Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:20])=[N:4][CH:5]=[N:6][C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.[CH2:21](S(O)(=O)=O)C.CCCCCC>C(OCC)(OCC)OCC>[Cl:20][C:3]1[N:4]=[CH:5][N:6]=[C:7]2[C:2]=1[N:1]=[CH:21][N:8]2[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: CCS(=O)(=O)O
Reactant: COc1ccc(CNc2ncnc(Cl)c2N)cc1OC
Solvent: CCOC(OCC)OCC
Solvent: CCCCCC
Product: COc1ccc(Cn2cnc3c(Cl)ncnc32)cc1OC

Procedure:
To a suspension of 15.6 g (52.8 mmols) of 5-amino-4-chloro-6-(3,4-dimethoxybenzylamino)pyrimidine in 100 ml of triethyl orthoformate was added 149 mg (1.36 mmols) of ethanesulfonic acid and the resulting mixture was heated at 80° for 15 min. Upon cooling and addition of hexane to the reaction mixture, a yellow precipitate formed which was collected by filtration; yield, 15.4 g (95.6%) mp 159°-163°. Recrystallization from EtOH--H2O gave the analytical sample; yield 13.2 g (82.2%) mp 160°-164°.
Reaction SMILES: [CH2:1]([N:4]([C:6]([NH:8][C:9]1[S:10][C:11]([O:14][CH3:15])=[N:12][N:13]=1)=[O:7])[NH2:5])[CH2:2][CH3:3].[CH2:16]=O.[OH-].[K+]>CO>[CH2:1]([N:4]1[C:6](=[O:7])[N:8]([C:9]2[S:10][C:11]([O:14][CH3:15])=[N:12][N:13]=2)[CH2:16][NH:5]1)[CH2:2][CH3:3]
Reactant: CCCN(N)C(=O)Nc1nnc(OC)s1
Reactant: C=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCN1NCN(c2nnc(OC)s2)C1=O
Reaction time: 0.33 h

Procedure:
2-Propyl-4-(5-methoxy-1,3,4-thiadiazol-2-yl)-semicarbazide (0.1 mole) dissolved in methanol (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. Aqueous formaldehyde (0.2 mole; 37% concentration) is then added to the reaction vessel with stirring. Dilute aqueous potassium hydroxide is added to the reaction mixture to adjust the pH to between 7 and 8 and stirring is continued for a period of about 20 minutes resulting in the formation of a solid precipitate. The precipitate is recovered by filtration, is recrystallized and is dried under vacuum to yield the desired product 2-propyl-4-(5-methoxy-1,3,4-thiadiazol-2-yl)-1,2,4-triazolidin-3-one.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.I[CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>O1CCCC1.CCOCC>[F:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:18][CH2:19]2)=[CH:6][CH:5]=1
Reactant: Fc1ccc(S)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCSc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.2 %

