Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:33])(=[O:32])[CH2:2][CH2:3][C@H:4]([NH:8][C:9]([C:11]1[CH:31]=[CH:30][C:14]([N:15]2[CH2:27][CH:26]3[N+:17]([C:18]4[C:19](=[O:29])[NH:20][C:21]([NH2:28])=[N:22][C:23]=4[NH:24][CH2:25]3)=[CH:16]2)=[CH:13][CH:12]=1)=[O:10])[C:5]([OH:7])=[O:6].[OH2:34]>>[CH:12]1[C:11]([C:9]([NH:8][C@H:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2][C:1]([OH:33])=[O:32])=[O:10])=[CH:31][CH:30]=[C:14]([NH:15][CH2:27][CH:26]2[N:17]([CH:16]=[O:34])[C:18]3[C:19]([N:20]=[C:21]([NH2:28])[NH:22][C:23]=3[NH:24][CH2:25]2)=[O:29])[CH:13]=1
Reactant: O
Reactant: Nc1nc2c(c(=O)[nH]1)[N+]1=CN(c3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)CC1CN2
Product: Nc1nc(=O)c2c([nH]1)NCC(CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)N2C=O

Procedure:
The reaction of this invention comprises mixing 5,10-methenyl-5,6,7,8-tetrahydrofolic acid (anhydroleucovorin), an amine base, and water and heating the mixture at a temperature of from about 50° C. to reflux for a period of time of from about 30 min to about 10 hours, perferably about 4-6 hours, at a pH of from about 5-7 to give leucovorin. The pH of the mixture is adjusted to and maintained at 5 to 7 by the addition or removal, as appropriate, of suitable amounts of the amine bases useful in this invention. The anhydroleucovorin may be used in the form of its internal salt (i.e. zwitterion) or as a salt with a suitable anion, preferably chloride, normally as a hydrate. After the ring opening reaction is complete, the reaction mixture is generally cooled and filtered. Slightly more than an equimolar (to anhydroleucovorin) amount of a water soluble calcium salt, e.g. chloride, bromide, iodide, nitrate, acetate, is then added either as an aqueous solution or as a solid to the filtrate and calcium leucovorin is precipitated by adding a water soluble organic solvent, e.g. a lower alkanol such as methanol, ethanol, isopropanol, or acetone. The calcium leucovorin is than removed by filtration, washed with a suitable solvent such as aqueous ethanol, ethanol, acetone, ether, ethyl acetate or the like and dried. Column chromatography is generally not required since the product so obtained meets or exceeds USP specifications.
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[CH2:3][C@H:4]([NH:13][C:14]([C@H:16]1[O:20]C(C2C=CC=CC=2)[O:18][C@@H:17]1[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:15])[C:5](=[O:12])[NH:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10]>C(O)(=O)C.[Pd]>[OH:18][C@@H:17]([C@H:16]([OH:20])[C:14](=[O:15])[NH:13][C@H:4]([C:5](=[O:12])[NH:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH:2]([CH3:32])[CH3:1])[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)[C@H]1OC(c2ccccc2)O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C
Temperature: 25 °C
Reaction time: 60 h
Yield: 83 %

Procedure:
Ethyl (4S,5S)-5-[(S)-3-methyl-1-(3-methylbutylcarbamoyl)butylcarbamoyl]-2-phenyl-1,3-dioxolane-4-carboxylate (2.07 g) obtained in Example 1 was dissolved in acetic acid (40 ml). Palladium black (0.40 g) was added to the resultant solution, and the solution was strongly stirred at room temperature for 60 hours under a hydrogen flow at 4.1 atm. After the catalyst was filtered off, the filtrate was condensed under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (a developing solvent; hexane:ethyl acetate=1:1→1:3) to obtain 1.38 g of a target compound. NMR data of the compound was as follows.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2ccc([N+](=O)[O-])cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ccc(N)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-Nitro-indole-1-carboxylic acid t-butyl ester (1 eq) was dissolved in methanol (0.1M), to this solution was added palladium on carbon (0.1 eq) in methanol under nitrogen. A hydrogen atmosphere was then inserted and resulting mixture allowed to stir for 3 hours at room temperature. The reaction mixture was then filtered through celite and solvent removed in vacuo to afford 6-Amino-2,3-dihydro-indole-1-carboxylic acid t-butyl ester as a white solid. MS: MH+235
