Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C@H:13]([NH:26][C:27](=[O:36])[C@H:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:29])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]([CH3:25])[CH2:23][CH3:24])=[CH:16][CH:15]=1.NN>CCO.CCOC(C)=O>[NH2:3][CH2:12][C@H:13]([NH:26][C:27](=[O:36])[C@H:28]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH3:29])[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][C@@H:22]([CH3:25])[CH2:23][CH3:24])=[CH:18][CH:19]=1
Reactant: CC[C@H](C)COc1ccc([C@H](CN2C(=O)c3ccccc3C2=O)NC(=O)[C@@H](C)c2ccccc2)cc1
Agent: NN
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC[C@H](C)COc1ccc([C@H](CN)NC(=O)[C@@H](C)c2ccccc2)cc1
Temperature: 55 °C
Yield: 96 %

Procedure:
To a solution of (S)-N-{(R)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-1-[4-((S)-2-methyl-butoxy)-phenyl]-ethyl}-2-phenyl-propionamide dissolved in 10 mL of EtOH, was added anhydrous hydrazine. The resulting mixture was heated to 55° C. 1.5 h. It was cooled to rt, and diluted with EtOAc. The solids were filtered off, and the filtrate concentrated and was purified by column chromatography on silica gel using 0%→10% MeOH/DCM to obtain 109 mg (96%) of the desired product. 1H NMR (400 MHz, MeOD) δ 7.19-7.33 (m, 5H), 7.05-7.12 (m, 2H), 6.79-6.88 (m, 2H), 5.12 (dd, J=8.8, 5.8 Hz, 1H), 3.77-3.86 (m, 1H), 3.69-3.77 (m, 2H), 3.21-3.29 (m, 2H), 1.81 (s, 1H), 1.57 (ddd, J=13.4, 7.6, 5.8 Hz, 1H), 1.47 (d, J=6.8 Hz, 3H), 1.22-1.35 (m, 1H), 1.02 (d, J=6.8 Hz, 3H), 0.96 (t, J=7.5 Hz, 3H); LCMS m/e calcd 355.2 [(M+H)+, for C22H31N2O2 355.2].
Reaction SMILES: FC(F)(F)C(O)=O.C1(SC)C=CC=CC=1.C1C(O)=CC=CC=1C.C([N:31]([CH2:39][C:40]1[S:44][C:43]([C:45]([NH:47][C@H:48]([C:63]([OH:65])=[O:64])[CH2:49][CH2:50][CH2:51][NH:52]C(OCC2C=CC=CC=2)=O)=[O:46])=[CH:42][CH:41]=1)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)(OC(C)(C)C)=O>>[N:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH2:32][NH:31][CH2:39][C:40]1[S:44][C:43]([C:45]([NH:47][C@H:48]([C:63]([OH:65])=[O:64])[CH2:49][CH2:50][CH2:51][NH2:52])=[O:46])=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccn1)Cc1ccc(C(=O)N[C@@H](CCCNC(=O)OCc2ccccc2)C(=O)O)s1
Solvent: CSc1ccccc1
Solvent: Cc1cccc(O)c1
Solvent: O=C(O)C(F)(F)F
Product: NCCC[C@H](NC(=O)c1ccc(CNCc2ccccn2)s1)C(=O)O
Reaction time: 1.5 h
Yield: 53.3 %

Procedure:
A mixed solution of trifluoroacetic acid (1.4 ml), thioanisole (0.36 ml), and m-cresol (0.32 ml) was added to the compound obtained in Example 14-3 (56.2 mg). After 1.5 hours, the reaction solution was concentrated. Methanol was added to the residue and the mixture was washed with hexane. The methanol layer was concentrated and the residue was crude-purified by silica gel column chromatography (3 g, chloroform/methanol/water=7/3/0.5) to obtain the title compound (18.2 mg) as colorless syrup.
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:7][CH:8]([O:18]CC)[C:9]1[N:10]=[CH:11][NH:12][C:13]=1[C:14](OC)=[O:15])C.C1(C)C=CC=CC=1>O>[CH:14]([C:13]1[N:12]=[CH:11][NH:10][C:9]=1[C:8]([O:7][CH3:5])=[O:18])=[O:15]
Reactant: CCOC(OCC)c1nc[nH]c1C(=O)OC
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1[nH]cnc1C=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Acetic acid (244 mmol, 34.7 equiv.) was added to a solution of methyl 4-(diethoxy-methyl)-1H-imidazole-5-carboxylate (7.04 mmol, 1 equiv.) in water (4.2 ml), and the resulting mixture was stirred for 6 h at 25° C. under nitrogen. Toluene was added to the reaction mixture, and the solvent was removed in vacuo in order thus to yield the desired product in the form of a yellow solid. This was used in the following stage without further purification. Yield: quantitative
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].ClC(OCC(C)C)=O.Cl.[NH2:23][C@H:24]([C:35]([OH:37])=[O:36])[CH2:25][CH2:26][CH2:27][NH:28][C:29](=[NH:34])[NH:30][N+:31]([O-:33])=[O:32]>CN(C=O)C>[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([NH:23][C@H:24]([C:35]([OH:37])=[O:36])[CH2:25][CH2:26][CH2:27][NH:28][C:29](=[NH:34])[NH:30][N+:31]([O-:33])=[O:32])=[O:6])[CH3:3]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N=C(NCCC[C@H](N)C(=O)O)N[N+](=O)[O-]
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O
Yield: 70.3 %