Procedure:
To a slurry of sodium hydride (47 mg, 60% in mineral oil, 1.2 mmol) in tetrahydrofuran at 0° C. was added 4-fluorothiophenol (0.1 mL, 0.94 mmol). The reaction mixture was warmed to rt. for 20 min, followed by addition of 4-(2-iodoeth-1-yl)-1-tert-butoxycarbonylpiperidine (265 mg, 0.78 mmol, from Step C). The reaction was then heated to reflux for 10 min, cooled and diluted with ether. The organic layer was washed with 1 N NaOH, dried over magnesium sulfate and concentrated to provide 252 mg (95%) of the title compound. ESI-MS: 340.0 (M+H); HPLC A: 4.07 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:17])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:8].[BH4-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:17])=[C:6]([CH:16]=1)[CH:7]([OH:8])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15]
Reactant: O=C(c1ccccc1F)c1cc(Cl)ccc1I
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC(c1ccccc1F)c1cc(Cl)ccc1I
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of 54 g (0.15 mole) of 5-chloro-2'-fluoro-2-iodobenzophenone and 28.4 g (0.75 mole) of sodium borohydride in 1000 ml of ethanol was stirred at 0° C. for 15 min. The solution was diluted with water and extracted with ether. The ether solution was washed with water, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give a deep yellow oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:4]=1[C:5](N(C)C)=[O:6].C(O)(=[O:19])C>O.[O-2].[O-2].[O-2].[Cr+6]>[C:5]([C:4]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:3]=1[CH:2]=[O:1])([OH:19])=[O:6]
Reactant: CC(=O)O
Reactant: CN(C)C(=O)c1cc([N+](=O)[O-])ccc1CO
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Product: O=Cc1ccc([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-hydroxymethyl-5-nitro-N,N-dimethylbenzamide (17 g.) in glacial acetic acid (340 ml.) was added chromium trioxide (17 g.) in water (17 ml.) and glacial acetic acid (340-1). The reaction mixture was stirred at room temperature for 5 minutes, and then poured into ice-water (2 liters). The aqueous was extracted with chloroform (3 × 500 ml.). The chloroform extracts were combined and neutralised by washing with 10% sodium bicarbonate solution. The chloroform exracts were then washed thoroughly with water and dried over magnesium sulphate. The solution was then filtered and the solvent evaporated off to yeild a gum.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][CH:9]([O:13][CH3:14])[CH2:10][NH:11][CH3:12].CC1OCCC1.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>O>[CH2:25]([O:24][C:22](=[O:23])[N:11]([CH2:10][CH:9]([O:13][CH3:14])[O:8][CH3:7])[CH3:12])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CNCC(OC)OC
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC1CCCO1
Product: COC(CN(C)C(=O)OCc1ccccc1)OC
Temperature: 20 °C

Procedure:
K2CO3 (13.8 g, 100 mmol, 1.76 eq.) and H2O (46 mL) were mixed to form a homogeneous solution. The solution was cooled to 20° C. N-methylaminoacetaldehyde dimethylacetal (12.8 mL, 100 mmol, 1.8 eq) and MeTHF (50 mL) were added. The resulting mixture was cooled to 2° C. Benzyl chloroformate (8.1 mL, 56.7 mmol, 1.0 eq.) was added by syringe over 10 minutes (addition was exothermic). The mixture was maintained at room temperature until completion of the reaction. The layers were separated and the organic layer was washed with 1N HCl (50 mL) and used directly in the next step.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)=[N:8][CH:9]=1)([CH3:3])[CH3:2].C([O:35][C:36](=[O:41])[C:37](Br)([CH3:39])[CH3:38])C>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][C:29]([F:32])([F:30])[F:31])=[CH:26][CH:27]=2)[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[O:20][C:37]([CH3:39])([CH3:38])[C:36]([OH:41])=[O:35])=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(N(CCCc2cccc(O)c2)Cc2ccc(OC(F)(F)F)cc2)nc1
Reactant: CCOC(=O)C(C)(C)Br
Product: CC(C)c1ccc(N(CCCc2cccc(OC(C)(C)C(=O)O)c2)Cc2ccc(OC(F)(F)F)cc2)nc1

Procedure:
Similarly prepared by alkylation of 3-(3-{(5-isopropylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}propyl)phenol with ethyl-2-bromo-isobutyrate followed by standard base-mediated hydrolysis.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][CH:3]=1>CO.[Ni]>[NH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[CH:2]([CH3:1])[CH2:3][NH2:4]
Reactant: Cc1cnnc2ccccc12
Agent: [Ni]
Solvent: CO
Product: CC(CN)c1ccccc1N

