Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH:13]3[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](Cl)=[O:29])=[CH:23][CH:22]=1>ClCCl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C@@H:13]3[CH2:14][CH2:15][C@H:16]([NH:19][C:28](=[O:29])[CH2:27][C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)[CH2:17][CH2:18]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: NC1CCC(Nc2ccnc3cc(Cl)ccc23)CC1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccc(F)cc1)N[C@H]1CC[C@@H](Nc2ccnc3cc(Cl)ccc23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of N-(7-chloroquinolin-4-yl)-cyclohexane-1,4-diamine (20 mg, 0.07 mmol) in dichloromethane (1.0 mL) and triethylamine (0.01 mL) at 20° C. was treated with (4-fluoro-phenyl)-acetyl chloride (12 mg, 0.07 mmol). The reaction was shaken at room temperature for 18 hours then concentrated. The crude compound was purified by reverse phase HPLC to provide the desired compound. MS (ESI (+)) m/e 412 (M+H)+; 1H NMR (500 MHz, DMSO) δ ppm 8.87 (d, 1 H), 8.74 (d, 1 H), 8.54 (d, 1 H), 8.01 (d, 1 H), 7.95 (m, 1 H), 7.80 (dd, 1 H), 7.31 (m, 2 H), 7.12 (m, 2 H), 6.97 (d, 1 H), 3.91 (br.s, 1 H), 3.80 (br.s, 1 H), 3.47 (s, 2 H), 1.57-1.98 (m, 8 H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH2:4][N:3]1C(OCC1C=CC=CC=1)=O>CCOC(C)=O.CCO.[Pd]>[CH3:1][C@H:2]1[NH:3][CH2:4][C@@H:5]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:9])[CH2:6][CH2:7]1
Reactant: C[C@@H]1CC[C@H](C(=O)Nc2ccccc2)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[C@@H]1CC[C@H](C(=O)Nc2ccccc2)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
A solution of phenylmethyl(2R,5S)-2-methyl-5-[(phenylamino)carbonyl]-1-piperidinecarboxylate (21 g, 59.6 mmol) in EtOAc (250 mL) and EtOH (250 mL) was degassed. Pd/C (10%, 6.34 g, 5.96 mmol) was added and then H2 was bubbled through the mixture. The reaction mixture was stirred at room temperature under H2 balloon overnight. The mixture was filtered through a pad of celite, and concentrated in vacuo to afford the crude title compound (12 g). LC-MS (ES) m/z=219 [M+H]+.
Reaction SMILES: [N+:1](/[C:3](/[C:19](/[N+:35]#[C-:36])=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([O:27][Si](C(C)(C)C)(C)C)=[CH:23][CH:22]=1)=[CH:4]\[C:5]1[CH:10]=[CH:9][C:8]([O:11][Si](C(C)(C)C)(C)C)=[CH:7][CH:6]=1)#[C-:2].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>O1CCCC1>[N+:1](/[C:3](/[C:19](/[N+:35]#[C-:36])=[CH:20]/[C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1)=[CH:4]\[C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)#[C-:2]
Reactant: [C-]#[N+]C(=C\c1ccc(O[Si](C)(C)C(C)(C)C)cc1)/C(=C/c1ccc(O[Si](C)(C)C(C)(C)C)cc1)[N+]#[C-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: [C-]#[N+]C(=C\c1ccc(O)cc1)/C(=C/c1ccc(O)cc1)[N+]#[C-]
Reaction time: 3 h
Yield: 119.4 %