Reaction SMILES: [CH2:1]([O:3][CH2:4]Cl)[CH3:2].[OH-].[Na+].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([C:29]3[NH:30][CH:31]=[CH:32][CH:33]=3)[S:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[CH:12][CH:11]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1.O>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[N:17]=[C:18]([C:29]3[N:30]([CH2:4][O:3][CH2:1][CH3:2])[CH:31]=[CH:32][CH:33]=3)[S:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[CH:14][CH:15]=1
Reactant: CCOCCl
Reactant: COc1ccc(-c2nc(-c3ccc[nH]3)sc2-c2ccc(OC)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOCn1cccc1-c1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)s1
Yield: 48 %

Procedure:
4,5-Bis(4-methoxyphenyl)-2-(pyrrol-2-yl)thiazole obtained in the same manner as described in Reference Example 6 (1.81 g, 5 mmole), chloromethyl ethyl ether (0.57 g, 6 mmole), and tetra-n-butylammonium bromide (0.16 g, 0.5 mmole) are refluxed in two phases of benzene (20 ml) and 50% aqueous sodium hydroxide (20 ml) for 20 minutes. To the mixture are added water and benzene under ice-cooling, and the mixture is shaken. The benzene layer is taken, washed with water, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue is subjected to silica gel column chromatography (solvent, ethyl acetate:cyclohexane=1:20) and is recrystallized from n-hexane to give 4,5-bis(4-methoxyphenyl)-2-(1-ethoxymethylpyrrol-2-yl)thiazole (1.01 g, yield: 48%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](Cl)=O.[Br:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2.C(O)(=O)C.C([BH3-])#[N:29].[Na+]>CO.C1COCC1>[Br:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2.[Br:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][CH:20]([NH:29][C@@H:8]([CH3:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)[CH2:19][CH2:18]2
Reactant: [BH3-]C#N
Reactant: O=C(Cl)Cc1ccccc1Br
Agent: O=C1CCc2cccc(Br)c2C1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: C[C@H](NC1CCc2cccc(Br)c2C1)c1ccccc1
Reaction time: 3 h

Procedure:
Initially, 8-Bromo-2-tetralone was prepared by substituting 2-bromophenylacetylchloride in the procedure described in A. H. Horn, C. J. Grol, D. Dijkstra, A. H. Mulder, J. Med. Chem. 21,825 (1978). Next, 8-bromo-2-tetralone (25 g, 111.1 mmol), S-(-)-alpha-methylbenzylamine (71.5 ml, 5 eq.), acetic acid (80 ml), 4 A molecular sieves (15 ml), THF (125 ml) and methanol (125 ml) were introduced into a flask and cooled to 0°. Sodium cyanoborohydride (1.5 g, 2 eq.) was added in portions over a 15 min period. The slurry was allowed to stir for 3 hr. The slurry was filtered and the solvent reduced to a syrup by evaporation in vacuo. The residue was partitioned between ether and 2N aqueous sodium hydroxide. The ether layer was washed with water (3×) and brine. After drying over anhydrous sodium sulfate the solvent was removed in vacuo. The viscous oil was placed on a flash silica gel column (5 cm×50 cm) and eluted with ethyl acetate/hexane (8%) to separate the higher Rf (+)-diastereomer (solidifies upon standing, 17 g). The solvent was raised to 12% to elute the lower Rf (-)-diastereomer (an oil, 16 g). In this manner the 8-bromo-N-[(S)-alpha-methylbenzyl]-2-aminotetralin was obtained.
