Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.CC[O-].[Na+].[Na].[C:16]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O.C(O)C.CCOCC>[CH2:18]([CH:17]([C:2](=[O:4])[C:1]([O:8][CH2:9][CH3:10])=[O:7])[C:16]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCCC(=O)OCC
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: CCCCC(C(=O)OCC)C(=O)C(=O)OCC
Reaction time: 16 h

Procedure:
100 ml of ether, then 13.55 ml of diethyl oxalate were added to a solution of sodium ethylate prepared by stirring 2.3 g of sodium and 150 ml of ethanol at 40° C. for one hour. The mixture was refluxed for 15 minutes, cooled down slightly and 50 ml of ethyl caproate were added. The mixture was stirred at ref lux for 3 hours and at 30° C. to 35° C. for 16 hours. 50 ml of water were added and the aqueous phase was separated by decanting, washed twice with ether and acidified with 2N hydrochloric acid. Extraction was carried out 3 times with ether and the combined organic phases were washed with water, then with a saturated solution of sodium chloride, dried and evaporated to dryness to obtain 9.5 g of the desired product which was used as is for the following step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[N:12]([CH2:15]O)[C:11](=[O:17])[O:10]2)=[CH:5][CH:4]=1.S(Cl)([Cl:20])=O>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[N:12]([CH2:15][Cl:20])[C:11](=[O:17])[O:10]2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(-n2oc(=O)n(CO)c2=O)cc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-n2oc(=O)n(CCl)c2=O)cc1

Procedure:
2-(4-Methoxyphenyl)-4-hydroxymethyl-1,2,4-oxadiazolidin-3,5-dione (0.03 mole) dissolved in chloroform (40 ml) and thionyl chloride (0.06 mole) dissolved in chloroform (10 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 2 hours. After this time the reaction mixture is stripped of solvent under reduced pressure, leaving a residue. This residue is dissolved in toluene, and the toluene solution is stripped of solvent and unreacted starting materials to yield the desired product 2-(4-methoxyphenyl)-4-chloromethyl-1,2,4-oxadiazolidin-3,5-dione as the residue.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=O.[O:21]=[C:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH:31][CH:32]=[O:33])[CH:28]=2)[NH:23]1>>[CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=[C:30]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH:31][CH:32]=[O:33])[CH:28]=2)[NH:23][C:22]1=[O:21]
Reactant: O=CNc1ccc2c(c1)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3ccc(NC=O)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Yield: 87.9 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-formamide as starting materials to give N-{3-[3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-formamide (48 mg, 87.9%) as an orange solid.
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH:10]1([CH:15]([C:21]([CH3:23])=O)[C:16](OCC)=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11]1.Cl>C(O)C>[CH:10]1([C:15]2[C:16](=[O:17])[O:2][C:1]3[CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[C:3]=3[C:21]=2[CH3:23])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)C(C(C)=O)C1CCCC1
Reactant: Oc1cc(O)cc(O)c1
Agent: Cl
Solvent: CCO
Product: Cc1c(C2CCCC2)c(=O)oc2cc(O)cc(O)c12

Procedure:
A solution of phloroglucinol (2.00 g) and ethyl 2-cyclopentylacetoacetate (3.14 g) in ethanol (40 ml) was treated with dry HCl at 0° C. for 2.5 hours and the solution kept at that temperature overnight. Solvent was evaporated and the precipitate purified with flash chromatography eluting with toluene-EtOAc-AcOH (8:1:1). Yield 1.22 g (29%).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12].O1CC[CH2:16][CH2:15]1.N1C=CC=CC=1>O>[Cl:7][CH2:8][CH2:9][CH2:10][C:11]([O:6][C:1]1([CH2:15][CH3:16])[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:12]
Reactant: OC1CCCC1
Reactant: C1CCOC1
Reactant: O=C(Cl)CCCCl
Solvent: O
Solvent: c1ccncc1
Product: CCC1(OC(=O)CCCCl)CCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.6 %

