Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.[CH3:35][C@H:36]1[CH2:41][N:40]([CH2:42][CH2:43][CH2:44]O)[CH2:39][C@@H:38]([CH3:46])[O:37]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[ClH:13].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:44][CH2:43][CH2:42][N:40]4[CH2:39][CH:38]([CH3:46])[O:37][CH:36]([CH3:35])[CH2:41]4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: C[C@@H]1CN(CCCO)C[C@H](C)O1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCN1CC(C)OC(C)C1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 127.1 %

Procedure:
Diethyl azodicarboxylate (209 mg, 1.2 mmol) was added dropwise to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (128 mg, 0.4 mmol), (prepared as described for the starting material in Example 2), cis-3-(2,6-dimethylmorpholino)-1-propanol (97 mg, 0.56 mmol) and triphenylphosphine (314 mg, 1.2 mmol) in methylene chloride (4 ml) under nitrogen. The mixture was stirred for 1 hour at ambient temperature and the solvent was removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5 followed by 90/10). The purified product was dissolved in methylene chloride and 2M ethereal hydrogen chloride (1 ml) was added. The solution was diluted with ether and left to stand. The resulting precipitate was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-7-(3-(2,6-dimethylmorpholino)propoxy)-6-methoxyquinazoline hydrochloride (130 mg, 59%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH2:25][N:24]([C:27]([O:29][C@H:30]1[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:32]([C:42]([O:44][CH3:45])=[O:43])[CH2:31]1)=[O:28])[CH2:23][CH2:22]2.CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH2:25][N:24]([C:27]([O:29][C@H:30]1[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:32]([C:42]([O:44][CH3:45])=[O:43])[CH2:31]1)=[O:28])[CH2:23][CH2:22]2)(=[O:5])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](OC(=O)N2CCc3cccc(O)c3C2)CN1C(=O)OC(C)(C)C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](OC(=O)N2CCc3cccc(OS(=O)(=O)C(F)(F)F)c3C2)CN1C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 69.4 %

Procedure:
Trifluoromethanesulfonic anhydride (1.76 g, 6.24 mmol) was added to a stirred, 0° C. mixture of 1-tert-butyl 2-methyl (2S,4R)-4-{[(8-hydroxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate (1.81 g, 4.30 mmol) and Et3N (1.31 g, 12.90 mmol) in DCM (20 mL) and stirred for 18 h. The resulting mixture was poured into saturated aqueous NaHCO3 and extracted into dichloromethane. The organic layer was washed with 10% citric acid solution, dried over Na2SO4 and concentrated to red oil. The oil was purified by column chromatography on silica gel (gradient elution, 10 to 70% EtOAc in hexanes) to give a yellow oil, 1-tert-butyl 2-methyl (2S,4R)-4-({[8-{[(trifluoro methyl)sulfonyl]oxy}-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}oxy)pyrrolidine-1,2-dicarboxylate (1.65 g, 69.4% yield). LRMS (ESI) m/z 453.2 [((M-Boc)+H)+; calcd for C17H20F3N2O7S: 453.4].
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[C:25]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])=[CH:24][CH:23]=[CH:22][C:8]=2[C:9]=1[C:10](=[O:21])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19]Br)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].[CH2:32]([NH:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH3:35].[I-].[Na+].[C:43](=[O:46])([O-:45])[O-].[K+].[K+]>C(#N)C>[C:26]([OH:28])(=[O:27])[C:43]([OH:45])=[O:46].[CH2:1]([C:5]1[O:6][C:7]2[C:25]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])=[CH:24][CH:23]=[CH:22][C:8]=2[C:9]=1[C:10](=[O:21])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][N:36]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:32][CH2:33][CH2:34][CH3:35])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCCCNCCCC
Reactant: CCCCc1oc2c(C(=O)OC(C)C)cccc2c1C(=O)c1ccc(CCCBr)cc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: CCCCc1oc2c(C(=O)OC(C)C)cccc2c1C(=O)c1ccc(CCCN(CCCC)CCCC)cc1
Product: O=C(O)C(=O)O
Yield: 98.2 %

