Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])[CH:5]=[C:4]([NH2:17])[N:3]=1.C1(C)C=C(C)C=C(C)C=1S([NH:29]O)(=O)=O.[S:32]1[CH:36]=[CH:35][N:34]=[C:33]1[CH:37]=O>>[NH2:17][C:4]1[N:3]2[N:29]=[C:37]([C:33]3[S:32][CH:36]=[CH:35][N:34]=3)[N:1]=[C:2]2[CH:7]=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])[CH:5]=1
Reactant: Cc1cc(C)c(S(=O)(=O)NO)c(C)c1
Reactant: Nc1cc(C(=O)c2ccc(F)cc2)cc(N)n1
Reactant: O=Cc1nccs1
Product: Nc1cc(C(=O)c2ccc(F)cc2)cc2nc(-c3nccs3)nn12

Procedure:
The title compound, MS m/e (%): 340 (M+H+, 100), was prepared in accordance with the general method of example 373 from (2,6-diamino-pyridin-4-yl)-(4-fluoro-phenyl)-methanone, o-mesitylene-sulfonylhydroxylamine, and thiazole-2-carbaldehyde. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient.
Reaction SMILES: C(N(CC)CC)C.[N:8](=[C:10]1[S:14][C:13]([CH3:16])([CH3:15])[N:12]=[C:11]1[CH3:17])[OH:9].[CH3:18][N:19]([S:23][N:24]([CH3:28])[C:25](F)=[O:26])[C:20]([F:22])=[O:21]>C1(C)C=CC=CC=1>[CH3:18][N:19]([S:23][N:24]([CH3:28])[C:25]([O:9][N:8]=[C:10]1[S:14][C:13]([CH3:16])([CH3:15])[N:12]=[C:11]1[CH3:17])=[O:26])[C:20]([F:22])=[O:21]
Reactant: CC1=NC(C)(C)SC1=NO
Reactant: CN(SN(C)C(=O)F)C(=O)F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1=NC(C)(C)SC1=NOC(=O)N(C)SN(C)C(=O)F
Temperature: -50 °C

Procedure:
8.3 ml of triethylamine are added dropwise to a suspension of 8.59 g of 5-oxo-2,2,4-trimethyl-3-thiazoline oxime in a solution of 10.0 g of bis-(N-methyl-N-fluorocarbonylamino)sulfide in 100 ml of absolute toluene, cooled to -50° C. The resulting clear solution is allowed to warm slowly to 0° C. during 11/2 hours, during which time a crystalline product is precipitated. The reaction mixture is poured into ice-cold brine and extracted with ethyl acetate. After drying the organic phase over anhydrous sodium sulfate and evaporating it, the resulting residue is purified by chromatography on silica gel (eluent:ethyl acetate/n-hexane 1:1). Crystallization from ethyl acetate/n-hexane yields 5-oxo-2,2,4-trimethyl-3-thiazoline O-[N-(N-methylfluoroformamidothio)-N-methylcarbamoyl]oxime, m.p. 77°-79° C.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:15]([CH3:18])[CH2:16]N.C(O)(=[O:21])C.N([O-])=O.[Na+]>O>[CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:15]([CH3:18])[CH2:16][OH:21]
Reactant: CC(CN)c1ccc2c(c1)Cc1ccccc1O2
Reactant: CC(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(CO)c1ccc2c(c1)Cc1ccccc1O2