Reaction SMILES: C(N1CCC(=O)CC1)(=[O:8])C1C=CC=CC=1.COC(C=[P:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O>C1(C)C=CC=CC=1>[C:34]1([P:21](=[O:8])([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Under N2, a mixture of 1-benzoyl-4-piperidone (10.2 g, 0.05 mol), methyl (triphenylphosphoranylidene) acetate (25 g. 0.074 mol) in toluene (100 ml) was heated at reflux for 7 hours. After stirring at room temperature overnight, the solid was filtered off to yield 13.9 g (100%) of triphenylphosphine oxide. The mother liquor was concentrated to dryness and the residue was treated with acetic acid (42 ml), H2O, (6 ml) and 12N HCl (6 ml). The mixture was heated at 80°-85° C. with stirring for 15 hours. The reaction was then concentrated to dryness and the residue was partitioned between saturated Na2CO3 and ethyl acetate. The aqueous layer was further extracted with ethyl acetate (1×), neutralized to pH 3 with 6N HCl and extracted with ethylacetate (4×). The organic layer was dried, filtered and concentrated to dryness to yield 7.2 g (59%) of title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:52])[C@@H:7]([NH:31][C:32](=[O:51])[NH:33][C@@H:34]([CH2:42][CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:30])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](ON1C(=O)CCC1=O)=[O:21])([CH3:4])([CH3:3])[CH3:2].[NH2:53][C@@H:54]([CH2:58][CH2:59][CH2:60][CH2:61][N:62]([CH2:77][C:78]1[N:79]([CH2:83][C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[CH:80]=[CH:81][N:82]=1)[CH2:63][C:64]1[N:65]([CH2:69][C:70](=[O:76])[O:71][C:72]([CH3:75])([CH3:74])[CH3:73])[CH:66]=[CH:67][N:68]=1)[C:55]([OH:57])=[O:56].CCN(C(C)C)C(C)C>CN(C=O)C>[C:72]([O:71][C:70](=[O:76])[CH2:69][N:65]1[CH:66]=[CH:67][N:68]=[C:64]1[CH2:63][N:62]([CH2:77][C:78]1[N:79]([CH2:83][C:84](=[O:85])[O:86][C:87]([CH3:90])([CH3:89])[CH3:88])[CH:80]=[CH:81][N:82]=1)[CH2:61][CH2:60][CH2:59][CH2:58][C@@H:54]([C:55]([OH:57])=[O:56])[NH:53][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13](=[O:30])[NH:12][CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:52])[NH:31][C:32](=[O:51])[NH:33][C@H:34]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:42][CH2:43][C:44](=[O:45])[O:46][C:47]([CH3:49])([CH3:50])[CH3:48])([CH3:73])([CH3:75])[CH3:74]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)CCCCCCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)Cn1ccnc1CN(CCCC[C@H](N)C(=O)O)Cc1nccn1CC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)CCCCCCC(=O)N[C@@H](CCCCN(Cc1nccn1CC(=O)OC(C)(C)C)Cc1nccn1CC(=O)OC(C)(C)C)C(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 22.8 %

Procedure:
A solution of (S)-di-tert-butyl 2-(3-((S)-1-tert-butoxy-6-(8-(2,5-dioxopyrrolidin-1-yloxy)-8-oxooctanamido)-1-oxohexan-2-yl)ureido)pentanedioate (0.291 g, 0.45 mmol), (S)-2-amino-6-(bis((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)hexanoic acid (0.22 g, 0.412 mmol) and DIPEA (1.0 mL) in DMF (4.0 mL) was stirred at room temperature for overnight. The solvent was evaporated to give a residue, which was purified by Biotage eluting with DCM/MeOH to give (7S,11S,26S)-26-(4-(bis((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)butyl)-7,11-bis(tert-butoxycarbonyl)-2,2-dimethyl-4,9,17,24-tetraoxo-3-oxa-8,10,16,25-tetraazaheptacosan-27-oic acid (0.1089 g, 21%). MS (ESI), 581 (M/2+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH2:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:24]([O:26][CH3:27])=[O:25])=[CH:5][C:4]=2[N:3]=1.[O:28]=[C:29]1[CH:33]=[CH:32][C:31](=[O:34])[N:30]1[CH2:35][CH:36]1[CH2:41][CH2:40][CH:39]([C:42](ON2C(=O)CCC2=O)=[O:43])[CH2:38][CH2:37]1.CCN(CC)CC>CN(C=O)C>[CH2:20]([C:13]1[N:14]([CH2:15][C:16]([OH:19])([CH3:17])[CH3:18])[C:10]2[C:9]3[CH:8]=[CH:7][C:6]([C:24]([O:26][CH3:27])=[O:25])=[CH:5][C:4]=3[N:3]=[C:2]([NH:1][C:42]([CH:39]3[CH2:38][CH2:37][CH:36]([CH2:35][N:30]4[C:29](=[O:28])[CH:33]=[CH:32][C:31]4=[O:34])[CH2:41][CH2:40]3)=[O:43])[C:11]=2[N:12]=1)[CH2:21][CH2:22][CH3:23]
Reactant: O=C(ON1C(=O)CCC1=O)C1CCC(CN2C(=O)C=CC2=O)CC1
Reactant: CCCCc1nc2c(N)nc3cc(C(=O)OC)ccc3c2n1CC(C)(C)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCc1nc2c(NC(=O)C3CCC(CN4C(=O)C=CC4=O)CC3)nc3cc(C(=O)OC)ccc3c2n1CC(C)(C)O
Temperature: 50 °C
Yield: 68 %

Procedure:
To a solution of 4-amino-2-butyl-1-(2-hydroxy-2-methylpropyl)-7-methoxycarbonyl-1H-imidazo[4,5-c]quinoline S7 (37 mg, 0.1 mmol, 1.0 equiv) and 2,5-dioxopyrrolidin-1-yl 4-[(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl]cyclohexanecarboxylate (66 mg, 0.20 mmol, 2.0 equiv) in DMF (2.0 mL) at 25° C. was added NEt3 (40 μL, 0.30 mmol, 3.0 equiv) in one injection. The reaction was heated at 50° C. for 24 h. The solvent was then removed in vacuo and the solid was redissolved in 1:9 MeOH/EtOAc (50 mL), washed successively with saturated NaHCO3 solution (15 mL), H2O (15 mL) and saturated aqueous NaCl (15 mL) and the organic layer concentrated. TLC and MS analysis indicated existence of both the imidazoquinoline starting material and the desired product. Purification by flash column chromatography on silica gel (CH2Cl2-1/9 MeOH/CH2Cl2, gradient) afforded the title compound 550 (40 mg, 68%) as a white solid: 1H NMR (CD3OD, 600 Hz) δ1.04 (t, J=7.2 Hz, 3H), 1.11-1.18 (m, 2H), 1.26 (br s, 6H), 1.51-1.66 (m, 4H), 1.68-1.85 (m, 3H), 1.91 (pent, J=7.2 Hz, 2H), 3.13 (t, J=7.2 Hz, 2H), 3.40 (d, J=7.2 Hz, 2H), 6.83 (s, 2H), 7.98 (d, J=9.0 Hz, 1H), 8.41 (d, J=9.0 Hz, 1H), 8.66 (s, 1H); 13C NMR (CD3OD, 150 Hz) δ 12.9, 22.3, 27.2, 28.5, 28.7, 29.5, 29.6, 36.6, 43.1, 45.4, 51.4, 54.9, 71.1, 119.9, 121.4, 123.7, 126.5, 126.6, 126.6, 128.0, 128.8, 130.5, 133.9, 135.2, 142.5, 144.3, 158.2, 159.9, 160.0, 166.8, 171.4; MS (APCI+): calcd C32H40N5O6 [M+H]+ 590.3. found 590.3.
