22 (s, 3H), 3.61 (m, 2H), 3.69 (s, 3H), 4.32 (m, 2H), 7.91 (s, 2H), 8.41 (s, 2H).