Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:14]2[CH2:15][O:16][C@H:12]([O:13]2)[C@H:11]([O:17][CH3:18])[C@@H:10]1[OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH3:22]I.O>CS(C)=O>[CH2:1]([O:8][C@@H:9]1[C@H:14]2[CH2:15][O:16][C@H:12]([O:13]2)[C@H:11]([O:17][CH3:18])[C@@H:10]1[O:19][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: CO[C@H]1[C@@H]2OC[C@@H](O2)[C@@H](OCc2ccccc2)[C@H]1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CO[C@H]1[C@@H](OC)[C@@H]2OC[C@@H](O2)[C@H]1OCc1ccccc1
Reaction time: 8 h
Yield: 51.4 %

Procedure:
1,6-Anhydro-4-O-benzyl-2-O-methyl-β-D-allopyranose (0.135 g) (see Example 29) was dissolved in dimethylsulphoxide (0.5 ml) and stirred with powdered potassium hydroxide (0.118 g). Methyl iodide (0.568 g) was added in two portions, and the reaction mixture was left overnight at room temperature. Water (10 ml) was added and the mixture was extracted with chloroform (3×10 ml). The combined extracts were washed with brine, filtered through Whatman 1PS paper, and evaporated to a red oil. This was subjected to preparative t.l.c. on silica gel eluted with ethyl acetate/hexane, 1:1, to yield the title compound as a colourless syrup (0.073 g); 1H-nmr data: 7.2-7.5 (m, Ph), 5.6 (d, H-1), 4.8 (m, PhCH2O), 4.55 (m, H-5), 3.3-3.7 (m, H-2,3,4,6,6'), and 3.40 and 3.57 (s, OMe).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:22])[C:5](=O)[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([O:19][CH3:20])=[CH:8][CH:7]=2.[C-:23]#[N:24].[K+]>C(O)(C)C.O>[C:23]([CH2:2][C:3]1[N:4]([CH3:22])[CH2:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([O:19][CH3:20])=[CH:8][CH:7]=2)#[N:24]
Reactant: COc1ccc2c(=O)n(C)c(CBr)c(-c3ccccc3)c2c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: COc1ccc2c(c1)C(c1ccccc1)=C(CC#N)N(C)C2
Temperature: 80 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To a solution of 3-(bromomethyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one (6.82 g, 19.0 mmol) in 100 mL of isopropanol was added a solution of potassium cyanide (2.48 g, 38.1 mmol) in 10 mL of water. The mixture was heated at 80° C. After one hour, another portion of potassium cyanide solution (300 mg in 5 mL of water) was added, and the reaction stirred for an additional hour. The solution was cooled to room temperature, and partitioned between EtOAc and saturated NaHCO3 solution. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude solid material was triturated with EtOAc/ether to provide the titled product (5.01 g, 86% yield). HRMS (ES) exact mass calculated for C19H16N2O2 (M+H+): 305.1285. Found 305.1269.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([N+:10]([O-])=O)=[CH:5][N:4]=1.[H][H]>[Pd].CO>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([NH2:10])=[CH:5][N:4]=1
Reactant: [H][H]
Reactant: CNc1ncc([N+](=O)[O-])c(N)n1
Agent: [Pd]
Solvent: CO
Product: CNc1ncc(N)c(N)n1
Reaction time: 6 h

Procedure:
N2-methyl-5-nitropyrimidine-2,4-diamine 48 (0.83 g, 4.9 mmol) and 10% palladium on carbon (0.52 g, 0.49 mmol) were combined under nitrogen. Methanol (16 mL) was added, and the atmosphere replaced with hydrogen from a balloon. The reaction was stirred rapidly for 6 h, at which point the atmosphere was replaced with nitrogen and the reaction mixture was filtered through celite, rinsing with methanol. The filtrate was concentrated in vacuo to give N2-methylpyrimidine-2,4,5-triamine 49 as a light pink solid. MS (ES+): 140 (M+H)+; Calc. for C5H9N5=139.16.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([CH3:12])[CH:3]=1.[NH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)C(C)C)(C)C>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)(=[O:10])=[O:9])=[C:4]([CH3:12])[CH:3]=1
Reactant: NCCN1CCOCC1
Reactant: Cc1cc(Br)ccc1S(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1S(=O)(=O)NCCN1CCOCC1
Temperature: 40 °C
Reaction time: 18 h
Yield: 99.4 %

