Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[CH:14][CH:15]=[C:16]([NH:17][C:18]4[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=4)[C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[CH2:28]([O:30][C:31](=[O:41])[C@H:32]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[NH2:33])[CH3:29].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[CH:14][CH:15]=[C:16]([NH:17][C:18]4[CH:26]=[CH:25][C:21]([C:22]([NH:33][C@H:32]([C:31]([O:30][CH2:28][CH3:29])=[O:41])[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:23])=[CH:20][CH:19]=4)[C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Reactant: Nc1nc2ccc3c(Nc4ccc(C(=O)O)cc4)cccc3c2c(=O)[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(Nc2cccc3c2ccc2nc(N)[nH]c(=O)c23)cc1)C(=O)OCC

Procedure:
A suspension of N-(7-(4-cyanoanilino)-1,2-dihydro-1-oxobenzo[f]-quinazolin-3-yl)pivalamide (82 mg, 0.20 mmol) in ethanol (1 ml) and 1N NaOH (4 ml) was stirred under nitrogen at reflux overnight. The solution was allowed to cool, acidified to pH 3 with concentrated HCl, the resulting suspension stirred for 30 minutes,then filtered. The solid was washed with water and dried at 120° C. under reduced pressure to give 4-((3-amino-1,2-dihydro-1-oxobenzo[f]quinazolin-7-yl)amino)benzoic acid. 1H NMR (DMSO-d6, 200 MHz) δ: 6.85 (d, J=9 Hz, 2H, Ar), 7.30 (br s, 2H, NH2), 7.39 (d, J=9 Hz, 1H Ar), 7.43 (d, J=8 Hz, 1H, Ar), 7.64 (t, J=8 Hz, 1H, Ar), 7.73 (d, J=9 Hz, 2H, Ar), 8.28 (d, J=9 Hz, 1H, Ar), 8.85 (s, 1H, C7—NH), 9.44 (d, J=9 Hz, 1H, Ar), 11.5-12.9 (2H, CO2H and N2H). A solution of the foregoing benzoic acid, L-glutamic acid diethyl ester hydrochloride (80 mg, 0.33 mmol) (Aldrich), benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (90 mg, 0.20 mmol) (Richelieu Biotechnologies), and triethylamine (90 l, 0.64 mmol) in DMF (6 ml) was stirred at room temperature for 1 hour, then concentrated under high vacuum. The residue was purified by chromatography on silica gel (10-15 g) three times eluting with methanol/methylene chloride. Water (˜5 ml) was added to a solution of the solid in ethanol, the ethanol removed under vacuum, and the solid filtered, washed with water, and dried under high vacuum to give diethyl N-(4-((3-amino-1,2-dihydro-1-oxobenzo[f]quinazolin-7-yl)amino)benzoyl)-L-glutamate (35 mg). 1H NMR (DMSO-d6, 200 MHz) δ: 1.14 (t, J=7 Hz, 3H, CH3), 1.16 (t, J=7 Hz, 3H, CH3), 1.85-2.15 (m, 2H, gluCH2), 2.40 (t, J=7 Hz, 2H, gluCH2), 4.03 (q, J=7 Hz, 2H, esterCH2), 4.08 (q, J=7 Hz, 2H, esterCH2), 4.30-4.45 (m, 1H, gluCH), 6.63 (br s, 2H, NH2), 6.85 (d, J=9 Hz, 2H, Ar), 7.29 (d, J=9 Hz, 1H, Ar), 7.35 (d, J=8 Hz, 1H, Ar), 7.56 (t, J=8 Hz, 1H, Ar), 7.71 (d, J=9 Hz, 2H, Ar), 8.18 (d, J=9 Hz, 1H, Ar), 8.36 (d, J=7 Hz, 1H, gluNH), 8.64 (s, 1H, C7—NH), 9.45 (d, J=9 Hz, 1H, Ar), 11.22 (br s, 1H, N2H). Mass spectrum (CI-CH4): 532 (M+1, 62.5%), Anal. Calculated for C28H29N5O6.H2O: C, 61.19; H, 5.69; N, 12.74. Found: C, 61.20; H, 5.44; N, 12.68.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[O:17][C:16](=[O:21])[C:15]([C:22]([OH:24])=O)=[CH:14]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12>CN(C=O)C>[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH:64][C:22]([C:15]3[C:16](=[O:21])[O:17][C:18]4[C:13]([CH:14]=3)=[CH:12][C:11]([Br:10])=[CH:20][CH:19]=4)=[O:24])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12
Reactant: O=C(O)c1cc2cc(Br)ccc2oc1=O
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2cc(Br)ccc2oc1=O
Temperature: 25 °C
Yield: 70.2 %