Procedure:
Reduction of 4-methyl-cinnoline (10 g, 69.5 mmol) in methanol (100 mL), using Raney nickel (3 g). The catalyst was removed and washed with methanol. The filtrate was treated with an excess of HCl in isopropanol; ether was then added and the solution cooled. The precipitate was filtered and dried; 9.4 g (60%).
Reaction SMILES: [Br:1]Br.[N:3]1[C:8]2[NH:9][CH2:10][CH2:11][CH2:12][O:13][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Br:1][C:5]1[CH:4]=[N:3][C:8]2[NH:9][CH2:10][CH2:11][CH2:12][O:13][C:7]=2[CH:6]=1
Reactant: c1cnc2c(c1)OCCCN2
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Brc1cnc2c(c1)OCCCN2
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A solution of bromine (960 mg, 6 mmol) in CH2Cl2 (50 mL) was added drop wise at 0° C. to a CH2Cl2 (30 mL) suspension of 6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocycloheptene (750 mg, 5 mmol) and solid K2CO3 (1 g). The mixture was stirred for 30 min at 20° C., then the excess bromine was quenched with a saturated solution of aqueous NaHSO3. The basic aqueous phase was separated, extracted with CH2Cl2, the combined organic layers were dried and evaporated to afford the title-compound (1.10 g, 96%). 1H NMR (300 Hz, DMSO-d6, δ): 7.78 (d, J=1.8 Hz, 1H), 7.30 (d, J=1.9 Hz, 1H), 6.35 (s, br, 1H), 4.10 (t, J=5.7 Hz, 2H), 3.24 (m, 2H), 1.92 (m, 2H), MS (ESI): m/e 229 and 231 (M+H)+.
Reaction SMILES: C(O)C.[F:4][C:5]1[CH:21]=[CH:20][C:8]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][S:18][CH3:19])=[CH:13][CH:12]=2)=O)=[CH:7][CH:6]=1.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[NH:23][NH2:24]>C(O)(=O)C>[CH2:27]([O:26][C:22]([NH:23][N:24]=[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][S:18][CH3:19])=[CH:13][CH:12]=1)[C:8]1[CH:20]=[CH:21][C:5]([F:4])=[CH:6][CH:7]=1)=[O:25])[CH3:28]
Reactant: CCOC(=O)NN
Reactant: CSCc1ccc(C(=O)c2ccc(F)cc2)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)NN=C(c1ccc(F)cc1)c1ccc(CSC)cc1
Yield: 61.7 %

Procedure:
An ethanol solution (100 ml) of 4-fluoro-4'-methylmercaptomethylbenzophenone (7.8 g), ethyl carbazate (9.4 g) and acetic acid (9 ml) was heated for 20 hours with refluxing. The solvent was distilled off under reduced pressure, and then the obtained oily substance was diluted with dichloromethane, and washed successively with an aqueous 5% sodium hydroxide solution, water and an aqueous saturated sodium chloride solution, followed by drying over anhydrous magnesium sulfate. The solvent was then distilled off to obtain 4-fluoro-4'-methylmercaptomethylbenzophenone ethoxycarbonylhydrazone (6.4 g) as an isomer mixture.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[CH:6]=[CH:5][C:4]=1[N+:18]([O-])=O.[H][H]>CO.[Pd]>[NH2:18][C:4]1[CH:5]=[CH:6][C:7]([CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])=[N:8][C:3]=1[O:2][CH3:1]
Reactant: [H][H]
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(OC)n1)OCC
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(Cc1ccc(N)c(OC)n1)OCC
Yield: 93.2 %

Procedure:
A mixture of diethyl [(6-methoxy-5-nitropyridin-2-yl)methyl]phosphonate (Compound 286C, 750 mg, 2.465 mmol) and Pd/C (0.247 mmol) in 3 mL methanol was stirred under 1 atmosphere of hydrogen at room temperature overnight. The crude mixture was filtered through celite and the product (630 mg, 93% yield) was used directly in next step. 1H NMR (DMSO-d6) δ=6.82 (d, J=7.6 Hz, 1 H), 6.66 (dd, J=7.7, 2.8 Hz, 1 H), 4.81 (s, 2 H), 3.97 (quin, J=7.3 Hz, 4 H), 3.84 (s, 3 H), 3.13 (d, J=21.2 Hz, 2 H), 1.18 (t, J=7.1 Hz, 6 H). MS (ES+): m/z 275.19 (100) [MH+]; HPLC: tR=0.81 min (UPLC, Analytical).
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)(OCC)=O)C.[H-].[Na+].[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]([CH:32]=O)[CH:23]=1>C1COCC1>[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24](/[CH:32]=[CH:9]/[C:10]2[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][CH:19]=2)[CH:23]=1
Reactant: CCOP(=O)(Cc1ccc(C(=O)OC)cc1)OCC
Reactant: O=Cc1cnc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(/C=C/c2cnc3ccccc3c2)cc1
Temperature: 0 °C
Yield: 97.8 %

