Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:16])=[C:9]([C:11](OCC)=[O:12])[N:10]=2)[CH:7]=1.O.[NH2:18][NH2:19]>CCO>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:16])=[C:9]([C:11]([NH:18][NH2:19])=[O:12])[N:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1nc2ccc(I)cn2c1C
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)NN)nc2ccc(I)cn12
Temperature: 80 °C

Procedure:
To a stirred solution of ethyl 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carboxylate (250 mg) in EtOH (5 ml) was added hydrazine hydrate (0.14 ml) at room temperature. The reaction vessel was sealed and heated at 80° C. for 16 h. The mixture was then cooled to room temperature, and the reaction mixture was concentrated in vacuo. The residue was washed with EtOAc to give the title compound (200 mg) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[O:10][CH3:11].N1C=CN=C1.C(O)(=O)C.C(OC1C=C(C(NC2C=CC(C(N)=N)=CC=2)C2NC(=O)N(C3N=CC=CN=3)N=2)C=CC=1OC)C.[C:55]([Si:59](Cl)([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)([CH3:58])([CH3:57])[CH3:56].Cl>C(OCC)(=O)C>[C:55]([Si:59]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:10][CH3:11])[CH:4]=1)([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)([CH3:58])([CH3:56])[CH3:57]
Reactant: COc1cc(CO)ccc1F
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CCOc1cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)ccc1OC
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving 9.17 g of (4-fluoro-3-methoxyphenyl)methanol [CAS No. 128495-45-4] in 100 ml of DMT, 5g of imidazole and 17g of t-butyl -chlorodiphenylsilane were added and the mixture was stirred overnight at room temperature. Next, 1N hydrochloric acid was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give t-butyl-(4-fluoro-3-methoxybenzyloxy)diphenylsilane as an oil.
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6]Br.Br[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.[P:19]([O-:26])(OCC)OCC.Cl>C1COCC1.C1(C)C=CC=CC=1.O>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[PH:19](=[O:26])[C:6]1[CH:5]=[CH:15][C:16]2[C:11](=[CH:10][CH:9]=[CH:18][CH:17]=2)[CH:12]=1
Reactant: BrCCBr
Reactant: CCOP([O-])OCC
Reactant: Brc1ccc2ccccc2c1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: O=[PH](c1ccc2ccccc2c1)c1ccc2ccccc2c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
Under an argon atmosphere, a solution of magnesium (2.94 g, 1.0 equivalent), a small amount of iodine and a small amount of 1,2-dibromoethane in THF (30 mL) was stirred at room temperature for 1 hr. A solution of 2-bromonaphthalene (25 g, 0.121 mol) in THF (20 mL) was added at 35°. The mixture was stirred at 40° C. for 30 min. and then stirred at 5° C. for 30 min. Then, a solution of diethyl phosphite (9.77 g, 0.5 equivalent) in THF (10 mL) was added at 5° C., and the mixture was stirred at 5° C. for 3 hrs. Water (20 mL) was added at 3° C. and then toluene (60 mL) and 6M—HCl (20 mL) were added. The mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned, and the organic layer was washed successively with water (10 mL), 5% aqueous NaHCO3 solution (10 mL) and 5% aqueous NaCl solution (10 mL). Then the organic layer was dried over anhydrous magnesium sulfate, filtered by gravity, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from diisopropyl ether-heptane to give the title compound (9.62 g, white crystals). yield 53.0%. melting point: 98.3° C.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[N:19]=[C:18](Cl)[CH:17]=[C:16]([Cl:21])[N:15]=2)=[CH:9][CH:8]=1)=[O:5].[CH3:27][C:28]1[CH:29]=[C:30]([NH2:33])[NH:31][N:32]=1.[I-].[Na+].C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.CN(C)C=O>[F:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([S:13][C:14]2[N:15]=[C:16]([Cl:21])[CH:17]=[C:18]([NH:33][C:30]3[NH:31][N:32]=[C:28]([CH3:27])[CH:29]=3)[N:19]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: Cc1cc(N)[nH]n1
Reactant: O=C(Nc1ccc(Sc2nc(Cl)cc(Cl)n2)cc1)c1c(F)cccc1F
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2cc(Cl)nc(Sc3ccc(NC(=O)c4c(F)cccc4F)cc3)n2)[nH]n1
Temperature: 90 °C
Reaction time: 18 h
Yield: 99.3 %

