Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].S(=O)(=O)(O)O.[N+:20]([O-])([OH:22])=[O:21]>>[C:1]([NH:4][C:5]1[C:13]([CH3:14])=[CH:12][C:11]([N+:20]([O-:22])=[O:21])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1c(C)cccc1C(=O)O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1c(C)cc([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.7 %

Procedure:
To a mixture of 0.72 g of 2-acetylamino-3-methylbenzoic acid and 8 ml of concentrated sulfuric acid was added dropwise 1.6 g of fuming nitric acid at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water. A deposited precipitate was collected by filtration to obtain 0.45 g of 2-acetylamino-3-methyl-5-nitrobenzoic acid of the formula:
Reaction SMILES: O=[C:2]1[NH:10][C:5]2[N:6]=[CH:7][N:8]=[CH:9][C:4]=2[C@:3]21[CH2:18][C:17]1[C:12](=[CH:13][CH:14]=[C:15]([C:19]([O:21]C)=[O:20])[CH:16]=1)[CH2:11]2.[ClH:23].[CH2:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH3:25].[Li+:31].[OH-:32].Cl>C1COCC1.CO>[O:32]=[C:14]1[CH:13]=[C:12]2[C:17]([CH2:18][C@@:3]3([CH2:11]2)[C:4]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[NH:10][CH2:2]3)=[CH:16][CH:15]1[C:19]([OH:21])=[O:20].[Cl-:23].[Li+:31].[ClH:23].[CH2:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH3:25]
Reactant: [OH-]
Reactant: COC(=O)c1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncncc21
Agent: Cl
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1C=C2C[C@@]3(CNc4ncncc43)CC2=CC1=O
Product: [Cl-]
Reaction time: 16 h

Procedure:
To a solution of a mixture of methyl (2R)-6′-oxo-1,3,6′,7′-tetrahydrospiro[indene-2,5′-pyrrolo[2,3-d]pyrimidine]-5-carboxylate (10 mg, 0.034 mmol) and triethylamine hydrochloride (0.034 mmol from previous step) in 1 mL of 1:1 THF/MeOH was added 1N LiOH (102 uL, 102 mmol). After 16 h, the reaction was neutralized to pH=7 with 3N HCl and then concentrated in vacuo. The crude material was azeotroped from benzene to afford the title compound as a mixture with 3 eq. of lithium chloride and 1 eq. triethylamine hydrochloride (13 mg). MS 282.1 (M+1). 1H NMR (500 MHz, DMSO d6): δ 11.57 (s, 1H); 8.69 (s, 1H); 8.11 (s, 1H); 7.84 (m, 2H); 7.40 (dd, J=8.3 Hz, 1H); 3.34-3.28 (m, 4H).
Reaction SMILES: CN(C(ON1[N:17]=[N:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][CH:26]([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[C:36]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[N:37][C:38]3[C:43]([C:44]=2[C:45](O)=[O:46])=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:30][CH2:29]1)[CH3:27].NN1CCCCCC1.CCN(CC)CC>C1COCC1.C(Cl)Cl>[N:16]1([NH:17][C:45]([C:44]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]=[C:36]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:35]=2[CH2:34][N:31]2[CH2:32][CH2:33][N:28]([CH:26]([CH3:25])[CH3:27])[CH2:29][CH2:30]2)=[O:46])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:15]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)N1CCN(Cc2c(-c3ccccc3)nc3ccccc3c2C(=O)O)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: NN1CCCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)N1CCN(Cc2c(-c3ccccc3)nc3ccccc3c2C(=O)NN2CCCCCC2)CC1

Procedure:
