Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:25])=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:32][CH3:33].[CH2:34]([NH:36][CH2:37][CH3:38])[CH3:35].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:34]([N:36]([CH2:37][CH3:38])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:25])=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:32][CH3:33])[CH3:35]
Reactant: CCNCC
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCCOc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccccc3)c2cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
(2-{[7-(3-Chloropropoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (68 mg), diethylamine (30 mg), and potassium carbonate (95 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (26 mg, yield 38%).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[N:8][N:9]2[CH2:13][CH2:12][NH:11][C:10]=12)([O-:5])=[O:4].S(O[CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)(C1C=CC(C)=CC=1)(=O)=O.O>C1COCC1>[N+:3]([C:6]1[CH:7]=[N:8][N:9]2[CH2:13][CH2:12][N:11]([CH2:25][CH2:26][CH:27]3[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[CH2:31][CH2:32]3)[C:10]=12)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1cnn2c1NCC2
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCN2CCn3ncc([N+](=O)[O-])c32)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 16.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 39 mg, 0.97 mmol) was added portionwise to a stirred solution of 7-nitro-2,3-dihydro-1H-pyrazolo[1,5-a]imidazole (0.125 g, 0.81 mmol) in anhydrous THF (10 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred for 10 min. before a solution of tert-butyl 4-(2-(tosyloxy)ethyl)piperidine-1-carboxylate (0.31 g, 0.81 mmol) in THF (5 mL) was added portionwise over 10 min. The reaction was stirred for 6 hr at room temperature followed by 18 hr at 50° C. Further sodium hydride (60% dispersion in mineral oil, 39 mg, 0.97 mmol) was added and stirring continued at 60° C. for a further 24 h. The reaction was cooled and water was added dropwise. The mixture was extracted with EtOAc and the combined organics were dried over MgSO4 and concentrated under reduced pressure. The crude residue was purified via silica gel chromatography (0-100% EtOAc/isohexane) to give tert-butyl 4-(2-(7-nitro-2,3-dihydro-1H-pyrazolo[1,5-a]imidazol-1-yl)ethyl)piperidine-1-carboxylate as a yellow oil (50 mg, 17%). 1H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 4.24-4.16 (m, 2H), 4.25-3.97 (m, 2H), 3.83-3.77 (s, 2H), 3.27 (s, 2H), 3.22 (t, J=6.8 Hz, 2H), 2.72-2.62 (s, 2H), 1.73-1.65 (m, 3H), 1.46-1.44 (m, 9H) 1.40-1.05 (m, 2H)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([C:6]([OH:8])=[O:7])[NH2:5].[O:9]1CC[CH2:11][CH2:10]1.C(OC(=O)C)(=O)C>O>[C:10]([NH:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3][O:2][CH3:1])(=[O:9])[CH3:11]
Reactant: COCC(N)C(=O)O
Reactant: C1CCOC1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COCC(NC(C)=O)C(=O)O
Reaction time: 16 h
Yield: 80 %

Procedure:
In a vessel, equipped with a mechanical stirrer, add at 20° C., 1.0 eq. of O-methyl-D,L-serine. Add 6 volumes of tetrahydrofuran and 0.65 volume of water. Add dropwise in 5 minutes 1.2 eq. of acetic anhydride. Stir mechanically the white suspension until complete conversion (HPLC monitoring, typical reaction time: 16 hours). At the end of the reaction the mixture becomes homogenous. Remove tetrahydrofuran as well as water azeotropically. Add toluene in order to remove completely water and acetic acid (KF and GC control). Crystallize the obtained crude solid in 6 volumes of acetone. Dry the wet solid at 40° C. under vacuum overnight. N-acetyl-O-methyl-D,L-serine (IX) is obtained as a white solid in 80% yield with a chemical purity of greater than 99% measured by HPLC.
Reaction SMILES: N1SC=C2C=C(N)C=CC=12.[C:11]1([C:17]2[N:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][N:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[S:26]([C:30]1[CH:35]=[CH:34][C:33]([NH-:36])=[CH:32][CH:31]=1)(=[O:29])(=[O:28])[NH2:27]>>[S:26]([C:30]1[CH:31]=[CH:32][C:33]([NH:36][C:23]([C:20]2[CH:21]=[N:22][C:17]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:18][CH:19]=2)=[O:25])=[CH:34][CH:35]=1)(=[O:28])(=[O:29])[NH2:27]
Reactant: O=C(O)c1cnc(-c2ccccc2)nc1
Reactant: [NH-]c1ccc(S(N)(=O)=O)cc1
Agent: Nc1ccc2nscc2c1
Product: NS(=O)(=O)c1ccc(NC(=O)c2cnc(-c3ccccc3)nc2)cc1

