Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:47]=[CH:46][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=4)[C:39]([O:41]C)=[O:40])[O:33][C:34]=3[CH3:35])=[C:26]([O:48][CH3:49])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH2:7]([O:6][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:47]=[CH:46][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=4)[C:39]([OH:41])=[O:40])[O:33][C:34]=3[CH3:35])=[C:26]([O:48][CH3:49])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:15]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3cccc(C(=O)OC)c3)oc2C)c(OC)c1)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3cccc(C(=O)O)c3)oc2C)c(OC)c1)OCC
Yield: 67.2 %

Procedure:
To a mixture of methyl 3-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoate (0.38 g), tetrahydrofuran (2 mL) and methanol (2 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was heated under reflux for 1 hr. To the reaction mixture were added 1N hydrochloric acid (2 mL) and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoic acid as colorless crystals (0.25 g, yield 68%) from a fraction eluted with ethyl acetate-hexane (4:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 148-149° C.
Reaction SMILES: [C:1](Cl)(=O)[C:2](Cl)=O.S1[CH:11]=[CH:10][N:9]=[CH:8]1.CN(C=O)C.[CH2:17]1[CH2:21]O[CH2:19][CH2:18]1>>[N:9]1[C:10]2[C:11](=[CH:19][CH:18]=[CH:17][CH:21]=2)[CH:2]=[CH:1][CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C1CCOC1
Reactant: c1cscn1
Solvent: CN(C)C=O
Product: c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
Oxalyl chloride (8.15 mL) is added dropwise to the cold mixture (10±5° C.) of Thiazole acid 8 (20.18 g) is dissolved in THF (300 mL) and DMF (300 μL) over a period of ˜5 min keeping the internal temperature at 10±5° C. The reaction mixture becomes yellow and homogenous. The cooling bath is removed and the mixture is allowed to reach ambient temperature over a period of ˜30 min. Gas evolution is observed. The mixture is stirred at ambient temperature for 30 min to 1 hour. A solution of aniline 7 (19.8 g), DMAP (140 mg) and THF (35 mL) was added at 10±5° C. Et3N (13.2 mL) was added in portions at 10±5° C. over a period of 10 min. The ice bath was removed and mixture was heated to 65±2° C. and stirred overnight (18 h). The mixture was allowed to reach ambient temperature, diluted with EtOAc (150 mL) and washed with water (150 mL). NaHCO3 (5%, 225 mL) was added to the organic portion and the mixture was stirred at ambient temperature for 30 min. The organic portion was concentrated under reduced pressure at approx. 40° C. EtOAc (150 mL) was added to the resulting material and the residual water was removed and the mixture was concentrated under reduced pressure at approx. 40° C. (to azeotrope water). EtOAc (94 mL) was added and the resulting slurry was stirred for 2-6 h and filtered. The solid was washed with EtOAc (30 mL) followed by heptane (30 mL) and air dried for 1 h to give the desired product in 70% yield.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7](O)[N:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:16])=O.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[Cl:16][C:7]1[N:8]=[C:9]([CH3:12])[CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[CH3:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc2c(C)ccnc2c(O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc2c(C)ccnc2c(Cl)n1
Temperature: 104 °C
Yield: 66.1 %

Procedure:
4,6-Dimethyl-[1,7]naphthyridin-8-ol (1.26 g, 7.23 mmol) and phosphorus oxychloride (6.7 mL, 72 mmol) in toluene (18 mL) are heated at 100° C. overnight. Phosphorus oxychloride (20 mL, 215 mmol) is added and the reaction mixture is heated at 104° C. for 1 d. The reaction mixture is cooled to RT and poured in a mixture of ice and water under stirring. After 30 min 20% NaOH is added until pH 6-7. The aqueous layer is extracted with DCM and the combined organic layers are washed with brine, dried and evaporated under reduce pressure to give a residue that is purified by flash chromatography (eluent 0-50% EtOAc/cyclohexane) to furnish 8-chloro-4,6-dimethyl-[1,7]naphthyridine (920 mg, 66%).
Reaction SMILES: [CH:1]1([S:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:12].[Na+].C(O)(=[O:16])C>>[CH:1]1([S:7]([CH2:8][CH2:9][CH2:10][OH:11])(=[O:16])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCSC1CCCCC1
Reactant: CC(=O)O
Reactant: [OH-]
Agent: [Na+]
Product: O=S(=O)(CCCO)C1CCCCC1

