Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(CC)C(C)C)(C)C>CO.O>[F:1][C:2]1[CH:9]=[C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(F)cc(F)cc1F
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CO
Product: N#Cc1c(F)cc(N2CCOCC2)cc1F
Temperature: 50 °C
Yield: 68.6 %

Procedure:
To a solution of 1.0 g (6.37 mmol) of 2,4,6-trifluorobenzonitrile in MeOH (25 mL) was added 0.6 mL (6.9 mmol) of morpholine and 1.2 mL (6.7 mmol) of N,N-diisopropylethylamine. The mixture was heated to 50° C. for 6 h then cooled to room temperature and diluted with H2O which caused a solid to precipitate from solution. The white solid was collected by filtration, washed with H2O and dried under vacuum to provide 0.98 g (68%) of 2,6-difluoro-4-morpholin-4-yl-benzonitrile as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[C:11]([CH2:12][CH2:13][C:4]=2[CH:3]=1)=[N:10][NH:9][C:8](=[O:14])[CH:7]=3.Br[CH2:18][CH2:19][CH2:20][Cl:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:21][CH2:20][CH2:19][CH2:18][O:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[C:11]([CH2:12][CH2:13][C:4]=2[CH:3]=1)=[N:10][NH:9][C:8](=[O:14])[CH:7]=3
Reactant: ClCCCBr
Reactant: O=c1cc2c(n[nH]1)CCc1cc(O)ccc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=c1cc2c(n[nH]1)CCc1cc(OCCCCl)ccc1-2

Procedure:
In a 50 mL round bottom flask, 8-hydroxy-5,6-dihydro-3H-benzo[f]cinnolin-2-one (575 mg, 2.69 mmol), 1-bromo-3-chloro-propane (0.27 mL, 2.69 mmol), and potassium carbonate (371 mg, 2.69 mmol) in acetonitrile (20 mL) was heated to reflux 14 h. The reaction was cooled and the solvent concentrated under vacuum. The slurry was partitioned between methylene chloride and water, separated, dried over MgSO4. Purification with silica gel chromatography eluting with methylene chloride/methanol (95:5) produced 106 mg (14%) as an amorphous solid. MS m/z 291 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([O:12][CH:13]([CH3:15])[CH3:14])[CH2:11][CH2:10]2)=[CH:5][C:4]=1C)#[CH:2].[CH2:17]([O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1)[CH3:18].[CH2:29](N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:13]([O:12][C:9]1([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[C:2][C:24]3[CH:25]=[CH:26][C:21]([C:20]([O:19][CH2:17][CH3:18])=[O:28])=[CH:22][CH:23]=3)=[CH:8][C:7]=2[CH3:29])[CH2:10][CH2:11]1)([CH3:14])[CH3:15]
Reactant: C#Cc1ccc(C2(OC(C)C)CC2)cc1C
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CCN(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OC(C)C)CC3)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
Using General Procedure F; 4-ethynyl-1-(1-isopropoxycyclopropyl)-3-methyl-benzene (Intermediate 81, 80.0 mg, 0.13 mmol) and ethyl-4-iodo benzoate (Reagent A, 100.0 mg, 0.36 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (25.0 mg, 0.13 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (91 mg, 0.13 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc-hexanes) afforded 75.0 mg (56%) of the title compound as an orange solid.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:16]C([O-])(C)C.[K+].CI>C1COCC1>[C:1]([N:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:16])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CCOC(=O)CCNC(=O)OC(C)(C)C
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)CCN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 80.8 %

Procedure:
To a solution of ethyl 3-aminopropionate hydrochloride (19 g) in THF (600 mL) was added triethylamine (44 mL), dimethylaminopyridine (1.5 g) and di-tert-butyldicarbonate (30 g) at 0° C. and the mixture was stirred at 40° C. for four hours. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give ethyl N-Boc-3-aminopropionate (16.7 g) as a colorless oil. To a solution of ethyl N-Boc-3-aminopropionate (5.0 g) in THF (50 mL) was added t-BuOK (2.8 g) and methyl iodide (4.9 g) at 0° C. and the mixture was stirred at room temperature for an hour. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give ethyl 3-(N-Boc-N-methylamino)propionate (4.3 g) as a colorless oil. Subsequently, the title compound was prepared from ethyl 3-(N-Boc-N-methylamino)propionate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1001.
Reaction SMILES: [CH2:1]([N:4]([CH2:23][CH2:24][CH3:25])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]#[C:18][Si](C)(C)C)[CH:16]=1)[C:10]([O:12]C)=[O:11])=[O:6])[CH2:2][CH3:3].[OH-].[K+]>CO.O.C(Cl)(Cl)Cl>[CH2:23]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]#[CH:18])[CH:16]=1)[C:10]([OH:12])=[O:11])=[O:6])[CH2:24][CH3:25]
Reactant: CCCN(CCC)C(=O)c1cc(C#C[Si](C)(C)C)cc(C(=O)OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: C#Cc1cc(C(=O)O)cc(C(=O)N(CCC)CCC)c1
Reaction time: 4 h
Yield: 105.9 %

