Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.S1C2C=CC=CC=2N=C1NC(C1C=CC=C2C=1CN(C1SC(CCCI)=C(C(OCC)=O)N=1)CC2)=O.[CH3:44][N:45]1[CH2:50][CH2:49][CH:48]([NH:51][C:52]2[CH:57]=[CH:56][C:55]([OH:58])=[CH:54][CH:53]=2)[CH2:47][CH2:46]1.[S:59]1[C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][C:62]=2[N:61]=[C:60]1[NH:68][C:69]([C:71]1[CH:72]=[CH:73][CH:74]=[C:75]2[C:80]=1[CH2:79][N:78]([C:81]1[N:86]=[C:85]([C:87]([O:89][C:90]([CH3:93])([CH3:92])[CH3:91])=[O:88])[C:84]([CH2:94][CH2:95][CH2:96]I)=[CH:83][CH:82]=1)[CH2:77][CH2:76]2)=[O:70]>>[S:59]1[C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][C:62]=2[N:61]=[C:60]1[NH:68][C:69]([C:71]1[CH:72]=[CH:73][CH:74]=[C:75]2[C:80]=1[CH2:79][N:78]([C:81]1[N:86]=[C:85]([C:87]([O:89][C:90]([CH3:92])([CH3:91])[CH3:93])=[O:88])[C:84]([CH2:94][CH2:95][CH2:96][O:58][C:55]3[CH:56]=[CH:57][C:52]([NH:51][CH:48]4[CH2:47][CH2:46][N:45]([CH3:44])[CH2:50][CH2:49]4)=[CH:53][CH:54]=3)=[CH:83][CH:82]=1)[CH2:77][CH2:76]2)=[O:70]
Reactant: CN1CCC(Nc2ccc(O)cc2)CC1
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1CCCI
Agent: CCOC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1CCCI
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(Nc2ccc(OCCCc3ccc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)OC(C)(C)C)cc2)CC1

Procedure:
The compound 104B was prepared as a TFA salt in a similar manner to the synthesis of step 2 of Example 51 by substituting compound 51A and compound 2C with compound 104A and compound 96D, respectively: APCI (+)/LC/MS: 733 (M+H)−.
Reaction SMILES: N([C:16]([O:18][C:19]([CH3:22])(C)C)=[O:17])[C@H:2]([CH2:14]O)[CH2:3][C:4]1C=C2C(C=CC=C2)=[CH:6][CH:5]=1.[C:23](OC(OC(C)(C)C)=O)(=O)OC(C)(C)C>C(O)(C)(C)C>[CH3:22][CH2:19][O:18][C:16]([CH3:23])=[O:17].[CH3:14][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccc2ccccc2c1
Solvent: CC(C)(C)O
Product: CCCCCC
Product: CCOC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
Boc-Nal-CH2OH. L-naphthylalaninol (2.72 g; 13.5 mmol) was dissolved in tert-butanol (60 ml) and di-t-butyl pyrocarbonate (3.16 g; 14.5 mmol) was added. The reaction was stirred at room temperature for 3 h, then the solvent was removed in vacuo. A white solid was crystallized from AcOEt/hexane (3.47 g; 92% yield): mp 131°-132° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][C:6]=1[CH3:15].[OH-].[Na+]>O1CCOCC1>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[CH3:15]
Reactant: COC(=O)c1ccc(OCCO)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(C(=O)O)ccc1OCCO
Temperature: 70 °C
Reaction time: 22 h
Yield: 44.1 %