Procedure:
A 50 ml round bottom flask was charged with 2,6-difluoro-N-[4-(4,6-dichloro-pyrimidin-2-ylsulfanyl)-phenyl]-benzamide (1.0 g, 2.3 mmol), 5-methyl-2H-pyrazol-3-ylamine (250 mg, 2.58 mmol), sodium iodide (351 mg, 2.34 mmol), diisopropylethyl amine (333 mg, 2.58 mmol) and dimethylformamide (5 ml) under nitrogen. The reaction mixture was stirred at 90° C. for 18 h, then allowed to cool to room temperature. The reaction mixture was diluted with ethyl acetate (25 ml), washed with saturated sodium bicarbonate solution and brine. The organic was dried over magnesium sulfate, filtered and concentrated in vacuo. The compound was purified by flash chromatography (75 to 80% ethyl acetate/petrol) to give the title compound (1.08 g, 98%). 1H NMR (DMSO) 2.00 (3H, s), 5.25 (1H, brs), 6.48 (1H, brs), 7.30-7.97 (7H, m), 10.28 (1H, s), 10.89 (1H, s), 11.90 (1H, s); MS (ES+): 473.4.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])=[O:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:30]([C:29]3[CH:28]=[C:27]([CH:35]=[CH:34][CH:33]=3)[C:25]([O:24][CH3:23])=[O:26])=[O:31])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.9 %

Procedure:
A mixture of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (2.0 g, 0.0059 mol) in DCM (60 mL) with 3-[(methyloxy)carbonyl]benzoic acid (1.16 g, 0.00648 mol) and HATU (2.68 g, 0.00706 mol) and TEA (1.19 g, 1.64 mL, 0.0118 mol) gave a yellow solution upon stirring overnight at RT. The solution was washed in turn with sat. aq. NaHCO3, H2O, and sat. aq. NaCl, then dried (Na2SO4), and concentrated to a viscous syrup/foam (3.68 g). This was purified on a ‘CombiFlash’ 40 g silica gel column (hexane-EtOAc) [20-100% EtOAc] to afford the title compound (3.02 g). LC-MS m/z 466.1 (M+H)+.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:22]=[CH:21][C:20](I)=[CH:19][N:18]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[NH:24]1[CH2:28][CH2:27][CH2:26][C:25]1=[O:29].C(=O)([O-])[O-].[K+].[K+]>[Cu]>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[N:18]=[CH:19][C:20]([N:24]5[CH2:28][CH2:27][CH2:26][C:25]5=[O:29])=[CH:21][CH:22]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCN1
Reactant: Ic1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1CCCN1c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Temperature: 150 °C

Procedure:
A mixture of 3-cyclobutyl-7-[(5-iodo-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E207) (252 mg, 0.6 mmol), 2-pyrrolidinone (153 mg, 1.8 mmol), potassium carbonate (83 mg, 0.6 mmol), copper powder (126 mg, 1.2 mmol) were heated in a microwave reactor at 150° C. for 1 minute. The reaction mixture was diluted with 2-pyrrolidinone (1 g, 12 mmol) and heated for a further 20 minutes at 200° C. The reaction mixture was cooled and applied to a SCX ion exchange cartridge (Varian bond-elute, 10 g) and washed with methanol and then a mixture of 0.880 ammonia/methanol. The combined basic fractions were concentrated in vacuo and the resulting residue purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (1:9:90) to afford the title compound (E217). MS (ES+) m/e 378 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[CH:10]=[C:9](F)[CH:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13].C([O-])([O-])=O.[K+].[K+].[OH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CS(C)=O>[N+:12]([C:6]1[CH:7]=[CH:8][C:9]([N:27]2[CH2:28][CH2:29][CH:24]([OH:23])[CH2:25][CH2:26]2)=[CH:10][C:5]=1[O:4][CH2:3][C:2]([F:16])([F:15])[F:1])([O-:14])=[O:13]
Reactant: OC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2CCC(O)CC2)cc1OCC(F)(F)F
Reaction time: 60 h
Yield: 92.3 %

