Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:3]=1.[CH3:27][S-:28].[Na+]>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:27][S:28][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cc(Cl)ncn3)CC2)CC1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CSc1cc(N2CCC(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The tert-butyl 1′-(6-chloropyrimidin-4-yl)-4,4′-bipiperidine-1-carboxylate (100 mg, 0.26 mmol) was dissolved in NMP (2.6 mL), and sodium methanethiolate (18.2 mg, 0.26 mmol) was added. The reaction was stirred at r.t. for 30 min. The reaction crude was diluted with ethyl acetate (10 mL) and was washed with water (10 mL, ×1) and brine (10 mL, ×1), dried over magnesium sulfate, filtered and concentrated by rotavapor. The crude mixture was purified by preparative TLC with 30% ethylacetate:hexane to yield the title compound.
Reaction SMILES: [N:1]([C:4]1[CH2:5][C@@H:6]2[CH2:20][C:19](=[O:21])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=[N+]=[N-].[C:22]([O:25][CH:26]=[CH2:27])(=[O:24])[CH3:23].C(=O)(O)[O-].[Na+]>ClCCl>[C:22]([O:25][CH:26]1[CH2:27][N:1]1[C:4]1[CH2:5][C@@H:6]2[CH2:20][C:19](=[O:21])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])(=[O:24])[CH3:23]
Reactant: C=COC(C)=O
Reactant: [N-]=[N+]=NC1=C(C(=O)OCc2ccccc2)N2C(=O)C[C@H]2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC1CN1C1=C(C(=O)OCc2ccccc2)N2C(=O)C[C@H]2C1
Reaction time: 72 h
Yield: 19 %

Procedure:
A solution of benzyl 2-azido-carbapen-2-em-3-carboxylate (5.3 mg, 19 micromol) and vinyl acetate (100 microliter) in dry dichloromethane (200 microliter) was treated with excess sodium bicarbonate and kept 3 days at ambient temperature. The mixture was filtered through florisil, the florisil was washed with ethyl acetate (25 ml), and the combined filtrate and wash was evaporated under vacuum. The residue was chromatographed on one 20 cm×20 cm 250 micron silica gel preparative thin layer chromatography plate developed with 9:1 (v/v) diethyl ether-ethyl acetate. Product was eluted with ethyl acetate and the eluate evaporated under vacuum to provide 1.2 mg (19%) benzyl 2-(2-acetoxyaziridin-1-yl)-carbapen-2-em-3-carboxylate; IR (CH2Cl2): 1770, 1735 cm-1 ; NMR (CDCl3): δ 1.92 bt (J=6.5 Hz, 1H), 2.08 t (J=7 Hz, 1H), 2.13 s (3H), 2.70 dd (J, 6 Hz, J2 =17 Hz, 1H), 2.76 dd (J1 =6 Hz, J2 =17 Hz, 1H), 2.86 dd (J1 =2 Hz, J2 =15 Hz, 1H), 3.24 dd (J1 =5 Hz, J2 =15 Hz, 1H), 4.16 m (1H), 4.79 bt (J=7 Hz, 1H), 5.17 s (2H), 7.37 m (5H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=c1cc(O)c2ccccc2[nH]1
Solvent: CC(=O)O
Product: O=c1[nH]c2ccccc2c(O)c1[N+](=O)[O-]
Temperature: 95 °C