Procedure:
To a solution of methyl 4-(2-hydroxyethoxy)-3-methyl-benzoate (1.87 g, 8.9 mmol) in dioxane (16 mL) was added 1N NaOH (5 mL) and the reaction mixture was heated at 70° C. for 18 hours. 5M NaOH (0.5 ml) was added and the reaction was stirred at 70° C. for 22 hours. The reaction mixture was cooled and solvent was concentrated in vacuo and the crude residue was dissolved in water (20 mL) and extracted with ethyl acetate (2×20 mL). The aqueous layer was acidified with 1 M HCl solution and extracted with ethyl acetate (2×20 mL). The organics were separated, dried with Na2SO4 and concentrated in vacuo to give 4-(2-hydroxyethoxy)-3-methyl-benzoic acid (0.77 g, 44%) as a white solid. ESI-MS m/z calc. 196.1. found 197.0 (M+1)+; Retention time: 0.72 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 12.51 (s, 1H), 7.96-7.49 (m, 2H), 7.00 (d, J=8.6 Hz, 1H), 4.87 (t, J=5.4 Hz, 1H), 4.06 (t, J=5.0 Hz, 2H), 3.75 (q, J=5.1 Hz, 2H), 2.17 (d, J=20.3 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[N:12]=[C:11]([NH2:13])[CH:10]=[N:9][C:8]=2[C:14]2[CH:19]=[CH:18]C=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[CH:20]1([C:23](Cl)=[O:24])[CH2:22][CH2:21]1.[N:26]1C=CC=CC=1>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:23]([CH:20]3[CH2:22][CH2:21]3)=[O:24])[CH:10]=[N:9][C:8]=2[C:14]2[CH:15]=[CH:16][N:26]=[CH:18][CH:19]=2)=[CH:4][CH:3]=1
Reactant: c1ccncc1
Reactant: Cc1ccc(-c2nc(N)cnc2-c2ccccc2)o1
Reactant: O=C(Cl)C1CC1
Product: Cc1ccc(-c2nc(NC(=O)C3CC3)cnc2-c2ccncc2)o1
Temperature: 70 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
To a stirred solution of 6-(5-methylfuran-2-yl)-5-phenylpyrazin-2-ylamine (42 mg, 0.166 mmol) in pyridine (1.8 mL) was added cyclopropanecarbonyl chloride (38 μL, 0.41 mmol). The solution was stirred at 70° C. for 6 h, evaporated, partitioned between dichloromethane and a 4% sodium bicarbonate aqueous solution, the aqueous phase extracted twice with dichloromethane, the organic layers washed with brine, dried (MgSO4) and evaporated. The residue was triturated with diethyl ether and methanol and the precipitate was collected by filtration and dried to furnish the title compound as a brown solid (43 mg, 81%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=O)[CH3:20])[N:14]=1)[CH3:12].[C:22]([C:26]1[CH:27]=[C:28]([CH:30]=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:32]=1)[NH2:29])([CH3:25])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[N:29][C:28]2[CH:30]=[C:31]([C:33]([CH3:35])([CH3:34])[CH3:36])[CH:32]=[C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:27]=2)[CH3:20])[N:14]=1)[CH3:12]
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1
Solvent: Cc1ccccc1
Product: CC(=Nc1cc(C(C)(C)C)cc(C(C)(C)C)c1)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1
Reaction time: 48 h

Procedure:
2-[1-(2,4,6-trimethylphenylimino)ethyl]-6-acetylpyridine (1.3 g, 4.64 mmol), prepared according to the method disclosed in WO02/28805, and 3,5-di-tert-butylaniline (1 g, 4.87 mmol) were dissolved in 100 ml of toluene. To this solution, 4 Å molecular sieves were added. After standing for 2 days the mixture was filtered. The solvent was removed in vacuo. The residue was washed with methanol and crystallised from ethanol. Yield 1.1 g (51%) of 2-[1-(2,4,6-trimethylphenylimino)ethyl]-6-[1-(3,5-di-tert-butylphenylimino)ethyl]pyridine.
Reaction SMILES: [CH3:1][C@@:2]1([OH:21])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[C:14]2=[N:15][CH:16]=[N:17][C:18]([NH:19][OH:20])=[C:13]2[CH:12]=[N:11]1.O(N)[CH3:23]>>[CH3:1][C@@:2]1([OH:21])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[C:14]2=[N:15][CH:16]=[N:17][C:18]([NH:19][O:20][CH3:23])=[C:13]2[CH:12]=[N:11]1
Reactant: CON
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ncc2c(NO)ncnc21
Product: CONc1ncnc2c1cnn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@]1(C)O

