Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COCCOC.Br[CH2:8][C:9]1[O:13][N:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[CH2:8][C:9]1[O:13][N:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=1
Reactant: OB(O)c1cc(F)ccc1F
Reactant: CCOC(=O)c1cc(CBr)on1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1cc(Cc2cc(F)ccc2F)on1
Yield: 58.7 %

Procedure:
1,2-Dimethoxyethane (8 mL) and water (2 mL) were added to the mixture of ethyl 5-(bromomethyl)isoxazole-3-carboxylate (1.00 g; 4.27 mmol), 2,5-difluorophenylboronic acid (0.773 g; 4.70 mmol), tetrakis(triphenylphosphine)palladium(0) (0.248 g; 0.640 mmol) and sodium carbonate (0.911 g; 8.55 mmol). The mixture was irradiated in a microwave oven at 130° C. for 20 minutes. After cooling, the reaction mixture was extracted with ethyl acetate and water. The organic layer was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (eluent: 5 to 40% of ethyl acetate in heptane) to give 0.67 g (59%) of ethyl 5-(2,5-difluorobenzyl)isoxazole-3-carboxylate as a yellow oil.
Reaction SMILES: [Cl:1][CH:2]([F:32])[C:3]([F:31])([F:30])[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:27]=[CH:28][CH:29]=1)[O:10][CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:12](O)=[O:13])=[O:5].S(Cl)([Cl:35])=O>>[Cl:1][CH:2]([F:32])[C:3]([F:31])([F:30])[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:27]=[CH:28][CH:29]=1)[O:10][CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:12]([Cl:35])=[O:13])=[O:5]
Reactant: CCCCCCCCCCCCC(Oc1cccc(NC(=O)C(F)(F)C(F)Cl)c1)C(=O)O
Reactant: O=S(Cl)Cl
Product: CCCCCCCCCCCCC(Oc1cccc(NC(=O)C(F)(F)C(F)Cl)c1)C(=O)Cl

Procedure:
An amount of 31.5 g of 2-[m-(3-chloro-2,2,3-trifluoro-propionamido)-phenoxy]-myristic acid is refluxed for 30 min with thionyl chloride. The excess thionyl chloride is removed by evaporation. The oil obtained slowly solidifies.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:9][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)[CH2:7][CH3:8].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[C:16]([N:14]1[CH:10]([O:9][CH2:6][CH2:7][CH3:8])[CH2:11][CH2:12][C:13]1=[O:15])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCOC1CCC(=O)N1
Reactant: O=C(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCOC1CCC(=O)N1C(=O)c1ccccc1
Yield: 57.9 %

Procedure:
18.6 cm3 of a 1.5M solution of n-butyllithium in hexane is added to a solution of 4 g of 5-(1-propyloxy) pyrrolidin-2-one in tetrahydrofuran at -60° C., while maintaining the temperature between -55° C. and -60° C. After agitation for 15 minutes at -60° C. a solution of 3.93 g of benzoyl chloride in 20 cm3 of tetrahydrofuran is added at this temperature. After allowing the mixture to return to ambient temperature, the solvent is evaporated under reduced pressure. The residue is chromatographed on silica (eluent: ethyl acetate-n-hexane 1-3) and 4 g of the expected product is obtained. b.p. =200° C. under 0.1 mbar.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]([CH3:16])[CH3:15])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:17]([O-])([O-])=O.[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH:14]([CH3:16])[CH3:15])[CH3:17])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Br)cc(NC(C)C)c1C
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cc(Br)cc(N(C)C(C)C)c1C
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a stirred solution of methyl 5-bromo-3-(isopropylamino)-2-methylbenzoate (0.5 g, 1.75 mmol) in acetonitrile (10 mL), Cs2CO3 (1.02 g, 2.63 mmol) and methyl iodide (1.45 g, 3.5 mmol) were added to it. The resulting reaction mixture was stirred at 80° C. for 4 h. Upon completion, the solvent was removed under reduced pressure and residue dissolved in water and extracted with ethyl acetate. Crude material obtained was purified by column chromatography over silica gel affording the desired compound product without further purification (0.39 g)
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:22]=[CH:21][N:20]=[CH:19][C:7]=3[CH2:8][N+:9]([O-])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.P(Cl)(Cl)Cl.[OH-].[NH4+]>C(Cl)Cl>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:22]=[CH:21][N:20]=[CH:19][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: [O-][N+]1=C(c2ccccc2F)c2cc(Cl)ccc2-c2ncncc2C1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClP(Cl)Cl
Solvent: ClCCl
Product: Fc1ccccc1C1=NCc2cncnc2-c2ccc(Cl)cc21

