Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)C.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[N:22]=[C:23]=S.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.O>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[NH:22][C:23]1[NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:3])=[O:13])=[CH:6][C:7]=2[N:12]=1
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 3,4-diamino-benzoic acid ethyl ester (5.00 g, 27.8 mmol) and 1,3-dichloro-2-isothiocyanato-benzene (5.66 g, 27.8 mmol) in 40 mL DMF was stirred for 2 h under argon. DCC (5.72 g, 27.8 mmol) was added and mixture heated to 80° C. for 45 min. After stirring the mixture was diluted with water and concentrated i.vac. The residue was diluted with ethanol and 1 M NaOH (aq). The mixture was heated to 100° C. and stirred overnight. Then ethanol was evaporated and the aq. phase was cooled, acidified with acetic acid, filtered and the solid washed with water.
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:30](OCC)=[O:31])[N:18]([CH2:28][CH3:29])[C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])=[CH:11][CH:10]=1>>[CH2:1]([NH:7][C:30]([C:17]1[N:18]([CH2:28][CH3:29])[C:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=2)[N:16]=1)=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1CC
Reactant: CCCCCCN
Product: CCCCCCNC(=O)c1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1CC

Procedure:
Using essentially the same procedure as Example 42, Step C, but using neat hexylamine (2 mL), ethyl 4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-1-ethylimidazole-2-carboxylate (25 mg, 0.060 mmol) from Example 42, Step B was converted to the title compound after purification by Prep TLC (25% ethyl acetate in hexanes).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH2:14])[CH2:10][C@H:9]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:27])=[N-]>C1COCC1.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:27][CH2:14]2)[CH2:10][C@H:9]1[C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=[N+]=[N-]
Reactant: C=C1CCN(C(=O)OC(C)(C)C)[C@H](C(=O)OCc2ccccc2)C1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC2(CC2)C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 88 %

Procedure:
To a solution of (S)-4-methylene-piperidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (intermediate 15 prepared by Method A, 120 g, 0.36 mol) in anhydrous THF (1 L) was added diazomethane in ether (500 ml) [which was prepared from methyl-3-nitro-1-nitroxoguanide (213 g) in 40% KOH (1 L)] at −25° C. to −35° C. slowly under the protection of nitrogen and warmed to room temperature slowly (about 4 hours) and stirred at room temperature for 10 hours. The mixture is filtered and the liquid phase was evaporated to obtain a crude that was purified by silica gel chromatography (petroleum ether/ethyl acetate from 10/1 to 5/1). (S)-6-Aza-spiro[2.5]octane-5,6-dicarboxylic acid 5-benzyl ester 6-tert-butyl ester was obtained as colourless oil (110 g), yield:88%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.O.[CH3:18]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:18])=[O:5]
Reactant: CO
Reactant: O=C(O)c1cc(Cl)ccc1Br
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cc(Cl)ccc1Br
Temperature: 25 °C

Procedure:
2-bromo-5-chlorobenzoic acid (4 g, 0.016 mol) was dissolved in MeOH (20 ml) and sulphuric acid (1 ml) was added. The reaction was refluxed for 3 h then cooled at RT. Water (20 ml) was added and the solid was filtered, dissolved in DCM and washed with saturated aqueous solution of NaHCO3. The organic solvent was dried (Na2SO4) and evaporated to obtain 4.17 g of the title compound as oil.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=4)[N:10]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:26][CH:25]=1)(=[O:22])=[O:23]
Reactant: COc1ccc(Nc2nc3c(Br)cccn3n2)cc1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Product: COc1ccc(Nc2nc3c(Nc4ccc(S(C)(=O)=O)cc4)cccn3n2)cc1

Procedure:
N(8)-(4-Methanesulfonyl-phenyl)-N(2)-(4-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-(4-methoxy-phenyl)-amine (50.0 mg, 0.157 mmol) and 4-methanesulfonyl-phenylamine (33.0 mg, 0.193 mmol) in a manner analogous to Example 30. The title compound was isolated as a brown foam (0.013 g, 20%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.08 (d, J=6.1 Hz, 1H), 7.89 (d, J=7.5 Hz, 2H), 7.49 (d, J=7.9 Hz, 2H), 7.35-7.30 (m, 3H), 6.95-6.90 (m, 3H), 6.85-6.80 (m, 1H), 6.58 (s, 1H), 3.82 (s, 3H), 3.07 (s, 3H). MS=410 (MH)+.
Reaction SMILES: [CH3:1][CH:2]([S:11][C:12]#[N:13])[C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.[BrH:15].C(O)(=O)C>>[Br:15][C:12]1[S:11][C:2]([CH3:1])=[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:13]=1
Reactant: Br
Reactant: CC(SC#N)C(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: Cc1sc(Br)nc1-c1ccccc1
Yield: 73.1 %