O-Benzotriazole-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (156 mg, 0.41 mmol) was added to a stirred mixture of 3-(4-(1-methylethyl)-piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid (100 mg, 0.26 mmol) [J. Med. Chem. 2001, 44, 1675-1689], 1-aminohomopiperidine (47 μL, 0.41 mmol) and Et3N (178 μL, 1.3 mmol) in THF (5 mL) and CH2Cl2 (1.5 mL), and the mixture was heated at reflux for 18 h under N2. The solvent was evaporated under reduced pressure, and the residue was dissolved in CH2Cl2 and washed with H2O, 0.5 N NaOH solution, and H2O. The organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC affording, after basic work up, the desired hydrazide (28 mg, 17%). 1H NMR (CD3OD, 360 MHz), Major rotamer δ 8.05 (1H, d, J=8.3 Hz), 7.96 (1H, d, J=8.3 Hz), 7.83-7.75 (1H, m), 7.72-7.60 (1H, m), 7.55-7.43 (5H, m), 3.66 (2H, s), 3.24-3.17 (4H, m), 2.53 (1H, septet, J=6.5 Hz), 2.45-2.10 (8H, m), 1.86-1.72 (8H, m), 1.00 (6H, d, J=6.5 Hz). MS (ES+) C30H39N5O requires: 485, found: 486 (M+H+, 100%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[ClH:11].[CH3:12]O>>[ClH:11].[NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: NC1CCC(C(=O)O)CC1
Reactant: CO
Agent: Cl
Product: COC(=O)C1CCC(N)CC1

Procedure:
To 5.109 g (35.680 mM) of 4-aminocyclohexane-carboxylic acid was added 50 ml of 10% HCl/methanol and the mixture was refluxed overnight. The solvent was then distilled off under reduced pressure and the residue was crystallized from methanol-diethyl ether to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][C:4]=1[CH3:12].C(Cl)(=O)C(Cl)=O.CS(C)=O.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:12])=[CH:5][C:6]([CH:7]=[O:8])=[CH:9][C:10]=1[CH3:11]
Reactant: COc1c(C)cc(CO)cc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C)cc(C=O)cc1C
Yield: 94.7 %

Procedure:
The aldehyde was synthesized according to the procedure of Example 46, Step 1 using the alcohol from Step 2 (7.5 g, 45 mmol), oxalyl chloride (6.35 g, 50 mmol), dimethylsulfoxide (8.8 g, 100 mmol) and triethylamine (10.2 g, 110 mmol) and in methylene chloride (100 ml). There was obtained 7 g (92%) of the desired aldehyde which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.Cl[C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:25]=[CH:24][N:23]=1.C(N(C(C)C)CC)(C)C.O>CC(N(C)C)=O>[F:29][C:28]([F:31])([F:30])[C:26]1[N:25]=[CH:24][N:23]=[C:22]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C@H:8]3[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]3)=[CH:4][CH:3]=2)[CH:27]=1
Reactant: FC(F)(F)c1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)cc2)C1
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(Nc3cc(C(F)(F)F)ncn3)cc2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
A mixture of (5)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (100 mg, 0.36 mmol), 4-chloro-6-(trifluoromethyl)pyrimidine (72 mg, 0.4 mmol) and diisopropylethylamine (70 mg, 0.54 mmol) was dissolved in dimethylacetamide (1.3 ml) and stirred at 80° C. overnight. For work-up water was added, and the mixture was extracted with ethyl acetate twice. The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (10 g silica gel, 20 to 40% ethyl acetate in heptane) to yield a white solid (135 mg, 89%). MS (ISP): 425.2 ([M+H]+).
