Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]4=[N:18][CH:19]=[CH:20][CH:21]=[C:16]4[N:15]=[C:14]3[C:22](O)=[O:23])[CH:8]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH:59]([N:62]1[CH2:67][CH2:66][CH:65]([NH2:68])[CH2:64][CH2:63]1)([CH3:61])[CH3:60]>CN(C=O)C>[CH:59]([N:62]1[CH2:67][CH2:66][CH:65]([NH:68][C:22]([C:14]2[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[O:23])[CH2:64][CH2:63]1)([CH3:61])[CH3:60]
Reactant: CC(C)N1CCC(N)CC1
Reactant: O=C(O)c1nc2cccnc2n1Cc1cc(-c2ccc(Cl)s2)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(NC(=O)c2nc3cccnc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
150.0 mg (0.41 mmol) 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-3H-imidazo[4,5-b] pyridine-2-carboxylic acid were dissolved in 4 mL DMF. Sequentially 142 μl DIPEA and 151.8 mg (0.41 mmol) HATU were added and the mixture was stirred for 20 min at room temperature. 74.3 mg (0.41 mmol) 1-Isopropyl-piperidine-4-ylamine-hydrochloride and another 71 μl DIPEA were added and the resulting mixture was stirred 3 h at room temperature. Concentration under reduced pressure and final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave pure 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-3H-imidazo[4,5-b]pyridine-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide as a light brown amorphous solid. The title compound was obtained as its hydroformiate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[OH:18])=[C:11]([O:19][CH3:20])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si:47]([O:64][CH2:65][CH:66]([CH2:79]O)/[CH:67]=[CH:68]/[P:69](=[O:78])([O:74][CH:75]([CH3:77])[CH3:76])[O:70][CH:71]([CH3:73])[CH3:72])([C:60]([CH3:63])([CH3:62])[CH3:61])([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.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Si:47]([O:64][CH2:65][CH:66](/[CH:67]=[CH:68]/[P:69]([O:74][CH:75]([CH3:77])[CH3:76])([O:70][CH:71]([CH3:72])[CH3:73])=[O:78])[CH2:79][O:18][N:15]1[CH:14]=[N:13][C:12]2[C:16]1=[N:17][C:9]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[N:10][C:11]=2[O:19][CH3:20])([C:60]([CH3:63])([CH3:62])[CH3:61])([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: COc1nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc2c1ncn2O
Reactant: CC(C)OP(=O)(/C=C/C(CO)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OC(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc2c1ncn2OCC(/C=C/P(=O)(OC(C)C)OC(C)C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
A mixture of 2-[di-(t-butoxycarbonyl)]amino-9-hydroxy-6-methoxypurine (0.62 g, 1.6 mmol), triphenylphosphine (0.43 g, 1.6 mmol), and diisopropyl (E)-3-(t-butyldiphenylsilyloxy)methyl-4-hydroxybut-1-enylphosphonate (0.6 g, 1.2 mmol) in anhydrous THF (15 ml) at 0° C. was treated dropwise, slowly, with diethyl azodicarboxylate (0.25 g, 1.6 mmol). After stirring overnight at room temperature, the solvent was removed in vacuo and the residue chromatographed on silica gel, eluting with acetone-hexane (1:2) to give (E)-9-[2-(t-butyldiphenylsilyloxy)methyl-4(diisopropoxyphosphoryl)but-3-enyloxy]-2-[di-(t-butoxycarbonyl)]amino-6-methoxypurine as a gum (0.7 g, 66%); υmax (KBr) 2977, 2932, 2858, 1792, 1757, 1734, 1592, 1472, and 1427 cm-1 ; δH (CDCl3) 1.06 [9H, s, C(CH3)3 ], 1.30 [12H, s, 2×CH(CH3)2 ], 1.43 (18H, s, 2×C(CH3) 3 ], 2.92 (1H, CH), 3.85 (2H, m, CH2), 4.15 (3H, s, OCH3), 4.4-4.75 [4H, CH2, 2×CH (CH3)2 ], 5.91 (1H, ddd, J 1, 17 and 19 Hz, PCH=CH), 6.77 (1H, ddd, J 8, 17 and 25Hz, PCH=H) , 7.3-7.85 (11H, m, 2×C6H5, H-8) (Found: C, 59.77; H, 7.52;N, 7.79%. C43H62N5O10PSi requires C, 59.50; H, 7.20; N, 8.07%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([OH:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1)=[O:5])C.[H-].[Na+].Br[CH2:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C>[CH3:24][C:23]([CH3:26])([CH3:25])[C:22](=[O:27])[CH2:21][O:11][C:9]1[N:8]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:7]=[C:6]([C:4]([OH:3])=[O:5])[CH:10]=1