Procedure:
A solution of 1-methyl-2-oxo-2-phenylethyl thiocyanate (1.00 g, 5.23 mmol) in 25% hydrogen bromide/acetic acid (10 ml) was stirred at 130° C. for 2 hours and at room temperature for 1 hour. Water was poured into the reaction solution, and the mixture was extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 971 mg (73.1%) of the desired product as an oil.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5]CC)=O.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][CH:21]([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[S:19])=[CH:13][CH:12]=1)#[N:10]>ClCCl>[O:8]=[C:2]1[C:3](=[O:5])[N:17]([C:14]2[CH:13]=[CH:12][C:11]([C:9]#[N:10])=[CH:16][CH:15]=2)[C:18](=[S:19])[N:20]1[CH:21]([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(NC(=S)Nc1ccc(C#N)cc1)C(C)(C)C
Solvent: ClCCl
Product: CC(N1C(=O)C(=O)N(c2ccc(C#N)cc2)C1=S)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
Ethyl chlorooxoacetate (5.60 mL, 50.0 mmol) was added to a stirring solution of the above thiourea (6.54 g, 25.0 mmol) in dichloromethane (170 mL) and the resulting mixture was stirred overnight at room temperature. Concentration, trituration of the residue with diethyl ether, and filtration afforded 5.77 g (73%) of 4-[4,5-dioxo-2-thioxo-3-(1,2,2-trimethyl-propyl)-imidazolidin-1-yl]-benzonitrile as a yellow solid: mp 219.6–219.9° C.; 1H NMR (DMSO-d6): δ 8.03 (d, 2H), 7.60 (d, 2H), 4.82 (q, 1H), 1.47 (d, 3H), 1.00 (s, 9H); IR (KBr): 3505, 2970, 2230, 1765, 1600 cm−1; MS (m/z) 315 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[C:5]#[N:6].Cl.[NH2:12][OH:13].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])/[C:5](=[N:12]/[OH:13])/[NH2:6]
Reactant: N#Cc1ccc(Cl)c(Cl)c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N/C(=N\O)c1ccc(Cl)c(Cl)c1

Procedure:
A solution of 3,4-dichlorobenzonitrile (2.000 g, 11.63 mmol), hydroxylamine hydrochloride (1.649 mL, 12.79 mmol) and sodium hydroxide (4.15 mL, 12.4 mmol) in ethanol (40 mL) was stirred at rt for 1 h. Concentrated and refluxed in hexane for 30 min and concentrated in vacuo. The product Intermediate 1A was used directly for the next step. HPLC/MS (Method C) RT=1.24 min [M+H]+ 204.9.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O:7][C:8]1[C:17]2[O:16][CH2:15][O:14][CH2:13][C:12]=2[CH:11]=[C:10]([CH:18]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:33]=[C:32]([CH3:34])[O:31][N:30]=3)=[CH:25][CH:24]=2)[C:19]([NH2:21])=[S:20])[CH:9]=1.[C:35](=O)([O-])O.[Na+].C(OCC)(=O)C>C(#N)C>[CH3:35][S:20][C:19](=[NH:21])[CH:18]([C:10]1[CH:9]=[C:8]([O:7][CH3:6])[C:17]2[O:16][CH2:15][O:14][CH2:13][C:12]=2[CH:11]=1)[NH:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:27][CH:28]=1
Reactant: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)C(N)=S)cc2c1OCOC2
Reactant: O=C([O-])O
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)C(=N)SC)cc2c1OCOC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
After adding 10.6 g of Me3O+BF4− to a solution of 28.2 g of a crude product of 2-(8-methoxy-4H-benzo[1,3]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]thioacetamide in 100 ml of acetonitrile, the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (27.2 g, crude product) as a light yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)=[O:12])=[C:6]([C:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=2)[CH:5]=1)(=[O:3])[CH3:2].[CH:34](O)([OH:36])[CH3:35].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.CCOC(C)=O>[C:28]1([C:6]2[CH:5]=[C:4]([C:1]3([CH3:2])[O:36][CH2:34][CH2:35][O:3]3)[CH:9]=[CH:8][C:7]=2[NH:10][C:11]([C:13]2[N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:27])[CH3:25])[CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)=[O:12])[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=1
Reactant: CC(O)O
Reactant: CC(=O)c1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC1(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)OCCO1
Yield: 68 %