Procedure:
A suspension of 4-hydroxycarbostyril (1.5g; 0.0093 mole) in glacial acetic acid (10 ml) was well stirred during the addition of concentrated nitric acid (2.5 ml, d, 1.42) and the mixture shaken at 95°C for a few minutes until dissolution was complete. The deep red solution soon deposited yellow crystals which after cooling were filtered off and washed with acetic acid and then ethanol. Drying in vacuo over phosphorous pentoxide afforded analytically pure 3-nitro compound m.p. 216°C (decomp) (Found C, 52.74; H, 3.14; N, 13.57; C9H6N2O4 required; C, 52.44; H, 2.93; N, 13.59%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)=[CH:4][C:5]([C:11]2([OH:38])[C@H:16]([O:17][Si](C)(C)C)[C@@H:15]([O:22][Si](C)(C)C)[C@H:14]([O:27][Si](C)(C)C)[C@@H:13]([CH2:32][O:33][Si](C)(C)C)[O:12]2)=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2.[CH3:48]S(O)(=O)=O>C1COCC1>[Br:1][C:2]1[C:3]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)=[CH:4][C:5]([C:11]2([O:38][CH3:48])[C@H:16]([OH:17])[C@@H:15]([OH:22])[C@H:14]([OH:27])[C@@H:13]([CH2:32][OH:33])[O:12]2)=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2
Reactant: COc1ccc(Cc2cc(C3(O)O[C@H](CO[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@H](O[Si](C)(C)C)[C@H]3O[Si](C)(C)C)c3c(c2Br)CCC3)cc1
Reactant: CS(=O)(=O)O
Solvent: C1CCOC1
Product: COc1ccc(Cc2cc(C3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3c(c2Br)CCC3)cc1
Temperature: -40 °C

Procedure:
To a solution of crude alcohol 14 (2.03 g) in anhydrous THF (11.9 mL) were added CH3SO3H (0.6 N in MeOH, 7.0 mL, 4.18 mmol) at −78° C. under nitrogen atmosphere. The mixture was slowly warmed up to −40° C. for 2 h. The reaction mixture was quenched with saturated NaHCO3 solution (15 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to provide the crude intermediate 15, which was used without further purification (0.94 g, 1.85 mmol, 80%). [M−OMe]+ 477.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[I-].[Na+].[CH3:11][O:12][C:13](=[O:26])[C:14]1[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[CH:17]=[C:16]([OH:23])[C:15]=1[CH:24]=[O:25].C(N(CC)CC)C>C(#N)C>[CH3:11][O:12][C:13](=[O:26])[C:14]1[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[CH:17]=[C:16]([O:23][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7])[C:15]=1[CH:24]=[O:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1c(C)c(OC)cc(O)c1C=O
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C)c1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
A mixture of 10.0 g of tert-butyl-dimethyl-chlorosilane and 10.0 g of sodium iodide in 50 ml of acetonitrile was stirred at room temperature for 1 h. The mixture was cooled to 0° C. and 14.0 g of 2-formyl-3-hydroxy-5-methoxy-6-methylbenzoic acid methyl ester were added at once followed by dropwise addition of 6.7 g of triethylamine over 15 min. The mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed successively with 2N potassium hydrogensulfate, saturated sodium bicarbonate and brine, dried over magnesium sulfate and evaporated in vacuo. The solid residue was recrystallized from ethyl acetate/hexane to-give 13.0 g of 3-(tert-butyl-dimethylsilanyloxy)-2-formyl-5-methoxy-6-methyl-benzoic acid methyl ester as white crystals, m.p; 125°-131° C.
Reaction SMILES: C([O:4][CH2:5][CH:6]=[C:7]([CH3:28])[CH2:8][CH2:9][CH:10]=[C:11]([C:23](OCC)=[O:24])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:22])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])(=O)C.[H-].[Al+3].[H-].[H-].C(OCC)(=O)C>CCOCC>[OH:24][CH2:23]/[C:11](/[CH2:12][CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:10]/[CH2:9][CH2:8]/[C:7](/[CH3:28])=[CH:6]/[CH2:5][OH:4]
Reactant: CCOC(=O)C(=CCCC(C)=CCOC(C)=O)CCC=C(C)CCC=C(C)C
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C/CO)CO