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCOC(=O)c1cc(O)n(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)COc1cc(C(=O)O)nn1-c1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 5 g 5-Hydroxy-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester in 12 ml of DMF was added at 0° C. 1.29 g of sodium hydride (60% in mineral oil). After 15 min at this temperature 3.85 g of 1-Bromo-3,3-dimethyl-butan-2-one were added. After 2 h at RT the mixture was poured on ice/water and extracted with ethyl acetate. The organic phase was washed with brine and dried over sodium sulfate followed by evaporation. The residue was taken up in 20 ml of THF and treated with 21.5 ml of 2M NaOH. After 2 h, additional 15 ml 2M NaOH were added. Finally, after 3 h the THF was evaporated and the residue acidified with 2M HCl resulting in the precipitation of a gum. The gum was dissolved in ethyl acetate and coevaporated with toluene. Stirring in ethyl acetate/hepatne 1:1 gave a gummy substance which solidified on evaporation.
Reaction SMILES: C([Li])CCC.[CH:6]([O:9][C:10]1[CH:21]=[CH:20][C:13]([O:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[CH:12][CH:11]=1)([CH3:8])[CH3:7].[CH:22](N1CCOCC1)=[O:23]>O1CCCC1>[CH:6]([O:9][C:10]1[CH:21]=[CH:20][C:13]([O:14][C:15]2[S:16][C:17]([CH:22]=[O:23])=[CH:18][N:19]=2)=[CH:12][CH:11]=1)([CH3:8])[CH3:7]
Reactant: O=CN1CCOCC1
Reactant: CC(C)Oc1ccc(Oc2nccs2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(Oc2ncc(C=O)s2)cc1
Reaction time: 4 h
Yield: 100.3 %

Procedure:
Butyl lithium (20 mL, of 2.5M solution, 0.05 mol) at −78° C. over 15 minutes was added to a solution of Example 1B (11.8 g, 0.05 mol) in dry tetrahydrofuran. After one hour at the same temperature, formylmorpholine (5.8 g, 0.05 mol) was added drop wise and the mixture was stirred for 4 hours and then quenched with sat. NH4Cl. The aqueous layer was extracted with ethyl acetate and the organic phase washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated and purified on silica gel (5˜35% ethyl acetate in hexane) to give 13.2 g of product as a yellow oil, 1H NMR (300 MHz, CDCl3) δ ppm 1.36 (d, J=5.88 Hz, 6H) 4.46-4.61 (m, 1H) 6.88-6.98 (m, 2H) 7.12-7.23 (m, 2H) 7.93 (s, 1H) 9.83 (s, 1H). MS (ESI), m/z 264.1 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1.C(=S)=S>>[Br:10][C:11]1[S:12][C:13]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])=[CH:14][CH:15]=1
Reactant: Brc1cccs1
Reactant: O=C(Cl)c1ccccc1
Solvent: S=C=S
Product: O=C(c1ccccc1)c1ccc(Br)s1
Reaction time: 2.5 h
Yield: 96.2 %

Procedure:
To a mixture of benzoyl chloride (2.81 g, 20.0 mmol) and 2-bromothiophene (3.42 g, 21.0 mmol) in carbon disulfide (120 mL) aluminum chloride (5.34 g, 40.0 mmol), was added in portions over 10 min with vigorous magnetic stirring. The reaction was next allowed to stir for 2.5 h before being quenched with 100 mL 1 M HCl (aq). The organics were separated, the aqueous layer extracted with carbon disulfide (3×50 mL), and the combined organics washed with water (3×100 mL) and dried over MgSO4. After filtration, the organics were concentrated in vacuo and the residue chromatographed on a silica gel column (hexane:ether=9:1) to yield 5.14 g (96%) of yellow crystals. mp 41-43° C.; 1H NMR (CDCl3): δ 7.84 (d, 2H, 3J=8.0 Hz), 7.62 (t, 1H, 3J=7.2 Hz), 7.52 (t, 2H, 3J=7.5 Hz), 7.40 (d, 2H, 3J=3.5 Hz), 7.15 (d, 2H, 3J=4.0 Hz).
