Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:44])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[C:30]([OH:37])[C:29]=2[CH2:38][CH2:39][CH3:40])[C:10]=1[CH2:41][CH2:42][CH3:43])C.[OH-].[Na+]>CO>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:44])=[O:3])=[C:10]([CH2:41][CH2:42][CH3:43])[C:11]=1[O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[C:30]([OH:37])[C:29]=1[CH2:38][CH2:39][CH3:40])(=[O:17])[CH3:16]
Reactant: CCCc1c(OCCOCCOCCOc2c(C(C)=O)ccc(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCOCCOCCOc2c(C(C)=O)ccc(OCCCC(=O)O)c2CCC)ccc(C(C)=O)c1O
Yield: 93.2 %

Procedure:
A soluton of 2.313 g of 4-[4-acetyl-3-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoic acid ethyl ester and 19 ml of 1.0N sodium hydroxide in 50 ml of methanol was stirred at reflux for 2 hours. Most of the methanol was removed in vacuo and the residue was acidified. The product was extracted with methylene chloride and the dried (magnesium sulfate) extract was concentrated in vacuo to give 2.058 g (93% yield) of 4-[4-acetyl-3-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoic acid as a viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([C:11]3[CH:12]=[C:13]([NH2:25])[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[F:24])[CH:16]=3)[C:5]2=[N:6][CH:7]=1.N1C=CC=CC=1.[CH2:32]([S:34](Cl)(=[O:36])=[O:35])[CH3:33]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([C:11]3[CH:12]=[C:13]([NH:25][S:34]([CH2:32][CH3:33])(=[O:36])=[O:35])[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[F:24])[CH:16]=3)[C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(Br)cnc32)c1
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(Br)cnc32)c1
Reaction time: 1 h
Yield: 76.68 %

Procedure:
To a solution of 5-(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-amine (133 mg, 0.33 mmol) in DCM was added pyridine (52 mg, 0.66 mmol, 2.0 eq.) followed by ethanesulfonyl chloride (76 mg, 0.66 mmol, 2.0 eq.). The mixture was stirred for 1 h, and quenched and extracted as in Example 2(b). The solvent was distilled off to afford the crude residue which was taken to the next step without further purification, yield 76.68% (125 mg); LC-MS (ESI): Calculated mass: 492.01; Observed mass: 493.0 [M+H]+ (rt: 1.72 min).
Reaction SMILES: [OH:1][NH:2][C:3]([CH3:10])([C:5]([NH:8][OH:9])([CH3:7])[CH3:6])[CH3:4].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1>CO>[OH:1][N:2]1[C:3]([CH3:10])([CH3:4])[C:5]([CH3:7])([CH3:6])[N:8]([OH:9])[CH:17]1[C:16]1[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(C)(NO)C(C)(C)NO
Solvent: CO
Product: COc1ccc(C2N(O)C(C)(C)C(C)(C)N2O)cc1
Yield: 34 %

Procedure:
A solution of 2,3-bis(hydroxylamino)-2,3-dimethylbutane (1.3 g, 8.8 mmol) and 4-methoxy-benzaldehyde (1.2 g, 8.8 mmol) in methanol (10 mL) was stirred at room temperature until reactants disappeared as TLC indicated. 1,3-Dihydroxy-2-(4-methoxyphenyl)-4,4,5,5-tetramethylimidazolidine was obtained by filtration, the filtrate was evaporated under reduced pressure to obtain the second crop of the title compound. The combined compound was then washed with petroleum ether and used for the next reaction (0.8 g, 34% yield). 1HNMR (400 MHz, DMSO): δ 7.63 (s, 1 H), 7.32 (d, 1 H, J=6.8), 6.87 (d, 1 H, J=5.8), 4.42 (s, 1 H), 3.72 (s, 3 H), 1.06 (s, 3 H), 1.02 (s, 3 H).
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1.[CH3:14][CH:15]([CH3:39])[CH2:16][NH:17][C@H:18]1[CH2:23][C@@H:22]([C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:25])[CH2:21][N:20]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:19]1.C(=O)([O-])[OH:41].[Na+]>O1CCCC1.O>[NH:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:3]1[C:2]([N:17]([CH2:16][CH:15]([CH3:39])[CH3:14])[C@H:18]1[CH2:23][C@@H:22]([C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:25])[CH2:21][N:20]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:19]1)=[O:41]
Reactant: ClC(Cl)(Cl)c1nc2ccccc2[nH]1
Reactant: O=C([O-])O
Reactant: CC(C)CN[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CN(C(=O)c1nc2ccccc2[nH]1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
2-(Trichloromethyl)-1H-benzimidazole (2.00 g) and tert-butyl (3S,5R)-3-{(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (2.84 g) were dissolved in tetrahydrofuran-water (3:2,150 ml), sodium hydrogen carbonate (6.45 g) was added and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitated white solid was collected by filtration, washed with ethyl acetate-hexane (1:1) and dried to give the object product (3.03 g).
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:4]1=2)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][Cl:30]>O.C(#N)C>[Cl:30][CH2:29][CH2:28][CH2:27][O:19][C:16]1[CH:17]=[CH:18][C:4]2[N:3]([CH2:1][CH3:2])[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]=2[CH:15]=1
Reactant: ClCCCBr
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCCl)ccc21
Temperature: 70 °C

