Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([S:39][CH2:40][C:41]5[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][N:42]=5)=[CH:35][CH:34]=4)=[O:31])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:34]=[CH:35][C:36]([S:39]([CH2:40][C:41]5[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][N:42]=5)=[O:58])=[CH:37][CH:38]=4)=[O:31])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nncn4CCC)cc2)CCCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nncn4CCC)cc2)CCCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To a solution of 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]thio]phenyl]-1,2,3,4-tetrahydro-1-benzazocine-5-carboxamide (0.70 g) in dichloromethane (20 ml) was added dropwise a solution of 3-chloro-perbenzoic acid (70%, 0.38 g) in dichloromethane (10 ml) and the mixture was stirred at −78° C. for 1 hour. To the reaction system was added an aqueous sodium thiosulfate solution, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate solution and saturated brine, and was dried with magnesium sulfate. The resultant was concentrated under reduced pressure, the residue was separated and purified with column chromatography (basic silica gel, ethyl acetate ethanol:ethyl acetate 1:19), followed by recrystallization (ethyl acetate-diisopropyl ether) to give 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzazocin-5-carboxamide (490.1 mg) as yellow crystals (Compound 47).
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[S:27])[NH2:26].Br[CH2:29][C:30](OC)=[O:31].CN(C)C=O>O>[O:31]=[C:30]1[CH2:29][S:27][C:25]([N:3]2[CH:2]([CH3:1])[CH2:8][C:7]3[CH:9]=[C:10]4[O:15][CH2:14][O:13][C:11]4=[CH:12][C:6]=3[C:5]([C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[N:4]2)=[N:26]1
Reactant: COC(=O)CBr
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(N)=S)OCO3
Solvent: O
Solvent: CN(C)C=O
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C1=NC(=O)CS1)OCO3
Temperature: 85 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
A mixture of 1.00 g (2.6 mmol) of the starting material I, 1.19 g (7.78 mmol) of methyl bromoacetate and 10 ml of dimethylformamide was stirred at 80-90° C. for 1 h. After diluting with water the obtained crude product was purified by refluxing in methanol to yield 1.00 g (91%) of the title compound; Mp.: 218-220° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[C:15]([CH:20]=C)[CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[O:30]1CCOCC1.I([O-])(=O)(=O)=O.[Na+]>O=[Os](=O)(=O)=O.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=[O:30])[C:14]=3[CH:13]=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C1COCCO1
Reactant: C=Cc1cccc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: Cc1cccc(C)n1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)cccc32)cc1
Reaction time: 0.33 h
Yield: 99 %

Procedure:
The experimental for Intermediate 5 Batch 1 was followed using OsO4 (27 mg, 0.11 mmol), 1-[(4-methylphenyl)sulfonyl]-4-vinyl-1H-indole (0.321 g, 1.08 mmol; Intermediate 4), 2,6-lutidine (0.251 mL, 0.23 mmol), dioxane (12 mL), sodium periodate (0.924 g, 4.32 mmol) and water (4 mL). The mixture was stirred for 20 min. and partitioned between 2M aqueous HCl (25 mL) and DCM (25 mL). The organic layer was dried, filtered, combined with Intermediate 5 Batch 1, and concentrated to give a total yield of 390 mg, 99% of a black solid. MS (ESI+) for C16H13NO3S m/z 300 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C1(C)C=CC(S(O[CH2:17][C@H:18]2[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]2)(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O>[CH3:23][C:20]1([CH3:24])[O:19][C@@H:18]([CH2:17][N:4]2[CH:3]=[C:2]([I:1])[CH:6]=[N:5]2)[CH2:22][O:21]1
Reactant: Ic1cn[nH]c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@H](Cn2cc(I)cn2)O1
Temperature: 100 °C
Yield: 95.9 %