Procedure:
To a solution of methyl 4-[(diethoxyphosphoryl)methyl]benzoate (0.911 g, 3.18 mmol; see Preparation 4(i) above) in THF (10 mL, dry) under a nitrogen atmosphere was added sodium hydride (0.678 g, 60%, 18.8 mmol). After cooling the reaction mixture to 0° C., quinoline-3-aldehyde (0.500 g, 3.18 mmol) in THF (10 mL, dry) was carefully added dropwise with stirring. The reaction mixture was stirred for 1 h at room temperature and then quenched with water. After neutralisation with dilute HCl, the two layers were separated, the water layer extracted with ethyl acetate and the organic layers were combined, dried (MgSO4), filtered and the solvent removed under reduced pressure to give a white solid. The product was purified by silica gel column chromatography using 25% ethyl acetate/n-hexane (RF=0.50) to give the sub-title compound (0.900 g, 98%), as a white solid, m.p.=92-94° C.
Reaction SMILES: [CH:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([CH3:13])[N:8]2[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:15]([O-])([OH:17])=[O:16]>FC(F)(F)C(O)=O>[CH:1]1([N:7]2[C:11](=[O:12])[C:10]([N+:15]([O-:17])=[O:16])=[C:9]([CH3:13])[N:8]2[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(=O)n(C2CCCCC2)n1C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c([N+](=O)[O-])c(=O)n(C2CCCCC2)n1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To trifluoroacetic acid (1940 mL) cooled to −15° C. was added 2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (535 g, 2231 mmol) and the reaction mixture was allowed to warm to 0° C. Nitric acid 90% (211 mL, 4461 mmol) was added dropwise over 90 minutes maintaining the temperature below 15° C. and the resulting mixture was stirred for 30 minutes at 10° C. The product mixture was slowly poured into ice water (8 L) and stirred for 30 minutes. The solid was collected by filtration and washed with water (2×2 L), saturated sodium bicarbonate solution (1×2 L), water (2×2 L), TBME (3×2 L) and heptane (2×2 L). The solid was dried in the vacuum oven to yield the title compound as a beige powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:22]2[CH2:23][CH2:24][N:19]([C:13]3[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=3[CH3:11])[CH2:20][CH2:21]2)=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Yield: 101.5 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 1 and using 5-bromopyridine-2-carboxylic acid (5 g) and 1-(2,4-dimethylphenyl)piperazine (4.8 g), the title compound (9.4 g) was obtained.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([NH2:13])([CH3:12])([CH3:11])[CH3:10]>O>[CH:1](=[N:13][C:9]([CH3:12])([CH3:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)N
Reactant: O=Cc1ccccc1
Solvent: O
Product: CC(C)(C)N=Cc1ccccc1
Reaction time: 15 h
Yield: 88.2 %

Procedure:
To a three neck round bottom flask, equipped with a cold water condenser, 30 g of water and 26.5 g of benzaldehyde were added. The mixture was mixed with a magnetic stirrer at room temperature for 3 minutes. t-Butyl amine (22.1 g) was added to the reaction flask in one portion, followed by vigorous stirring for 15 hours. The agitation was stopped and the reaction mixture was allowed to stand for at least 15 minutes. The lower aqueous layer was separated from the reaction mixture. The upper layer was collected and dried over magnesium sulfate to give 35.5 g of product. 1H NMR (300 Hz, CDCl3, ppm): 8.29 (1H, s), 7.77 (2H, m), 7.40 (3H, m), 1.33 (9H, s).
Reaction SMILES: [CH3:1][CH:2]([CH3:39])[C:3]([O:5][C@H:6]([O:10][C:11]([O:13]N1C(=O)[C@@H](OC(=O)C2C=CC=CC=2)[C@H](OC(=O)C2C=CC=CC=2)C1=O)=O)[CH:7]([CH3:9])[CH3:8])=[O:4].[NH2:40][CH2:41][CH2:42][CH2:43][P:44]([CH3:47])(=[O:46])[OH:45].C1COCC1>O>[C:3]([O:5][C@H:6]([O:10][C:11]([NH:40][CH2:41][CH2:42][CH2:43][P:44]([CH3:47])(=[O:45])[OH:46])=[O:13])[CH:7]([CH3:8])[CH3:9])(=[O:4])[CH:2]([CH3:1])[CH3:39]
Reactant: CP(=O)(O)CCCN
Reactant: CC(C)C(=O)O[C@H](OC(=O)ON1C(=O)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)C1=O)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(=O)O[C@H](OC(=O)NCCCP(C)(=O)O)C(C)C
Temperature: 19 °C
Reaction time: 4 h

