Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]Br.[CH:4]1([CH:10]2[CH:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[O:13][B:12]([CH:21](Cl)[CH2:22][CH:23]([CH3:28])[C:24]([CH2:26][CH3:27])=[CH2:25])[O:11]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>C1COCC1>[CH:4]1([CH:10]2[CH:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[O:13][B:12]([CH:21]([CH3:1])[CH2:22][CH:23]([CH3:28])[C:24]([CH2:26][CH3:27])=[CH2:25])[O:11]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: C=C(CC)C(C)CC(Cl)B1OC(C2CCCCC2)C(C2CCCCC2)O1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: C=C(CC)C(C)CC(C)B1OC(C2CCCCC2)C(C2CCCCC2)O1
Reaction time: 20 h

Procedure:
Methylmagnesium bromide (3.0 M in ether, 13.3 mL, 40 mmol) was added to a stirred solution of [4R-[2(S*,S*),4α,5β]]-4,5-dicyclohexyl-2-(5-chloro-2-ethyl-3-methylpenten-5-yl)-1,3,2-dioxaborolane (15.2 g, 40 mmol) in THF (250 mL) at -78° C. over a period of 20 min. The bath was allowed to warm to 20°-25° C. and the reaction mixture was stirred for 20 h. The solution was concentrated under vacuum and ether (200 mL) was added to the residue. The ethereal solution was washed with saturated aqueous ammonium chloride (2∞200 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to liquid [4R-[2(S*,S*),4α,5β]]-4,5-dicyclohexyl-2-(2-ethyl -3,5-dimethylpenten-5-yl)-1,3,2-dioxaborolane (12a) (13.8 g, 96%); 300 MHz 1H-NMR (CDCl3) δ0.84-2.27 (m, 37), 3.81 (m, 2), 4.68 and 4.74 (AB, 2); 75 MHz 13C-NMR (CDCl3) 12.3, 16.2, 20.2, 25.9, 26.0, 26.4, 27.4, 28.28, 28.34, 39.2, 39.5, 43.0, 83.2, 106.7, 156.3). HRMS: calcd for C23H41BO2 (M+) 360.3200, found: 360.3199.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:32]1[CH2:33][CH2:34][N:29]([C:26]3[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:28][CH:27]=3)[CH2:30][CH2:31]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Product: COc1nc2ccc(Cl)cc2nc1NC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 82 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(4-nitrophenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 82%). 1H NMR (300 MHz, DMSO-d6): δ 3.62-3.66 (m, 8H), 4.06 (s, 3H), 7.07 (d, J=9.0 Hz, 2H), 7.58 (d, J=8.4 Hz, 1H), 7.76-7.80 (m, 2H), 8.11 (d, J=9.0 Hz, 2H), 9.46 (s, 1H).
Reaction SMILES: [OH:1][C:2]1([C@H:5]2[CH2:9][O:8]C(C)(C)[N:6]2[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:4][CH2:3]1.CC1C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(=O)([O-])O.[Na+]>CO>[CH2:15]([O:14][C:12](=[O:13])[NH:6][C@@H:5]([C:2]1([OH:1])[CH2:3][CH2:4]1)[CH2:9][OH:8])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC1(C)OC[C@H](C2(O)CC2)N1C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C(N[C@H](CO)C1(O)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
To a solution of benzyl(4R)-4-(1-hydroxycyclopropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (2.45 g) in methanol (100 mL) was added pyridin-1-ium 4-methylbenzenesulfonate (2.33 g) at room temperature. The reaction mixture was stirred at room temperature overnight, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.68 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.Cl.[NH2:12][OH:13].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:12]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=2)[OH:13])=[CH:4][CH:5]=1)#[N:10]
Reactant: NO
Reactant: N#Cc1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN(O)Cc2ccc(C#N)cc2)cc1
Reaction time: 8 h

