Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[S:52][C:18]2[N:19]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[C:44]([C:50]#[N:51])=[C:45]([F:49])[CH:46]=[CH:47][CH:48]=4)=[CH:39][CH:38]=3)[C:20](=[O:35])[N:21]([CH2:24][C:25]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[O:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]>C(Cl)(Cl)Cl>[CH2:13]([C:15]1[S:52][C:18]2[N:19]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[C:44]=4[C:50]4[NH:3][C:4](=[O:7])[O:5][N:51]=4)=[CH:39][CH:38]=3)[C:20](=[O:35])[N:21]([CH2:24][C:25]([C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)=[O:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4cccc(F)c4C#N)cc3)c2s1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4cccc(F)c4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 30.1 %

Procedure:
A mixture of hydroxylammonium chloride (1.8 g), sodium hydrogencarbonate (2.7 g) and dimethyl sulfoxide (40 mL) was stirred at 40° C. for 30 min, 4′-{[6-ethyl-3-[2-(4-methoxyphenyl)-2-oxoethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}-3-fluorobiphenyl-2-carbonitrile (1.8 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and dissolved in methylene chloride (40 mL). N,N′-Carbonyldiimidazole (0.46 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.44 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound as colorless crystals (0.6 g, 51%).
Reaction SMILES: C(O[C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:8][CH:7]=1)C.[C:23](#[N:25])[CH3:24].C([Li])CCC>C1COCC1.C1CCCCC1>[N:16]1([CH2:15][CH2:14][CH2:13][O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][C:4](=[O:22])[CH2:24][C:23]#[N:25])=[CH:11][CH:10]=2)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: CC#N
Reactant: CCOC(=O)Cc1ccc(OCCCN2CCOCC2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: N#CCC(=O)Cc1ccc(OCCCN2CCOCC2)cc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
The [4-(3-morpholin-4-yl-propoxy)-phenyl]-acetic acid ethyl ester is then condensed with the lithium anion of acetonitrile by the following method: A solution of dry acetonitrile (0.254 mL) in 5 mL of THF, that had been cooled in a dry ice-acetone bath for 2 h under Ar(g), is treated dropwise with 2.43 mL of a 2M solution of n-butyl lithium in cyclohexane. This mixture is allowed to stir at −78° C. for an additional 1.5 h, and is subsequently treated with 1.15 gms. of [4-(3-morpholin-4-yl-propoxy)-phenyl]-acetic acid ethyl ester in dropwise fashion. The resulting solution is allowed to stir at −78° C. for an additional 30 minutes, and is then allowed to warm to room temperature overnight. The reaction mixture, subsequently, is vacuum filtered affording the desired nitrile, 4-[4-(3-morpholin-4-yl-propoxy)-phenyl]-3-oxo-butyronitrile, as a white solid (11% yield).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[CH3:26][C:27]1[CH:28]=[C:29]([NH:33]N)[CH:30]=[CH:31][CH:32]=1.CCN(CC)CC>C(O)C>[CH3:26][C:27]1[CH:28]=[C:29]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:30]=[CH:31][CH:32]=1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: Cc1cccc(NN)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cccc(-n2nccc2-c2nn(-c3cccc(C(F)(F)F)c3)ccc2=O)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 21.2 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (337 mg, 1.0 mmol) in ethanol (100 mL) were added 3-methylphenylhydrazine hydrochloride (237 mg, 1.5 mmol) and Et3N (0.28 mL, 2.0 mmol). The mixture was stirred at 100° C. for 3 h and the solvent was removed under reduced pressure. Preparative HPLC chromatography provided 3-[1-(3-methylphenyl)-1H-pyrazol-5-yl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as a pale yellow solid (84 mg, 21%).
Reaction SMILES: [SH:1][C:2]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH-].[Na+].CN(C=O)C.[Cl:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[CH2:31]Br)=[O:27])=[CH:24][CH:23]=1>C(O)C.O>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[CH2:31][S:1][C:2]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[O:27])=[CH:36][CH:37]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cccc(CBr)c1
Reactant: Cn1c(S)nc2ccccc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(SCc2cccc(C(=O)c3ccc(Cl)cc3)c2)nc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
To a solution of 2-mercapto-3-methyl-4(3H)-quinazolinone (1.0 g) and sodium hydroxide (250 mg) in 50% ethanol (15 ml)-DMF (15 ml) was added 3-(4-chloro-benzoyl)benzyl bromide (1.88 g) and the mixture was stirred at room temperature for 1 hour. This reaction mixtrue was poured in water and the resulting crystals were collected by filtration, rinsed with water and methanol, and recrystallized from methanol to provide the title compound as colorless solid (2.22 g). 1H-NMR (CDCl3) 8: 3.59(3H,s), 4.59(2H,s), 7.34-7.52(5H,m), 7.61-7.80(5H,m), 7.96(1H,d,J=2.0Hz), 8.22(1H,dd,J=8.0,1.4Hz).