Procedure:
2.4 g. of 2-(2-xanthenyl)-propylamine (obtainable from 2-(2-xanthenyl)-propionamide with LiAlH4) is dissolved in 50 ml. of 15% aqueous acetic acid and mixed, under ice cooling, with a solution of 1 g. of NaNO2 in 5 ml. of water. The mixture is heated for 1 hour to 80°, worked up as usual, and chromatographic purification on silica gel yields 2-(2-xanthenyl)-propanol, m.p. 86°-89°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].[CH3:24][C:25]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][CH:33]([N:36]3[CH2:39][CH2:38][CH:37]3[C:40]([O-:42])=[O:41])[CH2:32][CH2:31]2)[S:27][N:26]=1.[Li+]>>[CH:40]([OH:42])=[O:41].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:40]([CH:37]2[CH2:38][CH2:39][N:36]2[CH:33]2[CH2:32][CH2:31][N:30]([C:28]3[S:27][N:26]=[C:25]([CH3:24])[N:29]=3)[CH2:35][CH2:34]2)=[O:41])[C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: Cc1nsc(N2CCC(N3CCC3C(=O)[O-])CC2)n1
Agent: [Li+]
Product: Cc1nsc(N2CCC(N3CCC3C(=O)N3C[C@H](S(=O)(=O)c4ccccc4Cl)C[C@H]3C(=O)NC3(C#N)CC3)CC2)n1
Product: O=CO

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H and lithium 1-(1-(3-methyl-1,2,4-thiadiazol-5-yl)piperidin-4-yl)azetidine-2-carboxylate 20D carried out according to the general procedure L yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(1-(3-methyl-1,2,4-thiadiazol-5-yl)piperidin-4-yl)azetidine-2-carbonyl)pyrrolidine-2-carboxamide formate 1:1 epimers as a white solid (73%). MS ISP (m/e): 618.3 (100) [(M+H)]]+.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[NH2:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[C:9]([OH:14])[N:8]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:6][C:7]1[C:12]([F:13])=[CH:11][N:10]([CH2:2][CH:3]2[CH2:5][CH2:4]2)[C:9](=[O:14])[N:8]=1
Reactant: BrCC1CC1
Reactant: Nc1nc(O)ncc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(=O)n(CC2CC2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a solution of (bromomethyl)cyclopropane (1.0 g, 7.4 mmol) in DMF (20 mL) was added molecular sieves (—2 g), and the resulting mixture was stirred at room temperature. After 1 h, 4-amino-5-fluoropyrimidin-2-ol (1.9 g, 14.8 mmol) and K2CO3 (5.1 g, 37 mmol) were added, and the reaction mixture was heated at 90° C. for 12 h. After cooling to room temperature, the crude reaction mixture was filtered through a Büchner funnel, and the solid residue was washed with EtOAc. The collected filtrate was concentrated in vacuo to give a residue which was purified by normal phase chromatography (isocratic, 5% MeOH/EtOAc). Following recrystallization from methyl tert-butylether, 4-amino-1-(cyclopropylmethyl)-5-fluoropyrimidin-2(1H)-one (1.12 g, 83%) was isolated as a white solid: mp 224-226° C.; 1H NMR (400 MHz, methanol-d4) δ 7.86 (d, J=6.2 Hz, 1H), 3.61 (d, J=7.2 Hz, 2H), 1.24 (ddd, J=12.8, 7.6, 4.8 Hz, 1H), 0.65-0.50 (m, 2H), 0.39 (q, J=4.8 Hz, 2H); ESIMS m/z 184 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[NH2:14][C@@H:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][C@@H:15]([NH:14][C:3]2[C:2]([Cl:1])=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]=2)[CH2:16]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)c(Cl)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 78.5 %

Procedure:
A mixture of ethyl 5,6-dichloronicotinate (5.0 g), tert-butyl (3R)-3-amino-1-pyrrolidinecarboxylate (5.08 g) and K2CO3 (4.71 g) in DMF (40 ml) was stirred at 100° C. for 12 hours under atmospheric pressure of nitrogen. The reaction mixture was poured into a mixture of AcOEt and H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with n-Hexane-AcOEt (9:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl 6-{[(3R)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]amino}-5-chloronicotinate (6.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[CH2:11][C:12](=[O:18])[C:13]([O:16][CH3:17])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:11][C:12](=[O:18])[C:13]([O:16][CH3:17])([CH3:15])[CH3:14]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: COC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(C)(C)C(=O)COc1ccc(Cl)cc1Cl
Temperature: -20 °C
Yield: 85.7 %