Procedure:
Nucleoside 119 was prepared from the nucleoside 143 (Example 6, step 3) substituting hydroxylamine for methoxylamine.
Reaction SMILES: C([C:3]([OH:22])([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[C:4]1[N:8]([CH3:9])[C:7]([CH2:10][C:11]([O:13]C)=[O:12])=[CH:6][CH:5]=1)#N>[OH-].[Na+]>[CH3:9][N:8]1[C:4]([C:3](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:5][CH:6]=[C:7]1[CH2:10][C:11]([OH:13])=[O:12]
Reactant: COC(=O)Cc1ccc(C(O)(C#N)c2ccc(C)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C(=O)c2ccc(CC(=O)O)n2C)cc1

Procedure:
Methyl 5-[cyanohydroxy(4-methylphenyl)methyl]-1-methylpyrrole-2-acetate, 55 mg (0.185 mmole) was heated on a steam bath in 15 percent NaOH (1.5 ml) for 3.5 hours. The reaction was cooled on ice for one hour then filtered. The solid was dissolved in distilled water, hot filtered, cooled, 3 N HCl was added to precipitate 0.48 g (100 percent) of 1-methyl-5-(4-methylbenzoyl)pyrrole-2-acetic acid, mp 153°-158°, undepressed by admixture with authentic material.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:31])[C:15](=[O:30])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)=[C:4]([OH:32])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:40][C:41]([O:43][CH3:44])=[O:42]>CN(C=O)C.CCOC(C)=O>[CH3:44][O:43][C:41](=[O:42])[CH2:40][O:32][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([C:15](=[O:30])[C:16]1[CH:17]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[CH3:31]
Reactant: COC(=O)CCl
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 70 °C
Yield: 57.7 %

Procedure:
To a solution of N-[4-(4-fluoro-2-hydroxy-phenyl)-pyridin-3-yl]-N-methyl-3,5-bis-trifluoromethyl-benzamide (150 mg, 0.327 mmol, example 48) in DMF (5 mL) was added K2CO3 (90 mg, 0.654 mmol) and methyl chloroacetate (0.06 mL, 0.654 mmol, CAS RN 96-34-4) at 25° C. and the resulting mixture was heated to 70° C. for 16 hours. The mixture was diluted with EtOAc (25 mL), washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The crude material thus obtained was purified by column chromatography over silica gel (30% EtOAc in n-hexane) to give 100 mg of the title compound. Pale yellow solid (58%). MS (ESI): m/z=531.0 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9]1.Br[CH2:24][CH2:25][C:26]1([OH:36])[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1>>[OH:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([CH:10]2[CH2:11][CH2:12][N:8]([CH2:24][CH2:25][C:26]3([OH:36])[CH2:35][CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27]3)[CH2:9]2)(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: O=S(=O)(c1ccc(O)cc1)C1CCNC1
Reactant: OC1(CCBr)CCc2ccccc2C1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(O)cc1)C1CCN(CCC2(O)CCc3ccccc3C2)C1