Procedure:
4.5 g (0.0095 mol) of isopropyl 2-butyl-3-[4-(3-bromopropyl)benzoyl]-1-benzofuran-7-carboxylate are dissolved in 80 ml of acetonitrile. 3.68 g (0.0285 mol) of dibutylamine are then added, followed by 1.42 g (0.0095 mol) of sodium iodide and 3.94 g (0.0285 mol) of potassium carbonate. The mixture is brought to reflux for 15 hours and is then evaporated. Extraction is carried out with diethyl ether and the extract is washed with water and a sodium chloride solution. Purification is subsequently carried out by chromatography on silica (eluent: 100/3/0.2 dichloromethane/methanol/aqueous ammonia), which gives 2.91 g of the desired compound in the free base form (yield: 57%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13]C)[CH:9]=[N:8][CH:7]=[CH:6]2.[BrH:15]>C(O)(=O)C>[OH2:2].[BrH:15].[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[CH:9]=[N:8][CH:7]=[CH:6]2
Reactant: COc1cc2ccncc2cc1OC
Agent: Br
Solvent: CC(=O)O
Product: O
Product: Oc1cc2ccncc2cc1O
Yield: 88.4 %

Procedure:
1.9 g (10 mmol) of 6,7-dimethoxyisoquinoline was dissolved in a mixture of 15 ml of acetic acid and 15 ml of 40% hydrobromic acid, and the solution was stirred under reflux for 24 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure. The residue was recrystallized from a 1N hydrobromic acid aqueous solution to obtain 2.3 g (yield: 88.4%) of the above identified compound. The melting point, infrared spectrum and NMR spectrum agreed to those of the compound of Example 10.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[C:4]([C:18]2[CH:19]=[N:20][N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=2)[CH:3]=1.[NH2:31][C:32]1[CH:37]=[N:36][CH:35]=[CH:34][N:33]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[CH:5]=[C:4]([C:18]3[CH:19]=[N:20][N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=3)[CH:3]=[C:2]([NH:31][C:32]3[CH:37]=[N:36][CH:35]=[CH:34][N:33]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: Nc1cnccn1
Reactant: C[C@H](Nc1cc(-c2cnn(COCC[Si](C)(C)C)c2)cc(Cl)n1)c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Product: C[C@H](Nc1cc(-c2cnn(COCC[Si](C)(C)C)c2)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
68 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-4-(1-{[2-(trimethyl silyl)ethoxy]methyl}-1H-pyrazol-4-yl)pyridine-2-amine obtained by Step 3, 17 mg of 2-aminopyrazine, 15 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 21 mg of sodium t-butoxide and 8 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn, and the mixture was stirred at 100° C. for 1 hour under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 70 mg of the objective compound as colorless oil.
Reaction SMILES: [CH:1]1([S:4]([O-:6])=[O:5])[CH2:3][CH2:2]1.[Na+].Br[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1>C(#N)C.O>[CH:1]1([S:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: O=S([O-])C1CC1
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1cccc(CS(=O)(=O)C2CC2)c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
Sodium cyclopropanesulfinate (1.04 g; 8.1 mmol) was added to a solution of 1-(bromomethyl)-3-nitrobenzene (1.17 g; 5.4 mmol) in acetonitrile (50 mL) at room temperature. The batch was stirred at 90° C. for 4 hours. After cooling, the batch was diluted with water and extracted with DCM (2×). The combined organic phases were filtered using a Whatman filter and concentrated to give the desired product (1.26 g; 5.2 mmol) that was used without further purifications.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([CH3:12])[CH:6]=1.[I:14]N1C(=O)CCC1=O.FC(F)(F)S(O)(=O)=O>C(#N)C>[CH3:1][O:2][C:3](=[O:13])[NH:4][C:5]1[CH:6]=[C:7]([CH3:12])[C:8]([Br:11])=[CH:9][C:10]=1[I:14]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)Nc1ccc(Br)c(C)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Product: COC(=O)Nc1cc(C)c(Br)cc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.5 %