Procedure:
A stirred mixture of 13.04 g (0.08 mole) of 2,4-dichlorophenol, 15.61 g (0.08 mole) 1-bromo-3-methoxy-3-methyl-2-butanone, and 11.1 g (0.08 mole) powdered potassium carbonate in 300 ml acetonitrile was heated at reflux temperature for 30 minutes. The reaction mixture was cooled, filtered, and the solvent evaporated from the filtrate. The residual oil was taken up in hexane and cooled to -20° C., whereupon the product separated as a white crystalline solid. There was thus obtained 19 g (85.7% yield) of 1-(2,4-dichlorophenoxy)-3-methoxy-3-methyl-2-butanone, m.p. 45.5°-47.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[F:12].C(NCC)C.[CH:18]1([NH2:21])[CH2:20][CH2:19]1>O>[Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:7]=1)[NH:21][CH:18]1[CH2:20][CH2:19]1
Reactant: O=[N+]([O-])c1cc(F)c(Cl)cc1F
Reactant: NC1CC1
Solvent: O
Solvent: CCNCC
Product: O=[N+]([O-])c1cc(F)c(Cl)cc1NC1CC1
Reaction time: 16 h
Yield: 79.9 %

Procedure:
1-Chloro-2,5-difluoro-4-nitrobenzene (3.69 g, 19 mmol) is treated at 0° with diethylamine (2.3 g, 23 mmol) and cyclopropylamine (1.3 g, 23 mmol). After 1 hour at 0° the suspension obtained is stirred at 25° for 16 hours. The reaction mixture is taken up in water (150 ml) and extracted with ethyl acetate. The organic phase is washed with 10 percent sodium chloride solution and dried over magnesium sulfate. After distillation of the solvent the residue is recrystallized from ethanol (50 ml). There are obtained 3.5 g (79%) of 5-chloro-N-cyclopropyl-4-fluoro-2-nitroaniline with a m.p. of 73.5°-75.5°.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([C:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH:20]=2)(O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS([Cl:39])(=O)=O>ClCCl.O>[CH:1]([N:14]1[CH2:17][C:16]([C:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH:20]=2)([Cl:39])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OC1(c2coc3ccccc23)CN(C(c2ccccc2)c2ccccc2)C1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ClC1(c2coc3ccccc23)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-benzhydryl-3-(benzofuran-3-yl)azetidin-3-ol (760 mg, 2.14 mmol) in dichloromethane (10 mL) was added at 0° C. triethylamine (387 μL, 2.78 mmol) and then dropwise a solution of methanesulfonyl chloride (216 μL, 2.78 mmol) in dichloromethane (3 mL). The reaction mixture was stirred for 1 hour at room temperature, then diluted with water (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The crude title compound was obtained as a yellow gum (873 mg, 109%) and used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.CCCCCC.[Cl:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]([C@H:29]1[CH2:33][CH2:32][O:31][C:30]1=[O:34])[CH2:24][CH2:23][CH2:22]2>C(Cl)Cl>[Cl:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]([C@@H:29]([CH2:33][CH2:32][OH:31])[C:30]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:34])[CH2:24][CH2:23][CH2:22]2
Reactant: O=C1OCC[C@@H]1N1CCCc2cc(Cl)ccc21
Reactant: Nc1ccccc1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(Nc1ccccc1)[C@H](CCO)N1CCCc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.7 %