Procedure:
A mixture of 10.0 grams of alpha-bromo-p-cyanotoluene, 1.77 grams of hydroxylamine hydrochloride and 10.6 grams of anhydrous sodium carbonate in 50 ml of dry N,N-dimethylformamide (DMF) is allowed to stand overnight at room temperature. The DMF solvent is then removed under reduced pressure and the reidue is partitioned between methylene chloride and water. The organic layer is washed with water, dried over anhydrous sodium sulfate and then evaporated in vacuo to give a solid residue which upon trituration with ethanol yields the above-named compound as a white solid, melting at 172°-175° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:19])C=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH2:8]([CH:9]1[CH2:10][O:19]1)[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: c1ccc(CCC2CO2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 1820.8 %

Procedure:
A modified procedure of Woodward was used (Bernier, D. et al., The Journal of Organic Chemistry 2008, 73, 4229). A stirred solution of 4-phenyl-1-butene 62 (500 mg, 568 μl, 3.78 mmol) in CH2Cl2 (20 ml) was cooled to 0° C. m-CPBA (816 mg, 4.73 mmol) was added as a solid and the reaction mixture was stirred at 0° C. for 1.5 h, then r.t. for 24 h. The reaction mixture was poured into saturated K2CO3 solution (50 ml) and extracted with CH2Cl2 (2×50 ml). The combined organic phases were washed with saturated K2CO3 solution (50 ml) before being dried (MgSO4), filtered and concentrated to give a clear colourless liquid. This material was purified by column chromatography, eluting with petrol/EtOAc (9:1), to give the epoxide 61 (10.2 g, 91%) as a clear colourless liquid. The 1H, 13C, and IR data were consistent with the literature (Mitchell, J. M. et al., Journal of the American Chemical Society 2001, 123, 862; Elings, J. A. et al., European Journal of Organic Chemistry 1999, 1999, 837).
Reaction SMILES: [Cl:1]OC(C)(C)C.[CH:7]([C:10]1[CH:18]=[CH:17][C:13]([CH:14]=[N:15][OH:16])=[CH:12][CH:11]=1)([CH3:9])[CH3:8]>C(Cl)(Cl)(Cl)Cl>[CH:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([Cl:1])=[N:15][OH:16])=[CH:12][CH:11]=1)([CH3:9])[CH3:8]
Reactant: CC(C)(C)OCl
Reactant: CC(C)c1ccc(C=NO)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)c1ccc(C(Cl)=NO)cc1
Reaction time: 0.25 h
Yield: 72.9 %

Procedure:
A solution of 5.4 g of tert-butyl hypochlorite in 25 ml of carbon tetrachloride was added dropwise during 15 minutes into a solution of 6.8 g of 4-isopropylbenzaldoxime (m.p. 61°-63°, prepared in the manner described in Example II) in 50 ml of carbon tetrachloride while the temperature was maintained at 15°-23°. The green mixture was stirred for 15 minutes, then concentrated. The oil was crystallized from hexane to give 6 g of 4-isopropylbenzohydroximoyl chloride.
Reaction SMILES: [CH:1]1([O:6][CH2:7][C:8](Cl)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:11]([C:14]1[C:15]([NH2:23])=[N:16][N:17]2[CH:22]=[CH:21][CH:20]=[N:19][C:18]=12)([CH3:13])[CH3:12].CO>N1C=CC=CC=1>[CH:1]1([O:6][CH2:7][C:8]([NH:23][C:15]2[C:14]([CH:11]([CH3:13])[CH3:12])=[C:18]3[N:19]=[CH:20][CH:21]=[CH:22][N:17]3[N:16]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)COC1CCCC1
Reactant: CC(C)c1c(N)nn2cccnc12
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)c1c(NC(=O)COC2CCCC2)nn2cccnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product from Example 133C (1.5 mL of solution in CH2Cl2) was added to a solution of the product from Example 112C (86 mg, 0.49 mmol) in pyridine (1.0 mL) in a 4 mL vial. The reaction mixture was stirred at room temperature for 2 h. Methanol (0.5 mL) was added, and the solution was stirred for 30 minutes and then concentrated under vacuum. The residue was purified by flash chromatography (silica gel, eluted with hexanes-EtOAc, 70:30-0:100) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.45 (d, J=7.1 Hz, 6H) 1.57-1.69 (m, 2H) 1.70-1.87 (m, 6H) 3.24 (hept, J=7.1 Hz, 1H) 4.10-4.13 (m, 1H) 4.11-4.12 (m, 2H) 6.72 (dd, J=6.8, 4.1 Hz, 1H) 8.39 (dd, J=4.1, 1.7 Hz, 1H) 8.58 (dd, J=6.8, 1.7 Hz, 1H) 8.60 (s, 1H); MS (ESI) m/z 303 (M+H)+; Anal. Calculated for C16H22N4O2: C, 63.71; H, 7.44; N, 18.20. Found: C, 63.56; H, 7.33; N, 18.53.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[CH:24]([NH:27][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 70 %

