Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.CCN(C(C)C)C(C)C.[CH:21]1([C:24]2[NH:28][N:27]=[C:26]([NH2:29])[CH:25]=2)[CH2:23][CH2:22]1>CCO>[Cl:11][C:4]1[N:3]=[C:2]([NH:29][C:26]2[CH:25]=[C:24]([CH:21]3[CH2:23][CH2:22]3)[NH:28][N:27]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.8 %

Procedure:
To a solution of 2,6-dichloro-3-nitropyridine (0.67 g, 3.2 mmol) and DIEA (0.46 ml, 2.65 mmol) in EtOH (20 ml) was added 5-cyclopropyl-1H-pyrazol-3-amine (0.26 g, 2.12 mmol) solution in EtOH (5 ml) dropwise at 0° C. After addition, the reaction mixture was stirred at 25° C. for 24 hrs. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (hexane-EtOAc=5:1) to give the title compound as a yellow solid (0.58 g, 98%). 1H NMR (400 MHz) δ12.36 (s, 1H), 10.20 (s, 1H), 8.54 (d, J=8.4 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.39 (d, J=1.6 Hz, 1H), 1.94 (m, 1H), 0.96 (m, 2H), 0.71 (m, 2H). MS: Calcd.: 279. Found: [M+H]+ 280.
Reaction SMILES: [OH-].[Na+].Cl.N12CCC(CC1)C(=O)C2.C(CC(O)=O)#N.[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C:21](=[C:27]([C:31]#[N:32])[C:28]([O-:30])=[O:29])[CH2:20]2.[Na+].Cl>O>[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C:21](=[C:27]([C:31]#[N:32])[C:28]([OH:30])=[O:29])[CH2:20]2
Reactant: N#CC(C(=O)[O-])=C1CN2CCC1CC2
Agent: Cl
Agent: N#CCC(=O)O
Agent: O=C1CN2CCC1CC2
Solvent: O
Product: N#CC(C(=O)O)=C1CN2CCC1CC2
Temperature: 15 °C

Procedure:
40% Aqueous NaOH (370 ml, 3.7 mol) was added to a stirred suspension of 3-quinuclidinone hydrochloride (600 g, 3.7 mol) in water (300 ml) over 30 min while maintaining the temperature at 15°-25° C. The resulting mixture was then cooled to 15° C. and a solution of cyanoacetic acid (380 g, 4.5 mol) in water (150 ml) added in a steady stream over 30 min while stirring and maintaining the temperature at 15°-20° C. After the addition was complete, further 40% aq. NaOH (900 ml, 9.0 mol) was added gradually over 45 min while stirring and maintaining the temperature at 15°-20° C. The resulting reddish solution was then left to stir at ambient temperature for a further 2 h before cooling to 15° C. Seeding with authentic sodium 1-azabicyclo[2.2.2]oct-3-ylidenecyanoacetate induced crystallisation of the same, and the mixture was then chilled further to 7° C. with stirring until a thick slurry of the sodium salt was obtained. After stirring at this temperature for a further 45 min a mixture of conc HCl (725 ml) and water (725 ml) was added in a steady stream over 45 min while stirring and maintaining the temperature at 15°-20° C. After adjusting to pH7 the resulting slurry of the Stage 1 product was stirred at ambient temperature for an additional 45 min before using directly for Stage 2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:4]([CH3:16])[CH:3]=1.[NH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=2)[CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:4]([CH3:16])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(Cl)C1CCCCC1
Reactant: COC(=O)c1ccc(N)nc1
Product: COC(=O)c1ccc(NC(c2ccc(Br)cc2C)C2CCCCC2)nc1

Procedure:
Using 4-bromo-1-(chloro(cyclohexyl)methyl)-2-methylbenzene obtained in Example 16, step B and methyl 6-aminonicotinate, and in the same manner as in Example 1, step D, the title compound was obtained.