Procedure:
To a solution of 3-cyclohexylthio-1-propanol (60 g) in glacial acetic acid (250 ml) hydrogen peroxide (35% in water, 210 ml) was added at 10° C. followed by reflux for 2 h. After cooling the mixture was poured onto ice followed by extraction with ethyl acetate (1 l). The organic phase was washed several times with 1 M sodium hydroxide. Removal of solvent gave an oil which was treated at reflux temperature with 1 M sodium hydroxide (600 ml) for 1 h. Extraction with ethyl acetate, drying of the organic phase over magnesium sulfate, and removal of solvent in vacuo gave a colorless oil (37 g) of 3-cyclohexylsulfonyl-1-propanol which was used without further purification in the next step.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH3:13])=[C:7]2[C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])(O)=[O:2].[CH2:24]([S:28]([NH2:31])(=[O:30])=[O:29])[CH2:25][CH2:26][CH3:27].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CN(C)C=O>[CH2:24]([S:28]([NH:31][C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH3:13])=[C:7]2[C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])=[O:2])(=[O:30])=[O:29])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCS(N)(=O)=O
Reactant: Cc1[nH]c2ccc(C(=O)O)cc2c1C(=O)c1ccc(Cl)cc1Cl
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CN(C)C=O
Product: CCCCS(=O)(=O)NC(=O)c1ccc2[nH]c(C)c(C(=O)c3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
According to the method of Example 59, 5-carboxy-3-(2,4-dichlorobenzoyl)-2-methylindole (0.500 g) is suspended in N,N-dimethylformamide (10 ml), to which is added N,N′-carbonyldiimidazole (0.350 g), and stirred at room temperature for 2 hours. Next, 1-butanesulfonamide (0.296 g) and diazabicycloundecene (0.328 g) are added thereto, and stirred under heat at 100° C. for 6 hours. The reaction mixture is concentrated under reduced pressure, and the residue is made acidic with water and 3 M HCl added thereto, and then extracted with ethyl acetate. The organic layer is washed with a saturated saline solution, and dried with anhydrous sodium sulfate. The drying agent is removed through filtration, and the filtrate is concentrated under reduced pressure. The resulting oily residue is purified through silica gel column chromatography (eluent: chloroform/methanol=10/1), and recrystallized from ethanol-hexane to obtain a colorless crystal of 5-(1-butanesulfonylcarbamoyl)-3-(2,4-dichlorobenzoyl)-2-methylindole (97) (0.420 g).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)O)[OH:2].[C:9]([O-:12])([O-])=O.[K+].[K+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O>CN(C=O)C>[CH2:16]([O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[O:12][CH2:9][CH2:7][CH2:8][CH2:1][CH2:3][CH3:5])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Oc1ccccc1O
Reactant: O=C([O-])[O-]
Reactant: CCCCCCBr
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCOc1ccccc1OCCCCCC
Temperature: 70 °C
Reaction time: 15 h

Procedure:
Pyrocatechol (55.1 g; 0.5 mol) is dissolved in DMF (400 ml), and K2CO3 (207.3 g) is added. The mixture is heated to 70° C. 1-Bromohexane (198 g; 1.2 mol) is then added dropwise, and heating is carried out for 15 hours at 80° C. Further DMF (400 ml) and water (1 liter) are subsequently added. Extraction is then carried out with tert-butyl methyl ether (2×500 ml), and the organic phase is washed with water (3×100 ml) and dried over Na2SO4. After filtration, concentration to dryness by evaporation is carried out.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.[Li].C([Li])CCC.[CH:13](=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16]>>[CH2:14]([CH:13]([C:4]1[S:5][CH:6]=[C:2]([CH3:1])[N:3]=1)[OH:18])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)CC=O
Reactant: Cc1cscn1
Agent: [Li]
Agent: [Li]CCCC
Product: Cc1csc(C(O)CC(C)C)n1

Procedure:
d. Isobutyl (4-methyl-2-thiazolyl) carbinol was prepared by starting from 4-methyl-thiazole and substituting the hydrogen atom in the 2-position by lithium by reaction with butyllithium. The resulting metal-organic compound was reacted with isovaleraldehyde [cf. J.A.C.S. 74, 6260 (1952)]. The resulting product had a b.p. of 94° C./0.1 mm. Hg.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:24]([N:27]=[C:28]=[O:29])([CH3:26])[CH3:25]>C(Cl)Cl>[CH2:2]([O:9][C:10]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:28](=[O:29])[NH:27][CH:24]([CH3:26])[CH3:25])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)NC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Yield: 87.8 %