Procedure:
A mixture of 0.5 g (1.5 mmol) of 9-chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine-6-oxide, and 1.0 ml (10 mmol) of phosphorous trichloride in 20 ml of methylene chloride was heated at reflux for 2 hr. The mixture was poured over ice, basified with ammonium hydroxide and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue was crystallized from ether to give off-white crystals, mp 122°-124° C.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[C:12]([O:15][CH:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=1)[CH2:17][CH:18]=[CH2:19])(=[O:14])[CH3:13]>C(Cl)Cl>[C:12]([O:15][CH:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=1)[CH2:17][CH:18]1[CH2:19][O:9]1)(=[O:14])[CH3:13]
Reactant: C=CCC(OC(C)=O)c1ccc(C#N)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)OC(CC1CO1)c1ccc(C#N)cc1
Yield: 50 %

Procedure:
mCPBA (2.86 g; 70%) was added to a stirred solution of 4-acetoxy-4-(p-cyanophenyl)-1-butene (2.5 g; 11.6 mmol; from step (a) above) in DCM (20 mL), and the reaction mixture was refluxed for 3 h and then cooled. The m-chlorobenzoic acid was removed by filtration and the filtrate was washed with NaHCO3 (aq.), then with water, the phases were separated, dried, concentrated and purified by column chromatography (DCM) to give the sub-title compound in a 50% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:18][C:19]1[CH:39]=[CH:38][C:22]([C:23]([N:25]2[C:31]3[CH:32]=[CH:33][S:34][C:30]=3[CH2:29][N:28]3[CH:35]=[CH:36][CH:37]=[C:27]3[CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[S:34]1[C:30]2[CH2:29][N:28]3[CH:35]=[CH:36][CH:37]=[C:27]3[CH2:26][N:25]([C:23]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[CH3:1])=[CH:39][CH:38]=3)=[O:24])[C:31]=2[CH:32]=[CH:33]1
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3sccc32)cc1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3sccc32)cc1
Reaction time: 5 h

Procedure:
To a stirred solution of 3 mmol of 2-methylbenzoyl chloride in 10 ml of methylene chloride is added 5 mmol of triethylamine and 3 mmol of 4,10-dihydro-4-(4-aminobenzoyl)-5H-pyrrolo-[1,2-a]thieno[3,2-e][1,4]diazepine. The mixture is stirred for 5 hours. The reaction mixture is washed with water, 2N citric acid, NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give the desired product as a solid, m.p. 162°-188° C. (amorphous)
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[C:20]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH2:30])(=[O:22])[NH2:21]>>[C:20]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19])(=[O:22])[NH2:21]
Reactant: NC(=O)Cc1ccccc1N
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)Nc3ccccc3CC(N)=O)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and (2-carbamoylmethyl-phenyl)-amine to afford the title compound. MS: m/e=391 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1)[CH3:2].[NH2:13][C:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:29])=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:21]=2)[N:16](COCC[Si](C)(C)C)[N:15]=1.OP([O-])(O)=O.[K+].CO>C1COCC1>[Cl:29][C:19]1[CH:18]=[C:17]2[C:22]([C:14]([NH:13][C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=3)=[O:12])=[N:15][NH:16]2)=[CH:21][C:20]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOc1ccc(N=C=O)cc1
Reactant: C[Si](C)(C)CCOCn1nc(N)c2cc(-c3ccccc3)c(Cl)cc21
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(NC(=O)Nc2n[nH]c3cc(Cl)c(-c4ccccc4)cc23)cc1
Temperature: 50 °C
Yield: 71.8 %