Reaction SMILES: N1[C:6]2[CH2:7][CH2:8][CH2:9][C:5]=2C(=O)NC1=O.N1C=CC(=O)NC1=O.C[Si](C)(C)[CH2:22][CH2:23][O:24][CH2:25][Cl:26]>>[CH2:23]([O:24][CH2:25][Cl:26])[C:22]1[CH:8]=[CH:9][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=c1[nH]c2c(c(=O)[nH]1)CCC2
Agent: O=c1cc[nH]c(=O)[nH]1
Product: ClCOCc1ccccc1

Procedure:
In a similar manner to the procedures described in Reference Example 3, reactions were carried out using 6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-dione, instead of pyrimidine-2,4-dione, and using 2-(trimethylsilyl)ethoxymethyl chloride, instead of benzyloxymethyl chloride, to give the title compound (yield 71%) as a pale yellow powder.
Reaction SMILES: OO.[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([S:11]([CH2:13][CH3:14])=[O:12])[CH:7]=[CH:6][C:5]=1[NH:15][C:16](=[O:24])[C@:17]([OH:23])([CH3:22])[C:18]([F:21])([F:20])[F:19].CC[O:27]C(C)=O>O.C(O)(=O)C>[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([S:11]([CH2:13][CH3:14])(=[O:27])=[O:12])[CH:7]=[CH:6][C:5]=1[NH:15][C:16](=[O:24])[C@:17]([OH:23])([CH3:22])[C:18]([F:19])([F:20])[F:21]
Reactant: CCOC(C)=O
Reactant: CCS(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1Cl
Agent: OO
Solvent: O
Solvent: CC(=O)O
Product: CCS(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1Cl
Temperature: 95 °C

Procedure:
Hydrogen peroxide (15 ml of a 30 wt. % solution in water) was added to a solution of (R)-N-[4-ethylsulphanyl-2,3-dichlorophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 1) (1.88 g) in glacial acetic acid (26 ml) and the mixture was heated at 95° C. for 1.5 hours then cooled. EtOAc (200 ml) was added and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution (4×200 ml) and brine (250 ml) then was dried. Volatile material was removed by evaporation and the residue was purified by chromatography eluting with 0-50% EtOAc/isohexane to give the title compound (1.71 g) as a white solid. NMR: 1.1 (t, 3H), 1.61 (s, 3H), 3.5 (q, 2H), 8.02 (d, 1H), 8.31 (d, 1H); m/z 392.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:3])[CH3:2].[C:10]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)(=[O:12])[CH3:11]>>[OH:12][C:10]([CH3:11])([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH2:2][C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:3]
Reactant: CCCCCOC(C)=O
Reactant: CC(=O)c1ccncc1
Product: CCCCCOC(=O)CC(C)(O)c1ccncc1
Reaction time: 0.05 h

Procedure:
A 100 milligram quantity of the hydroxy ester described in Example III is pyrolyzed in a sealed tube at 400° C. for 3 minutes. Analysis of the pyrolysis mixture by gas chromatography indicates the presence of about 30% of a mixture in a 1:1 ratio of amyl acetate and 4-acetylpyridine. The remainder of the mixture contains unreacted starting material.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[CH:14]([O-])=[O:15].[Na+].C([O-])([O-])=O.[Na+].[Na+]>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.CN(C=O)C>[CH:14]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1)=[O:15]
Reactant: COC(=O)c1ccc(Br)cc1OC
Reactant: O=C[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C=O)cc1OC
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A slow stream of CO was passed into a suspension of methyl 4-bromo-2-methoxybenzoate (2.4 g, 0.010 mol), bis(triphenylphosphine)palladium(II) chloride (140 mg, 0.00020 mol), sodium formate (1.02 g, 0.0150 mol), and dry DMF (10 mL). The mixture was vigorously stirred at 110° C. for 2 h. After cooling, the mixture was treated with aqueous Na2CO3 solution and extracted with EtOAc. The extract was washed with brine, dried (Na2SO4), and concentrated. The residue was purified by column chromatography on silica gel with AcOEt-hexane as eluent (0 to 50%) to give a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=O.C(Cl)(=O)C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:8][CH2:9][C:10]2=[O:12]