Procedure:
Prepared using general procedure 60: To a solution of aniline (1.0 mL, 11.1 mmol) in CH2Cl2 (25 mL) under nitrogen at RT was added a solution of trimethylaluminum in hexane (2.0 M, 5.5 mL, 11.0 mmol) over 5 min. After stirring at RT for 20 min, a solution of (S)-3-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-dihydrofuran-2(3H)-one (2.32 g, 9.2 mmol) in CH2Cl2 (25 mL) was added over 10 min. Stirring was continued for 18 h at RT, then the reaction mixture was cooled to 0° C. and quenched by careful addition of aqueous 1M HCl (25 mL). Phases were separated, and the aqueous phase was extracted with CH2Cl2 (2×50 mL). The combined organic extracts were dried over MgSO4 and concentrated. Purification via silica gel chromatography using 2-10% MeOH in CH2Cl2 gave (S)-2-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)-4-hydroxy-N-phenylbutanamide as a white solid (2.56 g, 81%). 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 7.60 (dd, J=1.0, 8.5 Hz, 2H), 7.29 (dd, J=1.8, 14.1 Hz, 2H), 7.07-6.95 (m, 3H), 6.80 (d, J=9.0 Hz, 1H), 4.67 (t, J=4.9 Hz, 1H), 4.56 (t, J=7.2 Hz, 1H), 3.47 (dd, J=6.1, 11.2 Hz, 2H), 3.39-3.34 (m, 1H), 3.31-3.25 (m, 1H), 2.71-2.68 (m, 2H), 2.15-2.04 (m, 1H), 1.94-1.80 (m, 3H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=345.3; tR=3.44 min.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11](O)=[CH:10][N:9]=1.CI.CN(C)C=O>C(OCC)(=O)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([O:4][CH3:1])=[CH:10][N:9]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.7 %

Procedure:
Under a nitrogen atmosphere, potassium carbonate (5.52 g) was added to a mixture of 2-chloro-5-hydroxy-pyridine (2.591 g), methyl iodide (1.50 ml) and dimethylformamide (26 ml), and the mixture was stirred at room temperature for 18 hr. To the reaction mixture was added ethyl acetate and the mixture was placed in a separatory funnel. The organic layer was washed 4 times with aqueous ammonium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (2.403 g, 84%).
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])SC)#[N:2].[OH-].[NH4+:19]>C(O)C>[NH2:19][C:4]([NH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=[N:3][C:1]#[N:2]
Reactant: [NH4+]
Reactant: COC(=O)c1cccc(NC(=NC#N)SC)c1
Agent: [OH-]
Solvent: CCO
Product: COC(=O)c1cccc(NC(N)=NC#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the compound from Example D (1.0 g) and ammonium hydroxide (2 ml) in ethanol (20 ml) was heated at 70° in a sealed tube for 3.5 hours. The reaction mixture was cooled to room temperature and reduced to half its volume. After standing overnight at room temperature a white solid was obtained, which was isolated by filtration and washed with methanol. This afforded the title compound (389 mg) as a white solid.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][NH2:12])[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[F:22][C:23]([F:30])([F:29])[C:24](OCC)=[O:25]>C1COCC1>[Br:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][NH:12][C:24](=[O:25])[C:23]([F:30])([F:29])[F:22])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(C)(CN)Cc1cccc(Br)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(CNC(=O)C(F)(F)F)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 58 %

Procedure:
3-(3-Bromophenyl)-2,2-dimethylpropan-1-amine hydrochloride (1.52 g, 5.45 mmol) was dissolved in anhydrous THF (50 mL). Et3N (1.5 mL, 10.76 mmol) was added slowly to produce a white slurry. Ethyl trifluoroacetate (2 mL, 16.8 mmol) was added and the mixture was stirred at room temp for 15.5 h. Additional ethyl trifluoroacetate (˜0.75 mL, 6.2 mmol) and triethylamine (0.75 mL, 5.4 mmol) were added and the mixture was stirred for 4 h. The reaction mixture was concentrated under reduced pressure. The product was taken up in EtOAc and the solution was washed with saturated aqueous NaHCO3 (2×) and brine, dried over Na2SO4 and concentrated under reduced pressure to give N-(3-(3-bromophenyl)-2,2-dimethylpropyl)-2,2,2-trifluoroacetamide (30) as a yellow oil. Yield (1.84 g, 58% yield for two steps): 1H NMR (400 MHz, CDCl3) δ 7.39 (ddd, J=8.0, 2.0, 0.8 Hz, 1H), 7.29 (t, J=1.6 Hz, 1H), 7.17 (t, J=7.6 Hz, 1H), 7.05 (dt, J=7.6, 1.6 Hz, 1H), 6.16 (br s, 1H), 3.24 (d, J=6.8 Hz, 2H), 2.53 (s, 2H), 0.93 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[CH2:9][C:10]([O:12][CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:13]([O:12][C:10]([CH2:9][N:5]1[CH:6]=[CH:7][C:2](=[O:1])[CH:3]=[CH:4]1)=[O:11])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(CCl)OC(c1ccccc1)c1ccccc1
Reactant: Oc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Cn1ccc(=O)cc1)OC(c1ccccc1)c1ccccc1