Procedure:
After 15.9 g (0.084 mole) of BOC-Ala-OH was dissolved in 84 ml of DMF, 10.9 ml (0.084 mole) of NEM was added to the solution. Then, 10.9 ml (0.084 mole) of isobutyl chloroformate was dropwise added to the solution at -20° C. The resulting mixture was reacted for 10 minutes. After completion of the reaction, 84 ml of a solution of 32.8 g (0.084 mole) of HCl.H-Arg(NO2)-CHA and 32.8 ml (0.252 mole) of NEM in DMF was dropwise added to the reaction solution at -15° to -10° C. After the dropwise addition, the mixture was reacted at the same temperature for 23 hours and further at room temperature (15° to 20° C.) for 18 hours. After the reaction, DMF was removed by distillation under reduced pressure and the residue was dissolved in 600 ml of AcOEt. After washing 3 times with 200 ml of cold 5% hydrochloric acid and twice with 200 ml of saturated sodium chloride aqueous solution, the solution was dried over anhydrous magnesium sulfate and decolored with activated charcoal. After drying, magnesium sulfate and activated charcoal were filtered off and the solvent was removed by distillation under reduced pressure. Recrystallization of the residue gave 31.0 g (70.3%) of BOC-Ala-Arg(NO2)-CHA.
Reaction SMILES: OS(O)(=O)=O.[CH2:6]([O:9][C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([OH:20])=[O:19])=[O:11])[CH:7]=[CH2:8].[CH3:21]O>>[CH2:6]([O:9][C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([O:20][CH3:21])=[O:19])=[O:11])[CH:7]=[CH2:8]
Reactant: CO
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: O=S(=O)(O)O
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Temperature: 25 °C
Yield: 43 %

Procedure:
A catalytic amount of concentrated H2SO4 (4.5 mL) was added to a solution of Alloc-hydroxyproline (12) (43 g, 200 mmol) in MeOH (300 mL) at 10° C. (ice) and the reaction mixture was then heated at reflux for 2 h. After cooling to room temperature the reaction mixture was treated with TEA (43 mL) and the MeOH evaporated in vacuo. The residue was dissolved in EtOAc (300 mL), washed with brine (200 mL), dried (MgSO4), filtered and concentrated in vacuo to give a viscous oil. Purification by flash chromatography (40% EtOAc/Petroleum Ether) removed the high Rf impurity to provide the pure ester 13 as a transparent yellow oil (19.6 g, 43%): [α]23D=79.0° (c=0.35, CHCl3); 1H NMR (270 MHz, CDCl3) (Rotamers) δ5.98-5.78 (m, 1H, NCO2CH2CH═CH2), 5.35-5.16 (m, 2H, NCO2CH2CH═CH2), 4.65-4.45 (m, 4H, NCO2CH2CH═CH2, NCH2CHOHCH2 and NCHCO2CH3), 3.75 and 3.72 (s×2, 3H, OCH3), 3.70-3.54 (m, 2H, NCH2CHOHCH2), 3.13 and 3.01 (br s×2, 1H, OH), 2.39-2.03 (m, 2H, NCH2CHOHCH2); 13C NMR (67.8 MHz, CDCl3) (Rotamers) δ173.4 and 173.2 (CO2CH3), 155.0 and 154.6 (NC═O), 132.6 and 132.4 (NCO2CH2CH═CH2), 117.6 and 117.3 (NCO2CH2CH═CH2), 70.0 and 69.2 (NCH2CHOH), 66.2 (NCO2CH,CH═CH2), 57.9 and 57.7 (NCHCO2CH3), 55.2 and 54.6 (NCH2CHOH), 52.4 (OCH3), 39.1 and 38.4 (NCH2CHOHCH2); MS (EI), m/z (relative intensity) 229 (M+., 7), 170 (M—CO2Me, 100), 144 (M—CO2C3H5, 12), 126 (26), 108 (20), 68 (7), 56 (8); IR (Neat) 3438 (br, OH), 2954, 1750 and 1694 (br, C═O), 1435, 1413, 1345, 1278, 1206, 1130, 1086, 994, 771 cm−1; exact mass calcd for C10H15NO5 m/e 229.0950, obsd m/e 229.0940.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:20]=[C:19]([NH2:29])[N:18]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>C1COCC1>[NH2:29][C:19]1[N:18]=[C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([O:9][C:7]3[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][NH:1][C:35](=[O:36])[C:34]4[CH:38]=[CH:39][C:31]([F:30])=[CH:32][CH:33]=4)[CH:8]=3)=[CH:15][CH:14]=2)[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:20]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NCc1cc(Oc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1
Solvent: C1CCOC1
Product: Nc1nc(Nc2ccc(Oc3ccnc(CNC(=O)c4ccc(F)cc4)c3)cc2)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.7 %