Procedure:
DIEA (35.6 μL, 0.2 mmol) was added to 6-bromo-3-carboxy-coumarin (50.0 mg, 0.19 mmol) and HATU (77.7 mg, 0.2 mmol) in 2 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (38.9 mg, 0.19 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 61.4 mg of product in 68% yield: LCMS (ESI) m/z 461 (MH+).
Reaction SMILES: C([Mg:3][Br:4])C.Br[C:6]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:7]=1[F:16].[CH:17]([O:20][CH:21]([CH3:23])[CH3:22])([CH3:19])[CH3:18]>>[F:12][C:11]1[C:6]([Mg:3][Br:4])=[C:7]([F:16])[C:8]([F:15])=[C:9]([F:14])[C:10]=1[F:13].[CH:17]([O:20][CH:21]([CH3:23])[CH3:22])([CH3:19])[CH3:18]
Reactant: Fc1c(F)c(F)c(Br)c(F)c1F
Reactant: CC[Mg]Br
Solvent: CC(C)OC(C)C
Product: Fc1c(F)c(F)c([Mg]Br)c(F)c1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Air inside a reaction vessel of the same type as the one used in Example 1 was replaced with a nitrogen gas in a satisfactory manner, after which 70 ml of a diisopropyl ether (chain ether solvent) solution containing 0.066 mol of suspended ethyl magnesium bromide was charged to the reaction vessel. Meanwhile, 0.060 mol of bromopentafluorobenzene and 20 ml of diisopropyl ether (chain ether solvent) were charged to the dropping funnel. Then, the diisopropyl ether solution of bromopentafluorobenzene in the dropping funnel was dropped to the reaction vessel over 2 hours at room temperature, and the reaction solution was stirred for 12 hours at room temperature. Consequently, pentafluorophenyl magnesium bromide was obtained in the form of a colorless diisopropyl ether solution. The yield of pentafluorophenyl magnesium bromide measured in the same manner as Example 1 was 94.3 mol % based on bromopentafluorobenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:12].[CH3:13][O:14][C:15](=[O:31])[C:16]([O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[CH:29]=O)([CH2:19][CH3:20])[CH2:17][CH3:18].N1CCCC1>CO>[CH3:13][O:14][C:15](=[O:31])[C:16]([O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1/[CH:29]=[C:6]1\[C:7](=[O:11])[NH:8][C:9]2[C:5]\1=[CH:4][C:3]([F:12])=[C:2]([Cl:1])[CH:10]=2)([CH2:17][CH3:18])[CH2:19][CH3:20]
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C=O)C(=O)OC
Reactant: O=C1Cc2cc(F)c(Cl)cc2N1
Solvent: C1CCNC1
Solvent: CO
Product: CCC(CC)(Oc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)c(F)cc21)C(=O)OC
Temperature: 70 °C

Procedure:
To the mixture of 6-chloro-5-fluoro-1,3-dihydro-indol-2-one (500 mg, 2.7 mmol) and 2-(4-chloro-2-formyl-phenoxy)-2-ethyl-butyric acid methyl ester (844 mg, 2.97 mmol) in methanol (5 mL) was added pyrrolidine (95 mg, 1.35 mmol) dropwise. The mixture was then heated at 70° C. for 1 h. After cooled to room temperature, the mixture was partitioned between EtOAc and diluted HCl solution. The organic phase was washed with water, brine, dried over anhydrous Na2SO4 and concentrated to give the crude product as a red-yellow solid, which was used for the next step reaction without further purification.
Reaction SMILES: [CH3:1][CH:2](O)[C:3]#[CH:4].[C:6]1([NH2:16])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.C(O)CO>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Ru].[Ru].[Ru].F[P-](F)(F)(F)(F)F.[NH4+].C(OCC)C>[CH3:1][C:2]1[NH:16][C:6]2[C:7]([C:3]=1[CH3:4])=[CH:8][CH:9]=[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=21
Reactant: Nc1cccc2ccccc12
Reactant: C#CC(C)O
Agent: [Ru]
Agent: F[P-](F)(F)(F)(F)F
Agent: [C-]#[O+]
Solvent: CCOCC
Solvent: OCCO
Product: Cc1[nH]c2c(ccc3ccccc32)c1C
Temperature: 140 °C
Reaction time: 20 h
Yield: 95 %

