Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCO[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:16][CH:17]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:20]=2[O:19][CH2:18]1.[OH-].[Na+]>O>[CH3:16][CH:17]1[N:22]2[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11](=[O:13])[C:23]3[CH:24]=[C:25]([CH3:27])[CH:26]=[C:20]([C:21]=32)[O:19][CH2:18]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Cc1ccc2c(c1)OCC(C)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)c1cn2c3c(cc(C)cc3c1=O)OCC2C
Temperature: 130 °C

Procedure:
Diethyl ethoxymethylene malonate (19.8 g., 0.092 mole) is added to 3,4-dihydro-3,7-dimethyl-2H-1,4-benzoxazine (15.0 g., 0.092 mole) and the solution is heated at 110° to 120° C. for three hours. Polyphosphoric acid (100 g.) is added and the solution is gradually heated to 130° C. with occasional stirring. The solution is heated at 140° to 150° C. for one additional hour. The hot solution is poured into 300 ml. water with stirring, then neutralized with forty percent sodium hydroxide solution. The solid which precipitates is separated by filtration and washed with water. Recrystallization from ethanol gives ethyl 2,3-dihydro-3,9-dimethyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylate, m.p. 195°-197° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:29][O:30][CH3:31])=[C:10]([CH2:19][O:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]>FC(F)(F)C(O)=O.C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:29][O:30][CH3:31])=[C:10]([CH2:19][O:20][CH2:21][C:22]([OH:24])=[O:23])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(-c3cncc(C)c3)c(COCC(=O)OC(C)(C)C)c(COC)nc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1ncc2c(-c3cncc(C)c3)c(COCC(=O)O)c(COC)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
tert-Butyl {[1-ethyl-6-(methoxymethyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methoxy}acetate (50 mg) was dissolved in 80% trifluoroacetic acid-DCM (2 ml) and stirred at room temperature for 30 minutes. Solvent was evaporated and the residue was purified by flash column chromatography on silica gel (CHCl3-MeOH 95:5) to give {[1-ethyl-6-(methoxymethyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methoxy}acetic acid (25 mg) as colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[C:6]([F:12])[C:5]=1[F:13])[CH3:2].[NH2:14]OS(O)(=O)=O>>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:14])=[C:6]([F:12])[C:5]=1[F:13])[CH3:2]
Reactant: CCOc1ccc(C=O)c(F)c1F
Reactant: NOS(=O)(=O)O
Product: CCOc1ccc(C#N)c(F)c1F

Procedure:
4-Ethoxy-2,3-difluorobenzaldehyde (obtainable according to Example 7) is reacted with hydroxylamine -O-sulfonic acid according to J. Streith and C. Fizet, Helv. Chim. Acta 59, 2796 (1976), m.p.: 45° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12](Br)=[C:11]([N+:14]([O-:16])=[O:15])[C:10]([Br:17])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([NH2:20])[CH3:19]>>[CH2:1]([N:8]1[C:12]([NH:20][CH2:18][CH3:19])=[C:11]([N+:14]([O-:16])=[O:15])[C:10]([Br:17])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN
Reactant: O=[N+]([O-])c1c(Br)nn(Cc2ccccc2)c1Br
Product: CCNc1c([N+](=O)[O-])c(Br)nn1Cc1ccccc1
Yield: 89 %

Procedure:
3.61 (10 mmoles) of 1-benzyl-3,5-dibromo-4-nitropyrazole are heated at 60° C. in 120 ml of a 30-percent aqueous ethylamine solution for 1 hour. After cooling, the product separates in the form of colorless crystals with a melting point of 122° C. 2.88 g (89 percent of theory) of 1-benzyl-3-bromo-5-ethylamino-4-nitropyrazole are obtained.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[I:20])[C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:1]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[I:20])[C:13]([O:15][CH3:16])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(I)c(O)c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(I)c(Cc2ccccc2)c1
Yield: 105.5 %

Procedure:
47 ml (411 mmol) of benzyl chloride are added to a solution of 104 g (374 mmol) of methyl 3-hydroxy-4-iodobenzoate and 103 g (748 mmol) of potassium carbonate in 600 ml of methyl ethyl ketone, and the reaction medium is then refluxed for 8 hours. After cooling, the reaction medium is filtered, the precipitate is rinsed with ethyl acetate and the filtrate is evaporated to dryness. The residue is taken up in a mixture of water and ethyl acetate. The organic phase is dried over sodium sulfate, filtered and evaporated. 139 g (100%) of methyl 3-benzyl-4-iodobenzoate are obtained in the form of a white solid.
Reaction SMILES: C([Li])CCC.[CH:6](=[O:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24]>>[F:17][C:18]1[C:19]([F:24])=[CH:20][CH:21]=[CH:22][C:23]=1[CH:6]([OH:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCC=O
Reactant: Fc1ccccc1F
Agent: [Li]CCCC
Product: CCCCCCCCCC(O)c1cccc(F)c1F