Procedure:
A mixture of 4-bromo-2-methylbenzene sulfonyl chloride (700 mg, 2.6 mmol), 4-(2-aminoethyl)morpholine (372 mg, 2.86 mmol, 1.1 eq), and N,N-diisopropylethylamine (1.0 mL, 5.71 mmol, 2.2 eq) in anhydrous tetrahydrofuran (13 mL, 0.2 M) was stirred at 40° C. under nitrogen for 18 h. Solvent was removed at reduced pressure and the residue was partitioned between EtOAc and water. The organic phase was washed with water and brine, dried over Na2SO4, and concentrated at reduced pressure. The residue was purified by MPLC (eluting with 50% to 75% EtOAc/hexane) to give 939 mg (99%) of the desired product as a white solid. 1H-NMR (DMSO-d6) δ 7.73 (d, J=8.4 Hz, 1H), 7.68 (broad s, 1H), 7.65 (dd, J=2.1, 0.6 Hz, 1H), 7.55 (ddd, J=7.3, 2.1, 0.6 Hz, 1H), 3.41 (t, J=4.5 Hz, 4H), 2.88 (t, J=6.3 Hz, 2H), 2.56 (s, 3H), 2.19 (t,=6.6 Hz, 2H), 2.16 to 2.12 (m, 4H); MS LC-MS [M+H]+=363 & 365, RT=1.90 min.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:17])[NH2:16])=[O:8])(=O)C.C[O-].[Na+]>CO>[SH:4][CH2:5][CH:6]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:16])[NH2:17])=[O:8]
Reactant: COC(=O)CC(CSC(C)=O)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC(CS)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O

Procedure:
To a solution of Nα -[3-(acetylthio)-2-(methoxycarbonylmethyl)propanoyl]-L-arginine (1.9 g.) in methanol (10 ml.), sodium methoxide (0.56 g.) is added. After ten minutes, the solution is applied to a column of Dowex 50 resin and the column is washed with water until no more acidic material is eluted. Nα -[3-mercapto-2-(methoxycarbonylmethyl)propanoyl]-L-arginine is then eluted with a pyridine-acetate buffer of pH 6.5.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([CH3:14])[CH2:8][N:7]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1[O:33][CH3:34]>Cl.C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(C)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CC(C)O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(C)(F)C(=O)N2C
Temperature: 100 °C
Reaction time: 20 h
Yield: 31.9 %