Procedure:
The ester thus obtained was further reduced by aluminum hydride (prepared from 760 mg of lithium aluminum hydride and 880 mg of aluminum chloride) in 7 ml of ether. After completion of the reaction, ethyl acetate was added to the reaction mixture, and the precipitate was filtered off. The filtrate was evaporated to dryness, yielding 3.5 g of the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:15]1[C:16]([F:27])=[C:17]2[C:21](=[CH:22][C:23]=1[F:24])[NH:20][CH:19]=[C:18]2[CH:25]=[O:26]>>[F:27][C:16]1[C:15]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=2)=[C:23]([F:24])[CH:22]=[C:21]2[C:17]=1[C:18]([CH:25]=[O:26])=[CH:19][NH:20]2
Reactant: OCC1(c2ccc(Br)cc2)CCC1
Reactant: O=Cc1c[nH]c2cc(F)c(Br)c(F)c12
Product: O=Cc1c[nH]c2cc(F)c(-c3ccc(C4(CO)CCC4)cc3)c(F)c12

Procedure:
[1-(4-bromophenyl)cyclobutyl]methanol, prepared as described in Example 72 (steps 1 and 2), is treated with 5-bromo-4,6-difluoro-1H-indole-3-carbaldehyde, prepared as described in Example 6 (steps 1-4), in a manner similar as described in Example 6 step 5 to provide the title compound.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=O)[NH:8][C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:7]1[NH:8][C:4]2[CH:3]=[C:2]([I:1])[CH:11]=[CH:10][C:5]=2[N:6]=1
Reactant: O=c1[nH]c2ccc(I)cc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc2ccc(I)cc2[nH]1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
5-Iodo-1,3-dihydro-2H-1,3-benzimidazole-2-one (7 g) [see Preparation 24] was added to a solution of phosphoryl chloride (135 ml). The reaction mixture was then heated to 120° C. and stirred for 2 hours, after which time the phosphoryl chloride was removed under reduced pressure and the residue diluted with water. The residual aqueous solution was neutralised with aqueous potassium hydrogen carbonate solution and the product extracted with 90:10, by volume, dichloromethane:methanol, dried over magnesium sulphate and the solvent removed under reduced pressure to afford 2-chloro-6-iodo-1H-1,3-benzimidazole (3.68 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](/[C:11](=[CH:17]/OCC)/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10])[C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:21][C@@H:22]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][OH:24]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:9](/[C:11](=[CH:17]/[NH:21][C@@H:22]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][OH:24])/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CC(C)C[C@H](N)CO
Reactant: CCO/C=C(\C(=O)OCC)C(=O)c1cc(Br)cnc1Cl
Solvent: ClCCl
Product: CCOC(=O)/C(=C\N[C@H](CO)CC(C)C)C(=O)c1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
The crude ethyl (2Z)-2-[5-bromo-2-chloropyridin-3-yl)carbonyl]-3-ethoxyprop-2-enoate (Intermediate 13, 3.2 g) was dissolved in dichloromethane (30 mL) and (2S)-2-amino-4-methylpentan-1-ol (2.17 g, 14.7 mmol) was added. The mixture was stirred for 30 min at room temperature. Dichloromethane (70 mL) was added to the reaction mixture and the mixture was washed with water (2×100 mL). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give a thick mass which was purified by flash column chromatography. The product was eluted with the gradient of 20% ethyl acetate/petroleum ether to afford colorless thick mass 2.5 g (80%) of ethyl (2Z)-2-[(5-bromo-2-chloropyridin-3-yl)carbonyl]-3-{[(2S)-1-hydroxy-4-methylpentan-2-yl]amino}prop-2-enoate.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>C(O)(C)C>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCCOc1ccccc1
Reactant: OCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: OCCc1ccc(OCCCCOc2ccccc2)cc1
Yield: 70.5 %