Procedure:
Quantities: n-butyllithium (30 cm3, 10.0M in hexanes, 0.3 mol), decanal (47 g, 0.3 mol) and 1,2-difluorobenzene (34.5 g, 0.3 mol). The experimental procedure was as described in Example 16.
Reaction SMILES: [N:1]#[C:2]Br.[Br:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][C:6]=1[O:12][CH3:13]>CCOCC.C1COCC1>[Br:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][C:2]#[N:1])=[CH:7][C:6]=1[O:12][CH3:13]
Reactant: N#CBr
Reactant: COc1cc(N)ccc1Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(NC#N)ccc1Br
Reaction time: 72 h
Yield: 25.5 %

Procedure:
A mixture of cyanogen bromide (0.550 g, 5.19 mmol) and 4-bromo-3-methoxyaniline (Lancaster Synthesis Inc., P.O. Box 1000, Windham, N.H. 03087-9977) (2.2 g, 11 mmol) in ether/THF (6 mL) was stirred for 3 days under nitrogen atmosphere. The reaction was filtered, the filtrate evaporated, and the residue flash chromatographed on silica gel using 9/1 Hexane/acetone to give (4-bromo-3-methoxyphenyl)cyanamide (0.300 g, 12%). HRMS: calcd for 2 C8H7BrN2O+H+, 452.95562; found (ESI-FT/MS, [2M+H]1+), 452.9556.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[I:10]N1C(=O)CCC1=O>FC(F)(F)C(O)=O>[F:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]([CH3:9])=[CH:4][C:5]=1[I:10]
Reactant: Cc1ccc(F)cc1F
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(I)c(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of 2,4-difluoro-1-methylbenzene (6 g, 47 mmol) in trifluoroacetic acid (15 mL) was added N-iodosuccinimide (12.1 g). The mixture was stirred at rt overnight before it was poured into ice and extracted with hexanes. The organic layer was separated and washed with saturated Na2S2O3, NaHCO3, brine and then dried over MgSO4. The crude product was purified by silica gel chromatography to give 94A (10.7 g, 90% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 2.15-2.30 (m, 3H) 6.73-6.85 (m, 1H) 7.55 (t, J=7.69 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].C([N-]C(C)C)(C)C.[Li+].CON(C)[C:28](=[O:44])[CH:29]([O:42][CH3:43])[C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>C1COCC1>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:28](=[O:44])[CH:29]([O:42][CH3:43])[C:30]3[CH:31]=[CH:32][C:33]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[CH:34][CH:35]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Reactant: COC(C(=O)N(C)OC)c1ccc(N2CCOCC2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(N4CCOCC4)cc3)o2)cc(OC)c1Br
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 59 %

