Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:24]([O:26]C)=[O:25])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][O:22][CH3:23])=[CH:17][N:16]=2)=[N:11][CH:10]=1.[OH-].[Na+].O.Cl>C1COCC1>[F:1][C:2]1[C:3]([C:24]([OH:26])=[O:25])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][O:22][CH3:23])=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: COCc1ccc(Nc2ncc(Sc3ccnc(C(=O)OC)c3F)s2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCc1ccc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)nc1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
Methyl 3-fluoro-4-(2-(5-(methoxymethyl)pyridin-2-ylamino)thiazol-5-ylthio)picolinate (0.061 g, 0.150 mmol) was dissolved in THF (5 mL) and treated aq. NaOH (5N, 0.195 mL, 0.975 mmol). The reaction was stirred at 23° C. for 30 minutes, then water (1 mL) was added and the reaction was stirred for 30 more minutes. The reaction was then acidified with conc. HCl to pH ˜2 and water was added again. This was extracted with ethyl acetate/THF and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give the title material (0.035 g, 59%) as a solid which was used as such for the next reaction. HPLC ret. time (Condition B): 1.120 min. LC/MS (M+H)+: 393.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([N:12]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:11])=[CH:5][CH:4]=1.Cl[CH2:28][CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[NH:33][C:32]1=[O:40].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([N:12]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[CH:13]2[CH2:14][CH2:15][N:16]([CH2:28][CH2:29][CH2:30][N:31]3[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[NH:33][C:32]3=[O:40])[CH2:17][CH2:18]2)=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCNCC2)cc1
Reactant: O=c1[nH]c2ccccc2n1CCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)cc1
Temperature: 82 °C
Reaction time: 20 h

Procedure:
50ELH87 (0.05 g, 0.14 mmol, 1 eq.) was transferred to a 4 ml vial and dissolved in 1 ml of acetonitrile. Then, 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one (0.032 g, 1.1 eq.), sodium carbonate (0.022 g, 1.1 eq.) and KI (one crystal) were added and the vial was sealed and shaken for 20 h at 82° C. The mixture was extracted with distilled water (pH 10, sodium carbonate) and dichloromethane (3 times) the organic layers were dried with sodium sulfate and concentrated. The title compound was purified by HPLC and evaporated to dryness, forming a trifluoroacetic acid salt. Yield 8.8 mg (12%). UV/MS 100/100 (M+ 527), rt (A, MS) 2.851.
Reaction SMILES: [C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH:20]1[C:25]([OH:27])=[O:26].Cl>C(#N)C.[OH-].[Na+]>[C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([N:19]2[CH2:24][CH2:23][N:22]([C:8](=[O:9])[N:7]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:21][CH:20]2[C:25]([OH:27])=[O:26])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1CNCCN1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: O=C(O)C1CN(C(=O)N(c2ccccc2)c2ccccc2)CCN1C(=O)N(c1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 25.9 %

Procedure:
A solution of 946 mg (4 mmole) of 98% diphenylcarbamoyl chloride in 4 ml of acetonitrile was added dropwise to a stirring solution of 406.2 mg (2 mmole) of piperazine-2-carboxylic acid dihydrochloride [E. Felder, S. Maffei, S. Pietra and D. Pitre, Helv. Chim., Acta, 43, 888 (1960)] in 4 ml of 2.5N sodium hydroxide at a temperature between 0° and 5° C. After the addition was completed, the stirring was continued for 4 hours and the solution was acidified with 2N hydrochloric acid while cooling in an ice bath. The reaction mixture was concentrated under reduced pressure and the residue was extracted with chloroform. After washing with water, the chloroform solution was dried over MgSO4 and concentrated in vacuo. The only product which solidified on cooling was triturated with isopropyl ether to give 270 mg (26%) of (±)-1,4-bis-(diphenylcarbamoyl)piperazine-2-carboxylic acid, m.p. 244°-246° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:20][NH:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([N:21]([CH3:20])[C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1cccnc1
Reactant: CNC1CCCCC1
Product: CN(c1cccc2nc(NC(=O)c3cccnc3)nn12)C1CCCCC1

Procedure:
The title compound was prepared following procedure described for example 30 but starting from N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B4), 55 mg; 0.20 mmol; 1.0 eq.) and N-methylcyclohexylamine (1.0 mL) as an off white solid (30 mg, 43%). HPLC, Rt: 2.67 min. (purity 97.8%). LC/MS, M+(ESI): 351.4, M−(ESI): 349.4.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:5][CH:4]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(OC)(C)C>[CH3:16][C:11]1([CH3:17])[C:12]([CH3:15])([CH3:14])[O:13][B:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:4][CH:5]=2)[O:10]1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CC1(C)OB(c2ccc(CN3CCCCC3)cc2)OC1(C)C
Temperature: 25 °C