Procedure:
For instance, 4-hydroxypyridine is reacted with benzhydryl α-chloroacetate in a solvent such as N,N-dimethylformamide in the presence of potassium carbonate at a temperature of from 40° to 80° C. to form 1-benzhydryloxycarbonylmethyl-4-pyridone, followed by a reaction with phosphorus pentasulfide in a solvent such as tetrahydrofuran at a temperature of from 40° to 80° C. to obtain the product of the formula III.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]([CH3:13])[N:5]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[N:3]=1.C(N(CC)CC)C.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:7](=[O:12])[CH:6]([CH3:13])[N:5]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:4]=2[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CC1C(=O)Nc2cnc(Cl)nc2N1c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1C(=O)N(c2ccccc2)c2cnc(Cl)nc2N1c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 37 %

Procedure:
To a stirred solution of 2-chloro-7-methyl-8-phenyl-7,8-dihydropteridin-6(5H)-one (1.59 g, 5.78 mmol) in dichloromethane (75 mL) was added triethylamine (8.07 ml, 57.8 mmol), cupric acetate (2.09 g, 11.56 mmol) and phenylboronic acid (1.41 g, 11.56 mmol) followed by 4 Å molecular sieves (2 g). The resulting mixture was stirred for 48 h at rt with an air balloon on the top. The reaction mixture was then filtered over celite to give a clear solution. The solution was washed with aqueous saturated sodium bicarbonate (50 mL×2), dried over anhydrous sodium sulfate and evaporated to give a crude material, which was then purified by silica gel column chromatography (eluent: 2% methanol in dichloromethane) to give the desired product (750 mg, 37%). 1HNMR (300 MHz, CDCl3): δ 1.65 (d, J=6.9 Hz, 3H), 4.82 (q, J=6.9 Hz, 1H) and 7.36-7.65 (m, 11H).
Reaction SMILES: O.O.O.O.O.O.O.O.O.O.[O-:11][P:12]([O:15][P:16]([O-:19])([O-:18])=[O:17])(=[O:14])[O-:13].[Na+].[Na+].[Na+].[Na+].[CH2:24]([N:28]([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27]>O.CCO>[O-:13][P:12]([O:15][P:16]([OH:19])([OH:18])=[O:17])(=[O:11])[O-:14].[CH2:33]([NH+:28]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:34][CH2:35][CH3:36].[CH2:33]([NH+:28]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:34][CH2:35][CH3:36]
Reactant: O=P([O-])([O-])OP(=O)([O-])[O-]
Reactant: CCCCN(CCCC)CCCC
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCC[NH+](CCCC)CCCC
Product: O=P([O-])([O-])OP(=O)(O)O