Procedure:
A mixture of 10.31 g (45 mmol) of 4-phenoxybutylbromide, 6.22 g (45 mmol) of 2-(4-hydroxyphenyl)ethanol and 6.22 g (45 mmol) of pulverized potassium carbonate in 45 ml of isopropanol was refluxed for 24 hours. The resulting mixture was cooled, mixed with water and then extracted three times with ethyl acetate. The combined extracts were washed with water and then with saturated aqueous sodium bicarbonate. They were dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on 500 g of silica gel (Merck Si60, 0.04-0.063 mm) using methylene chloride/methanol (98:2) as eluent. The product-containing fractions were evaporated in vacuo to yield 2-[4-(Phenoxybutoxy)phenyl]ethanol in the form of 9.08 g of crystals.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH2:14]Cl.[C:16]([O-:19])(=[O:18])[CH3:17].[K+].CN(C=O)C>O>[C:16]([O:19][CH2:14][C:3]1[N:4]=[C:5]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:6]2[C:7](=[O:8])[C:2]=1[Br:1])(=[O:18])[CH3:17]
Reactant: CC(=O)[O-]
Reactant: Cc1cccc2nc(CCl)c(Br)c(=O)n12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1nc2cccc(C)n2c(=O)c1Br
Temperature: 40 °C
Reaction time: 3.5 h

Procedure:
A mixture of 3-bromo-2-(chloromethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (4.5322 g, 15.76 mmol), potassium acetate (2.320 g, 23.64 mmol), and DMF (60.0 mL) was stirred at 40° C. After 3.5 h, the mixture was concd under reduced pressure. To the residue was added water (100 mL) and the resulting precipitate was collected by filtration, washed with water (100 mL), and dried to give (3-bromo-6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)methyl acetate as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (1 H, dd, J=9.0, 7.0 Hz), 7.45 (1 H, dd, J=9.0, 0.8 Hz), 7.02-7.08 (1 H, m), 5.12 (2H, s), 2.95 (3 H, s), 2.14 (3 H, s); Mass Spectrum (ESI) m/e=310.9 [M+1 (79Br)] and 313.0 [M+1 (81Br)].
Reaction SMILES: [O:1]1[C:5]2=[CH:6][N:7]=[C:8]([CH2:10][OH:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([O:11][CH2:10][C:8]1[CH:9]=[C:4]2[CH:3]=[CH:2][O:1][C:5]2=[CH:6][N:7]=1)(=[O:14])[CH3:13]
Reactant: OCc1cc2ccoc2cn1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCc1cc2ccoc2cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.4 %

Procedure:
Furo[2,3-c]pyridin-5-ylmethanol (7.70 g, 51.63 mmol) is dissolved in pyridine (45 mL), treated with acetic anhydride (14.36 mL, 154.9 mmol) and stirred for 18 h at rt. The pyridine is removed in vacuo and the resulting residue dissolved in EtOAc (200 mL), washed with 50% saturated sodium bicarbonate (4×90 mL), dried over MgSO4 and concentrated in vacuo to afford 9.32 g (94%) of furo[2,3-c]pyridin-5-ylmethyl acetate as a yellow oil. MS (EI) m/z: 191 (M+), 277, 148, 119, 118, 86, 84, 77, 63, 51, 50.
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9](=[O:14])[O:10][C:11](=[O:13])[NH:12][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.[Cl-].[Na+].O>[OH:2][C:3]1[C:8]2[C:9](=[O:14])[O:10][C:11](=[O:13])[NH:12][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2[nH]c(=O)oc(=O)c12
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=c1[nH]c2cccc(O)c2c(=O)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of Example 385A (1.93 g, 10 mmol) in dichloromethane (100 mL) was treated with AlCl3 (2.6 g, 20 mmol), stirred at room temperature overnight, treated slowly with brine (100 mL) while vigorously stirring, and extracted with ethyl acetate. The desired product was obtained as a white solid after evaporation of the solvent. Yield: 1.74 g, 97.2%. 1H NMR (DMSO-d6) δ 6.55 (d, 1H), 6.65 (d, 1H), 7.50 (t, 1H), 10.35 (s, 1H), 11.62 (br s, 1H); MS (ESI(−)) m/e 178 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH2:16][CH3:17])[C:5]=1[CH:6]=O)[CH3:2].[CH:18]1([NH:24][OH:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH2:1]([O:3][C:4]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH2:16][CH3:17])[C:5]=1[CH:6]=[N+:24]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[O-:25])[CH3:2]
Reactant: CCOc1cc(OCC)c(C=O)c(OCC)c1
Reactant: ONC1CCCCC1
Product: CCOc1cc(OCC)c(C=[N+]([O-])C2CCCCC2)c(OCC)c1