Procedure:
N4-(4-{[2-(Aminomethyl)pyridin-4-yl]oxy} phenyl)-6-phenylpyrimidine-2,4-diamine (50 mg, 0.13 mmol, Example 39) and 4-fluorobenzoyl chloride (20.6 mg, 0.13 mmol) were suspended in THF (1 mL) and stirred at rt for 24 h. TLC and LC-MS indicated the reaction was completed. The mixture was extracted with EtOAc and washed with 1N aqueous sodium hydroxide solution (2×) and H20 (3×). The organic layer was dried and concentrated to give 68 mg of the crude product. The residue was purified by Prep-TLC (CH3OH:EtOAc=2:8) to obtain 38 mg (58%) of the title product as a yellowish oil. 1H NMR (CD3OD) δ 8.34 (d, 1H), 7.82 (m, 4H), 7.78 (d, 2H), 7.44 (m, 3H), 7.15 (t, 2H), 7.02 (d, 2H), 6.85 (d, 1H), 6.82 (s, 1H), 6.42 (s, 1H), 4.59 (s, 2H); MS ES 507 (M+H)+, calcd 507, RT=2.50 min; TLC (MeOH/EtOAc=20/80) Rf=0.57.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[CH:8]=2)=[CH:4][C:3]=1[F:16].C(N(CC)CC)C.Cl[C:25](OC1C=CC=CC=1)=[O:26].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>O1CCCC1.CN(C)C=O>[NH2:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:25]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[O:26])[CH:8]=2)=[CH:4][C:3]=1[F:16]
Reactant: C1COCCN1
Reactant: Nc1cc(Oc2ccc(N)c(F)c2)ccn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCOCC3)c2)cc1F
Yield: 6.3 %

Procedure:
To a solution of 4-(4-amino-3-fluorophenoxy)pyridin-2-ylamine (500 mg) in tetrahydrofuran (23 ml) was added triethylamine (0.318 ml), and then phenyl chloroformate (0.357 ml, 2.28 mmol) was added thereto while stirring in an ice bath, followed by stirring under a nitrogen atmosphere for 1 hr and 20 min. The reaction mixture was concentrated under a reduced pressure to give a residue, to which N,N-dimethylformamide (20 ml) and morpholine (0.994 ml) were added, followed by stirring at room temperature for 8 hrs. The reaction mixture was partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1, ethyl acetate, then ethyl acetate:methanol=10:1). The resultant solid was suspended in ethyl acetate:diethyl ether (1:10), filtered, washed with diethyl ether, and dried under aeration to provide the titled compound (48 mg, 6.3%) as pale red powder.
Reaction SMILES: C(OC1C=C(C=C([N+]([O-])=O)C=1C1C=CC=CC=1)C(O)=O)C1C=CC=CC=1.[N+:27]([C:30]1[C:31]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[C:32]([CH2:39][CH2:40][CH3:41])[CH:33]=[C:34]([CH:38]=1)[C:35]([OH:37])=[S:36])([O-])=O>>[NH2:27][C:30]1[C:31]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[C:32]([CH2:39][CH2:40][CH3:41])[CH:33]=[C:34]([CH:38]=1)[C:35]([OH:37])=[S:36]
Reactant: CCCc1cc(C(O)=S)cc([N+](=O)[O-])c1-c1ccccc1
Agent: O=C(O)c1cc(OCc2ccccc2)c(-c2ccccc2)c([N+](=O)[O-])c1
Product: CCCc1cc(C(O)=S)cc(N)c1-c1ccccc1