Procedure:
3-Butine-2-ol (0.631 g, 9 mmol), 1-napthylamine (0.859 g, 6 mmol), Ru3(CO)12 (16.0 mg, 0.025 mmol), ammonium hexafluorophosphate (0.041 g, 0.25 mmol) and 1 ml ethylene glycol were placed in a 10 ml round-bottomed flask, and the mixture was stirred at 140° C. for 20 hours. After cooling, diethyl ether (3 mL) was added, and the organic layer was washed twice with 1 M hydrochloric acid (2 mL) and once with water (2 mL). The organic layer was dried over sodium sulfate, and the solvent was distilled away, whereby 2,3-dimethylbenzo[g]indole (1.113 g; 5.7 mmol; yield, 95%; purity, 95% or more) was obtained.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:25])[C:5]([N+:22]([O-:24])=[O:23])=[C:6]([C:8]([C:20]#[N:21])([CH2:14][C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)C(OCC)=O)[N:7]=1.Cl>[OH-].[Na+]>[NH2:1][C:2]1[NH:3][C:4](=[O:25])[C:5]([N+:22]([O-:24])=[O:23])=[C:6]([CH:8]([CH2:14][C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[C:20]#[N:21])[N:7]=1
Reactant: CCOC(=O)C(C#N)(Cc1ccco1)c1nc(N)[nH]c(=O)c1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#CC(Cc1ccco1)c1nc(N)[nH]c(=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 76.2 %

Procedure:
A solution of 2-Amino-α-cyano-α-(2-furanyl-methyl)-1,6-dihydro-5-nitro-6-oxo-4-pyrimidineacetic acid, ethyl ester (5.0 g) in 1N NaOH (200 mL) is stirred at room temperature for 2 h. The reaction mixture is acidified (pH 1) by the dropwise addition of conc HCl and is stirred at room temperature for 2 min. The precipitate is collected by filtration, washed with water, and dried to give 2-Amino-α-(2-Furanylmethyl)-1, 6-dihydro-5-nitro-6-oxo-4-pyrimidineacetonitrile (3.02 g 73%). ##STR21##
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[CH3:2].[ClH:16].[CH2:17]([OH:19])[CH3:18]>>[ClH:16].[CH2:1]([O:3][C:4]1[CH:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:9]=[CH:8][C:5]=1[C:6](=[NH:7])[O:19][CH2:17][CH3:18])[CH3:2]
Reactant: CCOc1cc(C(F)(F)F)ccc1C#N
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1ccc(C(F)(F)F)cc1OCC
Temperature: 25 °C
Reaction time: 264 h
Yield: 67 %

Procedure:
2-Ethoxy-4-trifluoromethyl-benzonitrile (64 g) was dissolved in 750 mL of anhydrous ethanol. The solution was cooled to 0° C. and saturated with hydrogen chloride gas. The reaction flask was then sealed with a Teflon stopper and stirred at room temperature for 11 d. The progress of the reaction was checked every few days, and the solution was saturated again with hydrogen chloride gas. Nitrogen gas was bubbled through the solution to remove excess hydrogen chloride gas. The solvent was removed and the residue was triturated in diethyl ether to afford ethyl 2-ethoxy-4-trifluoromethyl-benzimidate hydrochloride (59.5 g, 67% yield) as white solids.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[OH:9].CC1C=CC2C=CC3C=CC(C)=NC=3C=2N=1.[OH2:27].CO>C(OCC)(=O)C.Cl[Cu]>[CH3:10][C:1]1[CH:6]=[C:5]([CH:4]=[C:3]([CH3:8])[C:2]=1[OH:9])[CH:7]=[O:27]
Reactant: O
Reactant: Cc1cc(C)c(O)c(C)c1
Agent: Cl[Cu]
Agent: Cc1ccc2ccc3ccc(C)nc3c2n1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(C=O)cc(C)c1O
Temperature: 25 °C
Reaction time: 9 h
Yield: 6278.4 %