Procedure:
A mixture of 2-chloro-9-cyclohexyl-7-fluoro-5,7-dimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (330 mg, 1 mmol), 4-amino-3-methoxybenzoic acid (184 mg, 1.1 mmol), isopropanol (10 ml), and concentrated hydrochloric acid (10 drops) was stirred at 100° C. for 20 h. Solid was filtered to give 146 mg product as white solid (32%). [M+H] calc'd for C23H28FN5O4, 458. found 458.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[Li]CCCC.[CH2:23]([O:25][C:26]([C:28]1[N:29]([CH2:39][CH:40]=[CH2:41])[CH:30]=[C:31]([C:33](=[O:38])[C:34]([F:37])([F:36])[F:35])[CH:32]=1)=[O:27])[CH3:24]>C1COCC1>[CH2:23]([O:25][C:26]([C:28]1[N:29]([CH2:39][CH:40]=[CH2:41])[CH:30]=[C:31]([C:33]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:6]=[CH:5]3)([OH:38])[C:34]([F:36])([F:35])[F:37])[CH:32]=1)=[O:27])[CH3:24]
Reactant: C=CCn1cc(C(=O)C(F)(F)F)cc1C(=O)OCC
Reactant: Fc1ccc(-n2ncc3cc(Br)ccc32)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cc1C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a chilled (−78° C.) solution of 5-bromo-1-(4-fluorophenyl)-1H-indazole (2.0 g, 6.8 mmol, 1.2 equiv.) in 20 mL of THF was added n-BuLi (2.5 mL, 6.2 mmol, 1.1 equiv.) followed by a chilled (−78° C.) solution of 1-allyl-4-(2,2,2-trifluoroacetyl)-1H-pyrrole-2-carboxylic acid ethyl ester (1.6 g, 5.7 mmol, 1.0 equiv.) in 3 mL of THF in one portion. After 30 minutes, the mixture was quenched with water, warmed to room temperature, diluted with brine, and extracted with EtOAc. The combined organics were dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (5-30% EtOAc-hexanes) to provide 890 mg (32%) of the title compound as a pale orange solid. MS m/z 488.30 (MH+).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][N:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:10]([NH2:12])=[O:11])=O)(C)(C)C.[OH-].[K+]>Cl>[NH2:8][C@@H:9]([CH2:13][N:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[N:16]=[CH:17][CH:18]=[CH:19][N:20]=1)[C:10]([NH2:12])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CN(c1ccccc1)c1ncccn1)C(N)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: NC(=O)[C@@H](N)CN(c1ccccc1)c1ncccn1
Temperature: 5 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-(phenyl-pyrimidin-2-ylamino)-propanoic acid amide (48.5 g, 136 mmol, >99.9% ee) is introduced at 40° C. in portions into hydrochloric acid (16% strength, 80 ml), and the resulting solution is stirred for 1 h at this temperature. After cooling to 5° C., the pH is adjUsted to 10 by adding concentrated potassium hydroxide solution. The precipitated solid is filtered off with suction and dried to give (S)-2-amino-3-(phenyl-pyrimidin-2-ylamino)-propanoic acid amide (35.3 g, 80% yield, 79% content, 99.8% ee) as a colorless solid, which can be further reacted or else crystallized again from aqueoUs solution, as desired.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[C:4]=1[CH2:13][C:14]#[N:15].[CH2:18](N)[CH2:19][NH2:20]>>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:10])([F:11])[F:12])[C:4]=1[CH2:13][C:14]1[NH:20][CH2:19][CH2:18][N:15]=1
Reactant: NCCN
Reactant: N#CCc1c(C(F)(F)F)cccc1C(F)(F)F
Product: FC(F)(F)c1cccc(C(F)(F)F)c1CC1=NCCN1

Procedure:
2-(2,6-Bis-trifluoromethyl-benzyl)-4,5-dihydro-1H-imidazole was prepared from (2,6-bis-trifluoromethyl-phenyl)-acetonitrile and ethylene diamine in analogy to Example 19 b): colourless crystals; MS (EI): 296.2 (M+.), 275.1 ((M-F)+.), 267.1 ((M-C2H5)+.), 227.1 (((M-imidazoline)+.), 100%).
Reaction SMILES: [C:1]([O:4][C@@H:5]([CH2:18][O:19]CC1C=CC=CC=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15])(=[O:3])[CH3:2].[H][H]>C1COCC1.[Pd]>[C:1]([O:4][C@@H:5]([CH2:18][OH:19])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([O:14][CH3:15])[O:16][CH3:17])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: COC(CCCCCOC[C@H](COCc1ccccc1)OC(C)=O)OC
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(CCCCCOC[C@H](CO)OC(C)=O)OC
Yield: 99.9 %