Procedure:
36.4 mg of 4-ethoxyphenyl isocyanate are added to 80 mg of 3-amino-5-phenyl-6-chloro-1-[(2-trimethylsilylethoxy)methyl]indazole in 1 ml of THF. The mixture is heated at 50° C. for 1 h and is then hydrolyzed in a saturated KH2PO4 solution and extracted with methylene chloride. After drying and evaporating, the crude product is purified by chromatography on silica with an AcOEt/hexane mixture. The product obtained is deprotected in 2 ml of a 1/1 MeOH/2N HCL mixture at reflux for 3 h. 62.5 mg of 1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(4-ethoxyphenyl)urea are obtained.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[CH3:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH2:18][C:19](=[O:25])[NH:20]2.N1CCCCC1>C(O)C>[CH3:14][C:7]1[NH:8][C:9]([CH:12]=[C:18]2[C:17]3[C:21](=[CH:22][CH:23]=[CH:24][C:16]=3[CH3:15])[NH:20][C:19]2=[O:25])=[C:10]([CH3:11])[C:6]=1[CH2:5][CH2:4][C:1]([OH:3])=[O:2]
Reactant: Cc1cccc2c1CC(=O)N2
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cccc2c1C(=Cc1[nH]c(C)c(CCC(=O)O)c1C)C(=O)N2
Yield: 37 %

Procedure:
3-(2-Carboxyethyl)-2,4-dimethyl-5-formylpyrrole (97.5 mg), 74 mg 4-methyl-2-oxindole and 75 μL piperidine in 3 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N of aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 60 mg (37%) of the title compound as a green solid.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([NH:8][CH2:9][CH3:10])[CH3:7].O>CCOCC>[Br:1][CH2:2][C:3]([N:8]([CH2:9][CH3:10])[CH2:6][CH3:7])=[O:4]
Reactant: CCNCC
Reactant: O=C(Br)CBr
Solvent: CCOCC
Solvent: O
Product: CCN(CC)C(=O)CBr
Temperature: -15 °C

Procedure:
Under a nitrogen atmosphere, a 1-liter flask is charged with 2-bromoacetylbromide (46.34 g, 230 mmol) and 300 ml ether. The flask is chilled to −15° C., and a solution of diethylamine (33.72 g, 460 mmol) in 200 ml ether is added over 1 hour to the flask. The resulting thick slurry is stirred cold for 1 additional hour, then warmed slowly to room temperature, and stirred overnight. The mixture is added to 250 ml cold water, and the resulting aqueous solution is extracted with ether (3 times, 200 ml ether each time). The combined ether extracts are washed with phosphoric acid (5 wt percent, 200 ml), aqueous potassium carbonate (8 wt percent, 200 ml) and thereafter brine (150 ml). The ether extract is then dried over sodium sulfate and concentrated in vacuo to a light brown residue. The residue is vacuum distilled to yield 2-bromo-N,N-diethylacetamide as a clear, colorless oil (22.99 g, 52% yield). 1H NMR (300 MHz, CDCl3), δ (PPM): 1.08 (t, 3H), 1.20 (t, 3H), 3.33 (q, 4H), 3.79 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.N1C=CC=CC=1.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[S:21]([NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)(=[O:23])=[O:22]
Reactant: Nc1nccs1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1nccs1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a slurry of 2-aminothiazole (15.08 g, 0.1506 mol) in methylene chloride (100 mL) and pyridine (24 mL, 0.30 mol) was added dropwise over 20 minutes a solution of 2,4-difluorobenzenesulfonyl chloride (10 mL, 0.07 mol) in 10 mL of methylene chloride. After stirring at room temperature for 48 hours the reaction was concentrated and purified by flash column chromatography eluting with hexane/ethyl acetate. LCMS Rt=1.21 minutes
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:36])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31](O)=[O:32])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:66][CH2:67][C:68]([NH:70][C@@H:71]([C:79]([OH:81])=[O:80])[CH2:72][CH:73]1[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]1)=[O:69]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:36])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31]([NH:66][CH2:67][C:68]([NH:70][C@@H:71]([C:79]([OH:81])=[O:80])[CH2:72][CH:73]4[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]4)=[O:69])=[O:32])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc4c(c3)OCO4)C(=O)N2c2ccc(Cl)cc2)cc1
Reactant: NCC(=O)N[C@H](CC1CCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc4c(c3)OCO4)C(=O)N2c2ccc(Cl)cc2)cc1)NCC(=O)N[C@H](CC1CCCCC1)C(=O)O
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To a stirred solution of {4-[(2R,3R)-3-{[2-(1,3-benzodioxol-5-yl)-2-oxoethyl]thio}-1-(4-chlorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetic acid (35.4 mg, 0.067 mmol)) in DMF (3 ml) was added N-methylmorpholine (35 μl, 0.23 mmol). TBTU (29.3 mg, 0.091 mmol) was added and the reaction mixture was stirred at 30° C. for 1 hour. Glycyl-3-cyclohexyl-D-alanine (18.4 mg, 0.081 mmol) was added and the mixture was stirred at ambient temperature for 60 hours. The formation of the ketone of the title compound was confirmed. M/z: 736.67 (M+1) and 734.71 (M−1). Without further purification, methanol (2 ml) and sodium borohydride (28.0 mg, 0.740 mmol) was added and the mixture was stirred for 20 minutes. Ammonium acetate (38.4 mg) was added and the solution was purified with preparative HPLC on a C8 column, UV 240/260 nm. A gradient from 20 to 45 MeCN in 0.1M NH4OAc buffer was used as eluent. The pure fractions were collected and the MeCN was removed under reduced pressure. The remaining water solution was acidified to pH 1 with HCl (1M) and extracted with DCM. The organic phase was passed through a phase separator and concentrated under reduced pressure. The residue was dissolved in MeCN and water. After lyophilisation, the title compound was obtained 1H-NMR (400 MHz, DMSO-d6): 0.70-1.68 (m, 13H), 2.78-2.88 (m, 2H), 3.75 (d, 2H), 4.13-4.21 (m, 1H), 4.23-4.28 (m, 1H), 4.49 (s, 2H), 4.56-4.64 (m, 1H), 5.02 (d, 0.5H), 5.04 (d, 0.5H), 5.56 (b, 1H), 6.70-6.79 (m, 2H), 6.82 (s, 1H), 6.96 (d, 2H), 7.18 (d, 2H), 7.30-7.37 (m, 4H), 8.04 (b, 1H), 8.20 (t, 1H). M/z: 736.69 (M−1).
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2.[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([F:24])=[CH:19][N:18]=1.C(N(C(C)C)CC)(C)C>>[Cl:16][C:17]1[N:22]=[C:21]([NH:2][CH:3]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9]3[C:4]2=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:20]([F:24])=[CH:19][N:18]=1
Reactant: NC1c2ccccc2-c2ccccc21
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cnc(Cl)nc1NC1c2ccccc2-c2ccccc21