Procedure:
Following procedures similar to those of Example 8 but substituting 4-amino-benzenesulfonamide (0.3 mmol) for 2,2-dioxo-2,3-dihydro-1H-2lamda*6*-benzo[c]isothiazol-5-ylamine, there is prepared 2-phenyl-pyrimidine-5-carboxylic acid (4-sulfamoyl-phenyl-amide as a solid. MS: 355 (M+H). IC50=5 nM.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[C:13]([O:17][C:18](=[O:37])[NH:19][C@H:20]([CH2:35]O)[CH2:21][C:22]([CH3:34])([CH3:33])[CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:16])([CH3:15])[CH3:14].[C:38]1(=[O:48])[NH:42][C:41](=[O:43])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:13]([O:17][C:18](=[O:37])[NH:19][C@H:20]([CH2:35][N:42]1[C:38](=[O:48])[C:39]2[C:40](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:41]1=[O:43])[CH2:21][C:22]([CH3:34])([CH3:33])[CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(CCOCc1ccccc1)C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(CCOCc1ccccc1)C[C@@H](CN1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
DEAD (4.49 ml, 28 mmol) is added to a stirred suspension of ((S)-5-benzyloxy-1-hydroxymethyl-3,-3-dimethyl-pentyl)-carbamic acid tert-butyl ester (prepared as described in EP 0702004 A2, Rueger et al., 10 g, 0.028 mmol), phthalimide (4.19 g, 0.028 mmol) and PS-triphenylphosphine (29.8 g, 56 mmol) in THF (500 ml), and the resulting reaction is stirred at room temperature for 3 days. The reaction is filtered to remove the PS-triphenylphosphine resin and the resin is washed with EtOAc (2×50 ml). The solvent is removed in vacuo and the residue is purified by flash chromatography (SiO2, EtOAc/iso-hexane) to afford [(S)-5-benzyloxy-1-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3,3-dimethyl-pentyl]-carbamic acid tert-butyl ester as a white solid; [M+H]+ 481.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:5]([O:7][CH3:8])=[O:6].[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][C:11]1[C:2]([NH:1][S:38]([C:35]2[CH:36]=[CH:37][C:32]([CH3:31])=[CH:33][CH:34]=2)(=[O:40])=[O:39])=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][C:10]=1[O:21][CH2:22][CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cc(N)c(Oc2ccccc2OC)c(OCCOC2CCCCO2)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc(C)cc2)c(Oc2ccccc2OC)c(OCCOC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.04 g of methyl 3-amino-4-(2-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate were dissolved in pyridine (30 ml), treated dropwise while cooling with ice with a solution of 0.953 g of 4-methyl-benzenesulphonyl chloride in toluene (10 ml) and subsequently stirred at RT for 20 hours. The reaction mixture was poured on to ice/3M HCl, the product was extracted with ethyl acetate and the organic phase was dried over magnesium sulphate. After removing the solvent there was obtained methyl 4-(2-methoxy-phenoxy)-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-5-(toluene-4-sulphonylamino)-benzoate as a yellow solid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:14][C:13]2[C:12]([F:15])=[C:11]([NH:16][C@@H:17]3[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]3[NH:23]C(=O)OC(C)(C)C)[N:10]=[C:9]([C:31]3[S:32][C:33]([CH3:36])=[CH:34][CH:35]=3)[C:8]=2[C:7]1=[O:37].[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]>>[NH2:23][C@@H:18]1[C@H:17]([NH:16][C:11]2[N:10]=[C:9]([C:31]3[S:32][C:33]([CH3:36])=[CH:34][CH:35]=3)[C:8]3[C:7](=[O:37])[NH:6][CH2:14][C:13]=3[C:12]=2[F:15])[CH2:22][CH2:21][O:20][CH2:19]1.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCOC[C@@H]4NC(=O)OC(C)(C)C)nc(-c4ccc(C)s4)c3C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2nc(N[C@@H]3CCOC[C@@H]3N)c(F)c3c2C(=O)NC3)s1