Procedure:
The title compound was prepared according to the procedure described in Example 11 using 2,4,6-triethoxybenzaldehyde and N-cyclohexylhydroxylamine. The title compound was isolated in 87.4% yield as a solid, m.p. 145.7° C.
Reaction SMILES: CC1C=C(C)N([C:8]([CH:10]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])N=1.[CH:24]1([C:27]2[O:31][C:30]([NH2:32])=[N:29][N:28]=2)[CH2:26][CH2:25]1>>[CH:24]1([C:27]2[O:31][C:30]([NH:32][C:8]([CH:10]3[C:23]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:17][C:16]4[C:11]3=[CH:12][CH:13]=[CH:14][CH:15]=4)=[O:9])=[N:29][N:28]=2)[CH2:26][CH2:25]1
Reactant: Nc1nnc(C2CC2)o1
Reactant: Cc1cc(C)n(C(=O)C2c3ccccc3Oc3ccccc32)n1
Product: O=C(Nc1nnc(C2CC2)o1)C1c2ccccc2Oc2ccccc21

Procedure:
The title compound, white solid, m.p. 246-248° C. and MS: m/e=333.1 (M+H+) was prepared in accordance with the general method of example 48a from (3,5-dimethylpyrazol-1-yl)-(9H-xanthen-9-yl)-methanone and 5-cyclopropyl-[1,3,4]oxadiazol-2-ylamine [J. Med. Pharm. Chem. 5, 617(1962)].
Reaction SMILES: C([O:4][C:5]([C:7]1([CH2:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])(C)C.[I-].[Na+].Br>CC(O)=O.C(Cl)Cl>[CH2:17]([CH:14]([CH2:15][CH3:16])[CH2:13][C:7]1([C:5]([OH:6])=[O:4])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)[CH3:18]
Reactant: CCC(CC)CC1(C(=O)OC(C)C)CCCCC1
Agent: Br
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC(CC)CC1(C(=O)O)CCCCC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 93.7 %