Procedure:
As described for example 12, 6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mol) instead of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid was converted using isopropylamine instead of 2,2,2-trifluoroethylamine to the title compound (trituration with tert-butylmethylether, 158 mg, 70%) which was obtained as a white solid. MS: m/e=353.3 [M+H]+.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[N:16]=[N:15]2)[CH2:10]1)C1C=CC=CC=1.Cl>CO.[Pd]>[ClH:1].[C:19]([C:17]1[N:16]=[N:15][N:14]([CH:11]2[CH2:12][CH2:13][NH:9][CH2:10]2)[CH:18]=1)([OH:21])=[O:20]
Reactant: O=C(O)c1cn(C2CCN(Cc3ccccc3)C2)nn1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C(O)c1cn(C2CCNC2)nn1
Reaction time: 20 h

Procedure:
To a solution of N-benzyl-3-(4-carboxy-1,2,3-triazol-1-yl)pyrrolidine hydrochloride (1 g, 0.0033 mol) in methanol (50 ml) was added 10% Pd/C (100 mg) and conc. HCl (0.5 ml). The suspension was hydrogenated at r.t. and 50 psi pressure for 20 hrs. The Pd/C was removed by filtration and the solution was concentrated. The residue was recrystallized from methanol/ether to obtain white crystalline title compound. Yield: 650 mg (93.25%). 1H NMR (D2O) δ: 2.51-3.56 (m, 2H), 3.62-3.75 (m, 2H), 3.92-4.00 (m, 2H), 5.52-5.67 (m, 1H), 8.67 (s, 1H).
Reaction SMILES: [C:1](=[O:13])([O:11][CH3:12])[O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.Cl[CH:15](Cl)[O:16]C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:1](=[O:13])([O:11][CH3:12])[O:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][CH3:10])=[C:7]([CH:15]=[O:16])[CH:8]=1
Reactant: COC(=O)Oc1ccc(OC)cc1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)Oc1ccc(OC)c(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, to a solution of 4-methoxyphenyl methyl carbonate (10.0 g) in dichloromethane (125 mL) was added a solution of titanium (IV) chloride (14.3 mL) in dichloromethane (25 mL) at 0° C., and then dichloro(methoxy)methane (5.8 mL) was added dropwise over 30 min. The reaction mixture was warmed to room temperature, and stirred for 30 min. Dichloromethane (about 70 mL) was evaporated, and ice (120 g) and 12N hydrochloric acid were added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (10.5 g) as a yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:27]=[CH:26][C:21]4[NH:22][C:23](=[O:25])[O:24][C:20]=4[CH:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Br[CH2:34][C:35]([NH2:37])=[O:36].[Br-]>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:27]=[CH:26][C:21]4[NH:22][C:23](=[O:25])[O:24][C:20]=4[CH:19]=3)[CH2:14][CH2:13]2)[CH2:34][C:35]([NH2:37])=[O:36])=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4ccc(F)cc4)CC3)cc2o1
Reactant: NC(=O)CBr
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)CN(CCCc1ccc(F)cc1)C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 19.1 %