Procedure:
In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro 4-pyrimidineamine, 9-aminofluorene hydrochloride and 2,4-dichloro-5-fluoropyrimidine with added diisopropylethylamine were reacted to produce 2-chloro-N-(fluoren-9-yl)-5-fluoro-4-pyrimidineamine. 1H NMR (CDCl3): δ 7.97 (d, 1H, J=2.3 Hz), 7.73 (d, 2H, J=7.6 Hz), 7.59 (d, 2H, J=7.6 Hz), 7.44 (t, 2H, J=7.6 Hz), 7.32 (app t, 2H, J=7.6 Hz), 6.50 (d, 1H, J=8.8 Hz), 5.45 (d, 1H, J=8.4 Hz).
Reaction SMILES: FC(F)(F)C(O)=O.ClC1C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)=C2N=C(C3C=CC(CN4CCOCC4)=CC=3)NC2=NC=1.[NH2:42][C:43]1[C:48]([NH2:49])=[C:47]([NH:50][C@@H:51]2[C@@H:56]3[CH2:57][C@@H:53]([CH:54]=[CH:55]3)[C@@H:52]2[C:58]([NH2:60])=[O:59])[C:46]([Cl:61])=[CH:45][N:44]=1.C(OC([N:69]1[CH2:74][CH2:73][N:72]([CH2:75][C:76]2[CH:81]=[CH:80][C:79]([CH:82]=O)=[C:78]([O:84][CH3:85])[CH:77]=2)[CH2:71][CH2:70]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[Cl:61][C:46]1[C:47]([NH:50][C@@H:51]2[C@@H:56]3[CH2:57][C@@H:53]([CH:54]=[CH:55]3)[C@@H:52]2[C:58]([NH2:60])=[O:59])=[C:48]2[N:49]=[C:82]([C:79]3[CH:80]=[CH:81][C:76]([CH2:75][N:72]4[CH2:73][CH2:74][NH:69][CH2:70][CH2:71]4)=[CH:77][C:78]=3[O:84][CH3:85])[NH:42][C:43]2=[N:44][CH:45]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: COc1cc(CN2CCN(C(=O)OC(C)(C)C)CC2)ccc1C=O
Agent: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(CN2CCNCC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 10 %