Procedure:
To a solution of 5.00 g (4-bromo-3-methyl-phenyl)-carbamic acid methyl ester in 50 ml acetonitrile were added at 0° C. 4.84 g N-iodosuccinimide and 0.18-ml trifluoromethanesulfonic acid. The mixture was stirred 18 h at room temperature. The solid was collected by filtration, washed with cold acetonitrile and dried to constant weight to yield 5.80 g (4-bromo-2-iodo-5-methyl-phenyl)-carbamic acid methyl ester as white crystals melting at 140-141° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]([CH3:30])[CH:24]=[N:25]2>>[CH3:30][N:23]1[C:22]2[C:26](=[N:27][CH:28]=[N:29][C:21]=2[NH:19][CH2:18][CH:15]2[CH2:14][CH2:13][N:12]([S:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:10])=[O:11])[CH2:17][CH2:16]2)[N:25]=[CH:24]1
Reactant: Cn1cnc2ncnc(Cl)c21
Reactant: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Product: Cn1cnc2ncnc(NCC3CCN(S(=O)(=O)CCc4ccccc4)CC3)c21

Procedure:
EXAMPLE 85 was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and 6-chloro-7-methyl-7H-purine (6-chloro-7-methyl-7H-purine was prepared according to G. B. Eilon, J. Org. Chem., 27:2478–2491 (1962): MS (m+1)=415.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[C:37]1([CH2:43][CH2:44]CO)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][CH2:44][CH2:43][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: OCCCc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCCc4ccccc4)c(C)c3C)c2cc1OC
Yield: 74.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-phenyl-1-propanol (31 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (56 mg, yield 71%).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:5]=1[N:6]=[C:7]2Cl.[F:18][C:19]([F:26])([F:25])[C@@H:20]([NH2:24])[CH:21]([CH3:23])[CH3:22].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1C[O:40]CC1>>[F:17][C:15]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([NH:24][C@H:20]([C:19]([F:26])([F:25])[F:18])[CH:21]([CH3:23])[CH3:22])[C:8]3[CH:9]=[CH:10][NH:11][C:2](=[O:40])[C:3]=3[C:4]=2[CH:16]=1
Reactant: C1CCOC1
Reactant: Fc1ccc2nc(Cl)c3ccnc(Cl)c3c2c1
Reactant: CC(C)[C@H](N)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CC(C)[C@H](Nc1nc2ccc(F)cc2c2c(=O)[nH]ccc12)C(F)(F)F
Temperature: 85 °C

Procedure:
To a solution of 1,5-dichloro-9-fluorobenzo[c]-2,6-naphthyridine (50 mg, 0.19 mmol) (Example 1, Step 5) in THF (3 mL), were added (2S)-1,1,1-trifluoro-3-methylbutan-2-amine (26 mg, 0.19 mmol) and lithium bis(trimethylsilyl)amide (0.56 mL, 1.0 M in THF, 0.56 mmol). The solution was heated to 85° C. for 1 hr then cooled to room temperature. The reaction mixture was quenched with methanol and concentrated under reduced pressure. The crude mixture was taken up in THF (1 mL) and HCl (1 mL, 6 N) and heated to 85° C. for 1.5 hr. The solution was cooled and worked up with EtOAc and saturated NaHCO3. The organic layers were combined, dried over MgSO4, filtered, and concentrated to afford the title product.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][O:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:5][N:6]=1.O.NN>C(O)C>[Cl:1][C:2]1[S:3][C:4]([CH2:7][O:8][NH2:9])=[CH:5][N:6]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1cnc(Cl)s1
Agent: NN
Solvent: CCO
Solvent: O
Product: NOCc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 118.2 %