Reactant: O=C(O)CCc1ccccc1Br
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CCc2c(Br)cccc21
Temperature: 0 °C

Procedure:
4-Bromo-indan-1-one was obtained by the following procedure: A solution of 3-(2-bromo-phenyl)-propionic acid (commercially available from Oakwood Products) (15.0 g, 65.5 mmol) in CH2Cl2 at 0° C. was reacted with oxalyl chloride (7.2 mL, 1.5 eq) followed by 2-3 drops of DMF. The mixture was stirred until no more gas evolution was observed. As the mixture was concentrated and the residue was dissolved in CH2Cl2, cooled to 0° C., and treated with AlCl3 (9.6 g, 1.1 eq). After 1 h the mixture was quenched with water and the layers were separated. The aqueous layer was extracted with Et2O (3×150 mL) and the combined organic extracts were washed with H2O (3×100 mL), saturated NaHCO3 (3×100 mL), brine (1×100 mL), dried over MgSO4 and concentrated. 4-Bromoindan-1-one, 10.5 g (76%) was obtained by chromatography using 10% EtOAc:hexane as eluant. Use of 4-bromo-indan-1-one in Method NINETEEN produced 4-(4-bromo-indan-2-yl)-1,3-dihydro-imidazole-2-thione (Compound 149).
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][C@H:22]1[CH2:26][CH2:25][S:24](=[O:28])(=[O:27])[NH:23]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH2:30][CH2:31][CH2:32][C:33]1[S:37][C:36]([C:38]([O:40][CH3:41])=[O:39])=[CH:35][CH:34]=1>CN(C=O)C>[Si:3]([O:20][CH2:21][C@H:22]1[CH2:26][CH2:25][S:24](=[O:28])(=[O:27])[N:23]1[CH2:30][CH2:31][CH2:32][C:33]1[S:37][C:36]([C:38]([O:40][CH3:41])=[O:39])=[CH:35][CH:34]=1)([C:16]([CH3:17])([CH3:18])[CH3:19])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CCCI)s1
Reactant: CC(C)(C)[Si](OC[C@H]1CCS(=O)(=O)N1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCCN2[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CCS2(=O)=O)s1
Temperature: 0 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
To a mixture of sodium hydride (37 mg, 1.54 mmol) in DMF (3.0 mL) cooled to 0° C. was added dioxide 8 (554 mg, 1.42 mmol). After 0.5 h a solution methyl 5-(3-iodopropyl)thiophene-2-carboxylate (485 mg, 1.56 mmol) in DMF (4.5 mL). The reaction was allowed to warm to room temperature on its own accord and stirred for 16 h. The reaction was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic portion was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 20% EtOAc/hex) afforded 751 mg (91%) of ester 9.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][C:21]=1[CH3:28])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([N:32]1[CH2:37][C:36](=[O:38])[N:35](C(=O)C)[CH2:34][C:33]1=[O:42])(=[O:31])[CH3:30].CC(C)([O-])C.[K+].O>CN(C)C=O.C(O)(C)(C)C>[C:29]([N:32]1[CH2:37][C:36](=[O:38])[NH:35][C:34](=[CH:24][C:23]2[CH:26]=[CH:27][C:20]([CH2:19][O:18][Si:1]([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:21]([CH3:28])[CH:22]=2)[C:33]1=[O:42])(=[O:31])[CH3:30]
Reactant: Cc1cc(C=O)ccc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CC(=O)N1CC(=O)N(C(C)=O)CC1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)(C)O
Solvent: O
Product: CC(=O)N1CC(=O)NC(=Cc2ccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(C)c2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