Procedure:
To a stirred suspension of 6-{trans-4-[3-(4-fluorophenyl)propylamino]-cyclohexyl}-3H-benzoxazol-2-one (110 mg, 0.81 mmol) in DMF (15 mL) was added NaHCO3 (140 mg, 1.6 mmol) and bromoacetamide (300 mg, 0.74 mmol). After 16 hours the reaction mixture was warmed to 50° C. After 4 hours, additional bromide (150 mg, 0.37 mmol) and NaHCO3 (31 mg, 0.37 mmol) were added, and the temperature was increased to 75° C. After 4 hours, the reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The combined organics were washed with water, saturated NaCl, dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography (silica, 95:4.75:0.25 CH2Cl2:MeOH:NH4OH) followed by conversion to the HCl salt gave compound 2-{[3-(4-fluorophenyl)propyl]-[4-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-cyclohexyl]amino}acetamide (60 mg, 17%), as a white solid: mp 266-270° C.; IR (KBr): 3331, 3149, 2943, 1762, 1691 cm−1; 1H NMR (500 MHz, DMSO-d6): δ 11.47 (s, 1H), 9.08 (br s, 1H), 7.96 (br s, 1H), 7.73 (br s, 1H), 7.29-7.25 (m, 2H), 7.17-7.01 (m, 3H), 6.99 (s, 2H), 4.05-4.02 (m, 1H), 3.81-3.78 (m, 1H), 3.47-3.38 (m, 1H), 3.22-3.12 (m, 3H), 2.63 (t, J=8 Hz, 2H), 2.57-2.52 (m, 1H), 2.14-1.87 (m, 6H), 1.71-1.49 (m, 4H); ESI-MS (m/z): 426 [M+H]+; HPLC: method A, 5.44 minutes (98.0%); HPLC: method E, 6.50 minutes (>99%); Anal. Calcd for C24H28FN3O3.HCl: C, 61.80; H, 6.37; N, 9.01. Found: C, 61.78; H, 6.27; N, 8.80.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([CH:19]2[CH2:21][CH2:20]2)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:24].OO.[OH-].[Na+]>CCO.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]2[O:24][C@H:16]2[C:17]([CH:19]2[CH2:21][CH2:20]2)=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: O=C(/C=C/c1ccc(OCc2ccccc2)cc1)C1CC1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(C1CC1)[C@@H]1O[C@H]1c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
(2E)-3-[4-(Benzyloxy)phenyl]-1-cyclopropyl-2-propen-1-one (6.25 g) was suspended in EtOH (67.5 ml), acetone (22.5 ml) To this mixture was added hydrogen peroxide 30% aqueous solution (4.5 ml), and 3M NaOH (4.5 ml), and the mixture was stirred at ambient temperature for l day. The mixture was diluted with H2O. White precipitates were collected and washed with H2O, and air dried to give {(2R,3S)-3-[4-(benzyloxy)phenyl]-2-oxiranyl}(cyclopropyl)methanone (6.27 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:9]([OH:17])[CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[CH3:16])[CH:6]=[CH:7][CH:8]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:9]([O:17][C:18](=[O:20])[CH3:19])[CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[CH3:16])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc([C@H](O)C[C@H]2CCCN2C)c1
Product: COc1cccc([C@@H](C[C@H]2CCCN2C)OC(C)=O)c1

Procedure:
According to the method of working described in Example 28, from 3.0 g of (R*,R*)-1-(3-methoxyphenyl)-2-(1-methyl-2-pyrrolidinyl)-ethanol and 30 ml of acetic acid anhydride there are obtained 1.56 g of the title compound as tough, colourless oil of b.p. 130° at 0.008 mm Hg.
Reaction SMILES: [NH:1]([C:5]1[S:6][C:7]([C:11]([OH:13])=O)=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3].[NH:14]1[CH2:18][CH2:17][C@@H:16]([CH2:19][O:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]1>CO>[NH:1]([C:5]1[S:6][C:7]([C:11]([N:14]2[CH2:18][CH2:17][C@@H:16]([CH2:19][O:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]2)=[O:13])=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: Cc1nc(NC(=N)N)sc1C(=O)O
Reactant: CC(C)(C)OC(=O)COC[C@@H]1CCNC1
Solvent: CO
Product: Cc1nc(NC(=N)N)sc1C(=O)N1CC[C@@H](COCC(=O)OC(C)(C)C)C1