Procedure:
The title compound, MS: m/e=402.4 (M+H+) was prepared from (RS)-4-(pyrrolidine-3-sulfonyl)-phenol trifluoroacetic acid salt and (RS)-2-(2-bromo-ethyl)-1,2,3,4-tetrahydro-naphthalen-2-ol.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[O:14][N:13]=[C:12]([C:15]2[N:16]=[C:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:26](=[O:38])[CH2:27][N:28]4[C:32]([CH3:33])=[CH:31][C:30]([C:34]([F:37])([F:36])[F:35])=[N:29]4)[CH2:22][CH2:21]3)[S:18][CH:19]=2)[CH2:11]1)(=O)[CH3:2].[NH2:39][OH:40].O>C(O)C>[OH:40][N:39]=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[O:14][N:13]=[C:12]([C:15]2[N:16]=[C:17]([CH:20]3[CH2:21][CH2:22][N:23]([C:26](=[O:38])[CH2:27][N:28]4[C:32]([CH3:33])=[CH:31][C:30]([C:34]([F:36])([F:37])[F:35])=[N:29]4)[CH2:24][CH2:25]3)[S:18][CH:19]=2)[CH2:11]1)[CH3:2]
Reactant: NO
Reactant: CC(=O)c1ccccc1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)(F)F)cc4C)CC3)n2)=NO1
Solvent: CCO
Solvent: O
Product: CC(=NO)c1ccccc1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)(F)F)cc4C)CC3)n2)=NO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-{4-[5-(2-acetylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (150 mg) in ethanol (5 ml) was added dropwise hydroxylamine (50% in water, 4 eq.) at room temperature. After stirring at room temperature overnight, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography. This gave 1-[4-(4-{5-[2-(N-hydroxyethanimidoyl)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (33 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:7][CH:6]([CH2:9][OH:10])[CH2:5][CH2:4]1.CC([O-])(C)C.[K+].[CH2:24]([Cl:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CS(C)=O>[ClH:31].[CH2:24]([O:10][CH2:9][CH:6]1[CH2:7][CH2:8][C:3]([N:2]([CH3:17])[CH3:1])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4][CH2:5]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: ClCc1ccccc1
Reactant: CN(C)C1(c2ccccc2)CCC(CO)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN(C)C1(c2ccccc2)CCC(COCc2ccccc2)CC1
Product: Cl
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 9.3 %

Procedure:
(4-Dimethylamino-4-phenylcyclohexyl)methanol (1.8 g, 7.7 mmol) was placed in abs. DMSO (10 ml), and a solution of potassium tert-butylate (1.73 g, 15.4 mmol) in DMSO (20 ml) was added dropwise over 15 min. The mixture was heated to 50° C. and stirred for 30 min, after which benzyl chloride (1.46 g, 11.6 mmol) in DMSO (10 ml) was added dropwise over 15 min. After stirring overnight at 50° C., water (20 ml) was added and the mixture was extracted with ether (3×30 ml) followed by DCM (3×30 ml). The combined extracts were washed with water (20 ml), dried, filtered and concentrated. The resulting residue (2.85 g) was heated to the reflux point with EE (30 ml) and filtered hot and the filtrate was kept overnight at 4° C. The solid which had precipitated out was filtered off with suction and dried (960 mg of a mixture of the diastereoisomeric target products), the mother liquor was concentrated to dryness and the resulting residue (1.37 g) was chromatographed on silica gel with ether to which an increasing amount of methanol was added. This gave 308 mg of the less polar diastereoisomer of (4-benzyloxymethyl-1-phenylcyclohexyl)dimethylamine, which was dissolved in 2-butanone (2 ml). The addition of chlorotrimethylsilane (129 μl) and water (9 μl) gave an oily residue, which yielded 258 mg of the corresponding hydrochloride after drying.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl.[NH2:12][CH:13]1[CH2:18][CH:17]2[CH2:19][CH:14]1[CH2:15][CH2:16]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH:14]12[CH2:19][CH:17]([CH2:16][CH2:15]1)[CH2:18][CH:13]2[NH:12][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: NC1CC2CCC1C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(NC2CC3CCC2C3)nc1