Procedure:
A mixture of 13.622 g(100 mmol) of mesitol, 285 mg (1.26 mmol) of neocuproine hydrate, 503 mg (5.0 mmol) of CuCl and 120 mL of methanol was stirred at ambient temperature for 9 hours under an oxygen blanket. The reaction mixture was then diluted with ethyl acetate and filtered. The methanol was stripped off and the residue diluted with additional ethyl acetate. The solution was washed twice with a 1% solution of ethylenediaminetetraacetic acid trisodium salt (EDTA-Na3.2H2O), water and brine, dried over MgSO4 and concentrated. There was obtained 13.92 g of an orange-gold solid which was shown by 1H NMR and GC to contain 11.88 g (79.2% yield) of 3,5-dimethyl-4-hydroxybenzaldehyde (DMHB).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:20][O:21][C:22](=[O:28])[C@H:23]([C@@H:25]([CH3:27])[OH:26])[NH2:24]>C(Cl)(Cl)Cl.CO>[CH3:20][O:21][C:22](=[O:28])[C@H:23]([C@@H:25]([CH3:27])[OH:26])[NH:24][C:16](=[O:18])[C@H:14]([CH3:15])[NH:13][C:11](=[O:12])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1)[C@@H](C)O

Procedure:
Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (from Example Dl 1 above) and L-threonine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.1 in 95:5 CHCl3/MeOH) and the product was purified by silica gel chromatography using 95:5 CHCl3/MeOH as the eluent.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH2:23][OH:24])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]=[O:24])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(CO)ccc1-2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C=O)ccc1-2
Reaction time: 5 h
Yield: 103 %

Procedure:
To a solution of [2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-methanol (713 mg, 2.1 mmol) in DCM (25 mL) was added Dess-Martin periodinane (1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, 971 mg, 2.3 mmol) portionwise. The reaction mixture was stirred for 5 h then diluted with DCM (50 mL) and washed with an aqueous saturated sodium bicarbonate solution (×3). The organic layer was dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, 0-10% EtOAc in DCM) to give the title compound as an off-white solid (736 mg, quant.). LCMS: RT=4.39 min, [M+H]+=341
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[CH2:16][CH2:17][CH2:18][O:19][CH3:20])[CH3:2]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[CH2:16][CH2:17][CH2:18][O:19][CH3:20])[CH3:2]
Reactant: CCOC(=O)COc1ccc([N+](=O)[O-])cc1CCCOC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(N)cc1CCCOC
Reaction time: 3 h

Procedure:
3.00 g (roughly 65%, 6.56 mmol) of the above prepared [2-(3-methoxy-propyl)-4-nitro-phenoxy]-acetic acid ethyl ester was hydrogenated at RT in 50 ml of EtOAc over 0.60 g of Pd/C (10%) under 1 atm. of H2-pressure. After 3 h at ambient temperature, the reaction mixture was filtered over Celite and carefully rinsed with EtOAc. Evaporation of the solvent, followed by flash chromatography (SiO2, hexane/EtOAc=1/1) produced 1.69 g of the title compound as light brown oil; from the more polar fractions, 0.784 g of 8-(3-methoxy-propyl)-4H-benzo[1,4]oxazin-3-one was isolated (cyclized reduced ortho-amino derivative), MS: 268.3 (MH+)+; side product: 221.1 (M)+.
Reaction SMILES: CO.[Cl:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:7][NH:8][C:9]1[C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][N:12]=[C:11]([N:20]2[CH2:24][CH2:23][CH2:22][C@H:21]2[CH2:25][OH:26])[N:10]=1.O.[Na]>O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:7][NH:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[C:11]([N:20]2[CH2:24][CH2:23][CH2:22][C@H:21]2[CH2:25][OH:26])[N:10]=1
Reactant: CCOC(=O)c1cnc(N2CCC[C@H]2CO)nc1NCc1ccc(OC)c(Cl)c1
Agent: [Na]
Solvent: O
Solvent: CO
Product: COc1ccc(CNc2nc(N3CCC[C@H]3CO)ncc2C(=O)O)cc1Cl
Reaction time: 8 h
Yield: 47.7 %