Reaction SMILES: BrC1C=CC(C2C=CC3C4C(=CC=CC=4)C=CC=3C=2)=CC=1.[CH:22]1[C:35]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[C:24](B(O)O)[CH:23]=1.[Br:39][C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[C:45](Br)[CH:46]=2)[CH:41]=1>>[Br:39][C:40]1[CH:41]=[C:42]2[C:47](=[CH:48][CH:49]=1)[CH:46]=[C:45]([C:33]1[CH:34]=[CH:35][C:26]3[CH:25]=[CH:24][C:23]4[C:28]([C:27]=3[CH:32]=1)=[CH:29][CH:30]=[CH:31][CH:22]=4)[CH:44]=[CH:43]2
Reactant: Brc1ccc2cc(Br)ccc2c1
Reactant: OB(O)c1ccc2ccc3ccccc3c2c1
Agent: Brc1ccc(-c2ccc3c(ccc4ccccc43)c2)cc1
Product: Brc1ccc2cc(-c3ccc4ccc5ccccc5c4c3)ccc2c1

Procedure:
Synthesis was performed in the same manner as in the synthesis of 2-(4-bromophenyl)phenanthrene except that: phenanthrene-3-boronic acid was used instead of phenanthrene-2-boronic acid; and 2,6-dibromonaphthalene was used instead of 4-bromoiodobenzene.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:9])=[O:5].[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>ClCCl>[Br:30][C:27]1[CH:28]=[CH:29][C:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])=[C:3]([CH:26]=1)[C:4]([NH:6][CH2:7][C:8]([NH:10][CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[CH2:16][CH2:17]1)=[O:9])=[O:5]
Reactant: Nc1ccc(Br)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc(Br)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 4-[[N-[2-amino-5-bromobenzoyl]glycyl]aminomethyl]-1-(4-chlorobenzyl)piperidine (25 mg, 0.05 mmol) with methanesulfonyl chloride (0.0045 mL), triethylamine (0.026 mL) and dichloromethane (2 mL) was stirred at room temperature for 17 hours. The resulting reaction mixture was purified by column chromatography (SiO2), loaded onto a Varian™ SAX column and washed with methanol (5 mL). The obtained crude product was eluted with a 0.1 M methanol solution of HCl (5 mL) and concentrated to thereby provide 4-[[N-[5-bromo-2-(methylsulfonylamino)benzoyl]glycyl]aminomethyl]-1-(4-chlorobenzyl)piperidine (Compd. No. 1581) (5.4 mg, 19%). ESI/MS m/e 573.0 (M++H, C23H28BrClN4O4S).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].OC1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1.C(N(CC)CC)C>CCO.CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:3]([O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][C:21]2[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=2)=[O:19])=[CH:22][CH:23]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: CN(C)c1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCO
Product: CCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
KOH (3.78 g, 67.6 mmol) was added to a solution of 1 (12.0 g, 41.0 mmol) dissolved in 250 mL of hot EtOH, and the mixture was refluxed for 24 hours. The solvent was filtered off, and following drying over P2O5 the white solid was suspended in 300 mL of toluene, and refluxed with oxalyl chloride (13.4 mL, 158.54) for 6 hours. Volatile components were removed, the yellow solid was taken in CH2Cl2 (100 mL), and added to a stirred solution containing p-hydroxybenzaldehyde (5.26 g, 43.1), triethylamine (36 mL, 0.261 mol), and DMAP (0.28 g, 2.3 mmol) in CH2Cl2 (100 mL). The mixture was let to stir at room temperature for three hours, and then heated to reflux for twelve hours. Following cooling to room temperature, the organic layer was washed with 1 M HCl (2×100 mL), and then distilled water (100 mL). The solvent was removed, and the product was obtained as an off-white solid following recrystallization from ethanol. Yield (8.5 g, 54%). 1H NMR: δH (CDCl3; 300 MHz): 0.91 (3 H, t, 3J=6.8 Hz, CH3), 1.21-1.58 (14 H, m, CH2), 1.85 (2 H, m, O—CH2—CH2), 4.07 (2 H, t, 3J=6.5 Hz, O—CH2), 7.00 (2 H, d, 3J=9.0 Hz, Ar—H), 7.42 (2 H, d, 3J=8.5 Hz, Ar—H), 7.98 (2 H, d, 3J=8.6 Hz, Ar—H), 8.16 (2 H, d, 3J=9.0 Hz, Ar—H), 10.03 (1 H, s, COH). 13C NMR: δC (CDCl3; 75 MHz): 14.5, 23.1, 26.4, 29.5, 29.7, 29.8, 30.0, 32.3, 68.8, 114.8, 121.2, 123.0, 131.6, 132.8, 134.3, 156.3, 164.3, 164.6, 191.4.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[CH:23]([O:26][C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C@H:38]([O:41]C(=O)C(F)(F)F)[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:25])[CH3:24].Br[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[Cl:56]>>[Cl:56][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=1[CH2:49][N:34]1[N:33]=[C:31]2[N:32]=[C:27]([O:26][CH:23]([CH3:24])[CH3:25])[N:28]=[C:29]([N:36]3[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37]3)[C:30]2=[N:35]1