Procedure:
2-Chloro-5-nitropyridine (158 mg, 1 mmol), 2-aminonorbornane hydrochloride (147 mg, 1 mmol), and finely ground potassium carbonate (419 mg, 3 mmol) were heated to 80° C. in 10 mL anhydrous DMF for 3.5 hrs. The mixture was diluted with EtOAc, extracted with H2O and dried over MgSO4. The EtOAc was filtered, evaporated to dryness to yield 220 mg. ES-MS calcd for C12H15N3O2 (m/e) 233.21, obsd 234.1 (M+H).
Reaction SMILES: CC[O-].[Na+].[Br:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:9]=O.[N:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N+]=[N-]>CCO>[Br:5][C:6]1[CH:7]=[C:8]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[NH:16][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:9]2
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: COc1ccc(C=O)cc1Br
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc2cc(Br)c(OC)cc2[nH]1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of sodium ethylate in ethanol (prepared from sodium (1.92 g; 83.70 mmol) and EtOH (40 mL)) was added dropwise to a cold (−10° C.) solution of 3-bromo-p-anisaldehyde (4 g; 18.60 mmol) and ethyl azidoacetate (ABCR, 27.80 ml; 46.50 mmol) in EtOH (60 mL). After the end of the addition, the reaction mixture was warmed up to 0° C. and stirred at RT for 5 hours. The heterogenous mixture was poured onto ice and stirred for 30 minutes. The solid was collected by filtration and dried under high vacuum. The solid was taken up in xylenes (60 mL) and heated to reflux for 3 hours. The solvent was evaporated and the residue was purified by silica column chromatography (c-Hexane/ethyl acetate, 80/20) to give the title compound as a pale yellow solid. 1H NMR (DMSO-d6) δ 11.87 (s, 1H), 7.89 (s, 1H), 7.05 (s, 1H), 6.98 (s, 1H), 4.31 (q, J=7 Hz, 2H), 3.85 (s, 3H), 1.32 (t, J=7 Hz, 3H). HPLC (Method A), Rt 4.28 min (Purity: 98.1%). LC/MS (Method B): 297.2 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]([O:10][C:11](=[O:19])[NH:12][C@H:13]1[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]1)([CH3:9])[CH3:8].C(N(CC)CC)C>CC(C)=O.O>[CH3:9][C:7]([O:10][C:11](=[O:19])[NH:12][C@H:13]1[CH2:17][CH2:16][C@@H:15]([O:18][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:14]1)([CH3:6])[CH3:8]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](OS(C)(=O)=O)C1
Temperature: 4 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
Methanesulphonyl chloride (0.98 ml, 12.6 mmol) was added to a stirred mixture of (1S-cis)-(3-hydroxycyclopentyl)carbamic acid 1,1-dimethylethyl ester (1.41 g, 7.01 mmol) and triethylamine (1.76 ml, 12.6 mmol) in acetone(55 ml) at 4° C. The resulting mixture, containing a white precipitate, was stirred at 4° C. for one hour, then at 21° C. for a further 2.25h, after which it was diluted with water(150 ml) and extracted with ethyl acetate (3×100 ml). The total organic solution was washed with water (50 ml), dried (MgSO4) and evaporated to a white solid. This was dissolved in hot diethyl ether(25 ml) and cooled to 4° C. for 2h, after which time, cyclohexane(25 ml) was added which caused a precipitate to form immediately. The mixture was left to stand at 4° C. for a further 3h, after which the solid was filtered off, washed with cold cyclohexaneldiethyl ether(2:1), then dried to give the title compound (1.202 g) as a white solid, m.p. 88-89° C., [α]D -11.11° (CHCl3 c=0.54%).
Reaction SMILES: C(OC([NH:8][C:9](=[N:64]C(OC(C)(C)C)=O)[NH:10][C:11]1[CH:63]=[CH:62][C:14]([C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH:27][C@H:28]([C:54]([O:56]C(C)(C)C)=[O:55])[CH2:29][C:30]3[N:34]=[CH:33][N:32](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:31]=3)=[O:26])=[C:20]([Cl:61])[CH:19]=2)=[O:16])=[CH:13][CH:12]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:10]([C:11]1[CH:63]=[CH:62][C:14]([C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH:27][C@H:28]([C:54]([OH:56])=[O:55])[CH2:29][C:30]3[N:34]=[CH:33][NH:32][CH:31]=3)=[O:26])=[C:20]([Cl:61])[CH:19]=2)=[O:16])=[CH:13][CH:12]=1)[C:9]([NH2:64])=[NH:8]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc(C(=O)Oc2ccc(CC(=O)N[C@@H](Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(=O)OC(C)(C)C)c(Cl)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)Nc1ccc(C(=O)Oc2ccc(CC(=O)N[C@@H](Cc3c[nH]cn3)C(=O)O)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
To a solution of tert-butyl N-{[4-({4-[N′,N″-bis(tert-butoxycarbonyl)carbamimidamido]benzoyl}oxy)-2-chlorophenyl]acetyl}-1-trityl-L-histidinate (265 mg) in dichloromethane (2.70 mL) was added trifluoroacetic acid (0.619 mL) under ice-cooling, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure and washed with water, and the filtrate was concentrated under reduced pressure. The residue was purified by ODS silica gel column chromatography (0.01 M hydrochloric acid-acetonitrile), and the purified product was dried under reduced pressure to obtain N-({4-[(4-carbamimidamidobenzoyl)oxy]-2-chlorophenyl}acetyl)-L-histidine 2 hydrochloride (54.1 mg).
Reaction SMILES: [N:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[OH:23])[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH:24][CH:25]([CH2:29][CH2:30]CC)[C:26]([OH:28])=O.[CH2:33](N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:24][C:25]([CH3:33])([CH2:29][CH3:30])[C:26]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[OH:23])[N:8]=2)[CH2:6][CH2:5]1)=[O:28]
Reactant: CCN(CC)CC
Reactant: Oc1ccccc1-c1nc(N2CCNCC2)c2ccccc2n1
Reactant: CCCCC(O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCC(C)(O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3ccccc23)CC1
Reaction time: 8 h