Procedure:
To a 3 L three necked round bottom flask fitted with a mechanical stirrer, temperature probe, and nitrogen inlet is added (25) (100 mmol), 3-aminopropylmethylphosphinic acid (100 mmol), THF (1 L), and water (100 mL). The suspension is stirred under a nitrogen atmosphere at 18-20° C. for 4 h during which time the reaction mixture becomes homogeneous. The THF is removed in vacuo and the reaction mixture is diluted with methyl tert-butyl ether (250 mL) and washed with 1N HCl (1×500 mL) and water (2×200 mL). The organic phase is separated and concentrated in vacuo to leave a white solid. The solid is purified by flash chromatography to afford the title compound (119) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[C:9]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:15]([C:10]1[C:9]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:17])=[O:16]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccccc1-c1ccccc1
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccccc2)c1Br
Yield: 71 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-biphenylsulfonamide was prepared in the same manner as described in Example 8b from 5-amino-4-bromo-3-methylisoxazole and 2-biphenylsulfonyl chloride in 71% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 145-147° C.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][C@H:11]2[NH:15][C:14](=[O:16])[CH2:13][CH2:12]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH:18]([N-]C(C)C)(C)C.[Li+].CI>C1COCC1>[C:1]1([CH3:17])[CH:2]=[CH:3][C:4]([S:7]([CH2:10][C@H:11]2[N:15]([CH3:18])[C:14](=[O:16])[CH2:13][CH2:12]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)C[C@@H]2CCC(=O)N2)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)C[C@@H]2CCC(=O)N2C)cc1
Temperature: -70 °C
Yield: 40 %

Procedure:
(5S)-5-(p-Toluenesulphonylmethyl)-2-pyrrolidinone (0.8 g, 3 mmol) was dissolved in dry THF and cooled to −70° C. Lithium diisopropylamide was slowly added and the reaction stirred for 20 minutes before addition of methyl iodide (2 ml, excess). The reaction was allowed to warm to ambient temperature for over 2 hours. The reaction was partitioned between ethyl acetate and water, the organic layer separated, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by flash chromatography eluting from methylene chloride to 5% methanol/95% methylene chloride and the product evaporated to give (5S)-5-(p-toluenesulphonyl-methyl)-1-methyl-2-pyrrolidinone (340 mg, 40%) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([CH:17]4[CH2:19][CH2:18]4)[C:11]=3[C:10](=[O:20])[N:9]2[C:21]2[CH:22]=[C:23]([N:31](C)[C:32](=O)OC(C)(C)C)[C:24]3[N:25]([C:27]([CH3:30])=[N:28][N:29]=3)[N:26]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([CH:17]4[CH2:18][CH2:19]4)[C:11]=3[C:10](=[O:20])[N:9]2[C:21]2[CH:22]=[C:23]([NH:31][CH3:32])[C:24]3[N:25]([C:27]([CH3:30])=[N:28][N:29]=3)[N:26]=2)=[CH:4][CH:3]=1
Reactant: Cc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)N(c1cc(N(C)C(=O)OC(C)(C)C)c3nnc(C)n3n1)C2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1cc(N2C(=O)c3c(c(C)nn3C3CC3)C2c2ccc(Cl)cc2)nn2c(C)nnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
To a stirred solution of tert-butyl (6-(4-(4-chlorophenyl)-1-cyclopropyl-3-methyl-6-oxopyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)-3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl)(methyl)carbamate (Example 112) (200 mg, 0.364 mmol) in CH2Cl2 (4 mL) was added TFA (0.561 mL, 7.29 mmol) and the resulting mixture was stirred at RT for 2 hr. The reaction was quenched with a saturated aq. NaHCO3 solution and extracted with CH2Cl2. The combined organic layers were washed with a saturated aq. NaHCO3 solution, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (CH2Cl2/MeOH 1-4%) followed by trituration in Et2O to afford the title product (130 mg, 0.290 mmol, 79% yield). tR: 4.73 min (HPLC 1); tR: 1.09 min (LC-MS 2); ESI-MS: 449 [M+H]+ (LC-MS 2); Rf=0.40 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01-1.08 (m, 2H) 1.19-1.26 (m, 2H) 1.90 (s, 3H) 2.45 (s, 3H) 2.85-2.94 (m, 3H) 3.77-3.84 (m, 1H) 6.41 (s, 1H) 7.03 (s, 1H) 7.31-7.36 (m, 2H) 7.37-7.42 (m, 2H) 8.01-8.10 (m, 1H).
Reaction SMILES: [CH2:1]([N:3]1C=CC(=O)C(OCC2C=CC=CC=2)=C1COC)C.[CH3:21][O:22][CH:23]([C:26]1O[C:28]([CH3:41])=[CH:29][C:30](=[O:40])[C:31]=1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:24][CH3:25].CN>>[CH3:1][N:3]1[C:28]([CH3:41])=[CH:29][C:30](=[O:40])[C:31]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:26]1[CH:23]([O:22][CH3:21])[CH2:24][CH3:25]
Reactant: CCC(OC)c1oc(C)cc(=O)c1OCc1ccccc1
Reactant: CCn1ccc(=O)c(OCc2ccccc2)c1COC
Agent: CN
Product: CCC(OC)c1c(OCc2ccccc2)c(=O)cc(C)n1C
Yield: 37.6 %