Reactant: Clc1ccccc1CBr
Reactant: CC(C)Oc1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: CC(C)Oc1nc(N2CC[C@H](O)C2)c2nn(Cc3ccccc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from Trifluoro-acetic acid (S)-1-(5-isopropoxy-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl ester and 1-(bromomethyl)-2-chlorobenzene. MS (m/e): 389.3 (MH+)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.F[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1>O>[N:1]1([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: N#Cc1ccc(F)cc1
Solvent: O
Product: N#Cc1ccc(N2CCOCC2)cc1
Temperature: 120 °C
Yield: 98.3 %

Procedure:
A mixture of morpholine (50 g, 0.6 mol) and 4-fluorobenzonitrile (24 g, 0.2 mol) is heated at 120° C. The conversion of the 4-fluorobenzonitrile is complete after 5 hours. Water (10 ml) is then added into the reaction mixture. The precipitate is filtered off, washed with water and dried under vacuum (30° C.) to give 37 g of the title-compound. Yield: 95%; m.p. 82-83° C.; MS 188 (100, M+); H1 NMR (CDCl3): δ 7.46 (dd, 2H), 6.81 (dd, 2H), 3.79 (t, 4H), 3.22 (t, 4H); C13 NMR (CDCl3): δ 153.69, 133.71, 120.07, 114.26, 101.16, 66.65, 47.49.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[O:15]=[C:16]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH2:17][CH2:18][CH2:19]Cl.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[O:15]=[C:16]([C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[CH2:17][CH2:18][CH2:19][N:11]1[CH2:12][CH2:13][CH2:14][CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:10]1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: COc1cccc(C2CCCNC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: COc1cccc(C2CCCN(CCCC(=O)c3ccc(F)cc3)C2)c1
Yield: 39.4 %

Procedure:
A mixture of 1.9 g (0.01 mole) of 3-(3-methoxyphenyl)piperidine, 4.0 g (3.3 ml, 0.02 mole) of 4-oxo-4-(4-fluorophenyl)butyl chloride, 27.6 g (0.20 mole) of potassium carbonate and 75 ml of methyl isobutyl ketone was heated under reflux for ca. 40 hours. The reaction mixture was then poured onto ice-water and the resulting mixture was extracted with ethyl acetate. The combined extracts were washed with water, followed by saturated sodium chloride solution, and then they were dried and evaporated in vacuo. The residue was chromatographed on 250 ml of silica gel, eluting with chloroform/metanol (95:5). The appropriate fractions were combined and evaporated in vacuo to give 1.4 g of the title compound as an amber oil (39% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([NH2:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[C:12]([O:16][O:17][C:18](=[O:24])[CH2:19][CH2:20][C:21](Cl)=[O:22])([CH3:15])([CH3:14])[CH3:13].C(OOC(=O)CCC(O)=O)(C)(C)C.O=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([NH:8][C:21](=[O:22])[CH2:20][CH2:19][C:18]([O:17][O:16][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:24])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1
Reactant: CC(C)(C)OOC(=O)CCC(=O)Cl
Reactant: CC1(C)CC(N)CC(C)(C)N1
Agent: CC(C)(C)OOC(=O)CCC(=O)O
Agent: O=O
Solvent: ClCCl
Product: CC1(C)CC(NC(=O)CCC(=O)OOC(C)(C)C)CC(C)(C)N1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