Procedure:
1-Ethyl-7-hydroxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (1.85 g) and potassium carbonate (1.2 g) were added to 50% water-containing acetonitrile (40 ml), and dissolved by heating to 70° C. 1-Bromo-3-chloropropane (2.1 ml) was added thereto, and heating was conducted under reflux for 6 hours. The reaction mixture was cooled to room temperature. Water was added, and extraction with ethyl acetate was performed. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→1:1). The purified product was concentrated to dryness under reduced pressure to give the title compound (2.18 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[C:10]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)#[C:11][CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:16]2[CH2:17][CH2:18][N:13]([C:10]#[C:11][CH3:12])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: CC#CN1CCNCC1
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC#CN1CCN(Cc2ccc(Cl)cc2)CC1

Procedure:
A mixture of 6.44 g. of 4-chlorobenzyl chloride, 4.97 g. of N-propynyl piperazine, 8.48 g. of sodium carbonate and 50 ml. of ethanol was refluxed for 18 hours. The mixture was then filtered and the filtrate evaporated in vacuo. The residual oil was dissolved in chloroform which solution was washed with water and then dried over magnesium sulfate. The mixture was then filtered and the filtrate was evaporated under vacuum and subsequently distilled to give a yellow oil of the expected N'-(4-chlorobenzyl)-N-propynyl piperazine, b.p. 162°-5° C./1.5 mm, which produces a single spot of T.L.C. and the expected NMR and IR spectra.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:25](OCC)[O:26]CC)=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl>CC(C)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:25]=[O:26])=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C(OCC)OCC)=C(C(=O)OCC)C1c1ccccc1Cl
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1Cl
Temperature: 25 °C

Procedure:
To a solution of diethyl 2-methyl-4-(2-chlorophenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (452 mg) in acetone (5 ml) was added 6N-hydrochloric acid (0.2 to 0.3 ml) and stirred at room temperature for an hour. After removing acetone, the residue was extracted with ethyl acetate twice and the extract was washed with water and dried. The solvent was removed from the extract to give diethyl 2-methyl-4-(2-chlorophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate. The product was recrystallized from a mixture of n-hexane and diethyl ether to give the pure product, m.p. 87° to 88° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1)=[O:4].[CH3:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>>[CH2:13]1[O:12][C:9]2[CH:10]=[CH:11][C:6]([N:5]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:3](=[O:4])[CH2:2][NH:1][C:31]([NH:30][C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([CH3:23])[CH:25]=3)=[O:32])=[CH:7][C:8]=2[O:14]1
Reactant: CC(C)(C)OC(=O)CN(C(=O)CN)c1ccc2c(c1)OCO2
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccc3c(c2)OCO3)c1
Yield: 49.8 %

Procedure:
Using a procedure similar to that described in Example 1, but starting with tert-butyl 2-[2-amino-N-(3,4-methylenedioxyphenyl)acetamido]acetate (2.4 g) and 3-methylphenyl isocyanate (1 g), and after recrystallisation in ethyl acetate, tert-butyl 2-{N-(3,4-methylenedioxyphenyl)-2-[3-(3-methylphenyl)ureido]acetamido}acetate (1.65 g), m.p. 142° C., is obtained.
Reaction SMILES: [Na].[NH2:2][C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:4]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.[C:21]([CH2:23][C:24](OCC)=[O:25])#[N:22].Cl>C(O)C.O>[NH2:22][C:21]1[N:7]2[N:6]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[C:4]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[C:3]2[N:2]=[C:24]([OH:25])[CH:23]=1
Reactant: Nc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: CCOC(=O)CC#N
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: Nc1cc(O)nc2c(-c3ccncc3)c(-c3ccc(F)cc3)nn12
Yield: 84.1 %