Procedure:
In an analogous procedure in the preparation of 1-ethyl-2-methoxymethyl-3-benzyloxy-pyridin-4(1H)-one using 2-(1-methoxypropyl)-3-benzyloxy-6-methyl-pyran-4(1 H)-one 4.32 g (15 mmol, 1 eq.) and 3.49 g (45 mmol, 3 eq.) of 40% aqueous methylamine yielded the title compound (1.7 g, 37.6%) after purification by column chromatography on silica gel (eluant: 15% CH3OH/85% CHCl3) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[C:13]([N:14]=1)=[CH:12][CH:11]=[C:10]1[C:5]=2[C:6](O)=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:8]=[N:9]1.P(Cl)(Cl)([Cl:23])=O>ClC(Cl)C>[Cl:1][C:2]1[S:3][C:4]2[C:13]([N:14]=1)=[CH:12][CH:11]=[C:10]1[C:5]=2[C:6]([Cl:23])=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:8]=[N:9]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2ccc3nc(Cl)sc3c2c1O
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cnc2ccc3nc(Cl)sc3c2c1Cl

Procedure:
A mixture of 3.0 g of ethyl 2-chloro-9-hydroxythiazolo- [5,4-f]quinoline-8-carboxylate, 20 ml of phosphorus oxychloride and 300 ml of dichloroethane was refluxed for 8 hours.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].[OH-].[Na+]>CO>[CH3:15][O:14][C:10](=[O:13])[CH2:11][CH2:12][N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3]
Reactant: C=CC(=O)OC
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)CCn1cc(C)c(=O)[nH]c1=O

Procedure:
Thymine (14 g, 0.11 mol) was suspended in methanol. Methyl acrylate (39.6 mL, 0.44 mol) was added, along with catalytic amounts of sodium hydroxide. The solution was refluxed in the dark for 45 h, evaporated to dryness in vacuo, and the residue dissolved in methanol (8 mL) with heating. After cooling in an ice bath, the product was precipitated by addition of ether (20 mL), isolated by filtration, washed with ether (3×15 mL), and dried over sicapent, in vacuo. Yield: 11.23 g (48%). M.p. 112°-119° C. Anal. for C9H12N2O4, found (calc.) C: 51.14 (50.94) H: 5.78 (5.70) N: 11.52 (13.20). The compound showed satisfactory 1H and 13C-NMR spectra.