Procedure:
To a solution of 2-(4-bromo-3,5-dimethoxyphenyl)furan (0.203 g, 0.72 mmol) in anhydrous THF (2 mL) under argon in an oven-dried flask cooled to −78° C. was added a solution of lithium diisopropylamide (2.0 M in THF/heptane/ethylbenzene; 0.4 mL, 0.8 mmol) dropwise. After stirring for 35 min at −78° C., a solution of N,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide (0.315 g, 1.1 mmol) in THF (2 mL) was added dropwise. After stirring for 25 min, the mixture was allowed to warm to room temp while stirring for 2 hrs. The reaction was quenched with the addition of saturated aqueous NH4C1 then brine and EtOAc were added. The layers were separated and the organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography (35-65% EtOAc-hexanes) provided an oil that was triturated with MeOH-Et2O (1:1) with sonication. The solid was collected on a Büchner, rinsed with MeOH-Et2O (1:1) and dried in vacuo to give 1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-morpholinophenyl)ethanone as a yellow solid. A second batch was collected from MeOH-Et2O (˜10%) to give additional product (0.220 g total, 59% yield). MS: m/z 516.1 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][CH2:9][C:10]([CH3:40])([CH3:39])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:38][CH2:37][C:21]2([O:26][CH2:25][CH2:24][N:23]([C:27]([C:29]3[N:30]=[C:31]([CH:34]([CH3:36])[CH3:35])[S:32][CH:33]=3)=[O:28])[CH2:22]2)[CH2:20][CH2:19]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:34]([C:31]1[S:32][CH:33]=[C:29]([C:27]([N:23]2[CH2:22][C:21]3([CH2:37][CH2:38][N:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]([CH3:40])([CH3:39])[CH:9]=[O:8])[CH2:19][CH2:20]3)[O:26][CH2:25][CH2:24]2)=[O:28])[N:30]=1)([CH3:36])[CH3:35]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCCCCCCC(C)(C)CO)CC3)C2)cs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCCCCCCC(C)(C)C=O)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
Trifluoroacetic acid (0.059 mL) was added to a solution of (9-(9-hydroxy-8,8-dimethylnonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (example 103, step c) (0.37 g) in DCM (20 mL) at 0° C. under argon and the mixture stirred for 5 min before addition of Dess-Martin periodinane (0.49 g). The reaction mixture was stirred at RT for 1.25 h then was quenched by addition of saturated sodium thiosulfate solution (20 mL) and saturated sodium bicarbonate solution (20 mL) then ethyl acetate was added and the mixture stirred for 5 min. The phases were separated and the aqueous layer was extracted with ethyl acetate (×2). The combined organic solutions were washed with saturated sodium bicarbonate solution. Acetic acid (0.066 mL) was added to the organic phase which was then dried over sodium sulphate, filtered and evaporated in vacuo to afford the crude subtitled compound as a yellow oil. Yield 0.40 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+]([O-])=O)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([SH:21])[CH:18]=[CH:19][CH:20]=1.CN(C=O)C.[H-].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]([S:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[CH:16]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: COc1cccc(S)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(Sc2cc(Br)cnc2C#N)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
A 10 mL round-bottomed flask was charged with 5-bromo-3-nitropicolinonitrile (300 mg, 1.31 mmol), 3-methoxybenzenethiol (0.150 mL, 1.31 mmol), and DMF (12 mL). NaH (37.8 mg, 1.58 mmol) was added and reaction stirred at room temperature for 10 minutes. The reaction was poured into water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting residue was purified on silica gel (10% EtOAc in Hexanes) to afford the title compound (345 mg, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=S.[Cl:11][C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:30])[CH2:24][CH2:25][C:26]([NH:28][NH2:29])=[O:27])[CH2:18][CH2:17]1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:27][C:26]([CH2:25][CH2:24][C:23]([NH:22][CH:19]2[CH2:20][CH2:21][N:16]([CH2:15][C:14]3[CH:31]=[CH:32][C:33]([Cl:34])=[C:12]([Cl:11])[CH:13]=3)[CH2:17][CH2:18]2)=[O:30])=[N:28][N:29]=1
Reactant: NNC(=O)CCC(=O)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: S=C=Nc1ccccc1Cl
Solvent: CN(C)C=O
Product: O=C(CCc1nnc(Nc2ccccc2Cl)o1)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Chloro-2-isothiocyanato-benzene (0.112 g) and N-[1-(3,4-dichlorobenzyl)-piperidin-4-yl]-3-hydrazinocarbonyl-propionamide (0.20 g) were stirred together in dimethylformamide (2 ml) at ambient temperature for 2 hours. AM resin (0.324 g, Novabiochem, 2% DVB 1.57 mmol/g) was added and the resulting mixture was stirred at ambient temperature for 16 hours. N-Cyclohexylcarbodiimide N-methyl polystyrene HL (0.638 g, Novabiochem, 1.69 mmol/g) was added and the resulting mixture was stirred at 80° C. for 24 hours, then allowed to cool. The reaction mixture was then filtered, washing with dimethylformamide (2×2 ml). The combined filtrates were evaporated and the residue was purified by reverse phase HPLC to give the title compound as a white solid. (0.028 g, m.pt. 154-156° C., MS [M+H]+ (APCI+) 508/510).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][C:3]=1[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:32][CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:12])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(CCCO)ccc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: Cc1cc(CCCBr)ccc1Cl
Yield: 89.6 %

Procedure:
Compound 67-2 (2.49 g) was dissolved in methylene chloride (45 ml), triphenylphosphine (3.90 g) and N-bromosuccinimide (2.64 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2.5 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.99 g) as a colorless oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]([CH3:20])([CH3:19])[C:17](=N)[N:16]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=3)[C:15]2=[S:34])=[CH:10][CH:9]=1)(C)(C)C.C[OH:37].O>Cl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]([CH3:20])([CH3:19])[C:17](=[O:37])[N:16]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([C:30]([F:31])([F:33])[F:32])[CH:23]=3)[C:15]2=[S:34])=[CH:10][CH:9]=1
Reactant: CO
Reactant: CC(C)(C)OC(=O)Nc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=N)C2(C)C)cc1
Agent: Cl
Solvent: O
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(N)cc1
Temperature: 25 °C