Procedure:
L-Proline benzyl ester hydrochloride (500 mg, 2.073 mmol) was dissolved in CH2Cl2 (10 ml). Triethylamine (600 mg, 6.0 mmol) and isopropylisocyanate (210 mg, 2.48 mmol) were added. After 18 h at room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (100 ml). This solution was washed with 0.3M KHSO4, sat. NaHCO3, water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (eluant: 3% methanol, 97% chloroform) to give a colourless oil identified as the title compound (528 mg, 1.82 mmol, 88%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:12][NH2:13].[CH:14]1([N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:26]3[CH:33]=[CH:32][C:29]([CH:30]=O)=[C:28]([O:34][CH3:35])[CH:27]=3)[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1>>[Br:8][C:6]1[CH:5]=[N:4][C:3]2[C:9](=[O:11])[N:13]([CH3:12])[C:30]([C:29]3[CH:32]=[CH:33][C:26]([O:25][CH:22]4[CH2:23][CH2:24][N:19]([CH:14]5[CH2:18][CH2:17][CH2:16][CH2:15]5)[CH2:20][CH2:21]4)=[CH:27][C:28]=3[O:34][CH3:35])=[N:1][C:2]=2[CH:7]=1
Reactant: COc1cc(OC2CCN(C3CCCC3)CC2)ccc1C=O
Reactant: Nc1cc(Br)cnc1C(=O)O
Reactant: CN
Product: COc1cc(OC2CCN(C3CCCC3)CC2)ccc1-c1nc2cc(Br)cnc2c(=O)n1C

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 3-amino-5-bromopyridine-2-carboxylic acid, methylamine and 4-[(1-cyclopentylpiperidin-4-yl)oxy]-2-methoxybenzaldehyde.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH:9]1([CH2:15][CH2:16][CH2:17][C:18]#[CH:19])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C.O>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]Cl>[CH:9]1([CH2:15][CH2:16][CH2:17][C:18]#[C:19][C:2]2[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=2)[NH2:5])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Nc1cccc(I)c1
Reactant: C#CCCCC1CCCCC1
Agent: Cl[Cu]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: Nc1cccc(C#CCCCC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 123.2 %

Procedure:
Under a nitrogen atmosphere, a mixture of 4.4 mL (0.037 mole) of 3-iodoaniline, 6.5 grams (0.043 mole) of 1-cyclohexyl-4-pentyne, 0.3 gram (catalyst) of bis(triphenylphosphine)palladium(II) chloride, 0.7 gram (catalyst) of copper(I) chloride, and 20.4 mL (0.146 mole) of triethylamine in 100 mL of acetonitrile was stirred at ambient temperature for about 18 hours. After this time the reaction mixture was poured into 200 mL of water, and this mixture then was extracted with three 100 mL portion of diethyl ether. The combined extracts were washed with three 100 mL portions of aqueous 10% citric acid solution and then with one 100 mL portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, using 10% methylene chloride in diethyl ether as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 11.0 grams of 3-(5-cyclohexylpentyn-1-yl)aniline that was about 91% pure. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].[CH2:42]([Cl:44])[Cl:43]>C(O)(=O)C>[NH3:1].[CH2:42]([Cl:44])[Cl:43].[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(OCCCN2CCCCC2)cc1
Reactant: Nc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: N
Product: c1ccc(NCc2ccc(OCCCN3CCCCC3)cc2)nc1
Reaction time: 16 h

Procedure:
A solution of the product of Example 9 (0.51 g), 2-aminopyridine (0.24 g), and acetic acid (0.12 mL) in DCM (7 mL) was treated with sodium triacetoxyborohydride (650 mg). After 16 h, the resulting mixture was treated with 10% sodium hydroxide (10 mL) and extracted with DCM (3×10 mL). The combined organic phases were dried (sodium sulfate) and evaporated. Chromatography of the residue (1-4% 2 M methanolic ammonia/DCM) gave the title compound as an off white solid (440 mg). 1H NMR (400 MHz, CDCl3): 8.05 (m, 1H), 7.35 (m, 1H), 7.23 (d, J=8.6 Hz, 2H), 6.83 (d, J=8.6 Hz, 2H), 6.53 (m, 1H), 6.32 (m, 1H), 5.05 (m, 1H), 4.37 (d, J=5.6, 2H), 3.95 (t, J=6.3 Hz, 2H), 2.44 (m, 2H), 2.37 (br, 4H), 1.94 (m, 2H), 1.59-1.53 (m, 4H), 1.45-1.38 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32](O)=[O:33])[C:27]2=[O:35])=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CC#N.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:32]([C:28]3[C:27](=[O:35])[N:26]([C:23]4[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=4)[CH:31]=[CH:30][CH:29]=3)=[O:33])=[CH:16][CH:17]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1
Reactant: Nc1ccc(Nc2cc(Cl)nn3ccnc23)cc1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(Nc1ccc(Nc2cc(Cl)nn3ccnc23)cc1)c1cccn(-c2ccc(F)cc2)c1=O
Temperature: 50 °C
Reaction time: 12 h
Yield: 9.8 %