Procedure:
(1Z,3Z)-2,3-diisocyano-1,4-bis(4-tert-butyldimethylsilyloxyphenyl)buta-1,3-diene (74.0 mg, 0.14 mmol) prepared in Reference Synthetic Example 10 was dissolved in tetrahydrofuran in nitrogen atmosphere, and acetic acid (21 ml, 0.36 mmol) was added under cooing with ice. Then, a 1.0 mol/l tetra-n-butylammonium fluoride/tetrahydrofuran solution (280 ml, 0.28 mmol) was slowly added dropwise. The reaction solution was returned to room temperature, followed by stirring for 3 hours, and the reaction solution was purified as it was by silica gel column chromatography (hexane:ethyl acetate=2:1) to give (1Z, 3Z)-2,3-diisocyano-1,4-bis(4-hydroxyphenyl)buta-1,3-diene (48.2 mg, 85%) as a yellow powder.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][C:6]([Cl:8])=[CH2:7])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[C:20](Cl)=[O:21]>C1C=CC=CC=1>[Cl:8][C:6](=[CH2:7])[CH2:5][N:4]([CH2:1][CH:2]=[CH2:3])[C:20](=[O:21])[C:19]1[CH:18]=[C:17]([CH3:16])[CH:25]=[C:24]([CH3:26])[CH:23]=1
Reactant: C=CCNCC(=C)Cl
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CCN(CC(=C)Cl)C(=O)c1cc(C)cc(C)c1
Temperature: 10 °C

Procedure:
A solution was formed by dissolving N-allyl-2-chloroallylamine (0.032 moles) in 40 ml. of benzene. Then, triethylamine (0.032 moles) was added thereto. This solution was then cooled to 10°C. in an ice bath. Then, 3,5-dimethylbenzoylchloride was diluted with 40 ml. of benzene and added to the amine solution. The temperature rose to about 35°C. with triethylamine hydrogen chloride separation. The next day the reaction mixture was washed two times with diluted HCl and then two times with dilute (5% solution) sodium carbonate and dried. The solvent was removed to yield 7.0 grams of product ND30 1.5367.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][CH2:12][CH2:13][C:14]([OH:16])=O.[CH3:17][C:18]1([CH3:26])[O:23][C:22](=[O:24])[CH2:21][C:20](=[O:25])[O:19]1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:17][C:18]1([CH3:26])[O:23][C:22](=[O:24])[CH:21]([C:14](=[O:16])[CH2:13][CH2:12][NH:11][C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[CH3:1])[C:20](=[O:25])[O:19]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: Cc1ccc([N+](=O)[O-])cc1NCCC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])cc1NCCC(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(2-Methyl-5-nitro-phenylamino)-propionic acid [2.95 gm, 13.2 mmol], 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid (2.08 gm, 14.5 mmol), and 4-dimethylaminopyridine (DMAP) [2.42 gm, 198 mmol) in anhy. dichloromethane (70 ml) at 0° C. was added 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (EDC.HCl) [3.04 gm, 158 mmol), and the resulting solution was stirred overnight at room temperature. The reaction mixture was washed (50 ml×4) with 5% potassium bisulfate (aq). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum, thereby affording crude 2,2-Dimethyl-5-[3-(2-methyl-5-nitro-phenylamino)propionyl]-[1,3]dioxane-4,6-dione (7), that was dissolved in 60 ml of ethyl acetate and refluxed for 4 hrs, The reaction mixture was cooled to room temperature and concentrated under vacuum. The crude product obtained was further purified by silica gel chromatography (eluent: 2% methanol in chloroform) to give desired produced i.e., 1-(2-Methyl-5-nitro-phenyl)-piperidine-2,4-dione [8] as yellow solid[Yield: 1.91 gm, 58.6%]
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[O:11][CH2:12][C:13]([N:15]1[CH2:20][C@H:19]([CH3:21])[N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:17][C@H:16]1[CH3:30])=[O:14].[N+:32](C1C=C(Cl)C=CC=1O)([O-:34])=[O:33].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC.O>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]([O:11][CH2:12][C:13]([N:15]2[CH2:20][C@H:19]([CH3:21])[N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:17][C@H:16]2[CH3:30])=[O:14])=[C:4]([N+:32]([O-:34])=[O:33])[CH:9]=1
Reactant: COC(=O)c1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1[N+](=O)[O-]
Yield: 92.5 %