Procedure:
2-O-Acetyl-3-O-benzyl-1-O-(6',6'-dimethoxyhexyl)-sn-glycerol (369 mg, 1.0 mmol) was hydrogenated in THF (10 ml) over Palladium/carbon (14 mg, 10%) until the uptake of hydrogen ceased (approx. 2.5 hr.). The solution was filtered through celite, and the filtrate was evaporated to yield a colourless oil (278 mg, 100%) which was used immediately. 1H N.M.R.δ: 5.04,q,l,J 5.0 Hz,H2; 4.40,t,l,J 5.7 Hz, --CH(OMe)2 ; 3.84, d,2,J 5.0 Hz, H3; 3.65, d,2J 5.2 Hz, OCH2 --; 3.56-3.44 m 2 H1; 3.35 s 6 OCH3 ; 2.5,s(b),1,OH; 2.14,s,3, COCH3 ; 1.7-1.3,m,8, --CH2 --.
Reaction SMILES: [C:1]1(C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:15][CH:14]2[CH:11]([CH2:12][NH:13]2)[CH2:10]1)=[O:8].C1(C2C=CC=CC=2)C([C:28](O)=[O:29])=CC=CC=1>>[CH:11]12[CH2:12][NH:13][CH:14]1[CH2:15][N:9]([C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[O:29][CH3:28])=[O:8])[CH2:10]2
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNC2C1
Product: COc1ccccc1C(=O)N1CC2CNC2C1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 19, substituting 2-methoxybenzoic acid for biphenyl-2-carboxylic acid. MS (ESI) mass calcd. for C13H16N2O2, 232.28; m/z found, 233.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:43][C@@H:44]([CH2:49][OH:50])[CH2:45][CH:46]([CH3:48])[CH3:47]>CC(N(C)C)=O>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:43][C@@H:44]([CH2:49][OH:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:9]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: CC(C)C[C@@H](N)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)C[C@H](CO)NC(=O)c1cnc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.6 %

Procedure:
5-Bromo-6-chloro-nicotinic acid (2.0 g, 8.46 mmol) was dissolved in DMA (20 mL). To the solution was added TBTU (3.1 g, 9.3 mmol), N,N-diisopropylethyl amine (7.4 mL, 42 mmol) and (D)-leucinol (1.1 g, 9.3 mmol). The reaction mixture was stirred for 16 h at room temperature. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica (cyclohexane/ethyl acetate gradient) to yield 2.6 g of the title compound as a yellow oil, MS (ISP) 337.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]([C@H:12]([OH:17])[C@H:13]([CH3:16])[CH:14]=[CH2:15])=[C:10]2[C:5]([C:6]([CH2:19][CH2:20][CH3:21])=[CH:7][C:8](=[O:18])[O:9]2)=[C:4]([O:22][CH:23]([CH3:25])[CH3:24])[CH:3]=1.N1C=CN=C1.[C:31]([Si:35](Cl)([CH3:37])[CH3:36])([CH3:34])([CH3:33])[CH3:32].O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[OH:1][C:2]1[C:11]([C@H:12]([O:17][Si:35]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:37])[CH3:36])[C@H:13]([CH3:16])[CH:14]=[CH2:15])=[C:10]2[C:5]([C:6]([CH2:19][CH2:20][CH3:21])=[CH:7][C:8](=[O:18])[O:9]2)=[C:4]([O:22][CH:23]([CH3:24])[CH3:25])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=C[C@@H](C)[C@@H](O)c1c(O)cc(OC(C)C)c2c(CCC)cc(=O)oc12
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: C=C[C@@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)c1c(O)cc(OC(C)C)c2c(CCC)cc(=O)oc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.9 %