Procedure:
2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (250 mg; 0.84 mmol), piperidine (94 mg; 1.1 mmol) and K2CO3 (140 mg; 1.01 mmol) in DMF (4 ml) are heated to 80° C. for 45 minutes. The reaction mixture is cooled to room temperature, diluted with TBME, filtered and evaporated to dryness to deliver the title compound as orange crystals.
Reaction SMILES: [CH3:1][C:2]1([C:8](=[O:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH2:7][O:6][CH2:5][O:4][CH2:3]1.[H-].[Na+].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>CN(C)C=O>[CH3:1][C:2]1([C:8](=[O:15])[CH:9]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH2:23][C:22]2[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH2:7][O:6][CH2:5][O:4][CH2:3]1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC1(C(=O)Cn2cncn2)COCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C(=O)C(Cc2ccc(Cl)cc2)n2cncn2)COCOC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
A solution of 105.5 g (0.5 mole) of 1-(5-methyl-1,3-dioxan-5-yl)-2-(1,2,4-triazol-1-yl)-ethan-1-one in 100 ml of dimethylformamide is added dropwise, at 20°-25° C., to a suspension, stirred under pure nitrogen, of 13.2 g (0.55 mole) of sodium hydride in 100 ml of dry dimethylformamide. The reaction mixture is then stirred for three hours at 25° C., after which a solution of 81 g (0.5 mole) of 4-chlorobenzyl chloride in 50 ml of dimethylformamide is added dropwise and stirring is then continued for 14 hours. 50 ml of ice water are then cautiously added dropwise and the mixture is concentrated under reduced pressure. The residue is partitioned between 400 ml of methylene chloride and 200 ml of water and the organic phase is washed with three times 200 ml of water, dried over Na2SO4 and evaporated down. 112 g (66.8%) of 1-(5-methyl-1,3-dioxan-5-yl)-2-(1,2,4-triazol-1-yl)-3-(4-chlorophenyl)-propan-1-one are obtained as a pale yellow resin.
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[F:10][C:11]([F:23])([F:22])[C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>N1C=CC=CC=1>[Br:1][C:2]1[C:7]([NH:8][S:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([F:10])([F:22])[F:23])[CH:13]=2)(=[O:20])=[O:19])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Nc1cc(Cl)cnc1Br
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)cnc1Br)c1cccc(C(F)(F)F)c1
Reaction time: 18 h

Procedure:
To a stirred solution of 2-bromo-5-chloro-pyridin-3-ylamine (2.07 g, 10.0 mmol) in anhydrous pyridine (20 mL) was added 3-(trifluoromethyl)benzenesulfonyl chloride (4.90 g, 20.0 mmol) and the progress of the reaction was followed by LCMS. The reaction mixture was stirred overnight (18 h), then concentrated to dryness. The residue was dissolved in THF (20 mL) and stirred 18 h with 1M TBAF (20 mL) in THF to cleave the bis-sulfonamide. The THF was subsequently evaporated and the residue was dissolved in ethyl acetate. The organic phase was then washed with water (2×100 mL), brine, and then dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using ethyl acetate-hexane to provide N-(2-Bromo-5-chloro-pyridin-3-yl)-3-trifluoromethyl-benzenesulfonamide as a white crystalline solid. MS m/z 417.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(O)(/C=C/B1O[C:23](C)([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1)C>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6](/[CH:25]=[CH:23]/[C:22]([CH3:28])([OH:21])[CH3:27])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(O)/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(O)/C=C/c1ccnc(Cl)n1
Temperature: 90 °C