Procedure:
To a solution of sodium (23 mg) in dry ethanol (3 ml) was added 5-amino-3-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole (254 mg) and ethyl cyanoacetate (113 mg). The mixture was refluxed for 5 hours and cooled. To the reaction mixture were added 1N-hydrochloric acid (2 ml) and water (5 ml). The separated solid was collected, washed with water and dried to give 7-amino-2-(4-fluorophenyl)-5-hydroxy-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine (270 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([OH:16])=[O:15])=[N:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][N:7]=1.OS(O)(=O)=O.[CH3:22]O>>[NH2:1][C:2]1[C:3]([C:14]([O:16][CH3:22])=[O:15])=[N:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][N:7]=1
Reactant: CO
Reactant: Nc1ncc(-c2cccnc2)nc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1nc(-c2cccnc2)cnc1N
Yield: 97 %

Procedure:
To 3-amino-6-(3-pyridyl)pyrazine-2-carboxylic acid (2 g, 9.251 mmol) in MeOH (50 mL) was added conc. H2SO4 (907.3 mg, 493.1 μL, 9.251 mmol) and the mixture heated to reflux for 2 hours. The solvent was removed in vacuo and the mixture neutralised with aq. Na2CO3. The resulting brown solid was collected by filtration and dried (2.08 g, 97% Yield). MS (ES+) 231
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH:17]([OH:20])(C)[CH3:18].C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:7]([O:20][CH2:17][CH3:18])=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)O
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: CCOc1nc(N)nc(-c2ccco2)c1Br

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, isopropanol and DBU in dioxane. EI-MS m/e (%): 299 (M{81Br}+, 43), 297 (M{79Br}+, 45), 257 ([M—C6H10]+, 98), 255 ([M—C6H10]+, 100), 206 (32), 94 (44), 43 (52).
Reaction SMILES: C(OC(=O)[N:7]([C@H:9]([C:11](=[O:37])[NH:12][C@H:13]1[CH2:19][S:18][C:17]2[C:20]([NH2:24])=[CH:21][CH:22]=[CH:23][C:16]=2[N:15]([CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)[C:14]1=[O:36])[CH3:10])[CH3:8])(C)(C)C.[C:39]([Cl:47])(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[ClH:47].[CH3:8][NH:7][C@@H:9]([CH3:10])[C:11]([NH:12][C@H:13]1[CH2:19][S:18][C:17]2[C:20]([NH:24][C:39](=[O:46])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:21][CH:22]=[CH:23][C:16]=2[N:15]([CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)[C:14]1=[O:36])=[O:37]
Reactant: C[C@@H](C(=O)N[C@H]1CSc2c(N)cccc2N(Cc2cccc3ccccc23)C1=O)N(C)C(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccccc1
Product: CN[C@@H](C)C(=O)N[C@H]1CSc2c(NC(=O)c3ccccc3)cccc2N(Cc2cccc3ccccc23)C1=O
Product: Cl

Procedure:
In a similar manner to that described for Example 22, [(S)-1-((R)-9-amino-5-naphthalen-1-ylmethyl-4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]thiazepin-3-ylcarbamoyl)-ethyl]-methyl-carbamic acid tert-butyl ester and benzoyl chloride were converted to the title compound. MS m/z 539 (MH+)
Reaction SMILES: [C:1]([O-:8])(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5].[NH4+:9].[NH4+].CCCCCCCC[N:19](CCCCCCCC)CCCCCCCC.C(O)CCCCCCCCCCC>>[C:1]([O-:8])(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5].[NH4+:19].[NH4+:9].[C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCCCCCCCN(CCCCCCCC)CCCCCCCC
Agent: O=C([O-])CCC(=O)[O-]
Agent: [NH4+]
Solvent: CCCCCCCCCCCCO
Product: O=C(O)CCC(=O)O