Procedure:
In a nitrogen atmosphere, a mixture of 69 g of 1-cyclopentyl alcohol, 118 g of 4-chlorobutyric acid chloride, and 250 g of tetrahydrofuran was ice cooled, and a mixture of 64 g of pyridine and 60 g of tetrahydrofuran was added dropwise thereto below 15° C. The reaction mixture was stirred for one day at room temperature and then ice cooled, after which 100 g of water was added dropwise to quench the reaction. This was followed by ordinary aqueous work-up and vacuum distillation (93° C./40 Pa), recovering 122 g (yield 93%) of 1-ethylcyclopentyl 4-chlorobutyrate.
Reaction SMILES: [CH2:1](OC1C=C(C=CC=1C)C=O)[CH3:2].[Cl:13][C:14]1[C:21]([OH:22])=[CH:20][C:19]([OH:23])=[CH:18][C:15]=1[CH:16]=[O:17].I[CH2:25][CH3:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:13][C:14]1[C:21]([O:22][CH2:1][CH3:2])=[CH:20][C:19]([O:23][CH2:25][CH3:26])=[CH:18][C:15]=1[CH:16]=[O:17]
Reactant: CCI
Reactant: O=Cc1cc(O)cc(O)c1Cl
Reactant: CCOc1cc(C=O)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)c(Cl)c(OCC)c1

Procedure:
The title compound was prepared analogously to 3-ethoxy-4-methyl-benzaldehyde (intermediate D10, vide infra) by reaction of 2-chloro-3,5-dihydroxy benzaldehyde with iodoethane in DMF using K2CO3 as base. MS (ISP): 229.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH2:10].C(N(CC)CC)C.[Cl:18][C:19]([Cl:24])([Cl:23])[C:20](Cl)=[O:21]>C(Cl)Cl>[NH2:10][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([NH:8][C:20](=[O:21])[C:19]([Cl:24])([Cl:23])[Cl:18])=[CH:5][C:4]=1[Cl:9]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Nc1cc(Cl)c(N)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1c(Cl)cc(NC(=O)C(Cl)(Cl)Cl)cc1Cl
Temperature: 5 °C
Yield: 113.6 %

Procedure:
2,6-Dichloro-1,4-benzenediamine (225 g., 1.27 mol) is suspended in methylene chloride (1.3 liters) containing triethylamine (245 mL, 1.7 mol). After the mixture is cooled to 5° C., trichloroacetylchloride (169 mL, 1.5 mol, Aldrich Chemical Co.) is added dropwise with stirring at a rate to maintain 5° C. Upon complete addition, the stirred reaction is allowed to reach room temperature. After 24 hours the mixture is filtered and the collected solid is washed with methylene chloride (700 mL). The filtrate is evaporated to a small volume. A solid is collected and washed with methylene chloride (250 mL) to yield 465 grams of N-(4-amino-3,5-dichlorophenyl)-trichloroacetamide. The product exhibits a mass spectral analysis of m/e+· 320 for C8H5Cl5N2O.
Reaction SMILES: C[C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-].[K+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]CC.O>C1(C)C=CC=CC=1>[CH2:2]([O:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6])[CH2:9][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCOCC(O)CO
Temperature: 25 °C
Yield: 82.3 %

Procedure:
(R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol (11 grams), powdered potassium hydroxide (20 grams) and hexadecyl bromide (27.96 grams) in toluene (150 ml) were stirred and refluxed for 6 hours, while removing the water formed by azeotropic distillation. The volume of the solvent was gradually reduced to about 40 ml. The reaction mixture was cooled to room temperature; water was added (100 ml) and the resulting mixture was extracted with dichloromethane (3×75 ml). The combined organic phase was washed with water (50 ml) and the solvent removed under reduced pressure. The residue was dissolved in 200 ml mixture of 90:10:5 methanol:water:concentrated hydrochloric acid (v/v) and the resulting solution was refluxed for 2 hours, followed by cooling to room temperature and addition of water (100 ml). The product was extracted with dichloromethane (3×100 ml), and the organic phase was washed consecutively with water (100 ml), saturated aqueous solution of sodium carbonate (100 ml) and again with water (100 ml). The solvent was removed under reduced pressure and the product was crystallized from hexane (200 ml) to give 21.69 grams (yield 82%) of pure 1-hexadecyl-glycerol, upon drying in a desiccator under reduced pressure.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C@H:11]([C:16](O)=[O:17])[CH2:12][C:13](O)=[O:14])(=[O:9])=[O:8])=[CH:3][CH:2]=1.B>O1CCCC1.CO>[C:1]1([CH3:19])[CH:2]=[CH:3][C:4]([S:7]([NH:10][C@@H:11]([CH2:12][CH2:13][OH:14])[CH2:16][OH:17])(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](CC(=O)O)C(=O)O)cc1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N[C@H](CO)CCO)cc1
Temperature: -5 °C
Reaction time: 8 h