Procedure:
5-Fluoro-2-nitrophenyl 2,2,2-trifluoroethyl ether (1.48 g, 6.19 mmol) was dissolved in 30 mL of DMSO with K2CO3 (1.11 g, 8.03 mmol) and 4-hydroxypiperidine (0.657 g, 6.50 mmol). The reaction was stirred for 2.5 days and quenched with H2O. The mixture was poured into EtOAc and H2O. The layers were separated, and the organic layer was washed with H2O (2×) and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford 1.83 g (92%) of the title compound of step B. 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J=9.5 Hz, 1H), 6.63 (dd, J=9.5, 2.4 Hz, 1H), 6.55 (d, J=2.4 Hz, 1H), 4.88 (q, J=8.8 Hz, 2H), 4.72 (d, J=4.2 Hz, 1H), 3.65-3.84 (m, 3H), 3.16 (ddd, J=13.3, 9.8, 2.9 Hz, 2H), 1.74 (br. s., 2H), 1.28-1.43 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH2:5][OH:6].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]OCC(F)(F)CCC1C=CC=CC=1>>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:6][CH2:5][CH2:4][CH2:3][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([F:13])[F:1]
Reactant: FC(F)(CCc1ccccc1)COCCCCCCBr
Reactant: OCCCC(F)(F)c1ccccc1
Product: FC(F)(CCCOCCCCCCBr)c1ccccc1

Procedure:
Obtained from Intermediate 22 (0.6 g, 3.22 mmol) by the procedure described in Intermediate 3. The title compound was obtained (1.98 g, 63% purity) as oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[Br:12][CH2:13][CH2:14]Br.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH2:14][CH2:13][Br:12]
Reactant: O=[N+]([O-])c1ccc(O)c(Br)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCBr)c(Br)c1
Temperature: 82.5 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
A portion (2.3 g, 10.6 mmol) of the 2-bromo-4-nitrophenol produced in (1) above and 1,2-dibromoethane (7.9 g, 42.1 mmol) were added to N,N-dimethylformamide (20 ml); to the mixture, potassium carbonate (1.6 g) was added, followed by stirring at 80-85° C. for 3 h. The reaction mixture was added to water (100 ml) and extraction was conducted with ethyl acetate, followed by the drying of the extract with magnesium sulfate and concentration. The residue was subjected to column chromatography using a 10:3:1 solvent system of n-hexane, ethyl ether and ethyl acetate as an eluent to yield the end compound 1-(2-bromo-4-nitrophenoxy-2-bromoethane (2.14 g).
Reaction SMILES: [F:1][C:2]([F:28])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C:9]3[CH2:10][CH2:11][C:12]4[CH:13]=[C:14]([O:21]C5CCCCO5)[CH:15]=[CH:16][C:17]=4[C:18]=3[CH2:19][CH2:20][C@:4]12[CH3:5].C(O)(=O)C(O)=O>CO.O>[F:1][C:2]([F:28])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C:9]3[CH2:10][CH2:11][C:12]4[CH:13]=[C:14]([OH:21])[CH:15]=[CH:16][C:17]=4[C:18]=3[CH2:19][CH2:20][C@:4]12[CH3:5]
Reactant: C[C@]12CCC3=C(CCc4cc(OC5CCCCO5)ccc43)[C@@H]1CCC2=C(F)F
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CO
Product: C[C@]12CCC3=C(CCc4cc(O)ccc43)[C@@H]1CCC2=C(F)F
Yield: 68.9 %