Procedure:
2-[(2-Chloro-1,3-thiazol-5-yl)methoxy]-1H-isoindole-1,3(2H)-dione (Bionet, 5.0 g), was suspended in ethanol (120 ml) and hydrazine monohydrate (0.83 ml) was added. The mixture was heated to reflux and stirred at this temperature for 4 hours. The mixture was cooled to room temperature and the solid material was removed by filtration. The filtrate was evaporated under reduced pressure. The residue was re-suspended in diethyl ether (400 ml) and 4M HCl in dioxane (4.25 ml) was added. The solid material was isolated by filtration and dried under vacuum, and gave the title compound (3.3 g). 13C-NMR (DMSO-d6) δ 152.5, 143.3, 133.5, 66.9.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)[C:3]#[CH:4].I[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1>>[CH3:1][C:2]1([CH3:14])[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=2)[C:13]2[CH:12]=[C:9]([C:10]#[N:11])[CH:8]=[CH:7][C:6]=2[O:5]1
Reactant: C#CC(C)(C)Oc1ccc(C#N)cc1
Reactant: O=[N+]([O-])c1ccc(I)nc1
Product: CC1(C)C=C(c2ccc([N+](=O)[O-])cn2)c2cc(C#N)ccc2O1

Procedure:
2,2-Dimethyl-4-(5-nitro-2-pyridyl)-2H-1-benzopyran-6-carbonitrile was prepared from 4-(1,1-dimethyl-2-propynyloxy)benzonitrile and 2-iodo-5-nitropyridine in an analogous manner to that described in Example 6(A).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([CH:18]([OH:22])[C:19]([OH:21])=[O:20])[CH:12]=[CH:11]2>CCCCCC>[CH2:1]([NH2+:3][CH2:4][CH3:5])[CH3:2].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([CH:18]([OH:22])[C:19]([O-:21])=[O:20])[CH:12]=[CH:11]2
Reactant: CCNCC
Reactant: COc1ccc2cc(C(O)C(=O)O)ccc2c1
Solvent: CCCCCC
Product: CC[NH2+]CC
Product: COc1ccc2cc(C(O)C(=O)[O-])ccc2c1

Procedure:
Anhydrous diethylamine (0.11 moles) is added dropwise to a stirred solution of 6-methoxy-2-naphthylglycolic acid (0.10 moles) in 100 ml. of n-hexane at 0°C. The precipitated diethylammonium salt is collected on a filter washed with n-hexane and dried in a vacuum desiccator to obtain 6-methoxy-2-naphthylglycolic acid, diethylammonium salt.
Reaction SMILES: [CH2:1]([CH:3]([CH2:40][CH3:41])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:26][NH:27][CH2:28][CH2:29][CH2:30][NH:31][CH2:32][CH2:33][CH2:34][NH:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH:9]=[C:10]([CH2:12][NH:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:11]=1)[CH3:2].[ClH:42]>>[Cl-:42].[CH2:40]([CH:3]([CH2:1][CH3:2])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:26][NH2+:27][CH2:28][CH2:29][CH2:30][NH2+:31][CH2:32][CH2:33][CH2:34][NH2+:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH:9]=[C:10]([CH2:12][NH2+:13][CH2:14][CH2:15][CH2:16][NH2+:17][CH2:18][CH2:19][CH2:20][NH2+:21][CH2:22][CH:23]([CH3:24])[CH3:25])[CH:11]=1)[CH3:41].[Cl-:42].[Cl-:42].[Cl-:42].[Cl-:42].[Cl-:42]
Reactant: CCC(CC)COc1cc(CNCCCNCCCNCC(C)C)cc(CNCCCNCCCNCC(C)C)c1
Reactant: Cl
Product: CCC(CC)COc1cc(C[NH2+]CCC[NH2+]CCC[NH2+]CC(C)C)cc(C[NH2+]CCC[NH2+]CCC[NH2+]CC(C)C)c1
Product: [Cl-]
Reaction time: 1 h
Yield: 59 %