Reaction SMILES: [C:1](NC(=N)O)([CH3:4])([CH3:3])[CH3:2].[NH:9]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:10]([C:12]([OH:14])=[O:13])[CH3:11]>>[NH:9]([C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[C@H:10]([C:12]([O:14][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:13])[CH3:11]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)NC(=N)O
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C

Procedure:
Reaction of 1 at room temperature with 400 mol % of tert-butanol and 1-2 mol % of freshly prepared CuCl gave a quantitative yield of analytically pure tert-butyl isourea 2 (R=But) in less than 1 h. The reaction was monitored using IR by following the disappearance of the carbodiimide absorption at 2130 cm-1 and the appearance of the isourea absorbance at 1660 cm-1. No purification other than evaporation of the excess tert-butanol was necessary to obtain the pure material. Isourea 2 (R=BUt) was then stirred with N-CBZ-Ala (10) in several solvents under a variety of reaction conditions to determine the most effective conditions for tert-butyl ester formation. In general, all the solvents examined gave reasonable yields of N-CBZ-Ala-OBut (15), but warm toluene, overnight, produced the best results. Several other N-BOC protected amino acids were treated with 2 (R=But) and gave good yields of tert-butyl esters under similar conditions. In each example, the yields were comparable if not slightly superior to those obtained using DIC. Esterification of the racemization sensitive CBZ-Ala-Phe (11) with 2 (R=But) gave the tert-butyl ester 20, shown by HPLC analysis to be a single diastereomer. Esterification of 11 using K2CO3 and tert-butyl bromide in DMA (Chevallet et al., Tetrahedron Lett., 34, p. 7409 (1993)) gave 20 with 2.5% racemization to the L,D diastereomer. Other isourea derivatives 2 (R=Bn, Pr1, Et Me) of 1 were synthesized, with results identical to that of 2 (R=But). Each isourea was formed rapidly and quantitatively at room temperature with 1-2 mole % CuCl and only a slight excess of alcohol. The quality of the CuCl catalyst was important, as older samples gave slower reactions and were required in up to 5 mol %. Surprisingly, each isourea, including the But, could be produced quantitatively without the use of catalytic CuCl, although heating and longer reaction times were required. In the case of DIC, no isourea was obtained without catalytic CuCl. All our results indicated that the presence or absence of the CuCl had no effect on esterifications.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[CH:41]=[O:42])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.[C:43]([Mg]Br)#[CH:44]>O1CCCC1>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])[C:22](=[O:23])[C:17]=4[C:16]=3[CH:41]([OH:42])[CH:43]=[CH2:44])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:13])[F:14])[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(C=O)c(-c3ccc(OC(F)F)c(OC4CC4)c3)n2COCC[Si](C)(C)C)c1=O
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)c1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 71-(a) except for using 1.02 g (1.64 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-formyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in the same manner as in Example 15-(a), and using 4 ml of tetrahydrofuran solution containing 1M ethynyl magnesium bromide in place of tetrahydrofuran solution containing ethynyl magnesium bromide, whereby 1.01 g of the title compound was obtained as a yellowish oil substantially quantitatively.