Procedure:
By coupling 2-guanidino-4-methyl-thiazole-5-carboxylic acid with tert.-butyl (R)-(pyrrolidin-3-ylmethoxy)-acetate according to the method given in Example 4 there is obtained tert.-butyl (R)-[1-(2-guanidino-4-methyl-thiazole-5-carbonyl)-pyrrolidin-3-ylmethoxy]-acetate as a pale yellow resinous foam, [α]D =+3.2°, (MeOH, c=0.5), MS: 398 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=[CH:11]/[CH2:12][CH:13]([C:49]1[CH:54]=[CH:53][C:52]2[O:55][CH2:56][O:57][C:51]=2[CH:50]=1)[CH:14]([N:16]([CH2:38][C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=1)[C:17]([CH2:19][CH:20]([C:33]([O:35]CC)=[O:34])[CH:21]([C:28]([O:30]CC)=[O:29])[CH2:22][C:23]([O:25]CC)=[O:24])=[O:18])[CH3:15].[OH-].[Na+].Cl.C(#N)C>O1CCCC1.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=[CH:11]/[CH2:12][CH:13]([C:49]1[CH:54]=[CH:53][C:52]2[O:55][CH2:56][O:57][C:51]=2[CH:50]=1)[CH:14]([N:16]([CH2:38][C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=1)[C:17]([CH2:19][CH:20]([C:33]([OH:35])=[O:34])[CH:21]([C:28]([OH:30])=[O:29])[CH2:22][C:23]([OH:25])=[O:24])=[O:18])[CH3:15]
Reactant: CCOC(=O)CC(C(=O)OCC)C(CC(=O)N(Cc1ccc2ccccc2c1)C(C)C(C/C=C/c1nc2ccccc2o1)c1ccc2c(c1)OCO2)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C(C/C=C/c1nc2ccccc2o1)c1ccc2c(c1)OCO2)N(Cc1ccc2ccccc2c1)C(=O)CC(C(=O)O)C(CC(=O)O)C(=O)O
Reaction time: 8 h
Yield: 52 %

Procedure:
The N-acylated product obtained in (1) was converted to triethyl 4-[N-{(1RS,2RS,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-methylendioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)carbamoyl]-1,2,3-butanetricarboxylate in the same manner as in Preparation Example 1. The resulting ester was dissolved in 1 ml of tetrahydrofuran, and after addition of 0.5 ml of 3N sodium hydroxide, it was left standing at room temperature overnight. The reaction solution was diluted with ethyl acetate, acidified with 1N hydrochloric acid, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was evaporated in vacuo. The residue was purified by medium pressure liquid chromatography [Lobar column™, size A, RP-8 (Merck & Co., Inc.); acetonitrile/0.1% aqueous trifluoroacetic acid=1/1] to give 14 mg (yield 52%) of the title compound as a white powder.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[C:5]([O:12][CH3:13])[CH:4]=1)=[CH2:2].[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[C:17]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:15]([F:14])[CH:16]=2)=[C:5]([O:12][CH3:13])[CH:4]=1)=[CH2:2]
Reactant: COc1ccc(B(O)O)cc1F
Reactant: C=Cc1cc(OC)c2cc[nH]c2c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1cc(OC)c2ccn(-c3ccc(OC)c(F)c3)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.4 %