Procedure:
To a 2 dram vial was added N1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)benzene-1,4-diamine (0.078 g, 0.3 mmol, prepared as described in Example XV1, step 1a), 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (0.10 g, 0.45 mmol, prepared as described in Example XVII, step 1e2), EDCI (0.086 g, 0.45 mmol), HOBt (0.061 g, 0.45 mmol), TEA (0.12 ml, 0.9 mmol), DMF (0.8 ml) and CH3CN (1.5 ml). The reaction was allowed to stir around 50° C. for 12 hrs. Upon cooling, the solvent was removed in vacuo and diluted with methanol (2 ml). The solution was purified by HPLC (20-100% methanol gradient), which yielded 0.014 g of the title compound as a TFA salt. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 11.88 (1H, s), 8.70 (1H, dd, J=7.12, 2.03 Hz), 7.71-7.91 (3H, m), 7.67 (1H, s), 7.50-7.63 (1H, m), 7.10-7.43 (5H, m), 6.64 (1H, s), 6.56 (1H, t, J=7.12 Hz). LC/MS, m/e 475 (M+1). HPLC Rt, 2.82 min. YMC ODSC18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:28])[C:20](=[O:29])[CH:19]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCOCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[C:20](=[O:29])[CH:19]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: O=C1C=C(OCCCCCCO)c2ccccc2C1=O
Reactant: N#Cc1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: N#Cc1ccc(OCCCCCCOC2=CC(=O)C(=O)c3ccccc32)cc1
Temperature: 10 °C
Reaction time: 10 h
Yield: 62.4 %

Procedure:
A mixture of 4-hydroxybenzonitrile (87 mg, 0.73 mmol), naphthoquinone 504 (200 mg, 0.73 mmol), PPh3 (191 mg, 0.73 mmol) in dioxane (10 mL) was cooled to 10° C. and treated with DEAD (140 mg, 0.80 mmol). The reaction mixture was stirred for 10 h, concentrated in vacuo and purified by chromatography (5% EtOAc in benzene) to afford 511 as a yellow solid (171 mg, 53%), 1H NMR (CDCl3) 8.13 (dd, J=7.3, 1.4 Hz, 1H), 8.86 (dd, J=7.7, 1.1 Hz, 1H), 7.67 (dt, J=7.5, 1.5 Hz 1H), 7.60 (dt, J=7.5, 1.5 Hz, 1H), 7.57 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.9 Hz, 2H),5.96 (s, 1H), 4.17 (t, J=6.4 Hz, 2H), 4.03 (t, J=6.3 Hz, 2H), 1.80-2.05 (m, 4H), 1.58-1.68 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=O)[NH:4][C:3]1=[O:13].C(N(CCC)CCC)CC.P(Cl)(Cl)([Cl:26])=O.[OH-].[Na+]>C(N(CCC)CCC)CC.C(Cl)(Cl)Cl>[Cl:26][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:2]([CH3:1])[C:3](=[O:13])[N:4]=1
Reactant: Cn1c(=O)[nH]c(=O)c2ccccc21
Reactant: O=P(Cl)(Cl)Cl
Agent: CCCN(CCC)CCC
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)nc(Cl)c2ccccc21
Reaction time: 1 h