To a stirred mixture of 4-(tert-butyldiphenylsilyloxymethyl)-3-methylbenzaldehyde (1.94 g) and 1,4-diacetyl-2,5-piperazinedione (991 mg) in a mixture of N,N-dimethylformamide (10 ml) and tert-butanol (10 ml) was added potassium tert-butoxide (561 mg) at 5° C. The mixture was stirred for 1 hour at room temperature and then poured into water (300 ml), and stirring was continued for 18 hours at room temperature. The resulting precipitates were collected by filtration and washed with water and isopropyl ether, and dried under reduced pressure to give 1-acetyl-3-(4-tert-butyldiphenylsilyloxymethyl-3-methylphenyl)methylene-2,5-piperazinedione (1.88 g) as a powder.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]=1.[Mg].[Br-].[CH3:9][C:10]1[O:15][CH2:14][N:13]([C:16]([CH3:20])([CH3:19])[CH:17]=[O:18])[C:12](=[O:21])[C:11]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>O1CCCC1.BrCCBr.C(OCC)(=O)C>[CH3:9][C:10]1[O:15][CH2:14][N:13]([C:16]([CH3:19])([CH3:20])[CH:17]([C:2]2[CH2:6][CH2:5][CH2:4][CH:3]=2)[OH:18])[C:12](=[O:21])[C:11]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C=O)CO1
Reactant: BrC1=CCCC1
Agent: Cl
Agent: [Br-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: BrCCBr
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(O)C2=CCCC2)CO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A part of a solution of 1-bromocyclopent-1-ene (3.9 g) in tetrahydrofuran was added to a stirred mixture of magnesium turnings (0.68 g) and 1 drop of 1,2-dibromoethane in tetrahydrofuran at 20° C. under an inert atmosphere. The mixture was heated to reflux and the remaining bromide solution added dropwise over 15 minutes. The mixture was stirred for 0.5 hour, cooled to 0° C., and a solution of 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropionaldehyde (4.0 g) in tetrahydrofuran added below 10° C. The mixture was stirred for 1 hour and ethyl acetate and hydrochloric acid (1N) added. The organic phase was washed (brine), dried (magnesium sulphate), evaporated and purified by silica gel column chromatography, eluting with n-hexane/ethyl acetate (2:1) to give 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methyl-1-(cyclopent-1-enyl)propan-1-ol (4.95 g), NMR: 1.45(s,3H), 1.60(s,3H), 1.90(s,3H), 1.80-1.92(2H), 2.15-2.53(4H), 4.37(d,1H), 5.04(d,1H), 5.20-5.30(2H), 5.63(s,1H), 7.22-7.41(5H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:20][O:21][CH:22]([C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[C:23]([O:25]C)=[O:24])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].O>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:20][O:21][CH:22]([C:27]2[CH:32]=[C:31]([C:33]([F:35])([F:34])[F:36])[CH:30]=[C:29]([C:37]([F:40])([F:38])[F:39])[CH:28]=2)[C:23]([OH:25])=[O:24])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COC(C(=O)O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-[1(-tert-butoxycarbonyl4-phenylpiperidin4-yl)methoxy]-2-(3,5-bis(trifluoromethyl)phenyl)acetate (11 g, 0.019 mol) in methanol (100 ml) at 0° C. was added potassium hydroxide (3.2 g, 5.7 mmol), followed by water (3 ml). The homogeneous solution was stirred at 0° C. for 1 hour. The methanol was removed in vacuo and pH4 buffer (100 ml) added to the residue. The product was extracted into diethyl ether (2×100 ml), the combined ethereal solutions dried (MgSO4), filtered and evaporated in vacuo. The resulting white foam was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([OH:24])=O)=[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]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[NH2:25][CH2:26][C:27]1([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[F:1][C:2]1[C:3]([C:22]([NH:25][CH2:26][C:27]2([C:40]3[CH:41]=[CH:42][N:43]=[CH:44][CH:45]=3)[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:31][CH2:32]2)=[O:24])=[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]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(c2ccncc2)CC1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccncc5)CCN(C(=O)OC(C)(C)C)CC4)c3F)s2)c1