Procedure:
The mixture of 2c (0.15 g, 0.3 mmol) in HCl aq, 3N. (1 ml) and methanol (4 ml) was heated to reflux for 2 h. After being cooled to room temperature, the reaction mixture was poured into cold water (5 ml) and extracted with dichloromethane (8 ml). The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane/acetone, 9:1) to yield 4-[3-(4-aminophenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile, 2d, [RD9] (0.118 g, 0.29 mmol, 97%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[O:11])[CH3:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br-:12].[Br-].[Br-].C[N+](C)(C)C1C=CC=CC=1.C[N+](C1C=CC=CC=1)(C)C.C[N+](C1C=CC=CC=1)(C)C>O1CCCC1>[Br:12][CH2:10][C:9]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1)=[O:11]
Reactant: [Br-]
Reactant: CC(=O)c1ncc(Cl)cc1Cl
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 161.1 %

Procedure:
To 5.00 g of 1-(3,5-dichloropyridin-2-yl)ethanone in 75 ml of tetrahydrofuran, 9.94 g of trimethylphenylammonium tribromide was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the precipitated solid was filtered off through celite, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 15:85) as the eluent to obtain 6.64 g of the desired product as a brown oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=O.[NH2:16][C:17]1[C:21]([C:22]#[N:23])=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:26][CH2:25]2)[NH:19][N:18]=1>C(O)(=O)C>[C:31]1([CH2:30][N:27]2[CH2:28][CH2:29][N:24]([C:20]3[C:21]([C:22]#[N:23])=[C:17]4[N:16]=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:4]=[C:5]([C:7]5[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=5)[N:18]4[N:19]=3)[CH2:25][CH2:26]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccncc1
Reactant: N#Cc1c(N)n[nH]c1N1CCN(Cc2ccccc2)CC1
Solvent: CC(=O)O
Product: N#Cc1c(N2CCN(Cc3ccccc3)CC2)nn2c(-c3ccncc3)cc(C(F)(F)F)nc12

Procedure:
A mixture of 3.9 g (0.014 moles) of 4,4,4-trifluoro-1-(4-pyridyl)-1,3-butanedione (U.S. Pat. No. 3,200,128), 3.9 g (0.014 moles) of 3-amino-5-(4-phenylmethyl-1-piperazinyl)-4-pyrazolecarbonitrile (prepared as described in Example 1) and 100 ml of glacial acetic acid was stirred at reflux for 16 hours.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:31](Br)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCOCC1>[C:31]([N:18]1[C:19](=[O:20])[C:21]([F:23])=[CH:22][N:15]([C@@H:7]2[O:8][C@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6]2)[C:16]1=[O:17])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(C)=O
Reactant: O=C(Br)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3ccccc3)c2=O)C[C@@H]1OC(C)=O
Reaction time: 0.25 h
Yield: 60.8 %

Procedure:
500 mg of 2'-deoxy-3',5'-di-O-acetyl-5-fluorouridine and 0.76 ml of triethylamine were dissolved in 10 ml of dry dioxane, and the resulting mixture was cooled with ice. To the mixture was added 850 mg of benzoyl bromide, and the resulting mixture was allowed to stand at room temperature for 15 minutes and then at 70° C. for 30 minutes. The same procedure as in Example 8 gave 400 mg (yield: 60.5%) of 3-benzoyl-2'-deoxy-3',5'-di-O-acetyl-5-fluorouridine. The absorption spectra of the present product were identical with those of the compound obtained in Example 8.
Reaction SMILES: [CH3:1][C:2]1([CH3:45])[CH2:7][O:6][CH:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=3[C:32]([NH:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH:37]([C:41]([O:43]C)=[O:42])[CH2:36]3)=[O:33])=[CH:14][CH:13]=2)[O:4][CH2:3]1.Cl>CO.C1COCC1.[OH-].[Na+]>[C:41]([CH:37]1[CH2:38][CH2:39][CH2:40][CH:35]([NH:34][C:32]([C:23]2[CH:24]=[C:25]([CH:30]=[CH:31][C:22]=2[O:21][CH2:20][CH2:19][CH2:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][CH2:8][CH:5]3[O:4][CH2:3][C:2]([CH3:45])([CH3:1])[CH2:7][O:6]3)=[CH:13][CH:14]=2)[C:26]([O:28][CH3:29])=[O:27])=[O:33])[CH2:36]1)([OH:43])=[O:42]
Reactant: COC(=O)c1ccc(OCCCc2ccc(OCCCC3OCC(C)(C)CO3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(OCCCc2ccc(OCCCC3OCC(C)(C)CO3)cc2)c(C(=O)NC2CCCC(C(=O)O)C2)c1
Reaction time: 15 h
Yield: 77.9 %