Procedure:
A suspension of 927 mg of 17-difluoromethylene-3-tetrahydropyranyloxy-estra-1,3,5(10),8-tetraene in 20 ml of methanol and 2.0 ml of water is refluxed with 950 mg of oxalic acid for 0.5 hour at a bath temperature of 100° C. Then, it is concentrated by evaporation in a vacuum diluted with ethyl acetate, washed three times with water, once with sodium bicarbonate solution as well as with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. After crystallization from hexane, 0.5 g of 17-difluoromethylene-estra-1,3,5(10),8-tetraen-3-ol is obtained as colorless crystals with a melting point of 127-128° C., [α]D22 =-1.5° (c=0.515% in pyridine).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][C:12]#[N:13])=[CH:6][CH:5]=1.[C:16]1([NH:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([NH2:13])[N:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:23]=2)=[CH:6][CH:5]=1
Reactant: NNc1ccccc1
Reactant: COC(=O)c1ccc(C(=O)CC#N)cc1
Solvent: CCO
Product: COC(=O)c1ccc(-c2cc(N)n(-c3ccccc3)n2)cc1

Procedure:
A mixture of methyl-4-(cyanoacetyl)benzoate (5.0 g, 24.6 mmol) and phenylhydrazine (2.42 ml, 24.6 mmol) in ethanol (100 ml) was heated to reflux for 20 hours. The mixture was cooled and the product was collected by filtration. The product was purified by trituration in hot acetonitrile, cooled and collected by filtration to give the product 4-(5-amino-1-phenyl-1H-pyrazole-3-yl)-benzoic acid methyl ester as a colorless solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28](Br)[C:27]=2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[N:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:42]1(B(O)O)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O.O1CCOCC1.C(OCC)(=O)C.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>[CH:7]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[C:27]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[C:28]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:29]=[CH:30][CH:31]=2)[N:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Fc1ccc(COc2c(Br)cccc2-c2cccc(C(c3ccccc3)c3ccccc3)n2)cc1
Reactant: OB(O)c1ccccc1
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: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Fc1ccc(COc2c(-c3ccccc3)cccc2-c2cccc(C(c3ccccc3)c3ccccc3)n2)cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
Potassium carbonate (2.1 g, 15.0 mmol, 3.0 equiv) was dissolved in water (20 mL) and added to compound 5 (2.6 g, 5.0 mmol, 1.0 equiv) and phenylboronic acid (0.73 g, 6.0 mmol, 1.2 equiv) in dioxane (20 mL). A stream of nitrogen was bubbled through the solution for 15 min and tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.025 mmol, 0.005 equiv) was added to the reaction. The reaction was refluxed for 4 hr at which point LC/MS and TLC indicated the reaction to be complete. The reaction was allowed to cool to room temperature, diluted with ethyl acetate (50 mL), the organic layer was separated and washed with saturated brine (50 mL). The organic layer was dried over sodium sulfate and absorbed onto silica gel (7 g) by concentration under reduced pressure. This material was purified on a silica gel column (60 g) by eluting with heptanes (500 mL), ethyl acetate (1%) in heptanes (500 mL), ethyl acetate (2%) in heptanes (500 mL) and ethyl acetate (3%) in heptanes (500 mL). The desired product was isolated pure in 85% yield (2.2 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][CH2:7]O.CN1CCOCC1.CS(Cl)(=O)=O.[CH2:24]([NH2:27])[CH2:25][NH2:26]>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][CH2:7][NH:26][CH2:25][CH2:24][NH2:27]
Reactant: NCCN
Reactant: OCCOc1cccc(Br)c1
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: NCCNCCOc1cccc(Br)c1