Procedure:
In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 4-(4-formyl-3-methoxy-benzyl)-piperazine-1-carboxylic acid tert-butyl ester were reacted to produce a material which following treatment with trifluoroacetic acid at 40° C. for four hours, followed by concentration and neutralization afforded the title compound (10%). 1H NMR (d-4 methanol): 8.30 (d, J=7 Hz, 1H), 8.11 (s, 1H), 7.40 (s, 1H), 7.27 (d, J=7 Hz, 1H), 6.47 (m, 2H), 5.09 (m, 1H), 4.34 (m, 2H), 4.13 (s, 3H), 3.73 (s, 1H), 3.56 (s, 4H), 3.44 (s, 4H), 3.07 (s 1H), 3.02 (s, 1H), 2.75 (s, J=8 Hz, 1H), 2.18 (m, 2H), 1.87 (s, 1H), 1.58 (d, J=8 Hz, 1H), 1.30 (s, 1H). MS: 508.2 (M+H). HPLC retention time: 1.66 minutes (G Method).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[C:11](OCC)(=[O:14])[C:12]#[CH:13].CC(C)([O-])C.[K+]>C(O)(C)(C)C.O>[OH:14][C:11]1[CH:12]=[CH:13][N:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: COc1ccc(NN)cc1
Reactant: C#CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1ccc(-n2ccc(O)n2)cc1
Reaction time: 12 h
Yield: 60.3 %

Procedure:
A solution of 72.7 g of 4-methoxyphenylhydrazine in 700 ml of tert-butanol was treated dropwise at 30° C. with 56.8 g of ethyl propiolate. A total of 118 g of potassium tert-butoxide was then introduced in portions with ice cooling into the mixture thus obtained. After 12 h at 25° C., the solvent was distilled off under reduced pressure and the residue thus obtained was taken up in water. The aqueous solution was washed with dichloromethane and then acidified with conc. acetic acid with cooling to a pH of 9, the product being deposited as a solid. After washing and drying, 60.3 g of the title compound (60% of theory) were obtained; m.p.: 167°-170° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]([NH2:26])([CH3:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>C(Cl)Cl>[CH3:17][C:18]([NH:26][C:14](=[O:16])[CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH3:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)CCNC(=O)OCc1ccccc1)c1ccccc1
Yield: 55.6 %

Procedure:
6.6 g of N-benzyloxycarbonyl-β-alanine, 4.0 g of α,α-dimethylbenzylamine and 7.4 g of triethylamine were dissolved in 400 ml of anhydrous methylene chloride. To this solution were then added 8.8 g of 2-chloro-1-methylpyridinium iodide slowly at room temperature, and the mixture was heated under reflux for 2 hours. The reaction mixture was then washed, in turn, with a 10% w/v aqueous solution of sodium hydroxide, with a 1N aqueous solution of hydrochloric acid and with a saturated aqueous solution of sodium chloride, and was then dried over anhydrous sodium sulfate. The solution was concentrated by evaporation under reduced pressure, to give 10.7 g of crude crystals. Recrystallization of these from a mixture of hexane and benzene afforded 5.6 g (yield 56%) of the title compound melting at 96°-97° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH3:14][CH:15]1[CH2:20][O:19][CH2:18][CH:17]([CH3:21])[NH:16]1.O>C(#N)C>[CH3:14][CH:15]1[N:16]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:17]([CH3:21])[CH2:18][O:19][CH2:20]1
Reactant: CCOC(=O)CBr
Reactant: CC1COCC(C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CN1C(C)COCC1C
Temperature: 60 °C
Reaction time: 12 h

Procedure:
Potassium carbonate (0.311 g, 2.25 mmol) and ethyl bromoacetate (0.319 g, 1.91 mmol) was added to the solution of 3,5-dimethylmorpholine (0.2 g, 1.73 mmol) in acetonitrile (4 mL) at room temperature. The reaction mixture was stirred at 60° C. for 12 h. The reaction mixture was transferred into iced-water and extracted with ethyl acetate (20 mL×3). The combined organic layers was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was used in the next step without further purification (Crude Yield: 54%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[C:20]([C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=1)#[N:21]>CCCCCC.C(OCC)(=O)C>[O:17]1[CH2:18][CH2:19][N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([C:20]#[N:21])=[CH:23][CH:24]=3)[N:3]=2)[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2ccc(C#N)cc2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#Cc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 40 %

Procedure:
Following the general procedure A, 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine was coupled with 4-cyanophenylboronic acid pinacol ester with reaction time of 15 h. Chromatography (hexane/ethyl acetate 1:1) gave the 40% of the title compound as a colorless solid.