Reaction SMILES: [NH2:1][OH:2].[CH3:3][O:4][C:5]1[CH:31]=[CH:30][C:8]([CH2:9][CH2:10][N:11]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:12][CH2:13][C:14](OCC)=[O:15])=[CH:7][CH:6]=1.Cl>C(OCC)C>[OH:2][NH:1][C:14](=[O:15])[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][C:8]1[CH:30]=[CH:31][C:5]([O:4][CH3:3])=[CH:6][CH:7]=1)[S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20]
Reactant: NO
Reactant: CCOC(=O)CCN(CCc1ccc(OC)cc1)S(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(CCN(CCC(=O)NO)S(=O)(=O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
Freshly prepared hydroxylamine reagent (6 mL; 6 mmol) was added to ethyl 3-[(4-methoxyphenethyl)-(4-methoxybenzenesulfonyl)-amino]-propionate (587 mg; 1.40 mmol) and the resulting mixture stirred overnight at room temperature. The mixture was poured into 1 N HCl (40 mL) and extracted with CH2Cl2 (2×40 mL). The combined extracts were washed with saturated aqueous NaCl (40 mL), dried over MgSO4, and evaporated under reduced pressure to give crude product. Trituration with diethyl ether afforded 408 mg (71%) of the title compound as a white solid. 300 MHz 1H-NMR (DMSO-d6): δ 2.24 (t, 2H), 2.68 (t, 2H), 3.21 (t, 2H), 3.31 (m, 2H), 3.72 (s, 3H), 3.84 (s, 3H), 6.84 (d, 2H), 7.11 (d, 4H), 7.71 (d, 2H), 8.78 (s, 1H), 10.49 (s, 1H).
Reaction SMILES: [OH-].[Li+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([P:33]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)(=[O:42])[O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[P:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)([O:5]C)=[O:4].Cl>O.O1CCOCC1>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([P:33]([O:43][CH2:44][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)(=[O:42])[O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[P:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:24])[O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:9][CH:8]=1)([OH:5])=[O:4]
Reactant: COC(=O)c1ccc(CC(P(=O)(OCc2ccccc2)OCc2ccccc2)P(=O)(OCc2ccccc2)OCc2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(CC(P(=O)(OCc2ccccc2)OCc2ccccc2)P(=O)(OCc2ccccc2)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 52.2 %

Procedure:
A solution of lithium hydroxide (84 mg, 2.0 mmol) in water (1.0 mL) is added to a solution of methyl ester 2 (455 mg, 0.6 mmol) in 1,4-dioxane (1.0 mL) at room temperature. The mixture is stirred at room temperature for 5 hours and a 1N solution of HCl (10 mL) is added. Dioxane is evaporated under reduced pressure and the mixture is diluted with EtOAc (20 mL). The separated aqueous layer is extracted with EtOAc (3×50 mL) and the combined organic layers are washed (brine), dried (MgSO4 anh.), filtered and evaporated. Flash-chromatography (HOAc:EtOH:EtOAc (0.1:1:9)) of the residue gives carboxylic acid 4 (210 mg, 48%). 1H NMR (CDCl3): δ 9.65 (1H, br. s), 7.98 (2H, d, J=8.1 Hz), 7.26 (20H, s), 7.13 (2H, d, J=8.1 Hz), 4.95 (8H, m), 3.31 (2H, td, J=16.7, 6.4 Hz), 2.82 (1H, tt, J=24.0, 6.4 Hz). 13C NMR (CDCl3): δ 170.0, 144.6 (t, J=7.6 Hz), 135.9, 135.8, 130.1, 129.0, 128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 68.3 (dd, J=19.6, 6.5 Hz), 39.4 (t, J=133.2 Hz), 31.2 (br. s).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:14]=[C:15]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:16]=[CH:17][C:18]=2[CH3:19])=[N:10][CH:11]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[C:9]([O:12][C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH:16]=[CH:17][C:18]=1[CH3:19])[N:10]=2
Reactant: N#C[S-]
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1Oc1ccc(N)cn1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1Oc1ccc2nc(N)sc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.2 %

Procedure:
Potassium thiocyanate (1.23 g, 12.7 mmol) was suspended in acetic acid (25 mL), and the mixture was stirred at room temperature for 10 min. A solution of tert-butyl {3-[(5-aminopyridin-2-yl)oxy]-4-methylphenyl}carbamate (1.00 g, 3.17 mmol) in acetic acid (25 mL) was added to the obtained solution, and the mixture was further stirred at room temperature for 10 min. A solution of bromine (531 mg, 3.32 mmol) in acetic acid (20 mL) was slowly added dropwise to the obtained solution. After the completion of the dropwise addition, the mixture was stirred at room temperature for 22 hr. The yielded yellow insoluble material was filtered off, and washed with acetic acid. The filtrate and the washing fluid were combined, and concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate (50 mL), and the solution was washed with water (50 mL), 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate), and the obtained solution was concentrated under reduced pressure to give the title compound (0.97 g, 82%) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]([NH:15][OH:16])=[NH:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH:17](OC)(OC)OC.B(F)(F)F.CCOCC>CO>[O:16]1[CH:17]=[N:14][C:13]([C:4]2[S:3][C:2]([NH2:1])=[N:6][C:5]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:15]1
Reactant: N=C(NO)c1sc(N)nc1-c1ccccc1
Reactant: COC(OC)OC
Agent: FB(F)F
Solvent: CCOCC
Solvent: CO
Product: Nc1nc(-c2ccccc2)c(-c2ncon2)s1

Procedure:
2-Amino-N-hydroxy-4-phenyl-thiazole-5-carboxamidine (1.0 g, 4.3 mmol) was dissolved in methanol (20 mL), and trimethyl orthoformate (1.2 mL, 11 mmol) containing boron trifluoride etherate (0.2 mL, 1.6 mmol) was added End the mixture was heated at reflux for 3 h. The reaction mixture was cooled, and the solvent was removed under reduced pressure at 20° C. The residue was extracted with ethyl acetate, and the solution was washed with saturated aqueous NaHCO3 dried over sodium sulfate and evaporated. The crude product was purified by flash column chromatography, eluted with the gradient of 10-18% ethyl acetate in hexanes to get the product (the product was eluted by 18% ethyl acetate in hexanes). Yield: 0.1 g, 10%
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][C:21]=1[N+:29]([O-:31])=[O:30]>O1CCCC1>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[O:25])=[CH:22][C:21]=1[N+:29]([O-:31])=[O:30]
Reactant: Nc1cccc2ccccc12
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc2ccccc12)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2.8 g (0.02 mol) of 1-naphthylamine and 2.0 g (0.02 mol) of triethylamine in 50 ml tetrahydrofuran is added dropwise at 15-20° C. a solution of 4.4 g (0.02 mol) of 4-chloro-3-nitro-benzoic acid chloride in 20 ml tetrahydrofuran. The solution is stirred for 30 minutes at ambient temperature. Then the solvent is evaporated off and the residue is chromatographed on silica gel, eluting with methylene chloride. The desired fractions are concentrated by evaporation, triturated with ether, suction filtered and dried.
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([CH:17]=O)[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:6][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([CH:17]=[CH2:1])[CH:16]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc(Br)cc(C=O)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cc(Br)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of methyltriphenylphosphonium bromide (350 mg, 0.97 mmol) in THF (3 mL) at −78° C. under nitrogen was added dropwise 2.5 M of n-butyllithium in tetrahydrofuran (0.31 mL, 0.78 mmol). The mixture was gradually warmed until a yellow color persisted. The mixture was cooled to 0° C. and a solution of methyl 3-bromo-5-formylbenzoate (157 mg, 0.65 mmol) in THF (2 mL) was added dropwise. After being stirred for 20 min at 0° C., the mixture was quenched with saturated aq. NH4Cl and extracted with EtOAc. The organic layer was separated and washed with brine, dried, and concentrated. The residue was purified by flash column to afford the title compound.