Procedure:
By replacing in Example 2, step D, 3-benzyloxy-5-nitro-4-phenylbenzoic acid with 5-nitro-4-phenyl-3-n-propylthiobenzoic acid, and following the procedure described, 5-amino-4-phenyl-3-n-propylthiobenzoic acid is obtained with a melting point of 190°-191° C.
Reaction SMILES: [Cl-].[C:2]1([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:38]=[CH:37][C:16]([CH2:17][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[C:15](OC)[CH:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[CH:52]([C:54]1[CH:66]=[CH:65][CH:64]=[CH:63][C:55]=1[O:56][CH2:57][C:58]([O:60][CH2:61][CH3:62])=[O:59])=O.[Cl-].[NH4+].[O:69]1CCC[CH2:70]1>>[CH3:70][O:69][C:38]1[CH:37]=[C:16]([CH:15]=[CH:14][C:13]=1[O:12][CH2:11][CH2:10][CH2:9][CH2:8][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:17]=[CH:52][C:54]1[CH:66]=[CH:65][CH:64]=[CH:63][C:55]=1[O:56][CH2:57][C:58]([O:60][CH2:61][CH3:62])=[O:59]
Reactant: C1CCOC1
Reactant: CCOC(=O)COc1ccccc1C=O
Reactant: COc1cc(OCCCCc2ccccc2)ccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Product: CCOC(=O)COc1ccccc1C=Cc1ccc(OCCCCc2ccccc2)c(OC)c1
Reaction time: 0.17 h

Procedure:
To a suspension of 260 mg of [4-(4-phenylbutoxy)-2-methoxybenzyl]triphenylphosphonium choride obtained in Reference Example 22 in 2.5 ml of tetrahydrofuran was dropwise added 0.36 ml of a 1.42M n-butyl lithium/hexane solution. The mixture was stirred for 10 minutes to form a dark red solution. The solution was dropwise added to a solution of 114 mg of ethyl o-formylphenoxyacetate in 1 ml of tetrahydrofuran at 0° C. using an injection tube. After stirring for 20 minutes, a saturated ammonium chloride aqueous solution was added thereto. The product was extracted with ether. After washing with water and then an aqueous saline solution, the ethereal layer was dried and concentrated. The crude product was fractionated and separated by TLC (developer; hexane:methylene chloride:acetone=8:2:1) to obtain 170 mg of ethyl o-[3-methoxy-4-(4-phenylbutoxy)styryl]phenoxyacetate.
Reaction SMILES: [N+:1]([CH2:4][CH:5]1[O:9][B:8]([OH:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]1=2)([O-:3])=[O:2].[N+:15]([O-])([OH:17])=[O:16]>>[N+:15]([C:12]1[CH:13]=[CH:14][C:6]2[CH:5]([CH2:4][N+:1]([O-:3])=[O:2])[O:9][B:8]([OH:10])[C:7]=2[CH:11]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: O=[N+]([O-])CC1OB(O)c2ccccc21
Product: O=[N+]([O-])CC1OB(O)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C