Procedure:
A solution of tert-butyl (3R,4R)-4-(2-(2,4-dimethoxybenzyl)-7-fluoro-4-(5-methylthiophen-2-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (31 mg, 0.051 mmol) in TFA (10 mL) was heated to 80° C. for 1 h. After the solvent was removed, the residue was dissolved in MeOH and DCM (8 mL) and was purified via preparative HPLC eluting with water (0.05% TFA) and ACN (15-30% gradient, 0.035% TFA). The collected fractions were combined and the solvent was stripped to dryness via rotary evaporation to give the title compound as a TFA salt (13.5 mg, 74%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.78 (d, J=13.18 Hz, 1H), 2.03-2.18 (m, 1H), 2.46 (s, 3H), 3.17 (d, J=4.88 Hz, 1H), 3.55-3.65 (m, 1H), 3.75 (d, J=13.18 Hz, 1H), 3.85 (br s, 1H), 3.96-4.06 (m, 2H), 4.41 (d, J=7.81 Hz, 2H), 6.84 (d, J=2.44 Hz, 1H), 7.22 (d, J=4.88 Hz, 1H), 7.92 (br s, 2H), 8.47 (s, 1H), 8.83 (d, J=3.42 Hz, 1H). [M+H] calc'd for C17H19FN4O2S, 363. found, 363.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH:18]=C)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.C[N+]1([O-])CC[O:26]CC1.S(=O)(O)[O-].[Na+]>C1COCC1.O.CC(O)(C)C>[CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH:18]=[O:26])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1
Reactant: C=CCN(CC(C)(C)C)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CC(C)(C)CN(CC=O)c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 81.3 %

Procedure:
To a solution of 4-[(2,2-dimethylpropyl)(2-propen-1-yl)amino]-2-(trifluoromethyl)benzonitrile (1.46 g, 4.95 mmol) in THF/water (20:1, 45 mL) at rt was added a solution of OSO4 (1.02 g of a 2.5 wt % solution in t-BuOH, 0.10 mmol) in THF/water (20:1, 5 mL), followed by NMO (1.22 g, 10.4 mmol) in one portion. The resulting mixture was stirred 22 hours at rt, cooled to 0° C. and sodium bisulfite (0.300 g) was added in one portion. The mixture was stirred 1 h, filtered through a pad of Celite (EtOAc wash) and the filtrate/washings were partitioned between EtOAc/water (required addition of NaCl to separated layers). The aqueous layer was extracted with EtOAc (×1), combined organics were washed with brine and concentrated in vacuo. The residue was dissolved in acetone (50 mL), a solution of NalO4 (2.22 g; 10.4 mmol) in water (20 mL) was added, the mixture was stirred two hours at rt and partially concentrated in vacuo to an aqueous residue. The residue was partitioned between EtOAc/water and the aqueous layer was further extracted with EtOAc (×1). Combined organics were washed (water, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 1.20 g of the title compound as a colorless solid: 1H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 7.57 (d, J=8.8 Hz, 1H), 6.96 (d, J=2.5 Hz, 1H), 6.74 (dd, J=8.9, 2.7 Hz, 1H), 4.31 (s, 2H), 3,33 (s, 2H), 1.02 (s, 9H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[CH3:30])[C:21]3=[O:31])[CH2:16][C:17](O)=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:45][OH:46]>C1COCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([N:20]3[C:28](=[O:29])[C:27]4=[C:26]([CH3:30])[CH:25]=[CH:24][CH:23]=[C:22]4[C:21]3=[O:31])[CH2:16][C:17]([NH:45][OH:46])=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C(CC(=O)O)N2C(=O)c3cccc(C)c3C2=O)cc1OC1CCCC1
Reactant: NO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(C(CC(=O)NO)N2C(=O)c3cccc(C)c3C2=O)cc1OC1CCCC1
Yield: 94.2 %