Reaction SMILES: [OH2:1].[OH-].[Na+].[CH3:4][N:5]([C:7]([N:9]=[C:10]([NH2:12])[NH2:11])=[NH:8])[CH3:6].Cl.C[C:15]([CH3:17])=[O:16]>>[CH3:4][N:5]([C:7]([NH:9][C:10]([NH2:12])=[NH:11])=[NH:8])[CH3:6].[C:15]([O-:1])(=[O:16])[CH3:17]
Reactant: CC(C)=O
Reactant: O
Reactant: CN(C)C(=N)N=C(N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)[O-]
Product: CN(C)C(=N)NC(=N)N
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 92.4 %

Procedure:
0.4 L of water, 241.50 g of sodium hydroxide, 9 L of acetone and 1 Kg of metformin hydrochloride were added to a 20 L reactor, and stirred for 2 hours and 40 minutes at room temperature. The resulting crystal was filtered and washed with acetone. 0.2 L of water and 1 L of acetic acid were added and stirred. The resulting crystal was filtered and washed with acetone, and then dried at 60° C. to obtain 1,056 g of metformin acetate (yield: 92.4%).
Reaction SMILES: P(Br)(Br)(Br)(Br)Br.[Br:7]Br.P(Br)(Br)Br.[C:13]1([CH2:19][CH2:20][CH2:21][CH:22](O)[CH3:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl.O>[Br:7][CH:22]([CH2:21][CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:23]
Reactant: BrBr
Reactant: CC(O)CCCc1ccccc1
Agent: BrP(Br)(Br)(Br)Br
Agent: BrP(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC(Br)CCCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a phosphorus pentabromide, prepared by addition of bromine (9.0 g.) in methylene chloride (10 ml.) to phosphorous tribromide (15.0 g.) in methylene chloride (15 ml.) at 0° C., is added 5-phenyl-2-pentanol (8.2 g.) in methylene chloride at 0° C. The mixture is stirred for 2.5 hours at 0° C. and is then allowed to warm to room temperature. Water (50 ml.) is added, the mixture stirred for one hour and the methylene chloride layer separated. The extraction is repeated and the combined extracts washed with water, saturated sodium bicarbonate solution, brine and then dried over magnesium sulfate. Concentration of the dried extracts gives 12.4 g. of title product as a light yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[NH:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]([NH2:20])=[O:19])=[CH:17][C:12]=2[N:11]=[CH:10]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:8][C:4]1[N:3]=[C:2]([N:11]2[C:12]3[CH:17]=[C:16]([C:18]([NH2:20])=[O:19])[CH:15]=[CH:14][C:13]=3[N:9]=[CH:10]2)[CH:7]=[N:6][CH:5]=1
Reactant: NC(=O)c1ccc2[nH]cnc2c1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc2ncn(-c3cncc(Cl)n3)c2c1
Temperature: 90 °C

Procedure:
A mixture of 2,6-dichloropyrazine (2.0 g, 13.4 mmol), 1H-benzimidazole-5-carboxamide (2.0 g, 12.3 mmol) and cesium carbonate (5.6 g, 17.2 mmol) in DMF (10 mL) was heated at 90° C. for 3 h. The solution was cooled to RT and diluted with ethyl acetate (20 mL) and filtered. The solid material was washed with chloroform-methanol (20 mL, 4:1) and the combined filtrates concentrated in vacuo. The residue thus obtained (3.02 g) was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[O:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:43]([O:45][C:46](=[O:68])[C@@:47]([OH:67])([CH3:66])[CH2:48][N:49]([CH2:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[C:62]([Cl:64])[CH:61]=[CH:60][C:59]=2[F:65])=[CH:54][CH:53]=1)[NH2:50])[CH3:44]>CN(C=O)C>[CH2:43]([O:45][C:46](=[O:68])[C@@:47]([OH:67])([CH3:66])[CH2:48][N:49]([CH2:51][C:52]1[CH:53]=[CH:54][C:55]([C:58]2[CH:63]=[C:62]([Cl:64])[CH:61]=[CH:60][C:59]=2[F:65])=[CH:56][CH:57]=1)[NH:50][C:7]([C:5]1[O:4][N:3]=[C:2]([OH:1])[CH:6]=1)=[O:9])[CH3:44]