Procedure:
N-(p-Toluenesulfonyl)-L-aspartic acid, 1, (110 g) was dissolved in tetrahydrofuran (300 mL) and the solution cooled to -5° C. under a nitrogen atmosphere. A 1.0 M solution of borane in tetrahydrofuran was added dropwise over 1 hour at 0 to -5° C. and the resulting solution stirred at 20° to 25° C. overnight. The solution was recooled to 0° C. and methanol (250 mL) was added dropwise over 30 minutes (caution! gas evolution). The solution was concentrated under vacuum to an oil which was redissolved in methanol (1 L) and the solution heated at reflux 1 hour. This solution was concentrated under vacuum to give a solid which was redissolved in methanol (1 L) and this solution heated at reflux for 2 hours. Finally the solution was concentrated to a solid which was dried under vacuum at 50° C. to give (S)-2-(p-toluenesulfonylamino)-1,4-butanediol, 2, as an off-white solid (97 g, 98%) which was used directly in the next step without further purification. A portion was recrystallized from isopropyl alcohol and hexanes: mp 90°-92° C.
Reaction SMILES: [C:1]1([C:7](=[O:14])[C:8](=[N:12]O)[C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][CH2:16][O:17][C:18]([CH2:20][C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=O)=[O:19].C([O-])(=O)C.[Na+]>[Zn].O.C(O)(=O)C>[C:7]([C:8]1[NH:12][C:21]([CH2:20][C:18]([O:17][CH2:16][CH3:15])=[O:19])=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:9]=1[CH3:10])(=[O:14])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)C(=NO)C(=O)c1ccccc1
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Cc1[nH]c(C(=O)c2ccccc2)c(C)c1C(=O)OCC
Temperature: 100 °C

Procedure:
A solution of 71 g. (0.37 mole) of 1-phenyl-1,2,3-butanetrione-2-oxime in 350 ml. glacial acetic acid and 50 ml. of water is added to 75.5 g. diethyl acetonedicarboxylate in 350 ml. of glacial acetic acid at 70° C. Concurrently, a mixture of 73 g. (1.12 mole) of zinc dust and 91.5 g. (1.12 mole) of anhydrous sodium acetate is added in portions at such a rate that the temperature is maintained near 100° C. After the additions are complete (about 45 minutes), the mixture is refluxed for one hour and poured into iced water. The resulting crude semisolid is collected by filtration and recrystallized twice from methanol to give ethyl 5-benzoyl-3-ethoxycarbonyl-4-methylpyrrole-2-acetate, m.p. 152-154° C. Analysis: Calcd. for C19H21NO5 : C, 66.46; H, 6.16; N, 4.08%. Found: C, 66.50; H, 6.20; N, 4.17%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:13]3[CH:18]=[CH:17][C:16](=[O:19])[NH:15][N:14]=3)[CH2:10][C@H:9]2[C:20]([O:22][CH3:23])=[O:21])=[CH:4][CH:3]=1.[C:24]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:13]3[CH:18]=[CH:17][C:16](=[O:19])[N:15]([CH3:24])[N:14]=3)[CH2:10][C@H:9]2[C:20]([O:22][CH3:23])=[O:21])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1CN(c2ccc(=O)[nH]n2)C[C@H]1c1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@@H]1CN(c2ccc(=O)n(C)n2)C[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
Methyl(3S,4R)-4-(4-chlorophenyl)-1-(6-oxo-1,6-dihydropyridazin-3-yl)pyrrolidine-3-carboxylate obtained in Step A of Preparation 22 was dissolved in DMF (5 ml). Cs2CO3 (1.11 g, 3.41 mmol) was added, and methyl iodide (0.71 mL, 11.40 mmol) was added dropwise. The reaction mixture was stirred at 20-30° C. for 2 hours and concentrated in vacuo. The obtained residue was diluted with EtOAc, washed with water and purified by column chromatography (eluent: EtOAc/Hex=1/1) to give the title compound (0.55 g, 70%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH2:17][C@H:16]1[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)C1C=CC=CC=1>[Pd].O1CCOCC1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:28]([C@@H:16]1[CH2:17][CH:18]([NH:21][C:22](=[O:27])[C:23]([F:26])([F:24])[F:25])[CH2:19][CH2:20][NH:15]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(NC1CCN(Cc2ccccc2)[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: [Pd]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F