Procedure:
3-(3-Cyclopentyloxy-4-methoxyphenyl)-N-hydroxy-3-(3-methylphthalimido)propionamide was prepared by the procedure of Example 1 from 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(4-methyl-1,3-dioxoisoindolin-2-yl)propanoic acid (5.44 g, 12.9 mmol), carbonyldiimidazole (2.19 g, 13.5 mmol) and hydroxylamine hydrochloride (1.16 g, 16.7 mmol) in THF (32 mL) to afford 3-(3-cyclopentyloxy-4-methoxyphenyl)-N-hydroxy-3-(3-methylphthalimido)propionamide as a white solid (5.33 g, 94.6%): mp, 187.5–189.5° C.; 1H NMR (DMSO-d6) δ 1.55–1.87 (m, 8H, C5H8), 2.61 (s, 3H, CH3), 3.12 (d, J=7.8 Hz, 2H, CH2), 3.70 (s, 3H, OCH3), 4.62–4.83 (m, 1H, OCH), 5.66 (t, J=7.8 Hz, 1H, CH), 6.90–7.10 (m, 3H, Ar), 7.52–7.80 (m, 3H, Ar), 8.79 (s, 1H, OH), 10.59 (s, 1H, NH); 13C NMR (DMSO-d6) δ 16.9, 23.5, 32.1, 34.2, 49.9, 55.5, 79.6, 112.1, 114.2, 119.7, 120.7, 127.8, 131.3, 131.6, 137.2, 146.7, 149.1, 166.0, 167.5, 168.3; Anal. Calcd. for C24H26N2O6: C, 65.74; H, 5.98; N, 6.39. Found: C, 65.63; H, 5.86; N, 6.24.
Reaction SMILES: [OH:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].N1C=CC=CC=1.[C:20](Cl)(=[O:28])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[O:21]([C:20]([O:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4])=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1)OC(=O)Oc1ccccc1
Yield: 114.1 %

Procedure:
To methyl 2(S)-hydroxy-3-phenylpropionate (5.0 g) and pyridine (8.78 g) in methylene chloride (50 ml) was dropwise added phenyl chlorocarbonate (4.78 g) under cooling at 0°-10° C. over 30 minutes. After the dropwise addition, the mixture was stirred at said temperature for 60 minutes, washed with 10% hydrochloric acid and water, dried over magnesium sulfate, and concentrated to dryness under reduced pressure. As a result, 9.51 g of methyl 2(S)-phenoxycarbonyloxy-3-phenylpropionate was obtained as a pale yellow, oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].N1C=CC=CC=1.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][N:20]=1>C1COCC1>[Cl:18][C:19]1[N:20]=[CH:21][C:22]([C:23]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[OH:11])=[O:24])=[CH:26][CH:27]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Nc1ccc(C(=O)O)cc1O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(O)c1ccc(NC(=O)c2ccc(Cl)nc2)c(O)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 85.4 %

Procedure:
To a stirred solution of 4-Amino-3-hydroxy benzoic acid (0.490 g, 0.0032 mols) and pyridine (0.76 g, 0.0096 mols) in 50 ml dry THF is added 6-chloronicotinoyl chloride (0.56 g, 0.0032 mols) and the solution is stirred under nitrogen atmosphere at RT for 10 hrs and then refluxed for 3 hrs. The reaction mixture is rotary evaporated and the residue is slurried in water and filtered to get the amide (0.8 g) which is taken for the next step without further purification.
Reaction SMILES: [ClH:1].[CH2:2]([O:6][CH:7]([O:38][CH2:39][CH2:40][CH2:41][CH3:42])[C@H:8]([CH2:31][CH2:32][CH2:33][NH:34][C:35](=[NH:37])[NH2:36])[NH:9][C:10](=[O:30])[C@H:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:12]C(OCC1C=CC=CC=1)=O)[CH2:3][CH2:4][CH3:5].[H][H]>CO.[Pd]>[ClH:1].[CH2:2]([O:6][CH:7]([O:38][CH2:39][CH2:40][CH2:41][CH3:42])[C@H:8]([CH2:31][CH2:32][CH2:33][NH:34][C:35](=[NH:36])[NH2:37])[NH:9][C:10](=[O:30])[C@H:11]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[NH2:12])[CH2:3][CH2:4][CH3:5]
Reactant: [H][H]
Reactant: CCCCOC(OCCCC)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCCOC(OCCCC)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)Cc1ccccc1
Yield: 96.1 %