Procedure:
A mixture of 4-iodopyrazole (1.40 g, 7.21 mmol), (R)-(−)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl p-toluenesulfonate (2.27 g, 7.93 mmol), Cs2CO3 (3.52 g, 10.8 mmol) and DMF (10 mL, 100 mmol) was heated to 100° C. for 16 hrs. The reaction mixture was diluted with EtOAc, washed with water (2×), dried with sodium sulfate, filtered and concentrated in vacuo to a solid which was purified using a Teledyne ISCO Combiflash® Rf system [0→20% EtOAc/Heptane] to afford 2.13 g of the title compound (96%). 1H NMR (400 MHz, CDCl3) d 7.55 (s, 1H), 7.52 (s, 1H), 4.43 (dd, J=4.8, 6.1 Hz, 1H), 4.24-4.28 (m, 2H), 4.08 (dd, J=6.3, 8.8 Hz, 1H), 3.76 (dd, J=6.1, 8.6 Hz, 1H), 1.39 (s, 3H), 1.34-1.37 (m, 3H). MS (ESI): m/z 309.01 [M+H]+. UPLC: tR=1.26 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([Br:21])[CH:15]=1.[C:22](=[O:24])=[O:23]>C1COCC1.CCOCC>[Br:13][C:14]1[CH:15]=[C:16]([Br:21])[CH:17]=[C:18]([F:20])[C:19]=1[C:22]([OH:24])=[O:23]
Reactant: O=C=O
Reactant: Fc1cc(Br)cc(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1c(F)cc(Br)cc1Br
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of n-BuLi (20 mL, 50.0 mmol) was added dropwise to a solution of diisopropylamine (5.6 g, 55.0 mmol) in 200 mL of THF at −70° C. The mixture was stirred at 0° C. for 15 minutes and then recooled to −70° C. A solution of 1,3-dibromo-5-fluorobenzene (12.7 g, 50.0 mmol, in 50 mL of THF) was added dropwise. The resulting mixture was stirred at −70° C. for 2 hours then poured into fresh dry ice and stirred overnight. The mixture was diluted with 1 L of ether and washed with water twice. The combined water layer was washed with ether then acidified to pH=2 with hydrochloric acid and extracted with EtOAc twice. The combined EtOAc layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to give 2,4-dibromo-6-fluorobenzoic acid as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[C:27]([CH2:29][O:30][C:31]2[C:35](/[CH:36]=[CH:37]/[C:38]3[N:39]=[C:40]([N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)[S:41][C:42]=3[CH3:43])=[CH:34][N:33]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[N:32]=2)[CH:26]=[CH:25][C:4]=1[O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH3:1][O:2][C:3]1[CH:28]=[C:27]([CH2:29][O:30][C:31]2[C:35](/[CH:36]=[CH:37]/[C:38]3[N:39]=[C:40]([N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)[S:41][C:42]=3[CH3:43])=[CH:34][N:33]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[N:32]=2)[CH:26]=[CH:25][C:4]=1[O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4nc(N5CCOCC5)sc4C)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/c2nc(N3CCOCC3)sc2C)ccc1OCc1nc(-c2ccc(CC(=O)O)cc2)oc1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
To a mixture of ethyl (4-{4-[(2-methoxy-4-{[(4-{(E)-2-[5-methyl-2-(morpholin-4-yl)-1,3-thiazol-4-yl]ethenyl}-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}phenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (0.43 g), tetrahydrofuran (12 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (1.5 mL), and the mixture was stirred at 50° C. for 2 hrs. To the reaction mixture were added 1N hydrochloric acid (1.5 mL) and water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give [4-(4-{[2-methoxy-4-({[4-{(E)-2-[5-methyl-2-(morpholin-4-yl)-1,3-thiazol-4-yl]ethenyl}-1-phenyl-1H-pyrazol-3-yl]oxy}methyl)phenoxy]methyl)-5-methyl-1,3-oxazol-2-yl}phenyl]acetic acid as crystals (0.22 g, yield 53%). Recrystallization from tetrahydrofuran-hexane gave orange prism crystals. melting point: 171-173° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18](/[C:21](/[CH3:25])=[CH:22]/[CH:23]=O)=[CH:17][CH:16]=1.[S:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]([CH3:25])[CH2:22][CH2:23][CH:30]2[S:26][C:27](=[O:32])[NH:28][C:29]2=[O:31])=[CH:19][CH:20]=1
Reactant: C/C(=C\C=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Reactant: O=C1CSC(=O)N1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(C(C)CCC2SC(=O)NC2=O)cc1
Yield: 6 %