Procedure:
To a solution of 4a (500 mg, 1.44 mmol) in dry CH2Cl2 (20 mL) at 0° C. was added DMAP (88 mg, 0.72 mmol), imidazole (196 mg, 2.88 mmol) and tert-butylchlorodimethylsilane (239 mg, 1.59 mmol). The reaction mixture was allowed to warm up to room temperature and stirred for 24 h. Water (10 mL) was then added, the organic layer was separated, dried (MgSO4), concentrated and submitted to silica gel chromatography (Solvent B) to obtain 5a (583 mg, 88%) as a syrup: [α]D20 +38.0° (c 1.1, CHCl3); 1H NMR (CDCl3): δ -0.04 (s, 3 H, --SiCH3), 0.14 (s, 3 H, --SiCH3), 0.87 [s, 9 H, --C(CH3)3 ], 0.97 (d, 3 H, J=6.88 Hz, --CHCH3), 1.00 (t, 3 H, J=7.44 Hz, --CH2CH2CH3), 1.38 and 1.40 (2d, 6 H, J=6.0 Hz, --CH(CH3)2), 1.62 (m, 2 H, --CH2CH2CH3), 2.59 (q, 1 H, J=6.9 Hz, --CHCH3), 2.86 (bt, 2 H, --CH2CH2 CH3), 4.62 [m, 1 H, J=6.06 Hz, --CH(CH3)2 ], 4.95-5.05 (m, 2 H, --CH=CH2), 5.29 [d, 1 H, J=6.5 Hz, --CHOSi(CH3)2 --], 5.85 (m, 1 H, --CH=CH2), 5.89 (s, 1 H, H-3), 6.24 (s, 1 H, H-6), 9.15 (s, 1 H, ArOH); 13C NMR (CDCl3): δ -0.33, -0.15, 13.91, 16.27, 18.06, 21.76, 21.85, 23.08, 25.68, 25.88, 38.96, 44.62, 70.67, 74.28, 97.54, 103.39, 106.57, 109.86, 115.71, 139.60, 152.98, 156.13, 158.95, 160.17, 160.75. Anal. Calcd for C26H40 O5Si: C, 67.78; H, 8.75. Found C, 67.91; H, 8.71.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18]C)=[O:17])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][NH:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc(NNC(=O)OC(C)(C)C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NNc1cccc(C(=O)O)c1
Temperature: 0 °C

Procedure:
The 4.68 g of unpurified 1-tert-butoxycarbonyl-2-(3-methoxycarbonylphenyl)hydrazine was dissolved in 75 ml of 1,4-dioxane, and 25 ml of aqueous 3N potassium hydroxide solution was added to the solution, followed by heating the mixture at reflux for one hour. The reaction mixture was cooled to 0° C., and about 25 ml of 3N hydrochloric acid was added to make the reaction mixture acidic. The mixture was subjected to salting out and the resultant was extracted with ethyl acetate (2×50 ml). The organic layers were combined, dried and concentrated to obtain 4.40 g of unpurified captioned compound.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:13]([OH:15])=O)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:3])[CH3:2].Cl.Cl.[CH2:18]([O:20][C:21](=[O:31])[C@H:22]([CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:30])[NH2:29])[NH2:23])[CH3:19].C(N(CC)CC)C.ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH3:19][CH2:18][O:20][C:21]([C@@H:22]([NH:23][C:13]([C@@H:5]([NH:4][C:1]([CH3:2])=[O:3])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:15])[CH2:24][CH2:25][CH2:26][N:27]=[C:28]([NH2:30])[NH2:29])=[O:31]
Reactant: CCOC(=O)[C@@H](N)CCCNC(=N)N
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](Cc1ccccc1)NC(C)=O
Temperature: -15 °C
Reaction time: 5 h

Procedure:
0.829 g (4 mmols) of N-acetyl-L-phenylalanine are dissolved in 40 ml of dimethylformamide. 1.10 g (4 mmols) of finely powdered L-arginine ethyl ester dihydrochloride, 0.56 ml (4 mmols) of triethylamine and 0.69 g (6 mmols) of N-hydroxysuccinimide are added and the mixture is cooled to -15° C. After adding 0.91 g (4.4 mmols) of dicyclohexylcarbodiimide, the mixture is stirred at -5° C. for 7 hours, at 5° C. overnight and at room temperature for 5 hours. The precipitate is filtered off and the solution is concentrated almost to dryness in vacuo on a rotary evaporator. After taking up the residue in 80 ml of water, the pH of the solution is adjusted to 6.0 with triethylamine and the solution is discharged onto a column (1.5×40 cm) of Cm- "Sephadex" (Trade Mark) C-25, equilibrated with 0.05 M triethylammonium acetate of pH 6.0. Elution is carried out with a linear gradient increasing to 0.2 M triethylammonium acetate of pH 6.0 (720 ml; 50 ml/hour; size of fraction: 8 ml). Fractions 75-110, which, according to spotting on filter paper and spraying with Sakaguchi reagent, contains most of the eluted material, is lyophilised. 0.5 ml of ethanol is added to the combined residues and the product is precipitated with 60 ml of ethyl acetate. The precipitate is dried over phosphorus pentoxide in a desiccator.
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[CH:7][N:6](S(C3C=CC=CC=3)(=O)=O)[C:5]=2[C:18]([O:20]C)=[O:19])[CH2:3][CH2:2]1.[OH-].[Li+]>O1CCCC1.O>[CH:1]1([C:4]2[CH:8]=[CH:7][NH:6][C:5]=2[C:18]([OH:20])=[O:19])[CH2:2][CH2:3]1
Reactant: COC(=O)c1c(C2CC2)ccn1S(=O)(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1[nH]ccc1C1CC1
Temperature: 100 °C
Yield: 81.6 %