Procedure:
To a solution of 2,4-dichloropyrimidine (71 mg, 0.476 mmol) in dioxane (4 mL) and sodium carbonate (2M in water, 0.25 mL, 0.5 mmol) were added (3E)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-2-ol (100 mg, 0.476 mmol) and tetrakis triphenylphosphine palladium(0) (55 mg, 0.048 mmol). The solution was degassed by bubbling nitrogen gas and heated to 90° C. for 2 hr. The solution was diluted with EtOAc, washed with brine, dried with MgSO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography on silica gel (0-100% EtOAc/hexanes) to afford (3E)-4-(2-chloropyrimidin-4-yl)-2-methylbut-3-en-2-ol as a colorless oil. MS ESI: [M+H]+ m/z 199.1. 1H NMR (500 MHz, CDCl3) δ 8.52 (d, J=5.1, 1H) 7.24 (d, J=15.6, 1H) 7.12 (d, J=5.1, 1H) 6.60 (d, J=15.6, 1H); 1.22 (s, 6H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]2[C:18]3[C:13](=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[N:3]=1.[NH2:23][C:24]1[CH:32]=[C:31]2[C:27]([CH2:28][O:29][C:30]2=[O:33])=[CH:26][CH:25]=1>>[O:33]=[C:30]1[C:31]2[C:27](=[CH:26][CH:25]=[C:24]([NH:23][C:2]3[N:3]=[C:4]([O:8][C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[C:18]=4[CH:17]=[CH:16][CH:15]=[C:14]5[NH:19][C:20](=[O:22])[CH3:21])[CH:5]=[N:6][CH:7]=3)[CH:32]=2)[CH2:28][O:29]1
Reactant: Nc1ccc2c(c1)C(=O)OC2
Reactant: CC(=O)Nc1cccc2c(Oc3cncc(Cl)n3)cccc12
Product: CC(=O)Nc1cccc2c(Oc3cncc(Nc4ccc5c(c4)C(=O)OC5)n3)cccc12
Yield: 4 %

Procedure:
Method JJ. This method is identical to Method II, but uses microwave heating. Using Method JJ (heating time: 30 minutes) with 2-chloro-6-(5-acetamidonaphtyl-oxy)-pyrazine (150 mg, 0.48 mmol) and 6-amino-1,3-dihydroisobenzofuran-1-one (89 mg, 0.60 mmol), the title compound was obtained (8 mg). Yield: 4%. 1H NMR (250 MHz, DMSO-d6) δ 2.21 (s, 3H), 5.24 (s, 2H), 7.17 (d, 1H, J=8.5 Hz), 7.45-7.51 (m, 3H), 7.63 (d, 1H, J=8.2 Hz), 7.68-7.75 (m, 3H), 7.92 (s, 1H), 7.98 (s, 1H), 8.05 (d, 1H, J=8.7 Hz), 9.92 (bs, 1H), 10.00 (bs, 1H). m/z 427.1 [(M+H)+ calcd for C24H18N4O4 426.1].
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[N:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([CH3:26])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Mg]Cl.C(O)(=O)C>C1COCC1.O.O.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Mn+3]>[CH2:1]([NH:8][C:9](=[O:17])[C:10]1[C:15]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH3:26])=[CH:14][C:13]([Cl:16])=[N:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccccc1)c1ccc(Cl)nc1
Reactant: Cc1ccccc1[Mg]Cl
Agent: [Mn+3]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccccc1-c1cc(Cl)ncc1C(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 89.1 %

Procedure:
A solution of 0.5 g (2.0 mMol) N-benzyl-6-chloro-nicotinamide in 5.0 ml THF was added over 25 minutes to 10.1 ml (10.1 mMol) of o-tolylmagnesium chloride solution (1M in THF) cooled to 0° C. After 2.5 hours stirring at room temperature, the reaction mixture was cooled again to 0° C. and 4.0 ml acetic acid were added over 15 minutes followed by 1.1 g (4.1 mMol) manganese triacetate dihydrate. After stirring for 1 hour at room temperature, the reaction mixture was filtered and the filtrate was poured onto 20 ml deionized water. Sodium bicarbonate was added portionwise to bring the pH to 7 and the phases were separated. The aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with water, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (eluent ethyl acetate/n-hexane 2:1) to yield 0.6 g (88%) N-benzyl-6-chloro-4-o-tolyl-nicotinamide as an orange resin.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]3[C:18]4[C:23]([CH2:24][CH2:25][C:14]=23)=[CH:22][C:21]([CH:26]=C)=[CH:20][CH:19]=4)=[CH:9][C:6]=1[C:7]#[N:8])([CH3:3])[CH3:2].C[N+]1([O-])CC[O:32]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[CH:26]([C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[C:15]1=[N:16][O:17][C:13]([C:10]3[CH:11]=[CH:12][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[C:6]([CH:9]=3)[C:7]#[N:8])=[C:14]1[CH2:25][CH2:24]2)=[O:32]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1ccc(OC(C)C)c(C#N)c1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc(-c2onc3c2CCc2cc(C=O)ccc2-3)cc1C#N
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 71.3 %