Procedure:
To a solution of (2R, 5S)-5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzoic acid methyl ester (1.0 g, 3.35 mmol) in butanone (35 ml) was added 2-nitro-4-chlorophenol (0.639 g, 3.69 mmol), potassium carbonate (0.925 g, 6.7 mmol) and potassium iodide (0.556 g, 3.35 mmol). The reaction mixture was heated at reflux overnight. The reaction mixture was then cooled, diluted with water and extracted with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered and concentrated to give an orange oil. Chromatography on silica gel gave the title compound (1.35 g, 93% yield).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C@@H:13]([NH:20][C:21]([C:23]1[C:27]2[CH2:28][C:29]([CH3:56])([CH3:55])[C:30]3[CH:31]=[N:32][C:33]([NH:36][C:37]4[CH:42]=[CH:41][C:40]([C:43](=[O:52])[NH:44][CH:45]5[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]5)=[CH:39][C:38]=4[O:53][CH3:54])=[N:34][C:35]=3[C:26]=2[O:25][N:24]=1)=[O:22])C1C=CC=CC=1>C1COCC1.NN.O>[NH2:3][C@@H:12]([C:26]1[CH:35]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:13][NH:20][C:21]([C:23]1[C:27]2[CH2:28][C:29]([CH3:55])([CH3:56])[C:30]3[CH:31]=[N:32][C:33]([NH:36][C:37]4[CH:42]=[CH:41][C:40]([C:43](=[O:52])[NH:44][CH:45]5[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]5)=[CH:39][C:38]=4[O:53][CH3:54])=[N:34][C:35]=3[C:26]=2[O:25][N:24]=1)=[O:22]
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)-c1onc(C(=O)N[C@H](CN3C(=O)c4ccccc4C3=O)c3ccccc3)c1CC2(C)C
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)-c1onc(C(=O)NC[C@@H](N)c3ccccc3)c1CC2(C)C
Temperature: 70 °C

Procedure:
To a solution of N-[(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-phenylethyl]-8-({2-methoxy-4-[(1-methylpiperidin-4-yl)carbamoyl]phenyl}amino)-5,5-dimethyl-4,5-dihydroisoxazolo[4,5-h]quinazoline-3-carboxamide (60 mg, 0.079 mmol) in THF (3 mL), 35% hydrazine in water (0.07 mL) was added and the reaction was warmed at 70° C. for 24 hours. The reaction was cooled at room temperature diluted with H2O (20 mL) and extracted with DCM (2×20 mL). The organic layers were dried over Na2SO4 and the solvent evaporated to dryness to yield the crude solid that was purified by flash chromatography on silica gel (DCM/MeOH/(NH3 7N in MeOH) to afford the title compounds.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][C@H:3]1[CH2:9][OH:10].[H-].[Na+].[C:13]1([N:19]2[CH2:24][CH2:23][N:22]([C:25](OC3C=CC([N+]([O-])=O)=CC=3)=[O:26])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[C:13]1([N:19]2[CH2:20][CH2:21][N:22]([C:25]([O:10][CH2:9][C@@H:3]3[CH2:4][N:5]([CH3:8])[CH2:6][CH2:7][N:2]3[CH3:1])=[O:26])[CH2:23][CH2:24]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccccc2)CC1
Reactant: CN1CCN(C)[C@H](CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(C)[C@H](COC(=O)N2CCN(c3ccccc3)CC2)C1
Temperature: 0 °C
Yield: 36.5 %

Procedure:
To a solution of 1,4-dimethyl-(S)-2-hydroxymethyl piperazine (Intermediate 3; 1.49 g, 10.3 mmol) in THF (20 mL) at 0° C. was added sodium hydride (1.24 g, 60% dispersion in mineral oil, 31.0 mmol). The reaction mixture was stirred for several minutes at 0° C. and then 4-nitrophenyl 4-phenylpiperazine-1-carboxylate (Intermediate 2; 3.72 g, 11.4 mmol) in THF (20 mL). The reaction mixture was allowed to warm to room temperature and stirred for 7 hours. The reaction mixture was then cooled to 0° C. and quenched with the drop-wise addition of sat aq NaHCO3 solution. The THF was removed in vacuo, the aqueous phase extracted with EtOAc (×3), combined organic phases washed with sat aq NaHCO3 solution (×6), dried (MgSO4) and concentrated in vacuo. The residue was suspended in water: formic acid solution [1:1] (20 mL), filtered and the filtrate was purified by reverse phase column chromatography (gradient eluting with methanol in water, with 1% formic acid in each solvent, 0-15%). The resulting residue was dissolved in DCM (50 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo to give [(2S)-1,4-dimethylpiperazin-2-yl]methyl 4-phenylpiperazine-1-carboxylate (1.25 g, 36%) as a pale yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:11]2[N:6]([C:7]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][C:17]4=[O:22])=[CH:12][C:8]=3[O:9][CH2:10]2)[C:5](=[O:23])[O:4]1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C(Cl)Cl>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:1][CH2:2][C@H:3]2[C@H:11]3[N:6]([C:7]4[CH:15]=[CH:14][C:13]([N:16]5[CH2:21][CH2:20][O:19][CH2:18][C:17]5=[O:22])=[CH:12][C:8]=4[O:9][CH2:10]3)[C:5](=[O:23])[O:4]2)=[O:33])=[CH:27][CH:26]=1
Reactant: NC[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: O=C(NC[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12)Nc1ccc(Cl)cc1
Yield: 84.4 %