Procedure:
A solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (4-acetyl-2-cyclohex-1-enyl-phenyl)-amide (as prepared in the previous step, 135 mg, 0.290 mmol), ethanediol (363 mg, 5.80 mmol) and catalytic p-toluenesulfonic acid (PTSA) in 21 mL of benzene were heated at reflux under Dean-Stark conditions for 4 h. The reaction was diluted with EtOAc (25 mL), washed with water (3×20 mL), dried (Na2SO4), and concentrated in vacuo. Purification of the residue using preparative TLC (10% MeOH—CHCl3) afforded 100 mg (68%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C27H36N4O4Si, 509.2 (M+H). found 509.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:13]([NH:15][C:16]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][C:17]=1[N+:24]([O-])=O)[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.CCOC(C)=O>[NH2:24][C:17]1[CH:18]=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:16]=1[NH:15][C@@H:13]([CH3:14])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10]([OH:12])=[O:11]
Reactant: C[C@H](Nc1cc(C#N)ccc1[N+](=O)[O-])[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@H](Nc1cc(C#N)ccc1N)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 4 h
Yield: 99.7 %

Procedure:
A mixture of (2S,3S)-2-(tert-butoxycarbonyl amino)-3-(5-cyano-2-nitrophenylamino)butanoic acid (5.35 g, 14.7 mmol) and PdC (10% dry basis, wet, 50% water) (535 mg, 251 μmol) in MeOH (60 ml) and EtOAc (60 ml) was shaken under H2 (50 PSI) for 4 h, then filtered through a bed of celite and concentrated to afford (2S,3S)-3-(2-amino-5-cyanophenylamino)-2-(tert-butoxycarbonylamino)butanoic acid (4.9 g, quant.) as a dark brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[C:12]([C:19]2([CH3:24])OCC[O:20]2)[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17].Cl>CC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[C:12]([C:19](=[O:20])[CH3:24])[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17]
Reactant: CC1(c2ccc([N+](=O)[O-])c(Nc3ccc(F)cc3F)c2)OCCO1
Agent: Cl
Solvent: CC(C)=O
Product: CC(=O)c1ccc([N+](=O)[O-])c(Nc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
A mixture of 2-[3-(2,4-difluorophenylamino)-4-nitrophenyl]-2-methyl-1,3-dioxolane (10 g) and 3N-hydrochloric acid (20 ml) in acetone (40 ml) was stirred overnight at room temperature. The mixture was concentrated under reduced pressure. To the residue were added a saturated aqueous solution of sodium bicarbonate and ethyl acetate. The organic layer was dried and concentrated to give an oil of 3'-(2,4-difluorophenylamino)-4'-nitroacetophenone (8.5 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][CH:17]4[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1.[Br:23][C:24]1[CH:25]=[N:26][C:27](Cl)=[N:28][CH:29]=1.CCN(C(C)C)C(C)C>CCO>[Br:23][C:24]1[CH:25]=[N:26][C:27]([N:19]2[CH2:20][CH2:21][CH2:22][CH:17]([CH2:16][N:13]3[C:11]4=[N:12][C:7]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=5)=[CH:8][N:9]=[C:10]4[N:15]=[N:14]3)[CH2:18]2)=[N:28][CH:29]=1
Reactant: Cn1cc(-c2cnc3nnn(CC4CCCNC4)c3n2)cn1
Reactant: Clc1ncc(Br)cn1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2cnc3nnn(CC4CCCN(c5ncc(Br)cn5)C4)c3n2)cn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
6-(1-methyl-1H-pyrazol-4-yl)-1-(piperidin-3-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (0.26 g, 0.89 mmol) was dissolved in EtOH (15 ml), and then 5-bromo-2-chloropyrimidine (0.33 g, 1.33 mmol) and DIPEA (0.77 ml, 4.43 mmol) were added, followed by stirring at 50° C. overnight. After the completion of the reaction, the reaction mixture was extracted with H2O, EA, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (EA:Hex=1:1), to give (1-((1-(5-bromopyrimidin-2-yl)piperidin-3-yl)methyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (0.28 g, 70%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:10]N1C(=O)CCC1=O>CN(C=O)C>[Cl:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: c1ccc2[nH]ccc2c1
Solvent: CN(C)C=O
Product: Clc1c[nH]c2ccccc12
Reaction time: 4 h
Yield: 69.8 %