Into a 250 ml flask equipped with a magnetic stirrer, thermometer, condenser, addition funnel and calcium chloride drying tube were placed 2,2,6,6-tetramethyl-4-aminopiperidine (20.3 g, 0.13 mole) and 50 ml of methylene chloride. The addition funnel was charged with 4-t-butylperoxy-4-oxobutanoyl chloride (13.2 g, 0.06 mole) and 50 ml methylene chloride. The acid chloride was added dropwise at 20°-23° C. over a 20 minute period, causing a slight exotherm. The reaction mixture was warmed to 30° C. over 60 minutes and then stirred at 30° C. for another 30 minutes. The reaction mixture was poured into a jacketed reactor and washed at 20°-25° C. with eight 50 ml portions of water. The organic material was dried with anhydrous magnesium sulfate and the solvent stripped under reduced pressure to give 9.3 g of a light amber-straw liquid. Liquid chromatography of this product showed it to contain two components, one of which was 4-t-butylperoxy-4-oxobutanoic acid. Iodometric analysis indicated 5.65% active oxygen content which corresponds to a mixture of 22% perester-acid and 78% perester-amide (C-VII). The infrared spectrum (neat) showed three carbonyl absorptions at 1650, 1700 and 1770 cm-1 (amide, acid and perester) and a broad absorption at 3300 cm-1. Based on the 78% assay, the product was prepared in 37% corrected yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5](Cl)[CH2:4][C:3]=1[N+:10]([O-:12])=[O:11].[Cu][C:14]#[N:15]>CN1CCCC1=O.C(OCC)(=O)C.O>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:14]#[N:15])[C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: N#C[Cu]
Reactant: NC1=C([N+](=O)[O-])CN(Cl)C(Cl)=C1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: N#Cc1nc(Cl)cc(N)c1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
A stirred suspension of 4-amino-1,6-dichloro-3-nitro-pyridine (17.5 g, 84.1 mmol) and copper (i) cyanide (15.1 g, 168.3 mmol) in 170 ml of 1-methyl-2-pyrrolidinone was lowered into an oil bath preheated to 180° C. and stirring continued for 30 minutes. The mixture was allowed to cool and diluted with ethyl acetate (700 ml) and water (700 ml) and the resultant suspension filtered. The organic layer was separated and further washed with water (500 ml) and 0.1N HCl (500 ml). The organic layer was then dried over sodium sulfate, filtered and concentrated under reduced pressure to give a brown solid which was washed with diethylether and dichloromethane to afford 4-amino-6-chloro-3-nitro-pyridine-2-carbonitrile (8 g).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:29][CH2:30][CH3:31])[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[S:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3[O:20][C:21]3[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=3[F:28])[CH:12]=2)[N:8]=[CH:7]1)[CH3:2].[N:32]1[CH:37]=[CH:36][CH:35]=C[CH:33]=1.ClC(OC1C=CC=CC=1)=[O:40].C1(N)CC1>CN(C=O)C>[CH:37]1([NH:32][C:33]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([O:20][C:17]3[CH:16]=[CH:15][N:14]=[C:13]4[CH:12]=[C:11]([C:9]5[N:8]=[CH:7][N:6]([CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:29][CH2:30][CH3:31])[CH:10]=5)[S:19][C:18]=34)=[C:22]([F:28])[CH:23]=2)=[O:40])[CH2:35][CH2:36]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOC(Cn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1)OCC
Reactant: c1ccncc1
Agent: NC1CC1
Solvent: CN(C)C=O
Product: CCOC(Cn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)c1)OCC
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
To a stirred solution of amine 262 (2.86 g, 6.46 mmol) and pyridine (1.04 mL, 12.93 mmol) in DMF (50 mL) at 0° C. was added phenyl chloroformate (973 μl, 7.76 mmol). After 30 min, cyclopropylamine (1.14 mL, 16.16 mmol) was added at 0° C. and the reaction mixture was heated at 60° C. for 45 min. More cyclopropylamine (1 mL, 14.18 mmol) was added and the reaction mixture was heated at 60° C. for an additional 10 min. After cooling to RT, the reaction mixture was quenched by addition of water to form a precipitate. The solid was collected by filtration, washed with water and dried under vacuum for 2 h. The residue was purified by Biotage (SNAP 80 g cartridge; MeOH/DCM: 0/100 to 10/90 over 20 CV). The desired fractions were collected, concentrated, triturated with MTBE and dried under high vacuum to afford the title compound 263 (2.95 g, 5.61 mmol, 87% yield) as a pink solid. MS (m/z): 526.60 (M+H).