Reaction SMILES: O.[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[C:5]([OH:10])[N:4]=1.N([O-])=O.[Na+].C(O)=O.[CH:18]([NH2:20])=O>[Pd]>[NH:4]1[C:5](=[O:10])[C:6]2[NH:20][CH:18]=[N:9][C:7]=2[N:8]=[C:3]1[NH2:2]
Reactant: NC=O
Reactant: Nc1cc(O)nc(N)n1
Agent: [Pd]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: Nc1nc2nc[nH]c2c(=O)[nH]1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
29.0 g (0.2 mol) 2,4-diamino-6-hydroxypyrimidine hydrate was nitrosed with 13.8 g (0.2 mol) sodium nitrite and 10.8 g (0.2 mol) 85% formic acid in 150 ml formamide and the pink-coloured suspension obtained was admixed with a further 42.4 g (0.8 mol) 85% formic acid. After stirring in 1.0 g of a palladium catalyst on active carbon according to example 1, it was heated for 3 hours to 120° C. In this process the suspension became colorless and was subsequently heated for 3 hours to 180° C. while removing a small amount of water by distillation. After cooling to 80° C., 100 ml water was added and the solid was suction filtered. The filter cake was washed twice with 50 ml water and dissolved in 320 ml of a 5% sodium hydroxide solution. The insoluble noble metal catalyst was removed by filtration and the filtrate was stirred for 30 minutes at 50° C. with 3 g active carbon. After separating the active carbon, guanine was precipitated by addition of 20% sulphuric acid to pH 9.0, suction filtered, washed twice with 50 ml water and dried in a vacuum at 80° C. 26.7 g (0.174 mol, 87% of theory) 98.4% pure guanine was obtained in this manner.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=43)[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].Cl([O-])(=O)(=O)=O.[Li+].CCN(C(C)C)C(C)C.[O:51]1[C:53]([CH3:55])([CH3:54])[CH2:52]1>C1COCC1.C(Cl)Cl.O>[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[C:23]4[CH:26]=[CH:27][C:28]([CH:30]5[CH2:35][CH2:34][N:33]([CH2:52][C:53]([CH3:55])([OH:51])[CH3:54])[CH2:32][CH2:31]5)=[CH:29][C:22]=4[O:21][CH2:20][CH2:19][N:18]3[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9]
Reactant: CC1(C)CO1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(CC(C)(C)O)CC3)cc1OCC2
Temperature: 45 °C
Reaction time: 18 h
Yield: 33.5 %

Procedure:
To a stirred suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoro acetate (300 mg, 0.61 mmol) in THF (8 mL) was added lithium perchlorate (65 mg, 0.61 mmol) and DIPEA (0.21 mL, 1.21 mmol) followed by 1,2-epoxy-2-methylpropane (0.54 mL, 0.81 mmol) and the mixture stirred at RT for 5 h before the addition of water (2.5 mL). After stirring for a further 18 h then DIPEA (0.16 mL, 0.92 mmol) added and the mixture heated at 45° C. for 5 h then at RT for 72 h. The reaction mixture was diluted with DCM and washed with water before being dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, preconditioned with 25% TEA in DCM, gradient 0 to 5% methanol in DCM) then freeze dried from methanol/water and triturated in petroleum ether to give 292 as a cream solid (92 mg, 34%). LCMS: RT=2.76 min, [M+H]+=451. 1H NMR 400 MHz (DMSO-d) δ: 8.32 (1H, d, J=8.28 Hz), 7.90 (2H, d, J=2.80 Hz), 7.05 (1H, dd, J=8.35, 1.77 Hz), 6.90 (1H, d, J=1.70 Hz), 7.27-4.48 (1H, m), 4.49 (4H, q, J=5.87 Hz), 4.03 (1H, s), 3.04 (2H, d, J=10.80 Hz), 2.46 (1H, s), 2.23 (4H, s), 1.70 (4H, s), 1.48 (6H, d, J=6.59 Hz), 1.10 (6H, s)
