Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[H-].[Na+].[C:14](=O)([O:18]CC)[O:15][CH2:16][CH3:17].Cl>O>[O:10]=[C:9]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][CH:11]1[C:14]([O:15][CH2:16][CH3:17])=[O:18]
Reactant: CCOC(=O)OCC
Reactant: O=C1CCCc2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C1CCc2ccccc2C1=O
Yield: 57.6 %

Procedure:
A suspension of 10 g (0.0684 mole) of α-tetralone, 3.56 g (0.0890 mole) of 60% sodium hydride and 32 g (0.2709 mole) of diethyl carbonate was heated under reflux for 1 hour, then poured into water, adjusted with conc. hydrochloric acid to a pH of 1 to 2, and extracted with ether. The ether layer was washed with water and then dried over magnesium sulfate. After evaporation of the solvent, the crude product was purified by silica gel column chromatography (hexane/ethyl acetate =9/1) to obtain 8.6 g of ethyl 1,2,3,4-tetrahydro-l-oxo-2-naphthalenecarboxylate, which was dissolved in tetrahydrofuran (220 ml) and then 1.90 g (0.0475 mole) of 60% sodium hydroxide was added under ice-cooling. After stirring for 30 minutes, 10.0 g (0.0599 mole) of ethyl bromoacetate was added, followed by stirring for 3 hours at room temperature. The reaction mixture was poured into ice-water, extracted with ether, and then the extract was subjected to washing with water, drying and solvent evaporation in a conventional manner. The crude product obtained was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to obtain 9.03 g of the following ethyl 2-ethoxycarbonyl-1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetate ##STR13##
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc([N+](=O)[O-])cn2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(N)cn2)CC1
Reaction time: 1 h

Procedure:
To a solution of 4-(5-nitro-pyrimidin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (927 mg, 3 mmol, prepared from 2-chloro-5-nitropyrimidine and N-Boc-piperazine) in tetrahydrofuran (20 mL) and methanol (30 mL) was added 10% palladium on carbon (240 mg) and the mixture was hydrogenated at 50 psi for 1 hr. The mixture was filtered and the solvents were evaporated. The residue was dried in vacuum to give 4-(5-amino-pyrimidin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [N+:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2)#[C-:2].[Si:13]([O:20][NH2:21])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].S(O)(C1C=CC(C)=CC=1)(=O)=O.O>C(Cl)(Cl)Cl>[Si:13]([O:20][N:21]=[C:8]1[C:9]2[C:5](=[CH:4][C:3]([N+:1]#[C-:2])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: [C-]#[N+]c1ccc2c(c1)CCC2=O
Reactant: CC(C)(C)[Si](C)(C)ON
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: [C-]#[N+]c1ccc2c(c1)CCC2=NO[Si](C)(C)C(C)(C)C
Yield: 74.9 %

Procedure:
5-isocyano-2,3-dihydroinden-1-one (6) (3.00 g, 19.1 mmol) was combined with 1.4 eq. of O-(tert-butyldimethylsilyl)hydroxylamine (3.94 g, 26.7 mmol) and TsOH-H2O (0.363 g, 1.91 mmol) in 100 mL CHCl3 and heated to reflux overnight. TLC showed a small amount of remaining starting material and two non-polar spots corresponding to the oxime isomers. The reaction mixture was filtered and concentrated to a brown semi-solid, then purified immediately by loading onto a silica column with DCM and eluting with 1% MeOH/DCM to give 4.1 g (75%) of 5-isocyano-2,3-dihydroinden-1-one O-tert-butyldimethylsilyl oxime (7).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:15])=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=2)[N:7]=1.[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(#N)C>[Br:16][CH2:15][C:8]1[N:6]2[N:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=[N:10][C:9]=1[C:11]([F:14])([F:13])[F:12]
Reactant: Cc1c(C(F)(F)F)nc2ccc(Cl)nn12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC#N
Product: FC(F)(F)c1nc2ccc(Cl)nn2c1CBr
Temperature: 25 °C
Yield: 35 %