Procedure:
Using compound (3S,3 aS)-3-aminomethyl-7-(3-oxomorpholin-4-yl)-3a,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-1(3H)-one (the product of step (e) in Example 1) (60 mg, 0.188 mmol), p-chlorophenylisocyanate (35 mg, 0.225 mmol), and TEA (28 mg, 0.282 mmol) as starting materials, DCM as solvent, preparation following the method as described in Example 21 afforded white compound 75 mg, yield 84.4%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:8]=[C:9]([NH:11][NH2:12])[CH:10]=1)=[O:4].CN([CH:23]=[N:24][C:25](=O)[CH:26]([CH3:28])[CH3:27])C>CC(O)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:8]=[C:9]([N:11]2[C:25]([CH:26]([CH3:28])[CH3:27])=[N:24][CH:23]=[N:12]2)[CH:10]=1)=[O:4]
Reactant: COC(=O)c1cc(NN)cc(-c2ccc(C)cc2)c1
Reactant: CC(C)C(=O)N=CN(C)C
Solvent: CC(=O)O
Product: COC(=O)c1cc(-c2ccc(C)cc2)cc(-n2ncnc2C(C)C)c1
Temperature: 90 °C

Procedure:
To a solution of 5-hydrazino-4′-methyl-biphenyl-3-carboxylic acid methyl ester (300 mg, 1.17 mmol) in HOAc (5 mL) was added N-dimethylaminomethylene-isobutyramide (233 mg. 1.4 mmol) in one portion. The mixture was heated to 90° C. for two hours. After removing the excess HOAc, the residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO™) to afford 5-(5-isopropyl-[1,2,4]triazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid methyl ester a yellow solid (293 mg, 74.6%).
Reaction SMILES: CN(C[C:5]1[C:6]([CH3:22])=[N:7][N:8]([CH2:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C:9]=1[CH3:10])C>CCO>[CH3:22][C:6]1[CH:5]=[C:9]([CH3:10])[N:8]([CH2:11][C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[N:7]=1
Reactant: Cc1nn(CC(=O)OCc2ccccc2)c(C)c1CN(C)C
Solvent: CCO
Product: Cc1cc(C)n(CC(=O)OCc2ccccc2)n1

Procedure:
The final compound was prepared using a method analogous to that of Example 14 step 14.2, benzyl 2-(4-((dimethylamino)methyl)-3,5-dimethyl-1H-pyrazol-1-yl)acetate replacing intermediate 14.1 and using EtOH instead of MeOH/AcOH. LC-MS (B): tR=0.23 min; [M+H]+: 212.17.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[CH2:16][CH2:15][CH2:14][C:8]=3[C:9](=[O:13])[NH:10][C:11]=2[CH:12]=1)=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:25])C=1>C(Cl)(Cl)Cl>[O:25]1[CH2:2][CH:1]1[C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[CH2:16][CH2:15][CH2:14][C:8]=3[C:9](=[O:13])[NH:10][C:11]=2[CH:12]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1ccc2c3c(c(=O)[nH]c2c1)CCC3
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2cc(C3CO3)ccc2c2c1CCC2
Reaction time: 15 h