Procedure:
3-Nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol (20.0 g, 104 mmol) was added in small portions with stirring over 2 h to fuming HNO3 (200 mL) at −45° C. (bath temp). The cold reaction mixture was then poured into crushed ice and allowed to warm to rt. The aqueous phase was extracted with EtOAc. The EtOAc phase was concentrated in vacuo and the residue was poured into crushed ice. The precipitate was filtered and washed with H2O. The solid was dissolved in EtOAc, dried (Na2SO4), and concentrated in vacuo to yield the title compound: yield (14.3 g, 58%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[CH2:26]([O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Cl)=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[CH2:26]([O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCC[Sn](CCCC)(CCCC)Cc1ccc(OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To a mixture of diisopropylamine (1.1 mL, 7.7 mmol) and tetrahydrofuran (20 mL) was added dropwise n-butyl lithium (1.6 M n-hexane solution, 4.5 mL, 7.1 mmol) at −78° C., which was stirred for 30 minutes at that temperature. Tributyltin hydride (1.7 mL, 6.5 mmol) was added dropwise to the reaction mixture at the same temperature and then stirred for 30 minutes at 0° C. The reaction mixture was cooled to −78° C., and a mixture of 4-benzyloxybenzyl chloride (1.5 g, 6.5 mmol) and tetrahydrofuran (10 mL) was added dropwise at that temperature. The reaction mixture was gradually warmed to room temperature. The reaction mixture was partitioned into water and n-heptane. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by neutral silica gel column chromatography (ethyl acetate:heptane=1:30) to obtain the title compound (2.6 g, 83%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:29])[C:13](=[N:26][C:27]#[N:28])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([C:24]#[N:25])([CH3:23])[CH3:22])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.[B:30]1(B2OC(C)(C)C(C)(C)O2)[O:34]C(C)(C)C(C)(C)[O:31]1.C([O-])(=O)C.[K+].C(Cl)Cl>O1CCOCC1.C(OCC)(=O)C>[C:27]([N:26]=[C:13]1[N:12]([CH3:29])[C:6]2[CH:7]=[N:8][C:9]3[CH:10]=[CH:11][C:2]([B:30]([OH:34])[OH:31])=[CH:3][C:4]=3[C:5]=2[N:14]1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:24]#[N:25])([CH3:22])[CH3:23])=[CH:17][CH:16]=1)#[N:28]
Reactant: Cn1c(=NC#N)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(Br)ccc3ncc21
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1c(=NC#N)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(B(O)O)ccc3ncc21

Procedure:
N-(8-bromo-1-(4-(2-cyanopropan-2-yl)phenyl)-3-methyl-1H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (2.463 mmol), bis(pinacolato)diboron (1.347 mmol), potassium acetate (2.246 mmol) and (1,1-bis(diphenylphosphino)ferrocene)-dichloropalladium (II) complex with DCM (50 mg) was dissolved in dioxane under argon atmosphere. The reaction mixture was refluxed for 8 h. The reaction mixture was cooled, diluted with ethyl acetate (15 mL) and filtered. The filtrate was concentrated. The crude product was purified (silica gel column ethyl acetate/petroleum ether) to obtain the title compound. 1HNMR (300 MHz, DMSO-d6): δ 9.17 (s, 1H), 8.05 (m, 4H), 7.86 (m, 6H), 7.26 (s, 1H), 3.88 (s, 3H), 1.78 (s, 6H); MS (m/z): 411(M+1)+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:13]=[C:14]([OH:32])[C:15]([CH3:31])=[C:16]([CH:30]=1)[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:18].[C:33]([Si:37]([CH3:40])([CH3:39])Cl)([CH3:36])([CH3:35])[CH3:34].C(N(CC)CC)C>CN(C)C=O>[Si:37]([O:32][C:14]1[C:15]([CH3:31])=[C:16]([CH:30]=[C:12]([N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])[CH:13]=1)[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:18])([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:40])[CH3:39]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1c(O)cc(N2C(=O)c3ccccc3C2=O)cc1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(O[Si](C)(C)C(C)(C)C)cc(N2C(=O)c3ccccc3C2=O)cc1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 20 °C
Reaction time: 24 h
Yield: 71.2 %

Procedure:
To a suspension of 1.0 g of p-nitrobenzyl 5-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-hydroxy-2-methylbenzoate in 30 ml of dimethylformamide were added 0.71 g of tert-butyldimethylchlorosilane and 0.48 g of triethylamine, and the mixture was stirred at 20° C. for 24 hours. The solvent was evaporated in vacuo, and the residue was partitioned between 2N hydrochloric acid and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and the solvent was evaporated in vacuo. The residual oil was chromatographed on silica gel using methylene chloride as eluent to yield 0.90 g of p-nitrobenzyl 3-(tert-butyldimethylsilyloxy)-5-(1,3-dioxo-1,3-dihydro-isoindol-2-yl )-2-methylbenzoate as white solid, m.p. 125°-127° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:33]1([C@@H:39]2[CH2:44][CH2:43][CH2:42][CH2:41][C@H:40]2O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.N(C(OCC)=O)=N[C:48](OCC)=[O:49]>C1COCC1>[C:33]1([C@H:39]2[CH2:44][CH2:43][CH2:42][CH2:41][C@H:40]2[C:48]([O:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=2)=[O:49])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: COC(=O)c1ccc(O)cc1OC
Reactant: O[C@@H]1CCCC[C@H]1c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(=O)[C@@H]2CCCC[C@@H]2c2ccccc2)cc1OC
Temperature: 0 °C