Procedure:
To a solution of indole (2.0 g, 17.0 mmol) in DMF (12 mL) at 10° C. under a nitrogen atmosphere was added N-chlorosuccinimide (2.49 g, 18.7 mmol). The reaction was stirred for 4 h then quenched with 10% sodium bisulfite solution. After stirring for 15 min the precipitated solid was collected by vacuum filtration. The filtered solid was washed with water then dissolved in dichloromethane. The solution was washed with water, brine and dried over sodium sulfate then concentrated in vacuo to give 3-chloroindole (1.8 g, 70%) as a yellow-brown solid: 1H NMR (CDCl3, 300 MHz) δ 8.06 (s, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.34-7.37 (m, 1H), 7.16-7.22 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:25](O)[C:26]1[O:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[O:30]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:25][N:20]1[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=[C:16]1[C:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:15]
Reactant: OCc1ccco1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3[nH]2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(c1nc2ccccc2n1Cc1ccco1)C1CCNCC1
Reaction time: 18 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazole-2-carbonyl)piperidine (1.16 mmol), furfuryl alcohol (0.10 mL, 1.16 mmol), and triphenylphosphine (0.33 g, 1.28 mmol) in tetrahydrofuran (5 mL). Add diethyl azodicarboxylate (0.20 mL, 1.28 mmol). After 18 hours, evaporate the reaction mixture in vacuo to give a residue. Partition the residue between ethyl acetate and water. Separate the organic layer and extract with water and saturated aqueous sodium chloride solution. Dry the organic layer over Na2SO4, filter, and evaporate invacuo to give the title compound. Chromatograph the residue on silica gel eluting with 5% acetone/dichloromethane to give 1-(t-butoxycarbonyl)-4-(1-(fur-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine. Cool 1-(t-butoxycarbonyl)-4-(1-(fur-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine (1.0 mmol), and dichloromethane (5 mL). Slowly add a cold solution of trifluoroacetic acid (1 mmol) in dichloromethane (2 mL). After 15 minutes, partition the reaction mixture between dichloromethane and saturated aqueous sodium bicarbonate solution. Separate the organic layer and extract with brine. Dry the organic layer over Na2SO4, filter, and evaporate invacuo to give the title compound.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:10])=[N:6][CH:7]=[N:8][CH:9]=1)(=[O:3])[CH3:2].C1C=CC=CC=1.C(O[CH:22](N(C)C)[N:23]([CH3:25])[CH3:24])(C)(C)C>CN(C=O)C>[CH3:22][N:23]([CH3:25])[CH:24]=[CH:2][C:1]([C:4]1[C:5]([CH3:10])=[N:6][CH:7]=[N:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1cncnc1C
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: Cc1ncncc1C(=O)C=CN(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a solution of 28.2 g of 5-acetyl-4-methylpyrimidine in 250 ml of a chilled 1:1 mixture of benzene and DMF was added 33.6 g of tert-butoxy-bis(dimethylamino)methane dropwise. The solution was stirred overnight at room temperature. The solvents were evaporated in vacuo to yield 36.2 g of 3-dimethylamino-1-(4-methylpyrimidin-5-yl)-2-propen-1-one as a brick-red solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([N+:12]([O-:14])=[O:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.CO.C(OCC)C.[CH2:22]([NH2:26])[CH2:23][CH2:24][CH3:25]>>[CH2:22]([NH:26][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([N+:12]([O-:14])=[O:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCN
Reactant: O=[N+]([O-])c1cccc2ccc(Cl)nc12
Solvent: CCOCC
Solvent: CO
Product: CCCCNc1ccc2cccc([N+](=O)[O-])c2n1
Temperature: 78 °C
Yield: 90 %