Procedure:
Methanol (50 mL) was added in ethyl (s)-4-((3-chloro-4-methoxybenzyl)amino)-2-(2-(hydroxymethyl)tetrahydropyrrole-1-yl)-5-pyrimidine carboxylate (8.75 g, 20.8 mmol). In water (20 mL) was dissolved sodium hydrate (1.66 g, 41.6 mmol), then the aqueous solution was added to the reaction solution. The reaction was conducted in an oil bath of 50 to 60° C. overnight. The reaction was monitored by LC-MS. The organic solvent was removed by rotary evaporation. The residual aqueous phase was adjusted to a pH of 3 to 4. Then solid was precipitated. The precipitation was filtrated and dried to give a solid (3.9 g, 48.1% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][C:7]2[S:11][C:10]([C:12]#[N:13])=[CH:9][C:8]=2I)=[CH:4][CH:3]=1.[CH3:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](B(O)O)=[CH:20][CH:19]=1.[F-].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][C:7]2[S:11][C:10]([C:12]#[N:13])=[CH:9][C:8]=2[C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]([CH3:17])=[CH:19][CH:20]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(B(O)O)c2ccccc12
Reactant: N#Cc1cc(I)c(Cc2ccc(Cl)cc2)s1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [F-]
Product: Cc1ccc(-c2cc(C#N)sc2Cc2ccc(Cl)cc2)c2ccccc12
Temperature: 25 °C
Yield: 90.9 %

Procedure:
A round-bottomed flask was charged with 5-(4-chlorobenzyl)-4-iodothiophene-2-carbonitrile (180 mg, 0.50 mmol), 4-methylnaphthalen-1-ylboronic acid (102 mg, 0.55 mmol), Pd2(dba)3 (9.2 mg, 0.010 mmol) and KF (126 mg, 2.17). After degassed, dioxane (2.0 mL) and P(Bu-t)3 (0.15 mL, 0.2M, 0.03 mmol) was added. The reaction mixture was stirred at rt until complete. 20 mL of water was added, and the reaction mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulphate and then concentrated. The residue was purified by flash chromatography (5% ethyl acetate in hexane). 0.17 g (91%) of product was obtained as a white solid.
Reaction SMILES: C(OC)(=O)C1C=CC(C([O-])=O)=CC=1.[K+:14].[C:15]([O:29]CCC)(=[O:28])[C:16]1[CH:27]=[CH:26][C:19]([C:20]([O:22][CH2:23][CH2:24][CH3:25])=[O:21])=[CH:18][CH:17]=1.[OH-].[K+].C1(C)C=CC=CC=1>C(O)CC>[C:20]([O:22][CH2:23][CH2:24][CH3:25])(=[O:21])[C:19]1[CH:26]=[CH:27][C:16]([C:15]([O-:29])=[O:28])=[CH:17][CH:18]=1.[K+:14]
Reactant: CCCOC(=O)c1ccc(C(=O)OCCC)cc1
Agent: COC(=O)c1ccc(C(=O)[O-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCCO
Product: CCCOC(=O)c1ccc(C(=O)[O-])cc1
Yield: 95 %

Procedure:
This compound was prepared by the procedure described for potassium monomethyl terephthalate. Typical reagent levels were as follows: dipropyl terephthalate (97.3 g, 0.39 mole), potassium hydroxide (22.0g, 0.39 mole), 100 ml of toluene and 200 ml of 1-propanol. After workup 92.0 g of product was recovered which represented a 95% yield.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]([CH3:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][Mg]Br.C(#N)C1C=CC=CC=1.[Br-]>O1CCCC1>[C:4]1([C:8]([OH:9])([CH3:10])[CH3:11])[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: CC(=O)c1cccc(Cl)c1
Reactant: C[Mg]Br
Agent: [Br-]
Solvent: N#Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(O)c1ccccc1