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.O=C1CCC(=O)N1[O:25][C:26](=O)[CH2:27][CH:28]([C:34](=[O:56])[NH:35][CH:36]([C:40]([N:42]1[CH2:46][CH2:45][CH2:44][CH:43]1[CH2:47][O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:41])[CH:37]([CH3:39])[CH3:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>CN(C)C=O>[CH2:2]([O:9][NH:10][C:26](=[O:25])[CH2:27][CH:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:34]([NH:35][CH:36]([C:40]([N:42]1[CH2:46][CH2:45][CH2:44][CH:43]1[CH2:47][O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:41])[CH:37]([CH3:39])[CH3:38])=[O:56])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCCCC(CC(=O)ON1C(=O)CCC1=O)C(=O)NC(C(=O)N1CCCC1COCc1ccccc1)C(C)C
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCC(CC(=O)NOCc1ccccc1)C(=O)NC(C(=O)N1CCCC1COCc1ccccc1)C(C)C

Procedure:
The coupling of fragment A and B is comprised of the following steps: (a) a solution of 14 in dimethylformide or any suitable solvent is treated with triethylamine followed by a solution of 8 in dimethylformamide or any suitable solvent to yield 3-(1-(2-(S)-benzyloxymethylpyrrolidine-1-carbonyl)-2-(S)-methylpropyl-carbamoyl)-octanoic acid tert-butyl ester 15; (b) treatment of 15 in dichloromethane with trifluoroacetic acid to yield 3-(1-(2-benzyloxymethyl-pyrrolidine-1-carbonyl)-2-methyl-propyl carbamoyl)-octanoic acid 16; (c) treatment of a solution 16 and hydroxysuccinamide 7 with dicyclohexylcarbodiimide or any suitable imide to afford 3-(1-(2-benzyloxymethyl-pyrrolidine-1-carbonyl)-2-methylpropylcarbamoyl)-octanoic acid 2,5-dioxo-pyrrolidin-1-yl ester 17; (d) fragment C is introduced by treatment of a suspension of O-benzylhydroxyamine hydrochloride 18 in dimethylformamide with triethylamine followed by a solution of 17 in dimethylformamide to afford N4-benzyloxy-N1-(1-(2-benzyloxymethyl-pyrrolidine-1-carbonyl)-2-methyl-propyl)-2-pentyl-succinamide 19. (f) hydrogenating 19 with hydrogen gas and palladium hydroxide in activated carbon wherein actinonin 1 is thereby formed (Scheme 4, FIG. 3C).
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:12]=[O:13].[C:14]([OH:17])(=O)[CH3:15]>>[CH3:2][N:3]([CH2:8][CH:9]1[CH2:10][CH2:11][O:17][C:14]2[CH:15]=[CH:4][CH:5]=[CH:6][C:7]=2[C:12]1=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)O
Reactant: C=O
Reactant: CNCCc1ccccc1
Agent: Cl
Product: CN(CCc1ccccc1)CC1CCOc2ccccc2C1=O
Temperature: 100 °C

Procedure:
A mixture of 24.4 g 3,4-dlihydro-2H-benzo[b]oxepin-5-one, 17.2 g N-methyl-2-phenylethylamine hydrochloride and 3.0 g paraformaldehyde in 200 ml glacial acetic acid was heated at 100° C. for 3 hours. Thereafter, the solvent was evaporated under vacuum and the residue was taken up in 200 ml water. The product was extracted three times with 100 ml diethyl ether each time. The aqueous phase was made alkaline with potassium carbonate and was extracted three times with 100 ml dichloromethane each time. After washing the extracts with saturated sodium chloride solution, drying them over sodium sulphate and concentrating them by evaporation under vacuum, 23.9 g (77.2% theoretical) of the title compound remained behind as a yellowish oil.