Procedure:
To a solution of 6-ethenyl-4-(methyloxy)-1H-indole (D8) (665 mg, 3.84 mmol) in dichloromethane (20 mL) was added 3-fluoro-4-methoxyphenylboronic acid (1.31 g, 7.71 mmol), triethylamine (1.1 mL, 7.91 mmol), copper (II) acetate (1.39 g, 7.68 mmol) and powdered 4A molecular sieves (1.0 g). The reaction mixture was stirred at room temperature in the presence of air for 18 hours. Further quantities of 3-fluoro-4-methoxyphenylboronic acid (330 mg), triethylamine (0.28 mL) and copper acetate (340 mg) were added and the mixture stirred at room temperature in the presence of air for a further 48 hours. The mixture was filtered and the solid washed with dichloromethane. The filtrate was concentrated at reduced pressure. The product was purified by silica gel chromatography eluting with 5-50% dichloromethane in hexane to yield the title compound (D9), (541 mg).
Reaction SMILES: [ClH:1].[C:2]([CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9](/[CH:12]=[C:13]2\[CH2:14][N:15]([CH:20]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[C:21]([CH:23]3[CH2:25][CH2:24]3)=[O:22])[CH2:16][CH2:17][CH:18]\2[SH:19])=[N:8]1)([OH:4])=[O:3].[C:33](OC(=O)C)(=[O:35])[CH3:34].C(N(CC)CC)C.Cl>ClCCl.O1CCOCC1.O>[ClH:1].[C:33]([S:19][CH:18]1[CH2:17][CH2:16][N:15]([CH:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[C:21]([CH:23]2[CH2:25][CH2:24]2)=[O:22])[CH2:14]/[C:13]/1=[CH:12]\[C:9]1[CH:10]=[CH:11][N:7]([CH2:6][CH2:5][C:2]([OH:4])=[O:3])[N:8]=1)(=[O:35])[CH3:34]
Reactant: O=C(O)CCn1ccc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S)n1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1ccn(CCC(=O)O)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 43 %

Procedure:
To a solution of (E)-3-{[1-(2-carboxyethyl)-1H-pyrazol-3-yl]methylidene}-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-sulfanylpiperidine hydrochloride (90 mg) in dichloromethane (4 ml) were added acetic anhydride (0.09 ml) and triethylamine (0.13 ml) under ice-cooling, and the resulting mixture was stirred at room temperature for 3.5 hours. Subsequently, water (0.40 ml) was added to the reaction mixture. The resulting mixture was concentrated in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of methanol and dichloromethane (3:200) as the eluent. To a solution of a colourless amorphous solid obtained in acetonitrile (3 ml) was added a 4N solution of hydrogen chloride in dioxane (0.07 ml) with stirring. The reaction mixture was concentrated in vacuo to afford the title compound (45 mg, yield: 43%) as a colourless amorphous solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.C(OC([N:16]1[C:20]([CH:21]2[CH2:23][CH2:22]2)=[CH:19][C:18]([NH2:24])=[N:17]1)=O)(C)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:8][C:4]1[CH:3]=[C:2]([NH:24][C:18]2[CH:19]=[C:20]([CH:21]3[CH2:23][CH2:22]3)[NH:16][N:17]=2)[CH:7]=[CH:6][N:5]=1
Reactant: Clc1cc(I)ccn1
Reactant: CC(C)(C)OC(=O)n1nc(N)cc1C1CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Clc1cc(Nc2cc(C3CC3)[nH]n2)ccn1
Temperature: 100 °C
Yield: 47.9 %

Procedure:
A mixture of 4-iodo-2-chloropyridine (0.26 g, 1.1 mmol), 3-amino-5-cyclopropyl-pyrazole-1-carboxylic acid tert-butyl ester (0.20 g, 0.89 mmol), Pd2 dba3 (0.016 g, 2 mol %), Xantphos (0.031 g, 6 mol %), and Cs2CO3 (0.41 g, 1.3 mmol) in degassed toluene (4 ml) was purged with N2 and heated to 100° C. in a sealed tube for 2 days. The mixture was diluted with THF and filtered to remove Cs2CO3. The filtrate was concentrated under reduced pressure and purified by column chromatography (hexane-EtOAc=3:1) to give the title compound (0.10 g, 48%). MS: Calcd.: 234. Found: [M+H]+ 235.