Procedure:
A mixture of 6-chloro-3-methyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazine x35 (3.45 g, 1 eq, 14.64 mmol), N-bromosuccinimide (NBS; 2.87 g, 1.1 eq, 16.11 mmol) and azo-bis-iso-butyronitrile (AIBN; 240 mg, 0.1 eq, 1.5 mmol) in acetonitrile (50 ml) is refluxed for 2 hours. After cooling to room temperature, the solvent is removed under reduced pressure and the crude product is purified by preparative chromatography on silicagel (CH2Cl2) affording 3-(bromomethyl)-6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazine x36.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:8]=1[O:9][C:10]1[N:15]=[CH:14][CH:13]=[CH:12][N:11]=1>O.CCO.[Fe]>[CH3:5][O:6][C:7]1[CH:19]=[C:18]([CH:17]=[CH:16][C:8]=1[O:9][C:10]1[N:11]=[CH:12][CH:13]=[CH:14][N:15]=1)[NH2:20]
Reactant: COc1cc([N+](=O)[O-])ccc1Oc1ncccn1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(N)ccc1Oc1ncccn1
Yield: 100 %

Procedure:
According to Scheme 3 Step 2: A suspension of iron (4.45 mmol, 248 mg), acetic acid (1.07 mmol, 61 μL) and of 2-(2-methoxy-4-nitrophenoxy)pyrimidine (0.89 mmol, 220 mg) in water/EtOH (1:1, 7 mL) was stirred at 80° C. for 30 minutes. After evaporation of EtOH, the aqueous phase was basified with a saturated solution of NaHCO3 and was extracted with AcOEt. The organic phase was washed with brine, was dried over MgSO4, was filtered and was concentrated under reduced pressure to yield 3-methoxy-4-(pyrimidin-2-yloxy)aniline (0.89 mmol, 193 mg, 100%) as an oil. The product was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1.C1(O)C=CC=CC=1>C(Cl)Cl>[Si:10]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([NH2:1])=[CH:3][CH:4]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: Nc1ccc(CO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: Oc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
A mixture of 4-aminobenzyl alcohol (30.0 g, 81.2 mmol), tert-butyldimethylsilyl chloride (12.24 g, 81.2 mmol), imidazole (11.05 g, 162.4 mmol) and anhydrous CH2Cl2 (200 mL) was stirred at room temperature overnight. TLC analysis showed the appearance of a new spot and the disappearance of starting phenol. The solvent was removed in vacuo and then the remaining oily product was loaded onto a silica gel column and purified by chromatography, eluting with 3:1 hexane-ethyl acetate to afford 15.41 g (80%) of the title compound as a pale orange oil: 1H NMR (DMSO-d6) δ6.95 (d, J=8.4, 2H), 6.53 (d, J=8.4, 2H), 4.96 (s, 2H), 4.50 (s, 2H), 0.88 (s, 9H), 0.04 (s, 6H); 13C NMR (DMSO-d6) δ147.65, 128.04, 127.58, 113.57, 64.69, 25.82, 17.97, -5.18; MS (EI, m/z) 237 (M+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:14][C:15](=[O:34])[NH:16][C@@H:17]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH:35]1[C:47]2[CH:46]([CH2:48][O:49][C:50]([NH:52][C@@H:53]([CH2:57][CH2:58][CH2:59][CH2:60][NH:61][C:62](=[O:100])[CH2:63][N:64]3[CH2:75][CH2:74][N:73]([CH2:76][C:77](=[O:83])[O:78][C:79]([CH3:82])([CH3:81])[CH3:80])[CH2:72][CH2:71][N:70]([CH2:84][C:85](=[O:91])[O:86][C:87]([CH3:90])([CH3:89])[CH3:88])[CH2:69][CH2:68][N:67]([CH2:92][C:93]([O:95][C:96]([CH3:99])([CH3:98])[CH3:97])=[O:94])[CH2:66][CH2:65]3)[C:54](O)=[O:55])=[O:51])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]=2[CH:38]=[CH:37][CH:36]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:35]1[C:47]2[CH:46]([CH2:48][O:49][C:50](=[O:51])[NH:52][C@@H:53]([CH2:57][CH2:58][CH2:59][CH2:60][NH:61][C:62](=[O:100])[CH2:63][N:64]3[CH2:65][CH2:66][N:67]([CH2:92][C:93](=[O:94])[O:95][C:96]([CH3:97])([CH3:98])[CH3:99])[CH2:68][CH2:69][N:70]([CH2:84][C:85](=[O:91])[O:86][C:87]([CH3:88])([CH3:89])[CH3:90])[CH2:71][CH2:72][N:73]([CH2:76][C:77]([O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[O:83])[CH2:74][CH2:75]3)[C:54](=[O:55])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[NH:14][C:15](=[O:34])[NH:16][C@H:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]=2[CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)CN1CCN(CC(=O)NCCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCN)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)[C@H](CCCCNC(=O)CN1CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 136 %