Procedure:
To a stirred solution of methyl 4-hydroxy-2-methoxybenzoate (310 mg, 1.7 mmol) in dry THF (1.25 mL) was added triphenylphosphine (446 mg, 1.7 mmol) and the solution was cooled to 0° C. A 500 mL volume of trans-2-phenyl-1-cyclohexanol (200 mg, 1.35 mmol) and diethyl azodicarboxylate (319 μL, 2.02 mmol) in THF was added dropwise via addition funnel over 0.5 h. The reaction was filtered and the solvent was removed under reduced pressure. The residue was chromatographed on a silica gel column packed in 92:8 hexanes:EtOAc and eluted with same. The appropriate fractions were combined and the solvent removed under reduced pressure to afford methyl 4-(cis-2-phenyl-1-cyclohexanoyloxy)-2-methoxybenzoate.
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:24]([CH2:25][C:26]4[N:30]([CH3:31])[N:29]=[N:28][N:27]=4)[CH2:23][CH2:22][C:21]([C:32]([O:34]C)=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>C1COCC1.CO>[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:24]([CH2:25][C:26]4[N:30]([CH3:31])[N:29]=[N:28][N:27]=4)[CH2:23][CH2:22][C:21]([C:32]([OH:34])=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2nnnn2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2nnnn2C)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 80.4 %

Procedure:
In THF (6.4 ml)/methanol (3.2 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(1-methyltetrazol-5-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.32 g). To the solution was added 1N sodium hydroxide solution (3.2 ml), and the mixture was stirred at room temperature for 14 hours. pH was adjusted to approximate 4 with 1N hydrochloric acid, and the solvent was concentrated to half under reduced pressure. The concentrated material was extracted with ethyl acetate/THF, and the extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was washed with hexane/ethyl acetate (5/1) to give 7-[4-(2-butoxyethoxy)phenyl]-1-(1-methyltetrazol-5-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.25 g).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:22]([C@H:24]([C@@H:26]([OH:42])[C@@H:27]([CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([OH:38])[C:32]=1[C:39]([OH:41])=[O:40])[CH3:28])[CH3:25])=[O:23])[C@H:4]1[O:8][C@@:7]([C@@H:11]2[O:16][C@@H:15]([CH3:17])[C@@:14]([OH:20])([CH2:18][CH3:19])[CH2:13][CH2:12]2)([CH2:9][CH3:10])[CH2:6][C@@H:5]1[CH3:21].[CH2:43](Cl)Cl.CI>[Ag]=O.CO>[CH3:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH2:29][CH:27]([CH3:28])[CH:26]([OH:42])[CH:24]([CH3:25])[C:22](=[O:23])[CH:3]([CH2:2][CH3:1])[CH:4]2[CH:5]([CH3:21])[CH2:6][C:7]([CH2:9][CH3:10])([CH:11]3[CH2:12][CH2:13][C:14]([CH2:18][CH3:19])([OH:20])[CH:15]([CH3:17])[O:16]3)[O:8]2)=[C:32]([C:39]([O:41][CH3:43])=[O:40])[C:33]=1[OH:38]
Reactant: ClCCl
Reactant: CC[C@@H](C(=O)[C@@H](C)[C@@H](O)[C@H](C)CCc1ccc(C)c(O)c1C(=O)O)[C@H]1O[C@](CC)([C@H]2CC[C@](O)(CC)[C@H](C)O2)C[C@@H]1C
Agent: O=[Ag]
Solvent: CI
Solvent: CO
Product: CCC(C(=O)C(C)C(O)C(C)CCc1ccc(C)c(O)c1C(=O)OC)C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C
Reaction time: 18 h

Procedure:
To a solution of 6.2 g. of crystalline antibiotic X-537A in 125 ml. of methylene chloride was added 4.6 g. of silver oxide and 14 g. of methyl iodide. After stirring for 18 hours, the reaction mixture was filtered and the filtrate concentrated to 7.07 g. of a light yellow oil, which was decolorized with Darco, giving 6.09 g. of a colorless foam. A portion (4 g.) of the foam was chromatographed on a florisil column (150 g.) eluting with a gradient between methylene chloride (1 1.) to ether (1 1. ) and then ether (500 ml.) to acetone (500 ml.). Rechromatography of the slightly yellow oil, recovered from the florisil column, on a 75 g. silica gel column and eluting with a gradient between methylene chloride (1 1.) and 15% ether/methylene chloride gave 200 mg. of a clear viscous oil, Bp. 170°d/005 mm. [α]D25 -7.19°, (1.1%, CH3OH).