Procedure:
A solution of 1.41 g (6.7 mmol) of 7-vinyl-1,2,3,5-tetrahydrocyclopenta[c]-quinolin-4-one in 200 ml of chloroform is mixed at room temperature with mCPBA. After 15 hours at room temperature, the batch is washed with saturated Na2SO3 (2×100 ml), dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with hexane-ethyl acetate yields 0.59 g of product.
Reaction SMILES: C1C2C(COC([NH:18][CH:19]([CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH2:54][C:55]3[N:56]([CH2:60][C:61]([N:63]([CH2:72][C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[CH2:64][C:65](=[O:71])[O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:62])[CH:57]=[CH:58][N:59]=3)[CH2:28][C:29]3[N:30]([CH2:34][C:35](=[O:53])[N:36]([CH2:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH:31]=[CH:32][N:33]=3)[C:20]([OH:22])=[O:21])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[NH2:18][C@@H:19]([CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH2:28][C:29]1[N:30]([CH2:34][C:35]([N:36]([CH2:37][C:38]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:44])[CH2:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:53])[CH:31]=[CH:32][N:33]=1)[CH2:54][C:55]1[N:56]([CH2:60][C:61](=[O:62])[N:63]([CH2:72][C:73](=[O:74])[O:75][C:76]([CH3:79])([CH3:78])[CH3:77])[CH2:64][C:65](=[O:71])[O:66][C:67]([CH3:69])([CH3:68])[CH3:70])[CH:57]=[CH:58][N:59]=1)[C:20]([OH:22])=[O:21]
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)Cn1ccnc1CN(CCCCC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)Cn1ccnc1CN(CCCC[C@H](N)C(=O)O)Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Yield: 79.1 %

Procedure:
A solution of 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-6-(bis((1-(2-(bis(2-tert-butoxy-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)hexanoic acid (190 mg, 0.173 mmol) and piperidine (0.50 mL) in DMF (0.50 mL) was stirred at room temperature for 1 hrs. The solvent was evaporated under reduced pressure to give a crude product. The crude product was purified by Biotage SP4 with a gradient method of 5-50% methanol in DCM to give (S)-2-amino-6-(bis((1-(2-(bis(2-tert-butoxy-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)hexanoic acid (0.120 g, 79%). 1H NMR (400 MHz, DMSO-d6) 6.92 (s, 2H), 6.76 (s, 2H), 5.01 (s, 4H), 4.32 (s, 2H), 4.31 (s, 2H), 3.92 (s, 4H), 3.44 (s, 4H), 3.01-2.99 (m, 1H), 2.30 (t, J=7.2 Hz, 2H), 1.60-1.57 (m, 2H), 1.43 (s, 18H), 1.35 (m, 18H). 1.30-1.12 (m, 4H); MS (ESI), 439.4 (M/2+H)+.
Reaction SMILES: [C-:1]1([CH:6]=O)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:13].[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].[BH4-].[Na+].C(O)(=O)C>CN(C=O)C.[OH-].[Na+].O>[C-:1]1([CH2:6][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:2]=[CH:3][CH:4]=[CH:5]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:13]
Reactant: O=C[c-]1cccc1
Reactant: NCCCCCC(=O)O
Agent: [Fe+2]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CCCCCNC[c-]1cccc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
After 1.38 g (6.4 mmol) of ferrocene-aldehyde (Aldrich Corp) was dissolved in 20 mL of a DMF solution, the mixture was mixed with a solution of 0.75 g (5.7 mmol) of 6-amino caproic acid (Merck Corp.) in 5 mL of NaOH and refluxed at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, and a solution of NaBH4 (0.63 g, 16.5 mmol) in 5 mL of water was added little by little into the reaction mixture (refer to FIG. 11). After 12 hours later, an aqueous acetic acid solution (10%) was slowly added until the pH reached 5. The reaction by-product ferrocene-CH2OH and unreacted 6-amino caproic acid dissolved in the organic phase was removed through extraction using ethylacetate. The aqueous phase was distilled at 50° C. under reduced pressure to obtain yellowish brown crystals. The yellowish brown crystals were recrystallized by dissolving the crystals in high-temperature ethanol to obtain planar, yellow crystalline N-(ferrocenyl methyl)-6-amino caproic acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[CH:13]([O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)([CH3:15])[CH3:14]>O1CCOCC1>[CH:13]([O:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]3[N:3]=2)=[CH:19][CH:18]=1)([CH3:15])[CH3:14]
Reactant: CC(C)Oc1ccc(N)cc1
Reactant: O=Cc1cnn2ccc(Cl)nc12
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(Nc2ccn3ncc(C=O)c3n2)cc1
Temperature: 120 °C