Procedure:
A mixture of 1-methylquinazoline-2,4-dione (8.8 g), tri-n-propylamine (8.6 g) and phosphorus oxychloride (80 ml) was stirred for 1 hour at 110°-120° C. The resultant mixture was cooled to ambient temperature and concentrated under reduced pressure to give a residue, which was dissolved in 2% tri-n-propylamine-chloroform solution. The solution was added dropwise to a mixture of 2 N sodium hydroxide aqueous solution and ice at alkaline pH. The aqueous layer was separated and extracted twice with chloroform. The combined chloroform layer was washed with water and with aqueous solution saturated with sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crystalline 4-chloro-1-methyl-1H-quinazoline-2-one.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[Br:22][C:23]1[S:27][CH:26]=[C:25]([CH2:28]O)[CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Br:22][C:23]1[S:27][CH:26]=[C:25]([CH2:28][O:20][C:17]2[CH:18]=[CH:19][N:14]([C:11]3[CH:12]=[CH:13][C:6]4[N:5]=[C:4]([CH:1]5[CH2:2][CH2:3]5)[N:8]([CH3:9])[C:7]=4[CH:10]=3)[C:15](=[O:21])[CH:16]=2)[CH:24]=1
Reactant: OCc1csc(Br)c1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4csc(Br)c4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 30.7 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (98 mg), (5-bromo-3-thienyl)methanol (135 mg) and tributylphosphine (211 mg) in THF (3 ml) was added 1,1′-(azodicarbonyl)dipiperidine (264 mg), and the reaction mixture was stirred at 60° C. for 3 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH-water to give the title compound (48.8 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Br[CH2:12][CH2:13][CH2:14][CH2:15][Br:16]>>[Br:16][C:15]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[CH:13]=[CH:12][N:7]2[CH2:8][CH2:9][CH2:10][CH2:2][Br:1]
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: BrCCCCBr
Product: BrCCCCn1ccc2c(Br)cccc21

Procedure:
The procedure is as for Example 39 using as substrate 5-bromo-1H-indole and 1,4-dibromobutane.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7][C:8]1([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:13](=[O:14])[O:12]C(C)(C)[O:10][C:9]1=[O:17])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O>[C:22]([O:21][C:19](=[O:20])[CH2:18][C:8]([C:13]([OH:14])=[O:12])([C:9]([OH:17])=[O:10])[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:26])([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)OC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CC(CC(=O)OC(C)(C)C)(C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The compound of Example 165 (200 mg, 0.54 mmol) was dissolved in a mixture of THF(10 mL) and water (2 mL). Lithium hydroxide monohydrate (46 mg, 1.07 mmol) was added and the mixture was stirred for 24 h at room temperature. The solvent was evaporated and the residue was dissolved in water (5 mL) and extracted with ether. The water phase was acidified by HCl to pH1 and extracted with ethyl acetate. After drying over sodium sulfate, filtration and evaporation, the solvent was evaporated to dryness. 1H NMR(CDCl3, 300 MHz): 1.43(s, 18H); 3.10(s, 4H).
Reaction SMILES: [F:1][C:2]([N+:17]([O-:19])=[O:18])([N+:14]([O-:16])=[O:15])[CH2:3][NH:4][CH2:5][C:6]([N+:11]([O-:13])=[O:12])([N+:8]([O-:10])=[O:9])[F:7].C(Cl)(Cl)Cl.Cl[C:25]1C=[CH:28][S:27][C:26]=1C(OCC)=O.C.C[OH:37]>[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]([N+:17]([O-:19])=[O:18])([N+:14]([O-:16])=[O:15])[CH2:3][N:4]([CH2:5][C:6]([N+:11]([O-:13])=[O:12])([N+:8]([O-:10])=[O:9])[F:7])[C:28](=[O:37])[S:27][CH2:26][CH3:25]
Reactant: CO
Reactant: CCOC(=O)c1sccc1Cl
Reactant: O=[N+]([O-])C(F)(CNCC(F)([N+](=O)[O-])[N+](=O)[O-])[N+](=O)[O-]
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCSC(=O)N(CC(F)([N+](=O)[O-])[N+](=O)[O-])CC(F)([N+](=O)[O-])[N+](=O)[O-]

Procedure:
A mixture of 55.0 g (0.19 mol) of bis(2-fluoro-2,2-dinitroethyl)amine, 38 ml of chloroform, 40 ml of ethyl chlorothiolformate and 20 ml of titanium tetrachloride was heated in an oil bath at 65°-67° C. for 17 hours (The reaction mixture was protected from atmospheric moisture with a drierite drying tube). Chloroform (100 ml) was added to the warm mixture which was then filtered through celite. The dark colored filtrate was pulled on a rotary evaporator to give a residue which was dissolved in methanol and treated with charcoal. After filtration, the solvent was removed with a rotary evaporator and the product was crystallized by dissolving in chloroform (55 ml) and cooling in the freezer. The yield was 48.0 g (67%), mp 74°-75° C., NMR (chloroform): δ1.26(t), 2.95(q), 4.83(d).