Procedure:
The procedure described in Example 1 was followed except that 20 g of a 25% solution of ammonium succinate was combined with 45 g tricaprylamine and 5 g dodecanol. The reaction mixture was heated for 1.5 hours at 120–125° C. and atmospheric pressure, resulting in a conversion of about 84% from ammonium succinate to a mixture of succinic acid and succinic acid ester.
Reaction SMILES: COC1C=CC(CO[CH2:11][CH2:12][O:13][CH2:14][C@H:15]2[CH2:26][CH2:25][C:24]3[S:23][C:22]4[N:21]=[CH:20][N:19]=[C:18]([O:27][CH:28]5[CH2:33][CH2:32][CH:31]([N:34]([CH3:42])[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:29]5)[C:17]=4[C:16]2=3)=CC=1.C(C1C(=O)C(Cl)=C(Cl)[C:47](=[O:48])C=1C#N)#N>ClCCl.O>[OH:48][CH2:47][CH2:11][CH2:12][O:13][CH2:14][C@H:15]1[CH2:26][CH2:25][C:24]2[S:23][C:22]3[N:21]=[CH:20][N:19]=[C:18]([O:27][CH:28]4[CH2:29][CH2:30][CH:31]([N:34]([CH3:42])[C:35](=[O:41])[O:36][C:37]([CH3:38])([CH3:39])[CH3:40])[CH2:32][CH2:33]4)[C:17]=3[C:16]1=2
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: COc1ccc(COCCOC[C@H]2CCc3sc4ncnc(OC5CCC(N(C)C(=O)OC(C)(C)C)CC5)c4c32)cc1
Solvent: O
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](COCCCO)CC4)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 64.3 %

Procedure:
A solution of tert-butyl N-(4-[[(3S)-3-([2-[(4-methoxyphenyl)methoxy]ethoxy]methyl)-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (700 mg, 1.17 mmol, 1.00 equiv) in dichloromethane (10 mL)/water (0.5 mL) was added DDQ (399 mg, 1.76 mmol, 1.50 equiv) and the resulting solution was stirred for 14 hrs at 25° C. under nitrogen. The resulting solution was diluted with water and extracted with 3×100 mL of ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1) to give tert-butyl N-(4-[[(3S)-3-[(3-hydroxypropoxy)methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (370 mg, 64%) as a colorless oil. MS: m/z 478 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([CH3:21])[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.C1C(=O)N([Br:34])C(=O)C1>>[Br:34][CH2:20][C:13]1[N:12]([CH3:21])[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10][CH:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)N(C)C(c2nccs2)=NC1c1ccc(F)cc1Cl
Product: CCOC(=O)C1=C(CBr)N(C)C(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 39.4 %

Procedure:
Ethyl 4-(2-chloro-4-fluorophenyl)-1,6-dimethyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.4 g, 1.02 mmol) was reacted with NBS (0.2 g, 1.12 mmol) according to the procedure as described in Example 1, Step B to give the title compound as yellow oil (0.19 g, 40%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[CH:21]=[C:22]([C:27]2[O:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])[CH:23]=[C:24]([CH3:26])[CH:25]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:33]([C:28]3[N:29]=[C:30]([CH3:32])[O:31][C:27]=3[C:22]3[CH:21]=[C:20]([CH3:19])[CH:25]=[C:24]([CH3:26])[CH:23]=3)=[O:34])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: Cc1cc(C)cc(-c2oc(C)nc2C(=O)O)c1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cc(C)cc(C)c3)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3,5-dimethyl-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:21]C1C=CC(B(O)O)=CC=1>>[F:21][C:4]1[CH:3]=[CH:2][C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)=[CH:6][CH:5]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Product: O=C1NCCc2c(-c3ccc(F)cc3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (100 mg, 0.54 mmol) and 4-fluorobenzeneboronic acid (79 mg, 0.57 mmol) were coupled to yield 2-(4-fluorophenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one, 107 mg (99%), as a pale-yellow solid. 1H NMR (300 MHz, d6-DMSO) δ 3.04 (m, 2H), 3.38 (m, 2H), 7.22 (app t, 1H, J=7.7 Hz), 7.39 (m, 2H), 7.56 (dd, 1H, J=8.0, 0.9 Hz), 7.64 (m, 3H), 8.05 (br t, 1H), 11.57 (br s, 1H); HRMS (FAB, MH+) Calcd for C17H14FN2O: 281.1090, Found: 281.1093; Anal. (C17H13FN2O.0.6 H2O) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=2)[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[NH:27])[NH:25][OH:26])=[CH:20][CH:19]=2)=[O:16])(=[O:10])=[O:9])[CH:7]=1.[C:33](N1C=CN=C1)(N1C=CN=C1)=[S:34].N12CCCC1=NCCC2>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=2)[C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[NH:27][C:33](=[S:34])[O:26][N:25]=3)=[CH:22][CH:23]=2)=[O:16])(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Nc1cccc(C(=O)Nc2ccc(C(=N)NO)cc2)c1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: C1CN=C2CCCN2C1
Solvent: CC#N
Product: COc1ccc(Cl)cc1S(=O)(=O)Nc1cccc(C(=O)Nc2ccc(-c3noc(=S)[nH]3)cc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 20.2 %