Procedure:
A mixture of 1-(2-Ethyl-butyl)-cyclohexanecarboxylic acid isopropyl ester (10 g, 39.4 mmol) and sodium iodide (886 mg, 5.91 mmol) in AcOH (80 mL) was stirred 50 min at room temperature and then heated to 100° C. 48% aq. HBr (30 mL, 265 mmol) was added dropwise over 30 min. and the reaction mixture was stirred 28 h at 100° C. The cooled reaction mixture was diluted with DCM (120 mL) and ice-water (120 mL). The organic phase was separated and washed with diluted aq. NaCl. The aqueous phases were extracted with another portion of DCM. The organic phases were combined, dried over sodium sulfate and concentrated. The residue (9.1 g) was taken up in 4N NaOH and ice (30 g). The alkaline solution (pH 12) was extracted with DCM (2×50 mL) and made acidic to pH 1 using aq. H2SO4. Extraction with DCM (3×100 mL), washing with diluted aq. NaCl, drying over sodium sulfate and evaporation afforded 7.84 g (94%) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid, purity 99.3% (GC area, after derivatization with diazomethane). 1H-NMR (CDCl3, 300 MHz): ppm 0.81 (t, 6H), 1.15-1.65 (m, 15H), 2.05-2.15 (m, 2H), 12 (broad s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[CH:15][CH:16]=[C:4]2[N:3]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Br:17][C:16]1[CH:15]=[N:14][N:5]2[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:7][C:2]([Cl:1])=[N:3][C:4]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1cc(N2CCOCC2)n2nccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1cc(N2CCOCC2)n2ncc(Br)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
There was dissolved, in methylene chloride (2 mL), 5-chloro-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidine (100 mg, 0.419 mM), then N-bromo-succinimide (78.8 mg, 0.443 mM) was added to the solution and the mixture was stirred at room temperature for one hour. This reaction liquid was diluted with a saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate. The extracts thus obtained were combined, dried over anhydrous sodium sulfate and the solvent was then distilled off. The resulting residue was purified by the silica gel column chromatography (methylene chloride) to thus give the title compound (80.7 mg, yield: 61%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].[N+:11]([C:14]1[CH:32]=[CH:31][C:17]([CH2:18][O:19][C:20](SC2N=C(C)C=C(C)N=2)=[O:21])=[CH:16][CH:15]=1)([O-:13])=[O:12]>O1CCCC1>[N+:11]([C:14]1[CH:15]=[CH:16][C:17]([CH2:18][O:19][C:20]([NH:7][CH2:6][C:5]2[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=2)[CH2:2][OH:1])=[O:21])=[CH:31][CH:32]=1)([O-:13])=[O:12]
Reactant: NCc1cccc(CO)c1
Reactant: Cc1cc(C)nc(SC(=O)OCc2ccc([N+](=O)[O-])cc2)n1
Solvent: C1CCOC1
Product: O=C(NCc1cccc(CO)c1)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
To 3-hydroxymethylbenzylamine (1.37 g) in tetrahydrofuran (30 ml), a solution of S-p-nitrobenzyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine (6.2 g) in tetrahydrofuran (20 ml) was added at room temperature, followed by stirring for 1 hours. The resulting precipitates were removed by filtration and the filtrate was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo to give an oily residue which was then crystallized from diethyl etherdichloromethane to give 3-(p-nitrobenzyloxycarbonyl)aminomethylbenzyl alcohol.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]2)[CH:5]=1.I[CH3:22]>CN(C=O)C.CCOC(C)=O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][C@H:14]2[CH2:15][CH2:16][C@H:17]([O:20][CH3:22])[CH2:18][CH2:19]2)[CH:5]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O[C@H]1CC[C@H](O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CO[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1
Temperature: 25 °C

Procedure:
0.6 g sodium hydride (60%) were added to a cooled solution (−7° C.) of 2.55 g 4-fluoro-2-(trans-4-hydroxy-cyclohexyloxy)-1-nitro-benzene and iodomethane in 30 ml DMF. The mixture was allowed to warm to rt overnight, diluted with EtOAc and washed with water and brine (3×). The organic phase was dried (MgSO4), passed through a hydrophobic frit and evaporated. The residue was purified by flash column chromatography (silica gel, 100% i-hexane→7:1 i-hexane:EtOAc).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][C:8](=[O:15])[NH:9][O:10][CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH2:43][C:44]([NH:46][C:47]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)=[O:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([NH:9][O:10][CH2:11][C:12]([NH:18][C@@H:19]([CH2:43][C:44](=[O:45])[NH:46][C:47]([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:36][CH2:37][CH3:38])[O:39][CH2:40][CH3:41])[CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)=[O:21])=[O:14])=[O:15])=[CH:16][CH:17]=1
Reactant: O=C(O)CONC(=O)NCc1ccc(Cl)cc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CONC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(4-chlorobenzyl)ureidooxy)acetic acid (Compound VI-11) 60 mg (0.23 mmol) was coupled with (S)-2-amino-N1—((S)-1,1-diethoxypropan-2-yl)-N1-(naphthalen-1-ylmethyl)-N4-tritylsuccinamide (Compound IV-19) 100 mg (0.16 mmol) to obtain the title compound.