Procedure:
To a stirred solution of methyl 3-[(dipropylamino)carbonyl]-5-[(trimethylsilyl)ethynyl]benzoate 26 (185.3 mg, 0.49 mmol) in MeOH (2.5 mL) was added a solution of KOH (2.9 mL of a 1 M solution in H2O, 2.9 mmol). The resulting homogeneous brown solution turned to a white/brown suspension, then to a clear brown solution. The reaction mixture was stirred for 4 h, diluted with CHCl3 (40 mL), separated and the organic layer was concentrated under reduced pressure to provide 3-[(dipropylamino)carbonyl]-5-ethynylbenzoic acid 27 (141.8 mg): 1H NMR (300 MHz, CDCl3): δ 8.22 (d, J=1 Hz, 1H), 8.05 (d, J=1 Hz, 1H), 7.71 (d, J=1 Hz, 1H), 3.48 (br s, 2H), 3.17 (s, 1H), 3.16 (br s, 2H), 1.71 (d, J=7 Hz, 2H), 1.55 (d, J=7 Hz, 2H), 1.00 (d, J=7 Hz, 3H), 0.78 (d, J=7 Hz, 3H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]3[O:31][CH:30]=[CH:29][C:7]=3[N:8]=[C:9]([NH:11][C:12]3[CH:20]=[C:19]4[C:15]([C:16]([CH3:28])=[N:17][N:18]4C(OC(C)(C)C)=O)=[CH:14][CH:13]=3)[N:10]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:4][C:5]2[C:6]3[O:31][CH:30]=[CH:29][C:7]=3[N:8]=[C:9]([NH:11][C:12]3[CH:20]=[C:19]4[C:15]([C:16]([CH3:28])=[N:17][NH:18]4)=[CH:14][CH:13]=3)[N:10]=2)[CH2:2][CH2:3]1
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2cc(Nc3nc(NC4CC4)c4occc4n3)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1n[nH]c2cc(Nc3nc(NC4CC4)c4occc4n3)ccc12
Reaction time: 4 h
Yield: 63.1 %

Procedure:
To a flask was added tert-butyl 6-(4-(cyclopropylamino)furo[3,2-d]pyrimidin-2-ylamino)-3-methyl-1H-indazole-1-carboxylate (12.5 g, 29.7 mmol), DCM (270 mL) and TFA (45.8 mL, 595 mmol). The mixture was stirred for about 4 h. The mixture was concentrated and the residue was dissolved in MeOH (100 mL). The resulting solution was added into stirred aqueous NaHCO3 (10 wt %, 1000 mL) and the mixture was allowed to stir for about 1 h. The resultant suspension was filtered. To the solid was added hot water (60° C., 1000 mL) and the mixture was stirred for about 45 min and then filtered. The solid was then added to a mixture of DCM (270 mL) and MeOH (30 mL) in a flask, the mixture was heated to reflux then additional MeOH (25 mL) was added portion wise over a period of about 45 min, until a clear solution formed. The solution was filtered while hot. The filtrate was cooled in an ice bath for about 1 h. The mixture was then filtered to provide the desired product (6 g). The filtrate was combined with silica gel (15 g, 200-400 mesh size) and concentrated to a free flowing powder. The material was purified via column chromatography (0-3% MeOH in DCM over 35 min; 120 g silica gel) to give additional product (2.2 g). The two batches of product were combined to give N4-cyclopropyl-N2-(3-methyl-1H-indazol-6-yl)furo[3,2-d]pyrimidine-2,4-diamine (8.2 g, 86%); LC/MS (Table 2, Method c) Rt=1.61 min.; MS m/z: 321 (M+H)+, 1H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 9.04 (s, 1H), 8.44 (s, 1H), 8.06 (d, J=2.1 Hz, 1H), 7.83 (s, 1H), 7.46 (d, J=8.7 Hz, 1H), 7.26 (dd, J=8.8, 1.7 Hz, 1H), 6.75 (d, J=2.1 Hz, 1H), 3.00 (td, J=7.1, 3.6 Hz, 1H), 2.41 (s, 3H), 0.90-0.83 (m, 2H), 0.68-0.61 (m, 2H). Syk IC50=A
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6]1(C)C=[CH:10][C:9](S(O)(=O)=O)=[CH:8][CH:7]=1.P([O-])([O-])([O-])=[O:18]>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][O:5][CH:10]1[CH2:9][CH2:8][CH2:7][CH2:6][O:18]1
Reactant: O=P([O-])([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCCCBr
Solvent: ClCCl
Product: BrCCCOC1CCCCO1
Reaction time: 1 h
Yield: 69 %