Procedure:
When n is the bridging group --C(CH3)2 --, an appropriately substituted or unsubstituted phenyl methyl ketone, for example, methyl (3-chlorophenyl) ketone, is prepared by the reaction of methylmagnesium bromide and an appropriate benzonitrile in tetrahydrofuran. The ketone is in turn treated with methylmagnesiun bromide in tetrahydrofuran, yielding the corresponding 2-phenylpropan-2-ol, which is then converted to the 2-bromo-2-phenylpropane by the treatment of the alcohol with lithium bromide and trimethylsilyl chloride in acetonitrile. The Grignard reagent of the 2-bromo-2-phenylpropane is then prepared and reacted with 1,4-cyclohexanedione mono-ethylene ketal in tetrahydrofuran, yielding the corresponding 1-(2-phenylpropan-2-yl)-1-cyclohexen-4-one. The so-prepared cyclohexenone is reduced with hydrogen gas in the presence of 10% palladium on charcoal, yielding the 4-(2-phenylpropan-2-yl)cyclohexanone, which is in turn reacted with cyanoguanidine, as previously described, yielding the targeted 2,4-diamino-6-(2-phenylpropan-2-yl)-5,6,7,8-tetrahydroquinazoline. Example 7 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5](O)=[O:6].N1C2C(=CC=CN=2)C=C1.[Cl-:23].[Cl-].[Cl-].[Al+3]>S(Cl)(Cl)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([Cl:23])=[O:6]
Reactant: [Cl-]
Reactant: O=C(O)c1cc(F)cc([N+](=O)[O-])c1
Agent: [Al+3]
Agent: c1cnc2[nH]ccc2c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)c1cc(F)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-fluoro-5-nitrobenzoic acid (2.90 g, 10.8 mmol) was dissolved in thionyl chloride (20.0 mL) and the reaction was heated to reflux overnight. The reaction was cooled and was concentrated to provide a white solid which was dried under vacuum overnight. Compound 2 (512 mg, 4.33 mmol) was dissolved in methylene chloride (10.0 mL), under an atmosphere of argon and aluminum trichloride (2.85 g, 21.4 mmol) was added. The reaction was stirred at room temperature for 1 hour. The 3-fluoro-5-nitrobenzoyl chloride formed above was dissolved in methylene chloride (10.0 mL) and was added to the reaction. The reaction was stirred at room temperature overnight. The reaction was quenched with methanol and concentrated under reduced pressure. The resulting solid was extracted with ethyl acetate and saturated sodium bicarbonate. The organic portion was dried with anhydrous magnesium sulfate, adsorbed onto silica and purified by silica gel flash chromatography with 40%-50% ethyl acetate:hexanes. The appropriate fractions were combined and concentrated to provide compound 295 as a white solid characterized by MS and 1H-NMR (139 mg, LRMS (ESI) [M+H+]+=286.1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[H-].[Na+].Br[CH2:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26]>CS(C)=O>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH2:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: OCc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCOc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 39.9 %

Procedure:
A solution of 2.6 g of 3-hydroxybenzyl alcohol in 10 ml of dry dimethylsulfoxide was added dropwise with stirring under ice cooling to a suspension of 0.88 g of 60% sodium hydride in 5 ml of dry dimethylsulfoxide. After the addition, the mixture was stirred at room temperature for 20 minutes, and 6 g of N-bromopropylphthalimide was added. The mixture was reacted at room temperature for 1 hour, and ice water was added. The mixture was extracted with ether, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was crystallized with ether to afford 2.6 g of N-[3-[3-(hydroxymethyl)phenoxy]propyl]phthalimide.
Reaction SMILES: C12N(C3C=NC4C(=CC=CC=4)N=3)CC1CCNC2.[C@@H:19]12[NH:26][CH2:25][C@@H:24]1[CH2:23][CH2:22][N:21]([C:27]([C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[N:36]1[N:40]=[CH:39][CH:38]=[N:37]1)=[O:28])[CH2:20]2.[NH2:41][C:42]1[CH:47]=[C:46](Cl)[N:45]=[C:44]([CH3:49])[N:43]=1>>[F:35][C:33]1[CH:32]=[CH:31][C:30]([N:36]2[N:40]=[CH:39][CH:38]=[N:37]2)=[C:29]([C:27]([N:21]2[CH2:22][CH2:23][C@@H:24]3[C@@H:19]([N:26]([C:46]4[N:45]=[C:44]([CH3:49])[N:43]=[C:42]([NH2:41])[CH:47]=4)[CH2:25]3)[CH2:20]2)=[O:28])[CH:34]=1
Reactant: Cc1nc(N)cc(Cl)n1
Reactant: O=C(c1cc(F)ccc1-n1nccn1)N1CC[C@H]2CN[C@H]2C1
Agent: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Product: Cc1nc(N)cc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-n4nccn4)C[C@@H]32)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using (1R,6S)-3,8-diazabicyclo[4.2.0]octan-3-yl(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 4-amino-6-chloro-2-methylpyrimidine. MS (ESI) mass calcd. for C20H21FN8O, 408.4; m/z found, 409.2 [M+H]+.