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (30 mg, 0.166 mmol) in dioxane was added 4-isopropoxyaniline (125 mg, 0.829 mmol). The mixture was heated in microwave for 20 minutes at 120° C. The solid formed was isolated by filtration and air dried to yield 5-(4-isopropoxyphenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde with impurities that will be removed in the final step. LCMS (M+1=297)
Reaction SMILES: C(O[C:5]1[N:10]=[C:9](NN)[N:8]=[C:7]([NH:13][NH2:14])[N:6]=1)CC.[C:15](Cl)(=[O:23])[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[OH:18]>CC(N(C)C)=O>[CH2:17]([O:18][NH:14][NH:13][C:7]1[N:6]=[C:5]([C:15](=[O:23])[C:16]2[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=2)[OH:18])[N:10]=[C:9]([C:15](=[O:23])[C:16]2[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=2)[OH:18])[N:8]=1)[CH2:16][CH3:15]
Reactant: CCCOc1nc(NN)nc(NN)n1
Reactant: O=C(Cl)c1ccccc1O
Solvent: CC(=O)N(C)C
Product: CCCONNc1nc(C(=O)c2ccccc2O)nc(C(=O)c2ccccc2O)n1

Procedure:
20 g of 2-propoxy-4,6-dihydrazino-s-triazine (melting point 130° C) are dissolved in 200 ml of dimethylacetamide and treated with 32 g of salicyloyl chloride at 10° - 20°, over the course of 30 minutes, whilst stirring and cooling externally. The reaction is exothermic. The homogeneous reaction mixture is stirred for a further 30 minutes at 20° C and is subsequently clarified by filtration and slowly treated with 500 ml of water whilst stirring, whereupon the reaction product precipitates as a white solid. The precipitate is filtered of, washed with water, dried at 80° C and purified by recrystallisation from dioxane. The 2-propoxy-4,6-disalicyloylhydrazino-s-triazine obtained (Stabiliser No. 4) has a melting point of 258°-260° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[OH-].[Na+]>CO.CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH2:18][CH2:17][CH2:16][CH2:15][Br:14]
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Reactant: BrCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)Cc1ccc(OCCCCBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-chloro-4-hydroxyphenylacetate and 1,4-dibromobutane (0.021 g, 0.044 mmol) in 0.5 mL of methanol was added 5N NaOH soln (0.04 mL, 5 eq) at rt. The reaction mixture was heated initially with a heat gun to reflux in order to dissolve the starting material. After heating, the reaction mixture stirred at ambient temperature for 1 h. The reaction mixture was diluted with EtOAc and 0.1N HCl (5 mL). The organic layer was separated from the aqueous portion, and washed with 0.1N HCl (5 mL) followed by 10 mL brine. The organic layer was dried (MgSO4), filtered, and evaporated in vacuo to afford the title compound. This compound was taken forward without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:8]#[N:9].[H-].[Na+].Cl.Cl[CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1>CN(C)C=O>[NH:24]1[CH:25]=[C:21]([CH2:20][C:7]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]#[N:9])[N:22]=[CH:23]1
Reactant: N#CC(c1ccccc1)c1ccccn1
Reactant: ClCc1c[nH]cn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(Cc1c[nH]cn1)(c1ccccc1)c1ccccn1
Reaction time: 1 h

Procedure:
A 19.42 g. portion of 2-(2-pyridyl)-2-phenylacetonitrile was stirred with 4.8 g. of 50% sodium hydride in 50 ml. of dimethylformamide, and reacted with 7.65 g. of 4-chloromethylimidazole hydrochloride in 25 ml. of dimethylformamide as described in Example 1. The mixture was stirred at 80°-90° C. for 1 hour, the solvent was removed by evaporation under vacuum, and wthe residue was worked up as described in Example 1 to obtain 11.87 g. of the free base named in the heading above, m.p. 111°-115° C. dec. The product was triturated twice with portions of diethyl ether, and was dissolved in chloroform. The solution was extracted with water and dried over sodium sulfate. Evaporation of the solvent under vacuum gave 11.84 g. of purified free base, m.p. 111°-115° C.