Procedure:
According to the same manner as that described in Example 13, (E)-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)-phenyl]-2-butenal was condensed with 2,4-thiazolidinedione, and then the resulting compound was subjected to catalytic hydrogenation to give 5-[3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]butyl]-2,4-thiazolidinedione (yield: 6%). This product was recrystallized from isopropyl ether. Pale yellow prisms, mp: 64-65° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].[N:18]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl.O>[NH:2]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][CH2:7][NH:8][C:9](=[O:14])[C:10]([F:11])([F:12])[F:13])[NH2:18]
Reactant: O=N[O-]
Reactant: Nc1cccc(CCNC(=O)C(F)(F)F)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cccc(CCNC(=O)C(F)(F)F)c1
Temperature: 2.5 °C
Reaction time: 0.75 h
Yield: 72.8 %

Procedure:
N-(3-aminophenethyl)-2,2,2-trifluoroacetamide hydrochloride (0.27 g, 1.0 mmol) was suspended in 6M HCl (2.0 mL) and cooled thoroughly in an ice bath. This was rapidly stirred while a solution of NaNO2 (73 mg) in H2O (1.0 mL) was added slowly. The mixture was stirred at 0-5° C. for 45 min and was then treated with SnCl2.2H2O (1.3 g, 5.8 mmol) in 6N HCl (4.0 mL). The resulting suspension was stirred at 0-5° C. for 3 h and then carefully quenched with 3N NaOH (15 mL) to pH 7-8. The mixture was diluted with Et2O, filtered through Celite® and the filter cake was washed with H2O and Et2O. The layers of the biphasic filtrate were separated and the aqueous extracted with Et2O (2×). The combined organics extracts were washed with brine (1×), dried (Na2SO4), filtered and evaporated to provided N-(3-hydrazinophenethyl)-2,2,2-trifluoroacetamide as a pale yellow oil (0.18 g, 72% yield), which was used without further purification. MS (ESI) m/z: 248.0 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[C:24]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)=[CH:23][C:22]([C:40](=[NH:43])[NH:41][OH:42])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:44][CH3:45])=[O:5])[CH3:2].C(N(CC)CC)C.Cl[C:54](Cl)([O:56]C(=O)OC(Cl)(Cl)Cl)Cl.O>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[C:24]([CH2:25][C:26]3[CH:27]=[C:28]([C:36]([F:39])([F:37])[F:38])[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=3)=[CH:23][C:22]([C:40]3[NH:43][C:54](=[O:56])[O:42][N:41]=3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:44][CH3:45])=[O:5])[CH3:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(C(=N)NO)cc2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@H]1CC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(-c3noc(=O)[nH]3)cc2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.4 %

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(N-hydroxy-carbamimidoyl)pyridin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (193 mg) and triethylamine (126 μl) are dissolved in dichloromethane (3 ml), and thereto is added triphosgene (268 mg) at 0° C. The mixture is stirred at room temperature for 30 minutes. To the reaction solution are added water and dichloromethane, and the organic layer is washed with saturated brine. Then the organic layer is dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; chloroform:methanol=1:0→97:3) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)pyridin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (33 mg). MS (m/z): 667 [M+H]+.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[C:6]1([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[S:1]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)Cl
Reactant: OCCCCCc1ccccc1
Product: NS(=O)(=O)OCCCCCc1ccccc1