Procedure:
To a suspension of the starting methyl 3-cyclopropyl-1-(phenylsulfonyl)-1H-pyrrole-2-carboxylate (0.9 g, 3 mmol) in tetrahydrofurane (4.6 mL) and water (2.3 mL) was added lithium hydroxide (0.29 g, 12 mmol) and this mixture was heated to 100° C. in a microwave vial during 4 hours. Next, the reaction mixture was poured into water (50 mL) and this aqueous phase was washed with diethyl ether (2×). Afterwards, the aqueous layer was acidified until pH=3 by adding solid phosphoric acid and extracted with ethyl acetate (3×). The organic solution was washed with water and brine, dried (Na2SO4) and concentrated in vacuum to give 370 mg of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[Br:23][C:24]1[CH:25]=[CH:26][C:27]([OH:35])=[C:28]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:29]=1.CN(C)C=O.[H-].[Na+]>O>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([O:35][CH2:2][C:3]2[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[CH:5][CH:4]=2)=[C:28]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:29]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: COC(=O)Cc1cc(Br)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cc(Br)ccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.7 %

Procedure:
To a mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (4.58 g), methyl 2-(5-bromo-2-hydroxyphenyl)acetate (3.0 g) and N,N-dimethylformamide (100 mL) was added sodium hydride (60%, oil, 0.54 g) under ice-cooling, and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentration of the organic layer, the residue was subjected to silica gel column chromatography to give crystals (4.46 g, 70%) of methyl 2-[5-bromo-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate from a fraction eluted with ethyl acetate-hexane (1:6, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 100-101° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([S:21][CH3:22])[NH:9][C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26].[H-].[Ca+2].[H-]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([S:21][CH3:22])[N:9]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(SC)[nH]c(=O)c1OCc1ccccc1
Reactant: COC(=O)CBr
Agent: [Ca+2]
Agent: [H-]
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(SC)n(CC(=O)OC)c(=O)c1OCc1ccccc1
Yield: 44.9 %

Procedure:
A solution of intermediate 1, 5-benzyloxy-2-methylsulfanyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester, (2.00 g, 6.24 mmol) in dry tetrahydrofuran (100 ml) was treated with methyl bromoacetate (1.05 g, 6.86 mmol) followed by powdered calcium hydride (0.59 g, 14.0 mmol) and the resulting mixture was heated under reflux for 18 h. The reaction mixture was then cooled, quenched by the addition of a few drops of acetic acid and concentrated in vacuo. The residue was then diluted with ethyl acetate, washed successively with saturated sodium bicarbonate and brine then dried over anhydrous magnesium sulfate. Evaporation of the solvent followed by chromatography on silica gel (elution toluene/ethyl acetate 95:5) gave 1.10 g (45% yield) of the title ester as a clear oil. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.31 (3H, t, J=7.2 Hz, CH3), 2.60 (3H, s, SCH3), 3.80 (3H, s, OCH3), 4.33 (2H, q, J=7.2 Hz, OCH2), 4.84 (2H, s, NCH2), 5.21 (2H, s, OCH2), 7.3–7.5 (5H, m, aromatics). HRMS (FAB POS) calculated for C18H21N2O6S [M+H+]: 393.112033. found: 393.112070.