Procedure:
A solution of 4.61 g. 3-bromopropanol in 150 ml. methylene chloride at 0° C. was treated with 5.1 ml. dihydropropyran followed by 55 mg. p-toluenesulphonic acid and then warmed to room temperature. After one hour, phosphate buffer (pH: 7.5) was added to the mixture. The organic layer was washed with brine, dried (Na2SO4) and evaporated. The yellow oil obtained was purified by chromatography on triethylamine-treated silica gel using a gradient solvent system (pure hexane-50% v/v ethyl ether/hexane) as eluent to give 2-(3-bromopropoxy)tetrahydro-2H-pyran in 69% yield as an oil, having a satisfactory NMR spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1F.[CH2:18]([SH:20])[CH3:19].[Na]>CS(C)=O.O.Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1[S:20][CH2:18][CH3:19]
Reactant: CCS
Reactant: O=c1[nH]c2cc(Cl)c(F)c([N+](=O)[O-])c2[nH]c1=O
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: CCSc1c(Cl)cc2[nH]c(=O)c(=O)[nH]c2c1[N+](=O)[O-]

Procedure:
A solution of 7-Chloro-1,4-dihydro-6-fluoro-5-nitroquinoxaline-2,3-dione (0.100 g, 0.385 mmol) and ethanethiol, sodium salt (0.130 g, 1.55 mmol) in DMSO (1.0 mL) was stirred at room temperature for 24 h. The resulting solution was diluted with water (5 mL) and acidified with concd HCl (4-5 drops) to pH~5. The precipitated solid was collected by filtration under vacuum, washed with water (10 mL), and dried under vacuum. to obtain 0.098 g (84%) pure (HPLC) title compound as a yellow powder; mp darkens at 323° C.; 1H NMR (DMSO-d6) δ 1.04 (t, 3H, J=7.2 Hz), 2.82 (q, 2H, J=7.5 Hz), 7.34 (s, 1H), 12.20 (s, 1H), 12.25 (s, 1H).
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][CH2:3]C1=O.[CH3:13][Mg]Br.Cl.CC[O:19][CH2:20][CH3:21]>O>[OH:1][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][CH2:3][C:20]([CH3:21])([OH:19])[CH3:13]
Reactant: CCOCC
Reactant: C[Mg]Br
Reactant: O=C1CC=Cc2ccccc2O1
Agent: Cl
Solvent: O
Product: CC(C)(O)CCCc1ccccc1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 5 g (31 mmol) of 1-benzoxepin-2-one in 50 ml of ether is added dropwise a solution of 62 mmol (2 eq) of methyl magnesium bromide in ether at 0° C. After addition is completed the reaction mixture is stirred 1 hour at 0° C. and acidified slowly at 0° C. with 1N HCl (20 ml). The reaction mixture is then diluted with water and extracted with ether. The combined organic extracts are dried (MgSO4), filtered and concentrated to obtain 5-(o-hydroxyphenyl)-2-methyl-2-pentanol as a colorless oil which is used directly in the next step.
Reaction SMILES: [C:1]([CH2:3][C:4](O)=O)#[N:2].[OH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C=O.[C:16](=O)=O>C(Cl)Cl.O1CCOCC1>[OH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:16][C:3](=[CH2:4])[C:1]#[N:2])[CH2:10][CH2:9]1
Reactant: N#CCC(=O)O
Reactant: OC1CCNCC1
Reactant: O=C=O
Agent: C=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: C=C(C#N)CN1CCC(O)CC1