Procedure:
To N1,N1′-((5-(2-ethylbutoxy)-1,3-phenylene)bis(methylene))bis(N3-(3-(isobutylamino)propyl) propane-1,3-diamine) from step 4 was which was added methanolic HCl (50 mL, 1.0M). The reaction mixture was stirred for 1 h, the reaction mixture was concentrated under reduced pressure and the solid collected by vacuum filtration. The solid was washed with Et2O (10 mL) and hot MeOH (10 mL) to afford the desired product (0.42 g, 59%) as a white solid. 1H NMR (500 MHz, D2O) δ 7.20 (s, 2H), 7.18 (s, 1H), 4.29 (s, 4H), 4.05 (d, J=6.0 Hz, 2H), 3.25-3.15 (m, 16H), 2.94 (d, J=7.0 Hz, 2H), 2.21-2.12 (m, 8H), 2.07-1.99 (m, 2H), 1.72 (p, J=6.5 Hz, 1H), 1.50-1.43 (m, 4H), 1.00 (d, J=7.0 Hz, 12H), 0.92 (t, J=6.0 Hz, 6H). 13C NMR (125 MHz, D2O) δ 159.6, 132.9, 123.4, 117.4, 71.4, 54.8, 50.8, 44.7, 44.6, 44.6, 44.1, 40.1, 25.5, 22.6, 22.5, 19.0, 10.2. LRMS [M+H]+577.6.
Reaction SMILES: O=[C:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[N+:9](/[CH:12]=[CH:13]/[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)([O-])=O.C[O-].[Na+].C(OC(=O)C)C.CCCCCC>CO.N>[CH3:7][O:6][C:4]([C:3]1[C:13]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[CH:12][NH:9][C:2]=1[CH3:8])=[O:5]
Reactant: O=[N+]([O-])/C=C/c1cccc2ccccc12
Reactant: COC(=O)CC(C)=O
Agent: C[O-]
Agent: N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)c1c(-c2cccc3ccccc23)c[nH]c1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
0.69 g(5.9 mmol) of methyl 3-oxobutanoate and 1.08 g(5.9 mmol) of 1-[(E)-2-nitroethenyl]naphthalene were added to 2.37 ml of 0.5M sodium methoxide in methanol, and the resulting mixture was stirred for 2 hours at 0° C. The reaction solution was diluted with 10 ml of cold methanol, through which ammonia gas was passed. Reaction was carried out for 12 hours at 0° C. under stirring. After reaction was completed, the solvent was removed under reduced pressure and the residue was subjected to column chromatography(eluent: ethylacetate/hexane=90/10, v/v; ethylacetate/hexane=70/30, v/v) to give 936 mg(3.53 mmol, Yield 59%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][C:14]([CH2:16][CH2:17][C@H:18]([NH:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([N:35](C(OCC2C=CC=CC=2)=O)[CH3:36])=[CH:31][CH:30]=1)=[O:28])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:15].[N:47]1([NH:53][C:54]([NH:56][C:57]2[C:62]3[C:63](=[O:80])[C:64]4[C:65](=[N:66][NH:67][C:68]=4[C:69]4[CH:79]=[CH:78][C:72]([O:73][CH2:74][C:75](O)=[O:76])=[CH:71][CH:70]=4)[C:61]=3[CH:60]=[CH:59][CH:58]=2)=[O:55])[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:36][NH:35][C:32]1[CH:31]=[CH:30][C:29]([C:27]([NH:26][C@@H:18]([CH2:17][CH2:16][C:14](=[O:15])[NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:75](=[O:76])[CH2:74][O:73][C:72]2[CH:71]=[CH:70][C:69]([C:68]3[NH:67][N:66]=[C:65]4[C:61]5[CH:60]=[CH:59][CH:58]=[C:57]([NH:56][C:54](=[O:55])[NH:53][N:47]6[CH2:48][CH2:49][O:50][CH2:51][CH2:52]6)[C:62]=5[C:63](=[O:80])[C:64]=34)=[CH:79][CH:78]=2)[C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])=[O:28])=[CH:34][CH:33]=1
Reactant: O=C(O)COc1ccc(-c2[nH]nc3c2C(=O)c2c(NC(=O)NN4CCOCC4)cccc2-3)cc1
Reactant: CN(C(=O)OCc1ccccc1)c1ccc(C(=O)N[C@@H](CCC(=O)NCCOCCOCCOCCN)C(=O)OC(C)(C)C)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNc1ccc(C(=O)N[C@@H](CCC(=O)NCCOCCOCCOCCNC(=O)COc2ccc(-c3[nH]nc4c3C(=O)c3c(NC(=O)NN5CCOCC5)cccc3-4)cc2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Compound 12 (0.71 g, 1.4 mmol) and compound 25 (0.57 g, 1.2 mmol) were dissolved in 10 ml DMF and HBTU (0.8 g, 2.1 mmol) was added as a solid followed by DIEA (0.52 ml, 3 mmol). The reaction mixture was stirred at room temperature for 3 days, diluted with EtOAc and the organic phase washed with saturated NaHCO3. The aqueous layer was back extracted with EtOAc twice and the combined organic layers dried over MgSO4, filtered and concentrated to an oil. This oil was purified by flash silica chromatography (2 to 5% MeOH/EtOAc) to give an orange oil (0.50 g, 0.52 mmol, 44%, compound 27).
Reaction SMILES: C([C:3](=[C:7](SC)SC)[C:4]([NH2:6])=O)#N.Cl[C:13]1[CH:14]=[C:15]([NH:19][C:20]2[C:24]([C:25]([NH2:27])=[O:26])=[C:23]([NH:28]CC3C=CC(O)=CC=3)[NH:22][N:21]=2)[CH:16]=[CH:17][CH:18]=1.[NH2:37][C:38]1C=CC(C2CCCCN2C2CCNCC2)=CC=1.O.NN>CCO>[NH2:28][C:23]1[NH:22][N:21]=[C:20]([NH:19][C:15]2[CH:14]=[CH:13][C:18]([N:6]3[CH:4]=[C:3]([CH3:7])[N:37]=[CH:38]3)=[CH:17][CH:16]=2)[C:24]=1[C:25]([NH2:27])=[O:26]
Reactant: CSC(SC)=C(C#N)C(N)=O
Reactant: Nc1ccc(C2CCCCN2C2CCNCC2)cc1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1NCc1ccc(O)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cn(-c2ccc(Nc3n[nH]c(N)c3C(N)=O)cc2)cn1
Temperature: 75 °C