Procedure:
To 2-isopropoxy-5-(7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazol-3-yl)benzonitrile (Preparation 15C, 0.088 g, 0.247 mmol) in THF (1.5 mL) was added N-methylmorpholine-N-oxide (50% in water) (0.17 mL, 0.370 mmol) followed by osmium tetroxide (0.039 mL, 4.94 μmol) at room temperature. The contents were stirred at room temperature for 3.5 h. Sodium periodate (0.106 g, 0.494 mmol) dissolved in 0.5 mL of water was added over a period of 2 min. at room temperature and the contents were stirred at room temperature for 1 h. The reaction mixture was concentrated and partitioned between ethyl acetate (15 mL) and water (10 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated to yield 5-(7-formyl-4,5-dihydronaphtho[1,2-c]isoxazol-3-yl)-2-isopropoxybenzonitrile (0.090 g, 0.176 mmol, 71% yield) as an orange-yellow solid. LC/MS M+1=359.1.
Reaction SMILES: [O:1]=[C:2]1[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]CC)=[O:11].[OH-].[K+].Cl>CO>[O:1]=[C:2]1[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CCCCCCCC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)O
Reaction time: 18 h

Procedure:
A suspension of 300 mg. of ethyl 9-oxoprostanoate in 20 ml. of aqueous methanol (1:1) containing 300 mg. of potassium hydroxide is stirred at 50° C. for 1 hour and then at room temperature for 18 hours. The resulting solution is acidified with 1N hydrochloric acid, concentrated and extracted several times with diethyl ether. The combined ether extracts are washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 256 mg. (94%) of product as an oil; λmax 5.75, 5.85 μ; nmr 1H broad singlet δ 9.89 (carboxyl proton, exchangeable).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[NH:15][C:14]([O:25][CH3:26])=[N:13][C:12]=1[CH2:27]C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC1C=C(C=C(C(=O)C)CC(OCC2C=CC=CC=2)=O)C=CC=1F.S(O)(O)(=O)=O.COC(=N)N.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[NH:15][C:14]([O:25][CH3:26])=[N:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)NC(OC)=N1
Agent: CC(=O)C(=Cc1ccc(F)c(F)c1)CC(=O)OCc1ccccc1
Agent: COC(=N)N
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: COC1=NC(C)=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)N1
Temperature: 70 °C
Reaction time: 20 h
Yield: 58 %

Procedure:
5-(Benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(3,4-difluorophenyl)pyrimidine. A suspension of benzyl 3-[(3,4-difluorophenyl)methylene]-4-oxopentanoate (16.0 g, 48.0 mmol), O-methylisourea hydrogen sulfate (16.65 g, 97.02 mmol), NaHCO3 (16.3 g, 130.2 mmol) in DMF (190 mL) was stirred at 70° C. for 20 h. After cooling to room temperature, the mixture was filtered and the filtrate was diluted with EtOAc (300 mL) and then washed with water (4×100 mL), brine (200 mL) and dried over Na2SO4. After removal of solvent, the residue was purified by column chromatography (SiO2, EtOAc/Hexane, 10%-30%) to get 5-(benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-methyl-6-(3,4-difluorophenyl)pyrimidine as a colorless oil (10.6 g, 58%). The NMR analysis showed it to be a mixture of amine/imine tautomers and was used as is in the next step.
Reaction SMILES: [CH:1]([Si:4]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[O:5][C:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=2[F:20])[CH2:8][CH:7]=1)([CH3:3])[CH3:2].I(C1C=CC=CC=1)=O.[N:35]([Si](C)(C)C)=[N+:36]=[N-:37]>ClCCl>[N:35]([CH:8]1[CH:9]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=2[F:20])[CH2:10][CH2:11][C:6]([O:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:21]([CH3:23])[CH3:22])[CH:24]([CH3:26])[CH3:25])=[CH:7]1)=[N+:36]=[N-:37]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)[Si](OC1=CCC(c2cc(F)c(F)cc2F)CC1)(C(C)C)C(C)C
Agent: O=Ic1ccccc1
Solvent: ClCCl
Product: CC(C)[Si](OC1=CC(N=[N+]=[N-])C(c2cc(F)c(F)cc2F)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In a three-neck flask, a stirred solution of triisopropyl{[4-(2,4,5-trifluorophenyl)cyclohex-1-en-1-yl]oxy}silane (26.06 g, 0.068 mol) in dichloromethane (260 mL) was cooled to −15° C. and treated with iodosobenzene (19.5 g, 0.089 mol) in four portions followed by azidotrimethylsilane (24 mL, 0.116 mol) while maintaining the temperature below −10° C. Stirring was continued for 1.5 h. The reaction mixture was allowed to warm to room temperature briefly, then cooled again back to −15° C. and filtered. The filtrate was evaporated under vacuum below 25° C. to give the title compound which was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[C:3]=1Br.C(=O)([O-])[O-].[K+].[K+].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[SH:24]>C(O)CO>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[C:3]=1[S:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[NH2:17]
Reactant: Nc1ccccc1S
Reactant: Nc1[nH]c(=O)[nH]c(=O)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Product: Nc1ccccc1Sc1c(N)[nH]c(=O)[nH]c1=O
Yield: 32 %