Procedure:
3.0 g of 10% palladium catalyst on carbon are added to a solution of 19.3 g (39.4 mmol) of (2R,4RS)-N-(1,2-dibenzyl-4piperidyl)trifluoroacetamide trifluoroacetate in 160 ml of dioxane under nitrogen, and hydrogenation is carried out under atmospheric pressure at room temperature. The reaction mixture is freed of catalyst over Celite® and the residue is washed with dioxane. The filtrate is evaporated to dryness and dried under high vacuum, resulting in the title compound which is used further without further purification; TLC: methylene chloride/methanol/conc. ammonia (90:9:1) Rf =0.24 and 0.3 (two poorly separated diastereomers)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:10]=O.O.[CH3:13][NH:14][CH3:15]>>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:13][N:14]([CH3:10])[CH3:15])=[C:4]([OH:9])[CH:3]=1
Reactant: C=O
Reactant: CNC
Reactant: Oc1ccc(F)c(F)c1
Solvent: O
Product: CN(C)Cc1cc(F)c(F)cc1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
400 g of 3,4-difluorophenol are initially charged in 408 ml of 40% aqueous dimethylamine solution and cooled to 0° C. At 0-5° C., 276 ml of 37% aqueous formaldehyde solution are added dropwise within 60 min. The mixture is kept at 5-10° C. for 2 hours and subsequently stirred at room temperature for 20 hours. The mixture is admixed with 600 ml of water. The organic phase is removed, the aqueous phase is extracted twice with dichloromethane, the combined organic phases are dried and the solvent is distilled off under reduced pressure. The crude product is subsequently fractionally distilled under reduced pressure. 395 g (65% of theory) of a colourless liquid having a boiling point of 93° C. at 16 mbar are obtained.
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][NH:8][C:9](=[O:20])[C:10]1[CH:15]=[CH:14][C:13]([S:16]([F:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:19][S:16]([C:13]1[CH:12]=[CH:11][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:21])=[O:5])=[O:20])=[CH:15][CH:14]=1)(=[O:18])=[O:17]
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(S(=O)(=O)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CNC(=O)c1ccc(S(=O)(=O)F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.9 %

Procedure:
A solution of the crude (4-fluorosulfonyl-benzoylamino)-acetic acid tert-butyl ester (541 mg, 1.70 mmol) (from step A above) in 2 mL of methylene chloride was treated with 2 mL of trifluoroacetic acid. The reaction mixture was stirred at room temperature for 72 h. The reaction mixture was concentrated in vacuo to provide crude (4-fluorosulfonyl-benzoylamino)-acetic acid (407.9 mg, 92%) as a solid that was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=[CH:6][N:5]2[C:17]=1[CH3:18].C([Li])(C)(C)C.[C:24](Cl)(=[O:26])[CH3:25].CO>C(OCC)C.CCCCC>[C:24]([C:8]1[CH:7]=[CH:6][N:5]2[C:17]([CH3:18])=[C:2]([CH3:1])[N:3]=[C:4]2[C:9]=1[NH:10][C:11](=[O:16])[C:12]([CH3:14])([CH3:15])[CH3:13])(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: Cc1nc2c(NC(=O)C(C)(C)C)cccn2c1C
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Solvent: CO
Product: CC(=O)c1ccn2c(C)c(C)nc2c1NC(=O)C(C)(C)C
Temperature: -40 °C

Procedure:
A vigorously stirred solution of 65.4 g of 2,3-dimethyl-8-pivaloylaminoimidazo[1,2-a]pyridine in 1.4 l of diethyl ether is treated dropwise at −78° C. under argon protective gas with 500 ml of a commercially available, 1.5 molar solution of t-butyllithium in n-pentane such that the temperature does not rise above −70° C. The mixture is then cooled to −90° C. in the course of 15 min and 54 ml of acetyl chloride are added dropwise to the dark-red suspension. The mixture is then allowed to warm to −40° C. (30 min), treated with 60 ml of methanol, the contents of the flask are poured onto 1 l of ice water and the aqueous phase is extracted three times with 150 ml of methylene chloride each time. The combined organic phases are washed three times with 100 ml of water each time, dried over sodium sulfate and the solvent is stripped off in vacuo. The residue is purified on silica gel (eluent: ethyl acetate/petroleum ether=3/7). 23.2 g of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.CS(C)=O.[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[F:1][C:2]1[C:3](=[O:9])[N:4]([C:5](=[O:8])[NH2:6])[C:21](=[O:22])[N:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)n1c(=O)c(F)cn(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
10.4 g. (0.08 mole) of 5-fluorouracil was dissolved in 100 ml. of dimethyl sulfoxide, then 14.3 g. (0.12 mole) of phenyl isocyanate was added thereto and stirred at room temperature for 1 hour. The milky reaction mixture was filtered off and a fine precipitate was obtained. The precipitate was suspended in hot ethanol and again filtered. There was obtained 16.2 g. (81.4% yield) of 5-fluoro-1-phenyl carbamoyluracil melting at 280° C.
Reaction SMILES: O=[C:2]1[CH:10]([C:11]([O:13]CC)=O)[CH2:9][CH:8]2[N:4]([CH2:5][CH2:6][CH2:7]2)[CH2:3]1.[Br:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=1>ClCCCl.O>[Br:16][C:17]1[CH:22]=[CH:21][N:20]2[C:11](=[O:13])[C:10]3[CH2:9][CH:8]4[N:4]([CH2:5][CH2:6][CH2:7]4)[CH2:3][C:2]=3[N:23]=[C:19]2[CH:18]=1
Reactant: CCOC(=O)C1CC2CCCN2CC1=O
Reactant: Nc1cc(Br)ccn1
Solvent: ClCCCl
Solvent: O
Product: O=c1c2c(nc3cc(Br)ccn13)CN1CCCC1C2
Yield: 19.9 %