Procedure:
A solution of (S)-di-tert-butyl 2-(3-((S)-6-amino-1-(tert-butoxy)-1-oxohexan-2-yl)ureido)pentanedioate (0.048 g, 0.10 mmol), (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-6-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)hexanoic acid (56 mg, 0.0607 mmol), EDCI (19 mg, 0.10 mmol), HOBt (13.5 mg, 0.10 mmol) and DIPEA (0.10 mL) in DCM (5.0 mL) was stirred at room temperature for 2 hrs. The solvent was evaporated to give a residue, which was purified by Biotage eluting with DCM to 10% MeOH in DCM to give (5S,12S,16S)-tri-tert-butyl 1-(9H-fluoren-9-yl)-3,6,14-trioxo-5-(4-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)butyl)-2-oxa-4,7,13,15-tetraazaoctadecane-12,16,18-tricarboxylate (115 mg) containing some impurity. MS (ESI), 697.0 (M+H)+.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[Cl:19].CN([CH:23]=[O:24])C>C1COCC1>[Br:13][C:14]1[CH:18]=[C:17]([CH:23]=[O:24])[S:16][C:15]=1[Cl:19]
Reactant: CN(C)C=O
Reactant: Clc1sccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1cc(Br)c(Cl)s1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
n-BuLi (2.5 M in hexanes, 105 mL) is slowly added to a solution of diisopropylamine (36.8 mL) in THF (600 mL) at 0° C. After 15 min, the mixture is cooled to −70° C. A solution of 3-bromo-2-chlorothiophene (49.4 g) in THF (20 mL) is added maintaining the internal temperature <−65° C. After 15 min, DMF (25.2 mL) is added. The mixture is stirred at −70° C. for 15 min and then allowed to warm to room temperature. The reaction mixture is quenched with saturated aq. NH4Cl solution (200 mL) and concentrated in vacuo to one-half volume. The residue is diluted with EtOAc (500 mL) and the aqueous layer is separated. The aqueous layer is extracted with EtOAc (2×100 mL). The combined organic layers are washed with brine (100 mL), dried (MgSO4), and concentrated to afford an oil. The oil is purified by column chromatography (heptane; heptane/EtOAc, 20/1; 10/1) and the resulting solid is suspended in heptane (75 mL) and filtered to afford 30.3 g (54%) of the title compound as a light yellow solid. Physical characteristics: M.p. 61-62° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.82, 8.14; 13C NMR (100 MHz, CDCl3) δ 181.6, 140.9, 138.5, 138.1, 112.8.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.BrC1C=CC(C(=[O:20])C)=CC=1.[OH-].[Cs+]>>[OH:20][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: CC(=O)c1ccc(I)cc1
Agent: [Cs+]
Agent: [OH-]
Product: CC(=O)c1ccc(O)cc1

Procedure:
Following general operating mode A, 4′-iodoacetophenone or 4′-bromo acetophenone (246 mg or 199 mg, 1.0 mmol) were reacted with cesium hydroxide at respectively 110 or 130° C. to afford the expected product in the form of a white solid at respective yields of 90% and 84% (eluant: ethyl acetate/heptane 20:80).
Reaction SMILES: [F:1][C:2]([F:16])([C:5]([F:15])([F:14])[C:6]([F:13])([F:12])[C:7]([F:11])([F:10])[CH2:8][OH:9])[CH2:3][OH:4].F[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[OH:9][CH2:8][C:7]([F:10])([F:11])[C:6]([F:13])([F:12])[C:5]([F:14])([F:15])[C:2]([F:16])([F:1])[CH2:3][O:4][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)CO
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=Cc1ccc(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)CO)cc1
Temperature: 97.5 °C

Procedure:
A mixture of 2,2,3,3,4,4,5,5-octafluoro-1,6-hexanediol (7.86 g), 4-fluorobenzaldehyde (1.24 g), NMP (10 mL), and potassium carbonate (4.14 g) was heated to 95-100° C. for 48 hrs. The mixture was further processed as described in Example 1 to provide 4-(6-hydroxy-2,2,3,3,4,4,5,5-octafluorohexyloxy)benzaldehyde.
Reaction SMILES: [N:1]1([C:6]([N:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[CH:16][C:17]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:18][C:11]=3[CH2:10][CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:23]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([NH:29][C:30]([NH:22][S:19]([C:17]2[CH:16]=[CH:15][C:12]3[CH2:13][CH2:14][N:8]([C:6]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:7])[CH2:9][CH2:10][C:11]=3[CH:18]=2)(=[O:21])=[O:20])=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN(C(=O)N1CCCC1)CC2
Reactant: O=C=NC1CCCCC1
Product: O=C(NC1CCCCC1)NS(=O)(=O)c1ccc2c(c1)CCN(C(=O)N1CCCC1)CC2