Reactant: CCOC(=O)[C@](C)(O)CN(N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Reactant: O=C(O)c1cc(O)no1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@](C)(O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(O)no1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-Hydroxyisoxazole-5-carboxylic acid (132 mg, 1.0 mmol) and HATU (389 mg, 1.0 mmol) were combined in DMF (3.7 mL), and the resulting mixture was stirred for 10 minutes at room temperature. DIPEA (343 μL, 2.0 mmol) and (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-hydrazino]-2-hydroxy-2-methyl-propionic acid ethyl ester (300 mg, 0.8 mmol) were added and the resulting mixture was stirred for 30 minutes. LC/MS showed desired product. The mixture was the evaporated under reduced pressure to yield the title compound (210 mg, 100% purity). MS m/z [M+H]+ calc'd for C23H23ClFN3O6, 492.13; Found 492.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:16])=[C:5]([CH2:9][CH2:10]C(OCC)=O)[CH:6]=[CH:7][CH:8]=1.[OH-:17].[Na+].C[CH2:20][OH:21]>>[CH3:1][O:2][C:3]1[C:4]([CH3:16])=[C:5]([CH:9]([CH3:10])[C:20]([OH:21])=[O:17])[CH:6]=[CH:7][CH:8]=1
Reactant: [OH-]
Reactant: CCOC(=O)CCc1cccc(OC)c1C
Reactant: CCO
Agent: [Na+]
Product: COc1cccc(C(C)C(=O)O)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of ethyl 3-(3-methoxy-2-methylphenyl)propanoate (36.3 g, 165 mmol, from Step B) in abs. EtOH (200 mL) and 5 N NaOH (99 mL) was heated to reflux for 30 min and cooled to ambient temperature. The reaction mixture was concentrated in vacuo, and the resultant solid mass was dissolved in H2O (100 mL) and cooled in an ice bath. Concentrated HCl (50 mL) was then added dropwise. At pH=4, an additional 300 mL H2O was added to facilitate stirring. The acidified mixture was stirred for 30 min, filtered, and the solids washed with H2O (2×100 mL) and Et2O (2×100 mL). After 3 hr, the solids were dried over P2O5 in vacuo overnight to give 29.3 g of the title compound as a white solid: 1H NMR (500 MHz, CD3OD) δ 2.15 (s, 3H), 2.50 (t, 2H, J=7.9 Hz), 2.90 (t, 2H, J=7.9 Hz), 3.78 (s, 3H), 6.75 (d, 2H, J=8.0 Hz), 7.05 (t, 1H, J=8.0 Hz).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:20]2[C:39]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][C:23]3[C:24]([C:34]([NH:36][CH3:37])=[O:35])=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[O:26][C:22]=3[CH:21]=2)[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][C:10]=1[Cl:43])C1C=CC=CC=1.B(Cl)(Cl)Cl.C(Cl)Cl>C(Cl)Cl.CCOC(C)=O>[Cl:43][C:10]1[CH:11]=[C:12]([N:15]([C:20]2[C:39]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][C:23]3[C:24]([C:34]([NH:36][CH3:37])=[O:35])=[C:25]([C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)[O:26][C:22]=3[CH:21]=2)[S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(OCc4ccccc4)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: ClB(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(O)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Yield: 42.9 %

Procedure:
A solution of 6-(N-(4-(benzyloxy)-3-chlorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (0.300 g, 0.485 mmol) in anhydrous DCM (12 mL) was cooled in an ice water bath and treated with 1M BCl3/DCM (2.00 mL, 2.00 mmol). After stirring in the ice bath for 10 minutes the solution was allowed to warm to RT. This solution was then combined with the solution from an analogous 50 mg scale reaction and poured into 50 mL of stirred ice water. The mixture was diluted with 50 mL of EtOAc, stirred vigorously for several minutes and the phases separated. The EtOAc solution was washed with water (2×), brine (1×), dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude material was subjected to flash chromatography (silica gel, gradient from DCM to 1:1 DCM/EtOAc) followed by recrystallization from hexane/EtOAc to afford the title compound (0.110 g, 37%) as a white powder. Impure fractions from the above chromatography were combined, concentrated, and subjected to RP-HPLC purification (C18, MeCN/water/0.1% formic acid) to afford an additional portion of the title compound (0.107 g, 36%) for a total yield of 73%. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.45 (s, 1H) 8.40-8.48 (m, 1H) 8.18 (s, 1H) 7.90-8.01 (m, 2H) 7.61 (d, J=2.6 Hz, 1H) 7.34-7.45 (m, 3H) 7.14 (s, 1H) 6.96 (d, J=8.8 Hz, 1H) 3.30 (s, 3H) 2.82 (d, J=4.6 Hz, 3H) 2.20-2.34 (m, 1H) 0.77-1.09 (m, 3H) 0.43 (br. s., 1H). LCMS (m/z, ES+)=529 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl.[Br:51][C:52]1[CH:53]=[C:54]([CH:58]=[CH:59][CH:60]=1)[CH:55]([OH:57])[CH3:56]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:40](=[O:42])[O:57][CH:55]([C:54]2[CH:58]=[CH:59][CH:60]=[C:52]([Br:51])[CH:53]=2)[CH3:56])=[C:18]([CH3:24])[CH:17]=1
Reactant: CC(O)c1cccc(Br)c1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OC(C)c4cccc(Br)c4)cc3C)c2cc1OC
Temperature: 25 °C
Yield: 58.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (88 mg) was added to toluene/triethylamine=1.0/1 (9 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (138 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-bromo-α-methylbenzyl alcohol (75 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (88 mg, yield 55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([N:35]=[C:36]=[S:37])=[O:34]>C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([NH:35][C:36]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][CH:18]=1)=[S:37])=[O:34]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(N=C=S)c1ccccc1Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4Cl)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 2-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (83 mg, yield 100%).
Reaction SMILES: CNCCN(C)C.[Li].[CH2:9]([Li])[CH2:10][CH2:11]C.[CH:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cu](C#N)C#N.C(Br)C=C>O1CCCC1>[CH2:11]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH:14]=[O:21])[CH:10]=[CH2:9]
Reactant: O=Cc1ccccc1
Reactant: [Li]CCCC
Agent: N#C[Cu]C#N
Agent: CNCCN(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCc1ccccc1C=O
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
To a stirred solution of 20.2 g (198.0 mmol) of lithium trimethylethylenediamine in 500 ml of dry tetrahydrofuran (THF) under nitrogen at -30° C. was added 79 ml (198.0 mmol) of 2.5M butyllithium (nBuLi) in hexanes dropwise over 15 minutes. The solution became pale yellow and was stirred at -30° C. for 30 minutes. To this solution was added 20.0 g (188.5 mmol) of benzaldehyde dropwise over 30 minutes. The solution became cloudy as the complex was formed and was stirred 1 hour. To this slurry was added 113 ml (283 mmol) of 2.5M nBuLi hexanes dropwise over 1 hour. This slurry was stirred for 24 hours and gradually cleared. The solution was then transferred via cannula into a slurry of 50.6 g (565 mmol) of copper cyanide in 500 ml of dry tetrahydrofuran under nitrogen at -78° C. The mixture was allowed to warm to -30° C. and stirred for 30 minutes. To this slurry was added 49 ml (565 mmol) of allyl bromide. The mixture instantly darkened upon addition. The reaction was quenched after 30 minutes with 3% aqueous ammonium hydroxide and saturated ammonium chloride. This biphasic solution was stirred overnight to ensure complete copper removal. The aqueous layer was extracted repetitively with ether to remove all product. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The yellow oil was purified by distillation at 62° C. at 0.03 torr affording 15.32 g (56%) of o-allylbenzaldehyde. 1H NMR: δ3.82 (d; 2H, J=6.17 Hz, CH2CH=CH2), 4.99 (d; 1H, J=17.1 Hz, one of CH=CH2), 5.09 (d; 1H, J=10.2 Hz, one of CH=CH2), 6.04 (m, 1H CH=CH2), 7.3 (d; 1H, J=7.8 Hz, aryl H), 7.40 (dd; 1H, J=7.6 Hz, aryl H), 7.54 (dd; 1H, J=7.4 Hz, 7.8 Hz, aryl H), 7.86 (d; 1H, J=7.6 Hz, aryl H), 10.26 (s; 1H aldehyde H).