Procedure:
The title compound was prepared by procedures of Example 33 from sulfamoyl chloride and 5-phenyl-1-pentanol. The oil obtained was further purified by chromatography using a column with methylene chloride as eluting agent. Evaporation of appropriate fractions gave a viscous oil which solidified on standing. The solid was recrystallized from ethyl ether-petroleum ether (bp range 30°-60° C.) to give the title compound as white solid, mp 63°-66° C. in 60% yield.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1.[NH2:19][C:20]1[C:21]([CH3:26])=[CH:22][CH:23]=[CH:24][CH:25]=1>CO>[ClH:1].[CH3:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][C:2]1[N:3]=[C:4]([N:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: Cc1ccccc1N
Reactant: CN(c1ccccc1)c1nc(Cl)nc2sccc12
Solvent: CO
Product: Cc1ccccc1Nc1nc(N(C)c2ccccc2)c2ccsc2n1
Product: Cl

Procedure:
2-Chloro-4-(N-methylphenylamino)thieno[2,3-d]pyrimidine (1.5 g, 0.0054 mol) and o-toluidine (1.3 g, 0.012 mol) were heated at 160° in an oil bath for 2 hours. The addition of methanol gave a solid which was collected by filtration and dried. Recrystallization from ethanolic HCl gave the title compound as a partial hydrochloride salt, (1.13 g), m.p. 210°-212°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:22]([O:29][CH2:30][CH:31](OS(C1C=C(Cl)C=CC=1Cl)(=O)=O)[CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>CN(C)C=O.C(OCC)(=O)C.O>[CH2:22]([O:29][CH2:30][CH:31]([CH2:32][O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[O:19][C:16]1[CH:17]=[CH:18][C:13]([C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(O)cc1
Reactant: O=S(=O)(OC(COCc1ccccc1)COCc1ccccc1)c1cc(Cl)ccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OC(COCc2ccccc2)COCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61.5 %

Procedure:
To a stirred solution of (R)-tert-butoxycarbonylamino-(4-hydroxy-phenyl)-acetic acid (1.0 g, 3.74 mmol) in dry N,N-dimethylformamide (20 mL) at 0° C. under an atmosphere of nitrogen was added sodium hydride (60% suspension in mineral oil) (0.33 g, 8.23 mmol) and the mixture stirred at 0° C. for 15 minutes. 2,5-dichloro-benzenesulfonic acid 2-benzyloxy-1-benzyloxymethyl-ethyl ester (2.20 g, 4.57 mmol) was added to the reaction mixture to form a yellow solution which was stirred at ambient temperature for 5 minutes before warming to 100° C. for 10 minutes. The reaction mixture which by now contained a heavy precipitate was cooled to ambient temperature, diluted with ethyl acetate, cooled to 0° C. and treated with an equal volume of water. The stirred mixture was acidified to pH≈4 with 1 M aqueous hydrochloric acid. The organic layer was separated and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with water (three times), dried over sodium sulfate, filtered through a thin pad of silica gel and concentrated in vacuo to give (R)-[4-(2-benzyloxy-1-benzyloxymethyl-ethoxy)-phenyl]-tert-butoxycarbonylamino-acetic acid (1.20 g, 80%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:4][CH2:3]1.[Br:17]C[C:19]#[N:20].[CH3:21]N(C=O)C>>[Br-:17].[C:19]([CH2:1][N+:2]1([CH3:21])[CH2:3][CH2:4][N:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:6][CH2:7]1)#[N:20]
Reactant: CN(C)C=O
Reactant: N#CCBr
Reactant: CN1CCN(c2nc3ccccc3o2)CC1
Product: C[N+]1(CC#N)CCN(c2nc3ccccc3o2)CC1
Product: [Br-]
Reaction time: 1 h