Procedure:
10.3 g of 6-amino-5-bromo-2,4(1H,3H)-pyrimidinedione, 7.0 g of potassium carbonate and 9.0 g of 2-aminothiophenol in 150 ml of ethylene glycol are heated at 170° C. under a nitrogen atmosphere for 4 hours. After filtration, the reaction mixture is poured onto 400 ml of water and decanted from the oily residue. After acidification with acetic acid, 4 g of 6-amino-5-(2-amino-phenylthio)-2,4(1H,3H)-pyrimidinedione are obtained, and are purified by recrystallization from ethanol/water.
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10]CC)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C=CC=CC=1.[Cl:19][C:20]1[C:26]([F:27])=[CH:25][C:24]([F:28])=[CH:23][C:21]=1[NH2:22]>>[Cl:19][C:20]1[C:26]([F:27])=[CH:25][C:24]([F:28])=[CH:23][C:21]=1[NH:22][C:8](=[O:10])[CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: Nc1cc(F)cc(F)c1Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(C)C(=O)Nc1cc(F)cc(F)c1Cl

Procedure:
The ester was prepared according to Procedure A using diethyl 2-methylmalonate (6.31 mL, 36.7 mmol), pyridine (3.96 mL, 48.9 mmol) and 2-chloro-3,5-difluoroaniline (4.00 g, 24.46 mmol) over 3 days. The residue was purified by column chromatography on silica gel (0-30% EtOAc/hexanes) to give ethyl 3-(2-chloro-3,5-difluorophenylamino)-2-methyl-3-oxopropanoate as a red oil. Mass Spectrum (ESI) m/e=292.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20]N(C)C)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:32][C:33]1[NH:34][CH:35]=[CH:36][N:37]=1.CC(O)=O.CCO>C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:20][N:34]4[CH:35]=[CH:36][N:37]=[C:33]4[N:32]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1ncc[nH]1
Reactant: CN(C)C=C(C(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CCC2)cc1)c1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nccn4cc3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
Compound 1 (1.2 g, 2.9 mmol) and 2-aminoimidazole (0.77 g 4.3 mmol) were added into a solution of AcOH (2 mL) and EtOH (10 mL). The mixture was heated to reflux and stirred overnight. The solution was cooled to r.t. and diluted with 30 mL of DCM. The organic phase was washed with 0.1N HCl(aq) and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography to give 1.2 g of 4-1 as a yellow solid. MS (ESI) m/e (M+H+): 441.3
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[O:5].[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:4](=[O:5])[CH2:3][CH2:2][N:28]2[CH2:29][CH2:30][CH:25]([C:21]3[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=3)[CH2:26][CH2:27]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)CCCl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: COc1ccc(C(=O)CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1

Procedure:
Procedure K (KI) and Scheme E (K2cO3) using 3-chloro-1-(4-methoxyphenyl)-1-propanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 409.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([Cl:11])[N:3]=1.FC(F)(F)C(O)=O.[NH2:19][CH2:20][CH2:21][NH:22][C:23]1[N:28]=[C:27]([NH2:29])[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.O>CS(C)=O>[Cl:11][C:4]1[N:3]=[C:2]([NH:19][CH2:20][CH2:21][NH:22][C:23]2[N:28]=[C:27]([NH2:29])[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][CH:24]=2)[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=1
Reactant: Clc1cc2nccn2c(Cl)n1
Reactant: NCCNc1ccc([N+](=O)[O-])c(N)n1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CS(C)=O
Product: Nc1nc(NCCNc2nc(Cl)cc3nccn23)ccc1[N+](=O)[O-]
Temperature: 120 °C

Procedure:
800 mg (4.13 mmol) of 5,7-dichloroimidazo[1,2-c]pyrimidine (Example 11A) are suspended in 20 ml of DMSO, and 1.62 g (4.54 mmol) of N6-(2-aminoethyl)-3-nitropyridine-2,6-diamine trifluoroacetate (Example 15A) and 1.6 g (12.38 mmol) of DIPEA are added. The mixture is heated at 120° C. for 16 h. After this time, water is added, and the precipitate which has separated out is filtered off with suction. It is washed with a little 2-propanol/water and the resulting solid is dried under high vacuum. 1.34 g (92% of theory) of the product are obtained as a solid.