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1>COCCOC>[Br-:1].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=1[CH2:2][C:3](=[O:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1ccccn1
Solvent: COCCOC
Product: CCOC(=O)C(=O)C[n+]1ccccc1N
Product: [Br-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl bromopyruvate (51.9 g, 266 mmol) was added dropwise to a solution of 2-aminopyridine (25 g, 266 mmol) in ethylene glycol dimethyl ether (270 mL), and the reaction then stirred at room temperature for 1 hour. The resulting precipitate was filtered off, the solid washed with ether and dried to afford the title compound as a pale yellow solid, 71.9 g.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:6]1([C:12]2[CH:18]=[CH:17][C:15]([OH:16])=[CH:14][C:13]=2[OH:19])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[H-].[Na+].[P:22](Cl)([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>O>[CH2:5]([O:1][P:22]([O:16][C:15]1[CH:17]=[CH:18][C:12]([CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]2)=[C:13]([O:19][P:22]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH:14]=1)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C:4]1[CH:33]=[CH:34][CH:35]=[CH:2][CH:3]=1
Reactant: Oc1ccc(C2CCCCC2)c(O)c1
Reactant: O=P(Cl)(OCc1ccccc1)OCc1ccccc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=P(OCc1ccccc1)(OCc1ccccc1)Oc1ccc(C2CCCCC2)c(OP(=O)(OCc2ccccc2)OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a tetrahydrofuran solution (10 ml) of 4-cyclohexylresorcinol (926 mg), sodium hydride (60% dispersion in liquid paraffin) (404 mg) was added and stirred at 0° C. for 30 minutes. Then, dibenzyl chlorophosphate (10 w/v % solution in benzene) (30 ml) was added dropwise. After stirring at room temperature for 3 hours, water (30 ml) was added to the reaction mixture, and the extraction was carried out with ethyl acetate (30 ml). Then, the extract was washed with saturated brine (20 ml), dried with anhydrous sodium sulfate and then concentrated. The residue (4.12 g) was subjected to silica gel chromatography (silica gel 90 g, chloroform to chloroform:methanol=100:1), to give 1,3-bis(dibenzylphosphonooxy)-4-cyclohexylbenzene (2.19 g, yield: 64%) as a yellow liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([O:30][CH2:31][CH2:32][CH3:33])[C:9]([N:11]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[NH:12]C(OCC1C=CC=CC=1)=O)=[NH:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.O1CCCC1.[Pd]>[C:1]([O:5][C:6]([N:8]([O:30][CH2:31][CH2:32][CH3:33])[C:9]([N:11]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[NH2:12])=[NH:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCON(C(=N)N(NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCON(C(=N)N(N)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
A mixture of [N,N′-di(tert-butoxycarbonyl)] 3-(Benzyloxycarbonylamino)-1-propoxyguanidine (760 mg, 1.7 mmol), as prepared in the preceding step, and 10% Pd/C (80 mg) in ethanol (20 mL) and tetrahydrofuran (20 mL) was hydrogenated under hydrogen (balloon) for 30 min. The catalyst was removed by filtration through Celite, the filtrate was concentrated in vacuo, and the residue was purified by Waters Sep-Pak (10 g, 95:5 methylene chloride:methanol saturated with ammonia) to give the title compound as a colorless oil (160 mg, −28%). 1H-NMR (300 MHz, CDCl3) δ 4.12 (t, J=6.1 Hz, 2H), 2.85 (t, J=6.7 Hz, 2H), 1.84 (pentet, J=6.2 Hz, 2H), 1.50 (s, 9H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].I[CH2:32][C:33]([F:36])([F:35])[F:34]>>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:32][C:33]([F:36])([F:35])[F:34])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: COC(=O)c1cccc(O)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: FC(F)(F)CI
Product: COC(=O)c1cccc(OCC(F)(F)F)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 48.4 %

Procedure:
In the same manner as described in Example 38, 0.40 g (0.937 mmol) of the product of Example 37 and 0.185 mL (1.873 mmol) of 2-iodo-1,1,1-trifluoroethane provided 0.231 g (48%) of the desired product as a colorless oil. Electrospray Mass Spec: 510.3 (M+H)+