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:14]([C:19]1[N:20]=[CH:21][N:22](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:23]=1)([OH:18])[CH:15]([CH3:17])[CH3:16])[CH:8]=[CH:7]2)[CH:2]=[CH2:3]>C1COCC1.CO.[C].[Pd]>[NH:22]1[CH:23]=[C:19]([C:14]([C:9]2[CH:8]=[CH:7][C:6]3[C:11](=[CH:12][CH:13]=[C:4]([CH2:1][CH2:2][CH3:3])[CH:5]=3)[CH:10]=2)([OH:18])[CH:15]([CH3:17])[CH3:16])[N:20]=[CH:21]1
Reactant: C=CCc1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 162.7 %

Procedure:
1-(6-Allylnaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.40 g) was dissolved in THF-methanol (1:2) (15 ml). To the solution was added 10% palladium carbon (140 mg), and the mixture was stirred at room temperature for 2 h under hydrogen atmosphere. The catalyst was filtered and washed with THF. The filtrate was concentrated. The residue was chromatographed on silica gel (eluent, hexane:THF=1:1) and crystallized from isopropyl ether-hexane to give the titled compound (1.28 g) as a colorless powder.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=O.C(Cl)(=O)C(Cl)=O.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[CH3:29].[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl.CN(C=O)C>[CH3:28][O:27][C:24]1[CH:23]=[C:22]([CH3:29])[C:21]([O:20][CH3:19])=[CH:26][C:25]=1[C:8](=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([CH3:1])([CH3:12])[CH3:11]
Reactant: COc1ccc(OC)c(C)c1
Reactant: CC(C)(C)CCCCCC(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C(=O)CCCCCC(C)(C)C)c(OC)cc1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1 g of 7,7-dimethyloctanoic acid is dissolved in 20 ml of DCM cooled to 0° C., 0.57 ml of oxalyl chloride is added and the mixture is then left stirring for 1 hour at 0° C. and for 2 hours at RT. 0.93 ml of 2,5-dimethoxytoluene and one drop of DMF are added, the mixture is cooled to 0° C., 940 mg of AlCl3 are then added and the mixture is left stirring for 1 hour at 0° C. and overnight at RT. It is poured into 10% HCl solution and extracted with ether, and the combined organic phases are then washed with 2N sodium hydroxide, dried and concentrated. The residue is chromatographed on silica, eluting with DCM/pentane (85/15; v/v) to give 1.05 g of the expected compound.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[CH3:20])[CH2:15]Br>CO>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[CH3:20])[CH2:15][CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)CC(=O)OC
Reactant: COc1cc(CBr)ccc1C
Solvent: CO
Product: COC(=O)C(Cc1ccc(C)c(OC)c1)C(=O)OC
Reaction time: 0.75 h
Yield: 95.4 %

Procedure:
A solution of 2.6 g (0.1124 g-atom) of Na in 50 mL of MeOH was treated with 12.9 mL (0.1124 mol) of dimethyl malonate and allowed to stir for 45 minutes. This was then treated dropwise with 24.17 g (0.1124 mol) of 3-methoxy-4-methylbenzyl bromide and the solution heated at reflux overnight. The solvent was removed under reduced pressure and the residue taken up in EtOAc. This was washed with 6% HCl, H2O, saturated NaHCO3, and saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure gave 28.54 g (95.5% yield) of the product as a pale yellow oil. The structure was confirmed by NMR spectroscopy.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:11])[NH:5][O:6][CH2:7][C:8]([OH:10])=O)[CH3:2].[NH2:12][C@@H:13]([CH2:37][C:38]([NH:40][C:41]([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)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[CH:25][CH:24]=[CH:23]2)=[O:15]>>[CH2:34]([O:33][CH:29]([O:30][CH2:31][CH3:32])[C@@H:28]([N:16]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[CH:25][CH:24]=[CH:23]2)[C:14](=[O:15])[C@@H:13]([NH:12][C:8](=[O:10])[CH2:7][O:6][NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:11])[CH2:37][C:38](=[O:39])[NH:40][C:41]([C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[CH3:36])[CH3:35]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCNC(=O)NOCC(=O)O