Procedure:
After N-benzyloxycarbonyl-L-phenylalanyl-L-argininal dibutylacetal hydrochloride (1.24 g, 2.05 mmols) was dissolved in methanol (100 ml), palladium black (1 g) was added to the solution. The mixture was stirred at room temperature for 2 hours in a hydrogen flow. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated to give 0.93 g (96%) of L-phenylalanyl-L-argininal dibutylacetal hydrochloride as oil.
Reaction SMILES: [N+](C1C=CC(C([O:12][CH2:13][C@@H:14]2[CH2:20][C@@H:19]3[C@@H:17]([CH2:18]3)[CH2:16][N:15]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=O)=CC=1)([O-])=O.O1CCCC1.CO.O.[OH-].[Li+]>[Cl-].[Na+].O.O>[OH:12][CH2:13][C@@H:14]1[CH2:20][C@@H:19]2[C@@H:17]([CH2:18]2)[CH2:16][N:15]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2C[C@H]1COC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2C[C@H]1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a mixture of tert-butyl (1R*,4S*,6R*)-4-({[(4-nitrophenyl)carbonyl]oxy}methyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (8.2 g) produced above, tetrahydrofuran (70 mL), methanol (70 mL) and water (35 mL) was added lithium hydroxide monohydrate (2.7 g). The mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with brine, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (3.5 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]#[C:10][C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)=[N:4][C:5](Br)=[CH:6][N:7]=1.CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH:35]3[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]3)(=[O:34])=[O:33])=[CH:28][CH:27]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CC#N.CCOC(C)=O.Cl.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH:35]3[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH2:40]3)(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[N:4][C:3]=1[C:9]#[C:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1
Reactant: Nc1ncc(Br)nc1C#Cc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(-c3cnc(N)c(C#Cc4cccc(O)c4)n3)cc2)CC1
Temperature: 60 °C

Procedure:
3-[2-(3-Amino-6-bromo-pyrazin-2-yl)ethynyl]phenol (100 mg, 0.3447 mmol), tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonylpiperidine-1-carboxylate (186.7 mg, 0.4136 mmol) and K3PO4 (146.3 mg, 0.6894 mmol) were combined in MeCN (2 mL)/water (0.5 mL) and Pd[P(tBu)3]2 (8.811 mg, 0.01724 mmol) was added. The reaction was heated at 60° C. for 15 hours. The reaction was cooled to ambient temperature and diluted with EtOAc and 1M HCl. The layers were separated and the aqueous layer extracted with EtOAc (×3). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The material was used directly in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[C:13]([C:14]2[O:18][N:17]=[C:16]([CH2:19]O)[CH:15]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:24])=O.N1C2C=CC=CC=2N=N1.[OH-].[Na+].C(OC)(C)(C)C>CN(C)C(=O)C>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[C:13]([C:14]2[O:18][N:17]=[C:16]([CH2:19][Cl:24])[CH:15]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ncccc1-c1cc(CO)no1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc2[nH]nnc2c1
Solvent: COC(C)(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)Nc1ncccc1-c1cc(CCl)no1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, tert-butyl{3-[3-(hydroxymethyl)isoxazol-5-yl]pyridin-2-yl}carbamate (781 mg, 2.68 mmol) was dissolved in N,N-dimethylacetamide (2.7 mL). To the solution was added the above solution of thionyl chloride-benzotriazole (1:1.1) in N,N-dimethylacetamide (6 mL, 14.4 mmol) dropwise under an ice water cooling, which was stirred at the same temperature for one hour and then stirred at room temperature. After one hour and 20 minutes, under the ice water cooling, a solution of thionyl chloride-benzotriazole (1:1.1) in N,N-dimethylacetamide (2.2 mL, 5.12 mmol) was added dropwise thereto, and the solution was stirred at room temperature for one hour. Under the ice water cooling, to the reaction solution were added 1N aqueous sodium hydroxide and tert-butylmethylether to adjust basic and then extracted. The organic layer was washed sequentially with 0.5N aqueous sodium hydroxide and 5% sodium chloride water, dried over anhydrous magnesium sulfate and then the solvent was evaporated under a reduced pressure to obtain a crude body of the title compound (953 mg) as a pale yellow oily product.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([N:16]=[N+:17]=[N-:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCl>[CH2:9]([N:16]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:18]=[N:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#Cc1ccccc1
Solvent: ClCCl
Product: c1ccc(Cn2cc(-c3ccccc3)nn2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 95 %

Procedure:
Phenylacetylene (103 mg, 1.0 mmol, 1.0 eq.) and benzyl azide (133 mg, 1.0 mmol, 1.0 eq.) were dissolved in an air-tight lockable vial with a septum in 10 mL dry dichloromethane. The Cu complex (catalytic or stoichiometric amounts) was added, the vial sealed and the reaction stirred at room temperature for 2 days. For the removal of the catalyst complex the reaction mixture was put in 50 mL methanol and stirred for 20 min. The complex was removed by filtering and the filtrate was concentrated. Removal of the solvent and drying of the product in high vacuum resulted in the compound 1-benzyl-4-phenyl-1H-1,2,3-triazole as light yellow solid with 95% yield (245 mg, 0.95 mmol). The identity of the product was proven by NMR-spectroscopy, infrared spectroscopy and high-resolution mass spectroscopy.