Procedure:
Cyanoacetic acid (8.5 g., 0.1 mole) was dissolved in 25 ml. of dioxane. 4-Hydroxypiperidine (10.1 g., 0.1 mole) was added within two minutes; the resultant slurry temperature rose to 33° C. After 1 hour of mixing, 37% aqueous formaldehyde (17 g., 0.2 mole) was run in over a 12 minute period. The temperature rose to 38° C. and carbon dioxide evolved steadily. All was in solution after about one-half of the formaldehyde was added and an additional twelve hours was used to complete the reaction. It was then stripped using a bath at 46° C. and 1-5 mm. of pressure. The residual oil, 17 g., was taken up in methylene chloride, washed with water, dried and stripped to leave 8.1 g. of nearly colorless product, b.p. 125° C./1 mm.
Reaction SMILES: N1C=CC=CC=1.[C:7]([OH:11])([CH3:10])([CH3:9])[CH3:8].[Cl:12][C:13]1[N:18]=[CH:17][N:16]=[C:15]([C:19](Cl)=[O:20])[C:14]=1[CH3:22]>ClCCl>[Cl:12][C:13]1[N:18]=[CH:17][N:16]=[C:15]([C:19]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:20])[C:14]=1[CH3:22]
Reactant: CC(C)(C)O
Reactant: Cc1c(Cl)ncnc1C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(Cl)ncnc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C. a solution of 5.8 mL pyridine and 15 mL tert.-butanol in 10 mL dichloromethane was added dropwise to 6.0 g 6-chloro-5-methyl-pyrimidine-4-carboxylic acid chloride in 10 mL dichloromethane. The reaction mixture was heated to RT and stirred for 30 min. The reaction mixture was diluted with dichloromethane and washed successively with a 2M sodium hydroxide solution, twice with a 10% aqueous citric acid solution and a sodium chloride solution. The organic phase was dried and evaporated down. The residue was taken up in dichloromethane and purified by flash chromatography. The product-containing fractions were evaporated down and dried.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[S:32][C:31]([S:33]([NH2:36])(=[O:35])=[O:34])=[N:30][N:29]=1>>[S:33]([C:31]1[S:32][C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:1])[F:25])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:14])=[N:29][N:30]=1)(=[O:35])(=[O:34])[NH2:36]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1nnc(S(N)(=O)=O)s1
Product: NS(=O)(=O)c1nnc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 5-amino-[1,3,4]thiadiazole-2-sulfonic acid amide [commercially available, CAS 14949-00-9] according to general procedure II.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:27])/[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:17])=[C:9]([O:28][CH3:29])[C:8]([CH3:30])=[C:7]2[C:3]=1[C:4](=[O:31])[O:5][CH2:6]2.[N:32]1[CH:37]=CC=CC=1.C(Cl)(Cl)=[O:39]>C1C=CC=CC=1>[C:37]([O:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:27])/[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:17])=[C:9]([O:28][CH3:29])[C:8]([CH3:30])=[C:7]2[C:3]=1[C:4](=[O:31])[O:5][CH2:6]2)(=[O:39])[NH2:32]
Reactant: c1ccncc1
Reactant: O=C(Cl)Cl
Reactant: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)OCCN1CCOCC1)C(=O)OC2
Solvent: c1ccccc1
Product: COc1c(C)c2c(c(OC(N)=O)c1C/C=C(\C)CCC(=O)OCCN1CCOCC1)C(=O)OC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 500 mgs of morpholinoethyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate in 10 ml of benzene cooled in an ice bath is added 0.1 ml of pyridine and 6 ml of a 12.5% solution of phosgene in benzene. The solution is stirred at 25° C. overnight, the precipitate filtered off and solvent removed from the filtrate under reduced pressure. The residue is dissolved in 5 ml of tetrahydrofuran and to this solution is added dropwise a solution of ammonia in tetrahydrofuran until the reaction is complete. The mixture is poured into water and extracted with ethyl acetate. The organic solution is dried over magnesium sulfate and evaporated to an oil which is chromatographed on silica gel, eluting with a 50:1 mixture of dichloromethane and methanol. The purified product is stirred with a mixture of ether and hexane and filtered giving morpholinoethyl (E)-6-(1,3-dihydro-4-carbamoyloxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:15])[CH2:11][CH2:12][CH2:13]O)([O-:3])=[O:2].C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:15])[CH2:11][CH2:12][CH2:13][Br:17])([O-:3])=[O:2]
Reactant: O=C(CCCO)c1ccccc1[N+](=O)[O-]
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(CCCBr)c1ccccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
A mixture of 1-(o-nitrophenyl)-4-hydroxy-1-butanone (1.33 g, 6.4 mmol) and CBr4 (2.32 g, 7.0 mmol) in toluene is treated with triphenylphospine (2.50 g, 9.5 mmol), heated at 60° C. with stirring under nitrogen for 24 hours, cooled to room temperature and poured onto water. The resultant aqueous mixture is extracted with ethyl acetate. The extracts are combined, washed with brine, dried over Na2SO4 and concentrated in vacuo to give a residue. The residue is purified by flash column chromatography (silica gel; gradient 1:4→1:2 ethyl acetate: hexanes as eluent) to give the title product as a brown oil, 0.90 g, 52% yield, identified by NMR and mass spectral analyses.
Reaction SMILES: C(C1C=CC=CC=1C)=C.C[C:11]([C:13]([O:15][CH:16]1[C@@]2(C)C(C)(C)[C@H:18](CC2)[CH2:17]1)=[O:14])=C.[C:26]([O:30]OC(C)(C)C)(C)(C)C>C1(C)C(C)=CC=CC=1>[C:13]([O:15][CH2:16][CH2:17][CH2:18][O:30][CH3:26])(=[O:14])[CH3:11]
Reactant: C=C(C)C(=O)OC1C[C@H]2CC[C@]1(C)C2(C)C
Reactant: CC(C)(C)OOC(C)(C)C
Agent: C=Cc1ccccc1C
Solvent: Cc1ccccc1C
Product: COCCCOC(C)=O
Yield: 516.1 %