Procedure:
3-(5-Chloro-2-methoxy-benzenesulfonylamino)-N-[4-(N-hydroxycarbamimidoyl)-phenyl]-benzamide (110 mg, 0.23 mmol) was diluted in acetonitrile (2 ml) under argon. 1,1′-Thiocarbonyldiimidazole (TCDI) (68 mg, 0.38 mmol, 1.65 equiv.) was then added, followed by 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) (114 mg, 3.95 equiv.). The mixture was stirred at room temperature for 6 hours, then the solvents were evaporated. The residue was diluted with water and the pH was adjusted to 4 with HCl 1N. The aqueous phase was extracted with ethyl acetate, and the organic phase evaporated. The residue was dissolved in NaOH 1N, and washed with ether. The aqueous solution was adjusted to pH 4 with HCl 1N and then extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated. Purification via flash chromatography (dichloromethane/methanol) yielded the title compound as a light yellow solid (24 mg, 20%), MS (ISP): m/e=515.1 (M−H).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH:4]([NH:6][C:7]1[CH:19]=[CH:18][C:10]([C:11]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:12])=[CH:9][C:8]=1[N+:20]([O-])=O)[CH3:5]>CCOC(C)=O.[Pd]>[NH2:20][C:8]1[CH:9]=[C:10]([CH:18]=[CH:19][C:7]=1[NH:6][CH:4]([CH3:5])[CH2:3][N:2]([CH3:1])[CH3:23])[C:11]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:12]
Reactant: CCN(CC)C(=O)c1ccc(NC(C)CN(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)c1ccc(NC(C)CN(C)C)c(N)c1
Reaction time: 8 h
Yield: 87.2 %

Procedure:
Following general procedure 2C: A mixture of 4-{[2-(dimethylamino)-1-methylethyl]amino}-N,N-diethyl-3-nitrobenzamide (0.516 g, 1.60 mmol) and 10% Pd/C in EtOAc (20 mL) was hydrogenated overnight at 35 psi. Usual work-up provided the title compound (0.408 g, 87%) which was used without further purification. 1H-NMR (CDCl3): δ 6.82 (dd, J=8.0 Hz, J=2.0 Hz, 1H), 6.77 (d, J=2.4 Hz, 1H), 6.62 (d, J=8.0 Hz, 1H), 3.52–336 (m, 6H), 2.52 (dd, J=12.0 Hz, J=9.6 Hz, 2H), 2.28–2.19 (m, 7H), 1.17 (m, 8H). MS (ESI) (M+H)+=293.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([CH:15]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:16](OCC)=[O:17])[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.C1COCC1.[Li+].[BH4-]>CO>[CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([CH:15]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:16][OH:17])[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: CCOC(=O)C(c1ccccc1)n1c(C)cc2c1ccc1nnc(C)n12
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2c(ccc3nnc(C)n32)n1C(CO)c1ccccc1
Reaction time: 4 h

Procedure:
Ethyl (1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-6-yl)(phenyl)acetate (0.008 g, 0.02 mmol, from Step 1) was dissolved in MeOH (0.5 mL) and THF (0.5 mL) and LiBH4 (0.0025 g, 0.10 mmol, 90% purity, Aldrich) was added. The reaction was stirred for 4 hours and additional LiBH4 (0.006 g, 0.25 mmol) was added and the reaction continued for a further 3 hours. The reaction was quenched by the addition of water and diluted with MeCN, filtered and purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) (5 mg, 70%).