Yield: 83 %

Procedure:
3-Fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinic acid (intermediate B in example 1, 612 mg, 1.7 mmol), tert-butyl 4-(aminomethyl)-4-(pyridin-4-yl)piperidine-1-carboxylate (amine intermediate “L”, 640 mg, 2.2 mmol), EDAC (649 mg, 3.4 mmol), HOBt (297 mg, 2.8 mmol) and diisopropyl-ethyl-amine (1.47 ml, 8.4 mmol) were dissolved in 15 ml NMP and stirred until LCMS showed complete consumption of acid starting material. (usually overnight) The product was precipitated out of the reaction mixture by addition of water, filtered, rinsed with water and dried. The title compound was isolated as a solid (1.01 g, 90% pure by HPLC, 83% yield). An analytical sample was purified by prep HPLC (C-18 reversed phase column, water/MeOH gradient, buffered with 0.1% TFA). Alternatively a water/acetonitrile gradient, buffered with 10 mM NH4OAc can be used. Product containing fractions were filtered through a cartridge filled with cation exchange resin (MCX from Waters or STRATA X-C from Phenomenex), rinsed with methanol, eluted with 2 M solution of ammonia in methanol and evaporated. The residue was dissolved in methanol, 1.0 equiv. aq. of 1.00 N HCl were added and the title compound was isolated as the mono-HCl salt by evaporation. LC/MS (M+H)+: 636. Ret. time: 1.66 min. (Condition M); analytical HPLC Ret. time: 16.74 min (Condition N).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[C:12]3[N:19]2[CH2:24][CH2:23][CH2:22][C@H:21]([NH:25]C(=O)OC(C)(C)C)[CH2:20]2)O1.FC(F)(F)S(O[C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([C:46]2[S:47][CH:48]=[CH:49][N:50]=2)[N:41]=1)(=O)=O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.COCCOC>[S:47]1[CH:48]=[CH:49][N:50]=[C:46]1[C:42]1[N:41]=[C:40]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[C:12]3[N:19]2[CH2:24][CH2:23][CH2:22][C@H:21]([NH2:25])[CH2:20]2)[CH:45]=[CH:44][CH:43]=1
Reactant: O=S(=O)(Oc1cccc(-c2nccs2)n1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccnc3ccc(B4OC(C)(C)C(C)(C)O4)cc23)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: COCCOC
Solvent: ClCCl
Product: N[C@H]1CCCN(c2ccnc3ccc(-c4cccc(-c5nccs5)n4)cc23)C1
Yield: 40 %

Procedure:
A solution of (S)-tert-butyl 1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4-yl)piperidin-3-ylcarbamate (1.0 equiv.), 6-(thiazol-2-yl)pyridin-2-yl trifluoromethanesulfonate (1.5 equiv.) and Pd(dppf)Cl2—CH2Cl2 (0.15 equiv.) in 3:1 DME/2M Na2CO3 was heated in a microwave at 100° C. for 20 minutes. Upon cooling, the solution was partitioned between EtOAc and Na2CO3(sat.) washed further with NaCl(sat.), dried over MgSO4, concentrated and purified by RP HPLC. Upon lyophilization, the Boc group was deprotected by treatment with 25% TFA/CH2Cl2, concentrated, purified by RP-HPLC and lyophilized to yield (S)-1-(6-(6-(thiazol-2-yl)pyridin-2-yl)quinolin-4-yl)piperidin-3-amine (40%). LC/MS=388.1 (M+H), LC=2.02 min.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Cl[CH2:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18]>CN(C=O)C>[O:19]=[C:17]([CH3:18])[CH2:16][CH2:15][CH2:14][N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(=O)CCCCl