Product: CCNC(=O)NOCC(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N(Cc1cccc2cccnc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-ethylureidooxy)acetic acid (Compound VI-13) 38 mg (0.23 mmol) was coupled with (S)-2-amino-N1—((S)-1,1-diethoxypropan-2-yl)-N1-(quinolin-8-ylmethyl)-N4-tritylsuccinamide (Compound IV-20) 100 mg (0.16 mmol) to obtain the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:40]=[CH:39][C:18]([CH2:19][N:20]2[CH:24]([C:25]([OH:27])=[O:26])[CH2:23][C:22]3([CH2:32][CH2:31][N:30]([CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)[CH2:29][CH2:28]3)[CH2:21]2)=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.S(Cl)(Cl)=O.[CH3:45]O>>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[CH:24]([C:25]([O:27][CH3:45])=[O:26])[CH2:23][C:22]3([CH2:32][CH2:31][N:30]([CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)[CH2:29][CH2:28]3)[CH2:21]2)=[CH:39][CH:40]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=C(O)C1CC2(CCN(C3CCCCC3)CC2)CN1Cc1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CC2(CCN(C3CCCCC3)CC2)CN1Cc1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The compound (102 mg) obtained in Example 5(1) was dissolved in methanol (1 mL) and, furthermore, thionyl chloride (0.25 mL) was added at 0° C. The reaction solution was stirred at 60° C. for 1 hour. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel chromatography (manufactured by Fuji Silysia Chemical Ltd., CHROMATOREX NH (trade name)) (dichloromethane:methanol=1:0→4:1) to obtain the title compound (96.4 mg) having the following physical properties.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:22]=[C:23]([CH2:26]O)[S:24][CH:25]=4)[N:17]=3)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:53]1[CH2:56][CH:55]([C:57]([O:59][CH2:60][CH3:61])=[O:58])[CH2:54]1.C(N(CC)C(C)C)(C)C>>[C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:22]=[C:23]([CH2:26][N:53]5[CH2:56][CH:55]([C:57]([O:59][CH2:60][CH3:61])=[O:58])[CH2:54]5)[S:24][CH:25]=4)[N:17]=3)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1cc(-c2noc(-c3cc(-c4ccccc4)c(C(F)(F)F)s3)n2)cs1
Reactant: CCOC(=O)C1CNC1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CN(Cc2cc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)cs2)C1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1f) using (4-{5-[4-phenyl-5-(trifluoromethyl)-2-thienyl]-1,2,4-oxadiazol-3-yl}-2-thienyl)methanol (0.10 g, 0.25 mmol) that was obtained in Example 3 (3c), carbon tetrabromide (0.17 g, 0.50 mmol), triphenylphosphine (0.13 g, 0.50 mmol), ethyl 3-azetidinecarboxylate hydrochloride (62 mg, 0.38 mmol), and N,N-diisopropylethylamine (0.11 ml, 0.63 mmol). Subsequently, the crude product of the title compound thus obtained was purified by thin layer chromatography on a silica gel plate using a mixed solvent of ethyl acetate and hexane (2:3) as the developing solvent to afford the title compound (73 mg) in a yield of 56% as a white crystalline solid.