Procedure:
A solution of 70.0 mg of methyl 4-(3-{4-[3-(5,5-dimethyl-1,3-dioxan-2-yl)propoxy]-phenyl}propoxy)-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate in 1 ml each of methanol, THF and 2 molar sodium hydroxide solution is stirred at a temperature of 60° C. for 2 hours. Then 1.1 ml of 2 molar hydrochloric acid are added, and the reaction mixture is left to stand open at room temperature for 15 hours. A precipitate separates out and is filtered off with suction and washed with water. If the precipitation is incomplete, extraction with ethyl acetate is possible. The organic extract is dried over anhydrous sodium sulphate and evaporated. 53.3 mg of a solid are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[C:15]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28]O)[CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:28][CH:25]3[CH2:26][CH2:27][N:22]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:23][CH2:24]3)=[CH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Oc1ccc(-c2ccc(Br)cn2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(Br)cn3)cc2)CC1
Yield: 60.4 %

Procedure:
1,1-Dimethylethyl 4-({[4-(5-bromo-2-pyridinyl)phenyl]oxy}methyl)-1-piperidinecarboxylate (0.27 g, 60%) was prepared as a white solid from 4-(5-bromo-2-pyridinyl)phenol (0.25 g, 1.0 mmol), N-Boc-4-piperidinemethanol (0.23 g, 1.0 mmol) and Ph3P (0.27 g, 1.0 mmol) in THF (7 mL) followed by diisopropyl azodicarboxylate (0.22 g, 94%, 1.0 mmol) in THF (3 mL) in a manner similar to Example 1, Step 2. 1H NMR (400 MHz, CDCl3): δ 8.69 (s, 1H), 7.92 (d, 2H, J=8.8 Hz), 7.85 (d, 1H, J=8.5 Hz), 7.57 (d, 1H, J=8.5 Hz), 6.97 (d, 2H, J=8.8 Hz), 4.25-4.10 (m, 2H), 3.86 (d, 2H, J=6.4 Hz), 2.85-2.70 (m, 2H), 2.05-1.90 (m, 1H), 1.90-1.80 (m, 2H), 1.46 (s, 9H), 1.35-1.20 (m, 2H); LRMS (ESI), m/z 446/448 (M+H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([O:19][C:20]([NH:22][C@H:23]1[C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[CH2:27][CH:26]=[CH:25][CH2:24]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH2:12]([O:19][C:20]([NH:22][C@@H:23]1[CH2:24][C@H:25]2[C@H:26]([O:9]2)[CH2:27][C@@H:28]1[C:29]([O:31][CH3:32])=[O:30])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)[C@H]1CC=CC[C@H]1NC(=O)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H]2O[C@H]2C[C@H]1NC(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 57 %

Procedure:
m-Chloroperbenzoic acid (5.56 g, 32.2 mmol) was added to a solution of methyl (1S,6R)-6-{[(benzyloxy)carbonyl]amino}cyclohex-3-ene-1-carboxylate (7.8 g, 27 mmol) in methylene chloride (150 mL) with stirring at about 0° C. The mixture was slowly warmed to room temperature and stirred overnight. The mixture was diluted with dichloromethane then washed with sat. NaHCO3 (3×). The organic layer was dried (MgSO4), filtered, and concentrated. The crude was purified on silica gel, eluted with 0-50% EtOAc in hexanes to give 4.7 g (57%) of the desired product as a white solid. LCMS calculated for C16H20NO5 (M+H)+: m/z=306.1. Found: 306.0. 1H NMR (300 MHz, CDCl3) δ 7.37-7.29 (m, 5H), 5.75 (d, J=9.9 Hz, 1H), 5.04 (s, 2H), 4.09 (dtd, J=14.0, 6.8, 6.0, and 3.2 Hz, 1H), 3.65 (s, 3H), 3.18 (d, J=5.9 Hz, 2H), 2.60 (dd, J=15.5 and 7.3 Hz, 1H), 2.48 (td, J=7.3, 6.6, and 3.2 Hz, 1H), 2.23-2.01 (m, 3H) ppm.