Procedure:
In the manner comparable with Example 1 3.54 g vinyl toluene, 5.69 g isobornyl methacrylate, 9.20 g 2-ethyl hexyl methacrylate, 7.15 g hydroxy ethyl methacrylate, and 1.28 g ditertiary butylperoxide dissolved in 11.94 g xylene and 5.97 g methoxypropyl acetate were polymerized.
Reaction SMILES: C(N[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1CCCC)=[O:7])(C)(C)C.[ClH:24].[CH2:25]([OH:28])[CH2:26]O>>[CH2:6]([C:12]1[CH:13]=[C:8]([CH:9]=[CH:10][C:11]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:6]([O:28][CH2:25][CH2:26][Cl:24])=[O:7])[CH2:8][CH2:9][CH3:10]
Reactant: Cl
Reactant: CCCCc1cc(-c2ccccc2)ccc1C(=O)NC(C)(C)C
Reactant: OCCO
Product: CCCCc1cc(C(=O)OCCCl)ccc1-c1ccccc1

Procedure:
To a 200 mL round bottomed flask with a stirring bar and a reflux condenser was added (N-tert-butyl)-3-butyl-4-biphenylcarboxamide (3.17 g, 10.24 mmol), ethylene glycol (25 mL) and 12N HCl (25 mL). This mixture was heated at reflux 72 h. The cooled mixture was extracted with EtOAc and the EtOAc extracts were combined, washed with H2O (3×) and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed on silica gel using 30% EtOAc in hexane as eluantto afford the title compound as an oil.
Reaction SMILES: [H-].[Li+].[CH2:3]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:4]([CH3:6])=[O:5].[Cl:15][C:16]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]I>>[C:4]([CH:3]([P:7](=[O:14])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:17]1[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:16]=1[Cl:15])(=[O:5])[CH3:6]
Reactant: CCOP(=O)(CC(C)=O)OCC
Reactant: COc1ccc(OCCCCCCCI)c(Cl)c1
Agent: [H-]
Agent: [Li+]
Product: CCOP(=O)(OCC)C(CCCCCCCOc1ccc(OC)cc1Cl)C(C)=O
Yield: 18.4 %