Procedure:
By the reaction of 2,3,4,5-tetrahydro-3-(1-pyrrolidinylcarbonyl)-1H-3-benzazepine-7-sulfonamide with cyclohexylisocyanate in a manner analogous to that described in Example 1, there is obtained 1-cyclohexyl-3-{[2,3,4,5-tetrahydro-3-(1-pyrrolidinylcarbonyl)-1H-3-benzazepin-7-yl]sulfonyl}urea, m.p. 139°-141° C. The starting material can be prepared by the reaction of 2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide hydrochloride with 1-pyrrolidinecarbonyl chloride in a manner analogous to that described in Example 1.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[O:11][CH2:12][CH2:13][CH2:14][CH:15]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[N:25]=[C:24]([NH2:26])[NH:23][N:22]=1.[BH4-].[Na+]>C(O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:26][C:24]2[NH:23][N:22]=[C:21]([NH2:20])[N:25]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CCCCOc1cccc(CN2CCCCC2)c1
Reactant: Nc1n[nH]c(N)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Nc1n[nH]c(NCCCCOc2cccc(CN3CCCCC3)c2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.3 %

Procedure:
A solution of 4-[3-(1-piperidinylmethyl)phenoxy]butanal (522 mg) and 3,5-diamino-1,2,4-triazole (200 mg) in absolute ethanol (20 ml) was heated under reflux for 2 h. The cooled solution was treated with sodium borohydride (200 mg) and stirred at room temperature for 18 hr. The mixture was evaporated in vacuo and the residue partitioned between ethyl acetate and water. The combined organic extracts were evaporated in vacuo and the residue was chromatographed on silica with methanol as eluant to give the title compound as an oil (250 mg), TLC silica (ethyl acetate:isopropanol:water:ammonia 25:15:8:2) 0.4, NMR (CDCl3) 2.8 t (1H); 3.0-3.3 m (3H); 5.3 m (2H); 6.2 m (2H); 6.6-6.8 m (4H); 7.7 m (4H); 8.0-8.8 m (10H).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:20]([NH:22][C@H:23]([C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:26]=1)=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[NH:56]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[C@H:57]([C:65]([OH:67])=O)[CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1.C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:56]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[C@H:57]([C:65]([NH:1][C@@H:2]([C:20]([NH:22][C@H:23]([C:39]([O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:26]=1)=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:10])=[O:11])=[O:67])[CH2:58][C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)OCc2ccccc2)cc1

Procedure:
Using 3.7 g Boc-D-Arg(Tos)-Tyr(Bzl)-OBzl, 1.40 g Boc-Phe-OH, 1.05 g HONB and 1.20 g DCC, the desired product was obtained in exactly the same manner as in Example 1-(II).
Reaction SMILES: [C:1]([C:7]1[C:8]([C:12]2[CH2:13][N:14](C)[CH2:15][CH2:16][CH:17]=2)=[N:9][NH:10][CH:11]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:19]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:20][CH2:21][C:22]#[CH:23].[C:30]1([S:36]([N:39]2[CH:43]=[C:42](I)[C:41]([C:45]3[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=3)=[N:40]2)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(OCC)C>CCOCC.C(OCC)(=O)C>[C:1]([C:7]1[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:9][NH:10][CH:11]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:20][CH2:19][CH3:24].[C:30]1([S:36]([N:39]2[CH:43]=[C:42]([C:23]#[C:22][CH2:21][CH2:20][CH2:19][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:41]([C:45]3[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=3)=[N:40]2)(=[O:37])=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C#CCCCc1ccccc1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c(-c2cccnc2)n1
Reactant: CCCCC#Cc1c[nH]nc1C1=CCCN(C)C1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCCCCC#Cc1c[nH]nc1-c1cccnc1
Product: O=S(=O)(c1ccccc1)n1cc(C#CCCCc2ccccc2)c(-c2cccnc2)n1
Yield: 80 %