Procedure:
2-chloro-8-nitroquinoline (0.20 g; 0.96 mmol) is suspended in 9.5 ml of 1-butylamine and the medium is heated under reflux (78° C.) for 15 hours. The yellow solution obtained is subsequently concentrated under vacuum. The crude reaction product is taken up in a minimum volume of CH3OH and poured over 3 ml of diethyl ether. After centrifugation, butyl ammonium chloride crystals are removed and the supernatant is concentrated under reduced pressure to yield N-butyl-8-nitro-2-quinoline amine in the form of a yellow oil (0.21 g; 0.86 mmol, yield=90%). NMR-1H (250 MHz, CDCl3) δ, ppm: 7.83 (dd, 3J (H, H)=7.5 Hz, 4J (H, H)=1.5 Hz, 1H); 7.77 (d, 3J (H, H)=9.0 Hz, 1H); 7.69 (dd, 3J (H, H)=8.0 Hz, 4J (H, H)=1.5 Hz, 1H); 7.14 (m, 1H), 6.67 (d, 3J (H, H)=9.0 Hz, 1H); 5.07 (s large, 1H); 3.47 (m, 2H); 1.60 (m, 2H); 1.39 (m, 2H); 0.93 (t, 3J (H, H)=7.5 Hz, 3H). NMR-13C (63 MHz, CDCl3) δ, ppm: 157.8 (Cq); 145.6 (Cq); 140.2 (Cq); 136.7 (CH); 131.5 (CH); 124.7 (CH); 124.1 (CH); 119.7 (CH); 113.3 (Cq); 41.3 (CH2); 31.5 (CH2); 20.2 (CH2); 13.8 (CH3). MS (CID, NH3): m/z=246 (MH+). Analysis (%) for C13H15N3O2: calculated C, 63.66. H, 6.16. N, 17.13. found C, 63.33. H, 6.21. N, 16.64.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH3:12][N:13]1[C:18]2=[CH:19][NH:20][C:21]([C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=3)[C:25]#[N:26])=[C:17]2[C:16](=[O:30])[N:15]([CH3:31])[C:14]1=[O:32].[C:33]([O:37][CH3:38])(=[O:36])[CH:34]=[CH2:35]>C(#N)C>[C:25]([C:24]1[CH:23]=[C:22]([C:21]2[N:20]([CH2:35][CH2:34][C:33]([O:37][CH3:38])=[O:36])[CH:19]=[C:18]3[C:17]=2[C:16](=[O:30])[N:15]([CH3:31])[C:14](=[O:32])[N:13]3[CH3:12])[CH:29]=[CH:28][CH:27]=1)#[N:26]
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)[nH]cc2n(C)c1=O
Reactant: C=CC(=O)OC
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CCn1cc2c(c1-c1cccc(C#N)c1)c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
DBU (0.656 mL, 4.35 mmol) was added to a solution of 3-(1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (Example 9 Step 4) (1.22 g, 4.35 mmol) and methyl acrylate (0.392 mL, 4.35 mmol) in acetonitrile (15 mL). The mixture was stirred at room temperature for 4 days. Further portions of methyl acrylate (0.392 mL, 4.35 mmol) and DBU (0.656 mL, 4.35 mmol) were added as required to allow the reaction to run to completion. The reaction was quenched with saturated NH4Cl(aq) and extracted with DCM (2×). The combined organic extracts were passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 20-100% EtOAc/hexane afforded a crude material which was triturated with DCM/diethyl ether/hexane to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ncccc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ncccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of methylnicotinic acid (500 mg, 3.6 mmol) in DCM (30 mL) is added oxalyl chloride (0.93 mL, 10.9 mmol) dropwise followed by DMF (1 drop). The reaction mixture is stirred at room temperature for 1 h and then concentrated in vacuo to give methylnicotinoyl chloride in a quantitative yield. A solution of I-83.1 (250 mg, 0.93 mmol) and methylnicotinoyl chloride (159.0 mg, 1.02 mmol) in DCM is stirred at room temperature for 1 h with the addition of more methylnicotinoyl chloride (28.9 mg, 0.19 mmol). The reaction mixture is then diluted with saturated aqueous NaHCO3 and the combined organics are dried over Na2SO4, The solvent is removed in vacuo to give I-110 (360 mg, quantitative).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH:4][N:5]=[C:6]1[C:10](=O)[CH2:9][CH2:8][S:7]1(=[O:13])=[O:12]>O.CO>[OH:4][N:5]=[C:6]1[C:10](=[N:2][OH:3])[CH2:9][CH2:8][S:7]1(=[O:13])=[O:12]
Reactant: NO
Reactant: O=C1CCS(=O)(=O)C1=NO
Agent: Cl
Solvent: O
Solvent: CO
Product: O=S1(=O)CCC(=NO)C1=NO
Yield: 49.7 %

Procedure:
5.4 g (77 mmol) of hydroxylamine hydrochloride, dissolved in 15 ml of water, are added to a solution of 11.4 g (70 mmol) of 2-hydroxyimino-3-oxotetrahydrothiophene dioxide in 100 ml of methanol. After 2 hours at room temperature the batch is completely concentrated and the residue is recrystallised from ethanol. 6.2 g (50%) of 2,3-dihydroxyiminotetrahydrothiophene dioxide, m.p. 181° C., are obtained.