Procedure:
[II; Ar is 2-Cl-4CH3OC6H3, Y is O(CH2)7, R is C2H5, R' is CH3CO] was prepared from 0.57 g of lithium hydride, 13.9 g of diethyl acetonylphosphonate and 27.8 g of 7-(2-chloro-4-methoxyphenoxy)heptyl iodide according to the procedure of Example 12(b). The product was chromatographed on Florisil and further purified by preparative thin layer chromatography (TLC) on silica gel to give 5.9 g of diethyl [1-acetyl-8-(2-chloro-4-methoxyphenoxy)octyl]phosphonate as a yellow oil; MIC vs. herpes simplex type 2=6 mcg/ml. The NMR spectrum was consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[C:28]5[C@H:35]([CH3:36])[CH2:34][C@@H:33]([O:37]C(=O)C6C=CC([N+]([O-])=O)=CC=6)[C:29]=5[N:30]=[CH:31][N:32]=4)=[CH:23][CH:22]=3)[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:49]([OH:55])([C:51]([F:54])([F:53])[F:52])=[O:50]>C(Cl)Cl>[OH:55][C:49]([C:51]([F:54])([F:53])[F:52])=[O:50].[OH:55][C:49]([C:51]([F:54])([F:53])[F:52])=[O:50].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:21]3[CH:22]=[CH:23][C:24]([C:27]4[C:28]5[C@H:35]([CH3:36])[CH2:34][C@@H:33]([OH:37])[C:29]=5[N:30]=[CH:31][N:32]=4)=[CH:25][CH:26]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(-c3ccc(C4(c5ccc(Cl)cc5)CCN(C(=O)OC(C)(C)C)CC4)cc3)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(-c3ccc(C4(c5ccc(Cl)cc5)CCNCC4)cc3)c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
tert-Butyl 4-(4-chlorophenyl)-4-(4-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)piperidine-1-carboxylate (36 mg, 0.069 mmol) was dissolved in DCM (3 mL) and cooled to 0° C. Then TFA (1.5 mL) was added dropwise. The resulting solution was stirred at 0° C. for 1 hour, concentrated under reduced pressure, dissolved in DMF (1 mL) and purified by reverse phase HPLC (0-100% AcCN/H2O) to give (5R,7R)-4-(4-(4-(4-chlorophenyl)piperidin-4-yl)phenyl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol di-TFA salt (9 mg, 31% yield). 1H NMR (DMSO-d6, 400 MHz) δ 9.09 (s, 1H), 7.88 (d, J=8.8 Hz, 2H), 7.52 (d, J=8.4 Hz, 2 H), 7.42 (q, J=4.8 Hz, 4H), 5.64 (d, J=6.0 Hz, 1H), 5.06 (q, J=6.8 Hz, 1H), 3.85 (br s, 1H), 3.05 (br s, 3H), 2.89 (m, 2H), 2.61 (br s, 3H), 2.11 (m, 2H), 1.16 (t, J=6.4 Hz, 3H), 1.04 (d, J=6.6 Hz, 3H). LCMS: M+1 420.4.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[C:26](=[O:27])[N:25]([CH3:28])[C:16]2[N:17]=[C:18](S(C)(=O)=O)[N:19]=[CH:20][C:15]=2[CH:14]=1.[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N+:36]([O-])=O)[C:31]=1[NH2:39].CC(C)([O-])C.[K+]>CN(C=O)C.CCOC(C)=O>[NH2:36][C:32]1[CH:33]=[CH:34][CH:35]=[C:30]([CH3:29])[C:31]=1[NH:39][C:18]1[N:19]=[CH:20][C:15]2[CH:14]=[C:13]([C:3]3[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=3[Cl:12])[C:26](=[O:27])[N:25]([CH3:28])[C:16]=2[N:17]=1
Reactant: Cc1cccc([N+](=O)[O-])c1N
Reactant: COc1cc(OC)c(Cl)c(-c2cc3cnc(S(C)(=O)=O)nc3n(C)c2=O)c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(Cl)c(-c2cc3cnc(Nc4c(C)cccc4N)nc3n(C)c2=O)c1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.7 %

Procedure:
To a mixture of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (9) (1.0 g, 2.26 mmol) and 2-methyl-6-nitrobenzenamine (684 mg, 4.5 mmol) in DMF (20 mL), potassium tert-butoxide (756 mg, 6.75 mmol) was added at ˜10° C., and the reaction mixture was stirred at room temperature for 5 minutes. The reaction mixture was diluted with EtOAc (150 mL), and the organic phase was separated, washed with water (2×150 mL) and then brine (150 mL), dried over sodium sulfate, filtered, and concentrated. The residue was recrystallizated with EtOAc to give 2-(2-amino-6-methylphenylamino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (10) (810 mg, yield 70%) as a yellow solid. MS (ES+) C23H19Cl2N5O5 requires: 515, 517. found: 516, 518 [M+H]+.