Procedure:
Compound 44C was prepared following the procedure as described for the synthesis of compound 44A (see Scheme 9) using pent-4-ynyl-benzene and 3-(1-phenylsulfonyl-4-iodo-1H-pyrazol-3-yl)-pyridine (36B). (flash chromatography with diethyl ether/PE (1/1)) to afford 3-[1-phenylsulfonyl-4-(5-phenyl-pent-1-ynyl)-1H-pyrazol-3-yl]-pyridine (43D) as an oil (80%). 1H-NMR (400 MHz, CDCl3): δ 9.3 (d, J=2 Hz, 1H), 8.6 (dd, J=5 Hz, 2 Hz, 1H), 8.33 (dt, J=8 Hz, 2 Hz, 1H), 8.22 (s, 1H), 8.09-8.05 (m, 2H), 7.68 (bt, J=8 Hz, 1H), 7.57 (bt, J=8 Hz, 2H), 7.35-7.25 (m, 3H), 7.21-7.15 (m, 3H), 2.74 ((t, J=7 Hz, 2H), 2.42 ((t, J=7 Hz, 2H), 1.96-1.87 (m, 2H). (TLC diethyl ether Rf 0.56).
Reaction SMILES: B(Br)(Br)Br.[CH3:5][N:6]([CH:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:35])[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[N:31][CH:30]=[N:29]3)=[C:24]([O:33]C)[CH:23]=2)[CH2:17][CH2:16]1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CO.[OH-].[Na+].[Cl:40]CCl>C(Cl)(Cl)Cl>[ClH:40].[CH3:5][N:6]([CH:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:35])[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[N:31][CH:30]=[N:29]3)=[C:24]([OH:33])[CH:23]=2)[CH2:17][CH2:16]1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClCCl
Reactant: COc1cc(C(=O)N2CCC(N(C)CCc3ccccc3)CC2)ccc1-n1cncn1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN(CCc1ccccc1)C1CCN(C(=O)c2ccc(-n3cncn3)c(O)c2)CC1
Product: Cl
Temperature: -30 °C
Reaction time: 8 h

Procedure:
24 ml of a 1N solution of boron tribromide in dichloromethane was dropwise added, at -40° C., to a solution of 1.0 g of 4-[N-methyl-N-(2-phenylethyl)amino]-1-[3-methoxy-4-(1,2,4-triazol-1-yl)benzoyl]piperidine in 20 ml of chloroform. The mixture was stirred overnight at that temperature and then returned to room temperature. The mixture was cooled to -30° C. and 10 ml of methanol was dropwise added thereto. The mixture was poured into ice water. The resulting mixture was made basic with a 25% aqueous sodium hydroxide solution and stirred for a while. The organic layer was separated, water-washed, and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (eluant: methylene chloride/methanol=50/1 to 9/1) and then converted into a hydrochloride to obtain 0.42 g of 4-[N-methyl-N-(2-phenylethyl)amino]-1-[3-hydroxy-4-(1,2,4-triazol-1-yl)benzoyl]piperidine hydrochloride as a white amorphous.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[CH:17][C:18]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([NH:25][NH2:26])=[O:24])=[CH:21][CH:20]=3)=[C:12]2[N:11]=1)([CH3:3])[CH3:2].[N:29]#[C:30]Br.C([O-])(O)=O.[Na+]>O1CCOCC1.O.CCOC(C)=O>[NH2:29][C:30]1[O:24][C:23]([C:22]2[CH:27]=[CH:28][C:19]([C:18]3[CH:17]=[N:16][N:13]4[CH:14]=[CH:15][C:10]([N:5]5[C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][O:7][C:6]5=[O:9])=[N:11][C:12]=34)=[CH:20][CH:21]=2)=[N:25][N:26]=1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(C(=O)NN)cc3)c2n1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4nnc(N)o4)cc3)c2n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 49 %

Procedure:
To a suspension of (S)-4-(5-(4-isopropyl-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)benzohydrazide (50 mg, 0.131 mmol) in 3 mL of p-dioxane was added cyanogen bromide (30.6 mg, 0.289 mmol) followed by a solution of NaHCO3 (13.3 mg, 0.158 mmol) in 1.5 mL of water. The resulting mixture became a clear tan solution within 3 minutes, and was allowed to stir at ambient temperature for 17 hours. The reaction was diluted with EtOAc, and the organic layer was washed with water and brine. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude was purified by silica gel flash column chromatography (0-8% MeOH in dichloromethane) to afford 26 mg (49%) of (S)-3-(3-(4-(5-amino-1,3,4-oxadiazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyloxazolidin-2-one. 1H NMR (400 MHz, DMSO-d6) δ 9.11 (d, 1H), 8.79 (s, 1H), 8.26 (d, 2H), 7.91 (d, 1H), 7.82 (d, 2H), 7.23 (s, 2H), 4.97 (m, 1H), 4.52 (d, 2H), 2.76 (m, 1H), 1.06 (d, 3H), 0.86 (d, 3H); LCMS (APCI+) m/z 406.4 [M+H]+.