Procedure:
Tetrasodium diphosphate decahydrate (1.5 g, 3.4 mmol) was dissolved in water (34 ml) and the solution was applied to a column of dowex in the H+ form. The column was eluted with water. The eluent dropped directly into a cooled (ice bath) and stirred solution of tri-n-butylamine (1.6 ml, 6.8 mmol) in EtOH (14 ml). The column was washed until the pH of the eluent increased to 6. The aq. ethanol solution was evaporated to dryness and then co-evaporated twice with ethanol and twice with anhydrous DMF. The residue was dissolved in DMF (6.7 ml). The pale yellow solution was stored over 4 Å molecular sieves.
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[CH2:14][N:13]([C:15]([O:17]C(C)(C)C)=O)[C@H:12]([C:22]([OH:24])=O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:25]=[C:26]1[C:31](C(Cl)=O)=[CH:30][CH:29]=[C:28]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[O:27]1.[CH2:40]([N:42]1[C:54]2[CH:53]=[CH:52][C:51]([NH2:55])=[CH:50][C:49]=2[C:48]2[C:43]1=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH3:41]>>[CH2:1]([O:8][N:9]=[C:10]1[CH2:14][N:13]([C:15]([C:31]2[C:26](=[O:25])[O:27][C:28]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:29][CH:30]=2)=[O:17])[C@H:12]([C:22]([NH:55][C:51]2[CH:52]=[CH:53][C:54]3[N:42]([CH2:40][CH3:41])[C:43]4[C:48]([C:49]=3[CH:50]=2)=[CH:47][CH:46]=[CH:45][CH:44]=4)=[O:24])[CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccccc2)C[C@H]1C(=O)O
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CCCCCc1ccc(C(=O)Cl)c(=O)o1
Product: CCCCCc1ccc(C(=O)N2CC(=NOCc3ccccc3)C[C@H]2C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)c(=O)o1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 93% purity by LC/MS. MS(ESI+): m/z=619.6.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[N:16]=[CH:17][C:10]=2[N:9]([CH3:30])[C:8]1=[O:31])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[N:16]=[CH:17][C:10]3[N:9]([CH3:30])[C:8](=[O:31])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:12](=[O:13])[C:11]=3[C:14]=2[CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:19][CH:20]=1
Reactant: CC(C)CCc1c(-c2ccc(Cl)cc2)ncc2c1c(=O)n(CCCOC=O)c(=O)n2C
Agent: [Li]O
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)CCc1c(-c2ccc(Cl)cc2)ncc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.2 %

Procedure:
To a solution of 3-(6-(4-chlorophenyl)-5-isopentyl-1-methyl-2,4-dioxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)propyl formate (13 mg, 0.029 mmol) in THF (0.5 mL) and H2O (0.5 mL) was added LiOH.H2O (2.46 mg, 0.058 mmol). The reaction was stirred at RT for 30 min then diluted with EA (5 mL). The organic layer was washed with brine (1 mL), dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 6-(4-chlorophenyl)-3-(3-hydroxypropyl)-5-isopentyl-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (6.9 mg, 57% yield) as a white solid. 1H NMR (CDCl3) δ: 8.65 (s, 1H), 7.49-7.41 (m, 2H), 7.38-7.31 (m, 2H), 4.28 (t, J=6.1 Hz, 2H), 3.71 (s, 3H), 3.64-3.53 (m, 2H), 3.27-3.13 (m, 2H), 3.07 (t, J=6.9 Hz, 1H), 2.02-1.90 (m, 2H), 1.53 (dd, J=13.2, 6.6 Hz, 1H), 1.31 (dd, J=16.3, 6.7 Hz, 2H), 0.78 (d, J=6.6 Hz, 6H). LCMS: MH+ 416 and TR=3.048 min.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH3:11][C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[CH:17][NH:18]2)=[CH:14][CH:13]=1.[OH-].[Na+]>O>[CH3:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([CH:8]=[O:9])=[CH:17][NH:18]2)=[CH:14][CH:13]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc2cc[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc2c(C=O)c[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Phosphorus oxychoride (3.2 ml, 34.3 mmol) was added dropwise to dimethyl formamide (26 ml) over ten minutes at ~5° C. To this solution was added a dimethyl formamide (32 ml) solution of 6-methylindole (3.307 g, 25.2 mmol) over 10 minutes. The mixture was slowly warmed to ambient temperature, then heated to 50° C. for four hours. The mixture was cooled to ambient temperature, then poured onto ice (500 g). The aqueous solution was left to stand for 16 hours. Sodium hydroxide (6.0 g) was dissolved in water (22 ml) and added dropwise to the brown solution. The resultant yellow precipitate was boiled and filtered hot. It was left to cool to room temperature, then to 5° C. The precipitate was filtered off and washed with water (800 ml), dried at the pump, then further dried in vacuo at 50° C. for 16 hours to yield a yellow solid.