Procedure:
A 150 mg portion of 2-(4-methyl-1-piperazinyl)-benzoxazole was dissolved in 3 ml of DMF. Under cooling with ice, 0.052 ml of bromoacetonitrile was added to the thus prepared solution, and the reaction was carried out for 1 hour at the same temperature and then for 24 hours at room temperature. The reaction solution was concentrated under a reduced pressure, and 5 ml of acetone was added to the resulting residue. The precipitate thus formed was collected by filtration, washed with acetone and then dried to obtain 228 mg of the title compound.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[C:20]1([C:26]23[CH2:35][CH:30]4[CH2:31][CH:32]([CH2:34][CH:28]([CH:29]4[CH2:36][C:37](O)=[O:38])[CH2:27]2)[CH2:33]3)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:20]1([C:26]23[CH2:27][CH:28]4[CH2:34][CH:32]([CH2:31][CH:30]([CH:29]4[CH2:36][C:37]([N:12]4[CH2:13][CH:14]5[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]5)[CH2:11]4)=[O:38])[CH2:35]2)[CH2:33]3)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Reactant: O=C(O)CC1C2CC3CC1CC(c1ccccc1)(C3)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)CC1C3CC4CC1CC(c1ccccc1)(C4)C3)C2
Reaction time: 0.5 h
Yield: 21 %

Procedure:
Triethylamine 14.0 gl was added to a methylene chloride 1 ml solution of (1S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 15.9 mg and stirred at O@C for 30 min. 5-phenyl-2-adamantyl acetic acid 22.6 mg and WSC 19.3 mg were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 64 hours. The reaction mixture was washed with saturated aqueous sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (1S)-3-(5-phenyl-2-adamantylacetyl)1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 3 ml solution of lithium aluminum hydride 3.8 mg and refluxed under heating for 1.5 hours. The reaction mixture was cooled, then water was added thereto and the insoluble material was removed by filtration. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform: acetone 20:1) to obtain the product. Yield: 7.0 mg (Yield 21%)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].Br[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1.Br>C(#N)C>[Br-:10].[C:15]([CH2:14][CH2:13][CH2:12][CH2:11][N:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N+:5]([CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)=[CH:4]1)([OH:17])=[O:16]
Reactant: Clc1nc[nH]c1Cl
Reactant: BrCc1ccc2ccccc2c1
Reactant: O=C(O)CCCCBr
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: O=C(O)CCCCn1c[n+](Cc2ccc3ccccc3c2)c(Cl)c1Cl
Product: [Br-]

Procedure:
4,5-dichloroimidazole (1.00 g, 7.36 mmol) was dissolved in acetonitrile. Potassium hydroxide (0.828 g, 14.72 mmol) was added to the solution and allowed to reflux for 30 min. 1 equivalent of 5-bromopentanoic acid (1.33 g, 7.36 mmol) was added to the solution and refluxed for 5 h. Solution was filtered to remove the KBr precipitate and placed back onto reflux. An equivalent of 2-(bromomethyl)naphthalene (1.63 g, 7.36 mmol) was added to solution and refluxed for 2.5 h. The solution was neutralized with 6M HBr, volatiles removed in vacuo, and the resulting white precipitate was collected and analyzed. 1H NMR (300 MHz, DMSO-d6): δ 1.61, 1.80, 2.25, 3.51, 5.76, 7.61, 8.05, 9.74, 12.07.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][CH:14]([CH3:51])[CH2:15][O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][CH:50]=[C:24]23)[CH2:19][CH2:18]1>C(OCC)(=O)C>[OH:13][CH:14]([CH3:51])[CH2:15][O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][CH:50]=[C:24]23)[CH2:19][CH2:18]1
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)O)CC2)c2ccnn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)O)CC2)c2ccnn12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.91 g), sodium hydrogen carbonate (1.38 g) and dimethyl sulfoxide (5 mL) was stirred at 50° C. for 30 min, 4′-({4-[trans-4-(2-hydroxypropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.57 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.21 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.20 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, then with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.48 g, 76%).