Procedure:
A solution of 2-(4-(piperazin-1-yl)quinazolin-2-yl)phenol (70 mg, 0.23 mmol) in DMF (0.5 mL) was added to 2-hydroxyhexanoic acid (39.3 mg, 0.297 mmol). Triethylamine (63 μL) was added at room temperature, then a solution of HATU (113 mg) in 0.5 mL DMF. The reaction was stirred overnight. Purification using reverse phase HPLC (10-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)) gave 2-hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-methylbutan-1-one. LC/MS: m/z 421.3 (M+H)+ at 2.60 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][CH:9]=O)[C:6]2[N:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]=[CH:3]1.[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([CH2:25][N:26]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(O)(=O)C.C(Cl)(Cl)Cl>[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([CH2:25][N:26]([CH:34]3[CH2:39][CH2:38][N:37]([CH2:9][CH2:8][N:7]4[C:2](=[O:1])[CH:3]=[N:4][C:5]5[CH:14]=[CH:13][CH:12]=[N:11][C:6]4=5)[CH2:36][CH2:35]3)[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: O=CCn1c(=O)cnc2cccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cnc3cccnc32)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.7 %

Procedure:
To 0.13 g of (3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)acetaldehyde, a solution of 0.23 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate in 4 mL of dichloromethane, 38 μL of acetic acid and 0.21 g of sodium triacetoxyborohydride were added, and the mixture was stirred at room temperature for 3 hours. Chloroform and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by flash silica gel column chromatography using gradient elution with chloroform:methanol=100:0 to 90:10 to obtain 0.24 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)carbamate as a light brown oily substance.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([OH:43])[CH2:22][O:23][C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[S:44](Cl)([C:47]1[CH:53]=[CH:52][C:50]([CH3:51])=[CH:49][CH:48]=1)(=[O:46])=[O:45]>N1C=CC=CC=1>[CH2:1]([O:19][CH2:20][CH:21]([O:43][S:44]([C:47]1[CH:53]=[CH:52][C:50]([CH3:51])=[CH:49][CH:48]=1)(=[O:46])=[O:45])[CH2:22][O:23][C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
In 9 ml of pyridine was dissolved 5.0 g (8.52 mmole) of 3-O-octadecyl-1-O-tritylglycerol, and after 1.95 g (10.22 mmole) of tosyl chloride was added to the solution, the mixture was stirred at room temperature overnight and concentrated to dryness under reduced pressure. The residue was dissolved in 50 ml of water and 50 ml of dichloromethane, and after shaking thoroughly, the dichloromethane layer was separated out. The organic layer was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column (50 g), with n-hexane.ethyl acetate (193:7) used as an eluent, to give 5.3 g (yield of 83.9%) of colorless needles.