Procedure:
A solution of ethyl 6-oxooctahydroindolizine-7-carboxylate (230 mg, 1.1 mmol), 4-bromopyridin-2-amine (188 mg, 1.1 mmol) and excess PPA (2 g) in 1,2-dichloroethane was stirred at 80° C. overnight. After the suspension was diluted with water (20 mL) and adjusted to pH 8. The mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were concentrated to give the crude product. 70 mg of the desired product was obtained after column chromatography. MS (ESI): 320, 322 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C([Li])CCC.Cl[Si:26]([CH3:29])([CH3:28])[CH3:27]>C(COC)OC>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[CH:11]=[C:10]([Si:26]([CH3:29])([CH3:28])[CH3:27])[O:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(-c2ccoc2-c2ccc(F)cc2)cc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: COCCOC
Product: C[Si](C)(C)c1cc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)o1
Reaction time: 1 h
Yield: 91.3 %

Procedure:
A solution of 2,3-bis(4-fluorophenyl)furan (7.0 g, 27 mmoles) in 100 ml of dry dimethoxyethane was cooled to -35° and treated dropwise with n-butyl lithium (1.6M; 18.8 ml, 30 mmoles). The solution was stirred at -35° for one hour and treated with chlorotrimethylsilane (3.0 g, 27.6 mmoles). The reaction mixture was stirred at -35° for one hour and at room temperature for 24 hours. The mixture was concentrated in vacuo, suspended in 180 ml of carbon tetrachloride, and filtered through 50 g of silica gel. The filtrate was concentrated to an oil which crystallized on standing to yield 8.1 g (90%) of the title compound, m.p. 82°-83°. PMR (CDCl3) δ0.33 (s, 9H, Si(CH3)3); 6.87 (s, 1H, H--C=C--O), 6.9-7.8 (m, 8H, 2-p-FC6H4). MS: m/z 328.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[CH:15][CH:16]=[N:17][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:18]Br>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[C:15]([Br:18])[CH:16]=[N:17][C:9]1=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCOc2cccnc21
Reactant: BrBr
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOc2cc(Br)cnc21
Yield: 47.6 %

Procedure:
To a solution of 4-(tert-butoxycarbonyl)-3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazine (2.0 g, 8.46 mmole) in MeOH (40 mL) was added Br2 (0.53 mL, 10.2 mmole) dropwise at 0° C. After 1 hr the mixture was concentrated. The residue was taken up in 1:1 Et2O/hexanes and filtered. The filtrate was concentrated under reduced pressure to give the title compound (1.27 g, 48%) as an oil which solidified under vacuum: 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1 H), 7.33 (s, 1 H), 4.25 (m, 2 H), 3.92 (m, 2 H), 1.54 (s, 9 H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][C:6]=1[O:15][CH2:16][CH2:17][OH:18])(=[O:3])[CH3:2].[OH-].[Na+].Cl>C(OCC)(=O)C>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[O:15][CH2:16][CH2:17][OH:18])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(NC(C)=O)c(OCCO)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(C(=O)O)cc1OCCO
Reaction time: 1 h
Yield: 32.7 %

Procedure:
A sample of methyl 4-acetylamino-3-(2-hydroxyethoxy)benzoate (1.51 g, 0.0060 mol) was suspended in 1N NaOH (12.0 mL, 0.0119 mol). After stirring for 1 h, thin-layer chromatographic analysis (SiO2, ethyl acetate) showed disappearance of starting material along with appearance of a new lower-running spot (Rf =0.1) indicating the reaction was complete. The reaction mixture when neutralized with concentrated HCl formed a white precipitate. The material was collected by filtration, washed with water, and then dried in vacuo at acetone reflux to give 0.47 g (34%) of the title compound as a tan solid, mp 207.5°-208.5° C.