Procedure:
Dissolved 0.500 g 2-cyano-3,3-bis(methylthio)acrylamide in 15 mL EtOH and added 4-methyl-1′-[(4-aminophenyl)1,4′-bipiperidine (1.0 eq.). Stirred reaction at 75° C. until starting amide was absent by HPLC. Once complete (18 hrs), reaction was brought to room temperature and filtered to obtain a light yellow powder as product. Product was allowed to dry under vacuum for 1 hr. Product was then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was added dropwise. Reaction was heated at 75° C. until intermediate was absent (HPLC). Once intermediate was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((4-(4-methyl-1H-imidazol-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [CH3:1][NH2:2].[OH-].[Na+].[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1>C(Cl)Cl>[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:2][CH3:1])=[O:11])=[CH:8][CH:7]=1
Reactant: CN
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CNC(=O)c1ccc(F)cc1
Yield: 94 %

Procedure:
To a solution of 30 mL MeNH2 (40% wt in H2O) was added 139 mL of 1N NaOH. To this was added 130 mL of CH2Cl2 followed by 4-fluorobenzoyl chloride (22 grams, 139 mmol) while the mixture was rapidly stirred. After 1 hour the organic layer was separated, washed with H2O, dried over Na2SO4 and solvent removed under vacuum to yield 20 grams (94% yield) solid. 1H NMR (500 MHz, DMSO) δ: 2.78 (d, 3, J=5), 7.28 (t, 2, J=9), 7.91 (m, 2), 8.46 (br s, 1). 13C NMR (125 MHz, DMSO) δ: 26.13, 114.95, 115.13, 129.49, 129.56, 130.87, 130.90, 162.67, 164.64, 165.46.