Agent: [K]
Solvent: CN(C)C=O
Product: CC(=O)CCCN1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 30 h
Yield: 34.1 %

Procedure:
24.59 g (132.8 mmol) of potassium phthalimide are added to a solution of 14.3 ml (124.4 mmol) of 5-chloro-2-pentanone in 100 ml of DMF and the mixture is left to stir at room temperature for 3 h and at 60° C. for 30 h. After filtering, the filtrate is partitioned between water and dichloromethane. The phases are separated and the organic phase is washed successively with water, twice with an 0.2N solution of NaOH and water and then dried over sodium sulfate. After filtering, the solvent is removed in vacuo and the residue is chromatographed through silica gel using heptane/ethyl acetate=6/4. 9.8 g (34%) of (14.1) are obtained after concentrating the product fractions.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[OH:12][C:13]1[C:18]([CH2:19][CH2:20][CH3:21])=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=1[C:23](=[O:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[OH:12][C:13]1[C:18]([CH2:19][CH2:20][CH3:21])=[C:17]([O:22][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=2)[CH:16]=[CH:15][C:14]=1[C:23](=[O:25])[CH3:24]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(OCc2cccc([N+](=O)[O-])c2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add 3-bromomethyl nitrobenzene (10.00 g, 46.3 mmol) to a solution of 1-(2,4-dihydroxy-3-propyl-phenyl)-ethanone (8.99 g, 46.3 mmol) in dimethylformamide (60 mL). After 10 minutes add potassium carbonate (9.60 g, 69.4 mmol) and cesium carbonate (15.08 g, 46.3 mmol). Stir at room temperature for one hour, then heat to 70° C. for 1.5 hours. Cool and add water (250 mL). Triturate for 15 minutes. Filter. Wash the solid with water several times, and then wash with hexanes. Dry to afford the title compound as an off white/light gray powder (12.9 g, 85%): 1H NMR (DMSO-d6) δ 0.91 (t, 3H), 1.52 (m, 2H), 2.58 (s, 3H), 2.63 (m, 2H), 5.42 (s, 2H), 6.72 (d, 1H), 7.73 (t, 1H), 7.83 (d, 1H), 7.90 (d, 1H), 8.21 (d, 1H), 8.34 (s, 1H), 12.88 (bs, 1H).
Reaction SMILES: [Na].[O:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][OH:11])[CH2:4][CH2:3]1.[Br:12][C:13]1[CH:14]=[C:15]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][C:26](F)=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH:16]=[CH:17][CH:18]=1>C1COCC1.O>[Br:12][C:13]1[CH:14]=[C:15]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:11][CH2:10][CH2:9][CH2:8][N:5]4[CH2:6][CH2:7][O:2][CH2:3][CH2:4]4)=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: OCCCN1CCOCC1
Reactant: O=[N+]([O-])c1cc2c(Nc3cccc(Br)c3)ncnc2cc1F
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cc2c(Nc3cccc(Br)c3)ncnc2cc1OCCCN1CCOCC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
Sodium metal (27.6 mmol, 0.63 g) was added to a solution of 3-morpholinopropan-1-ol (22.0 mmol, 3.20 g) in THF (60 mL) under N2. The resulting suspension was stirred at 20° C. for 2 hours and then cannulated into a solution of 4-[(3-bromophenyl)amino]-7-fluoro-6-nitro-quinazoline, J. Med Chem., 1996(39):918) (2.0 g, 5.51 mmol) in THF (50 mL) under N2. The solution was then heated at reflux for 24 hours before being diluted with water and extracted with EtOAc. The combined organic extracts were dried over anhydrous Na2SO4, concentrated under reduced pressure and chromatographed on alumina eluting with EtOAc/hexane (1:1) to MeOH/CH2Cl2/EtOAc (2:3:5) to give 4-[(3-bromophenyl)amino]-7-[(3-morpholino)propyloxy]-6-nitroquinazoline (1.75 g, 65%) as a yellow powder, mp (MeOH) 216-220° C.