Procedure:
To a magnetically stirred, ambient temperature solution of 2-(3-bromo-phenoxy)-ethanol (3.6 g, 16.7 mmol) and N-methylmorpholine [109-02-4] (2.2 mL, 20.0 mmol) in ethyl acetate (200 mL) was added methanesulfonyl chloride [124-63-0] (1.3 mL, 16.8 mmol). The reaction was stirred over night then washed with brine and the phase separated ethyl acetate extract dried (MgSO4) and added to a stirred ambient temperature solution of ethylenediamine [107-15-3] (33.3 mL, 497.0 mmol) in ethyl acetate (300 mL) from a pressure equalizing addition funnel over the course of 15 minutes. The addition funnel was replaced with a condenser and the reaction refluxed for 4 h then cooled and washed with brine. The ethyl acetate phase was dried (CaSO4) and evaporated to obtain N1-(2-(3-bromophenoxy)ethyl)ethane-1,2-diamine as 4.7 g of clear yellow liquid. LRMS (ESI) m/z 259.1/261.1 [(M+H)]+, calc'd for C10H15BrN2O: 259.15.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]#[C:16][C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.C1(NC2CCCCC2)CCCCC1.S(Cl)([Cl:42])=O>ClCCl>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]#[C:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([Cl:42])=[O:22])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(CC#Cc3ccc(C(=O)O)cc3)ccc21
Reactant: O=S(Cl)Cl
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(CC#Cc3ccc(C(=O)Cl)cc3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.9 g (8.3 mmol) of 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoic acid and 100 ml of dichloromethane are introduced into a round-bottomed flask under a stream of nitrogen and 2.4 ml (12.1 mmol) of dicyclohexylamine are added dropwise. The mixture is stirred at room temperature for one hour, 1.2 ml (11.7 mmol) of thionyl chloride are added dropwise and the mixture is stirred for one hour. The reaction medium is evaporated to dryness, the residue is taken up in ethyl ether, the dicyclohexylamine salt is filtered off and the filtrate is evaporated. 3 g (100%) of the crude acid chloride are collected, which product will be used in its current state for the rest of the synthesis.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.C([Sn](CCCC)(CCCC)[C:31]([O:33]CC)=[CH2:32])CCC.O.Cl>CN(C)C=O.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:6]2[C:5]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[C:31](=[O:33])[CH3:32])=[CH:12][CH:13]=1
Reactant: Clc1ccc(-n2c(-c3ccc(Cl)cc3Cl)nc3c(Cl)ncnc32)cc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)c1ncnc2c1nc(-c1ccc(Cl)cc1Cl)n2-c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A solution of 6-chloro-9-(4-chlorophenyl)-8-(2,4-dichlorophenyl)-9H-purine I-(1A-1)d (202 mg, 0.49 mmol) and tetrakis(triphenylphosphine) palladium(0) (60 mg, 0.049 mmol) in dimethylformamide (1.5 ml) was degassed and to it was added tributyl-(1-ethoxyvinyl)-stannane (250 μl, 0.74 mmol). The reaction mixture was heated to 100° C. until completed as shown by TLC. A solution of 2:1 of H2O/conc. HCl (1.5 ml) was added to the reaction mixture and the heating continued for 1 hour. The reaction was diluted with ethyl acetate and washed with water. The organic layers were combined, dried (Na2SO4), filtered, and concentrated to dryness. The crude material was purified via TLC preparative plate using 30% ethyl acetate/hexanes as the solvent to afford the desired product I-(15A-1)a (50 mg, 25%): +ESI MS (M+1) 417.3; 1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 7.58 9 (d, J=8.7 Hz, 1H), 7.43–7.30 (m, 4H), 7.21 (d, J=8.7 Hz, 2H), 2.92 (s, 3H).
Reaction SMILES: N.[C:2]1([CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]([CH3:28])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[C:9]#[N:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(OC)(O[CH3:33])(=O)=O>[N+]([O-])([O-])=O.[Fe+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>[C:2]1([C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]([CH3:28])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)([CH3:33])[C:9]#[N:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COS(=O)(=O)OC
Reactant: CN1CCC(c2ccc(OC(C#N)c3ccccc3)cc2)c2ccccc21
Agent: [Fe+3]
Agent: N
Agent: O=[N+]([O-])[O-]
Product: CN1CCC(c2ccc(OC(C)(C#N)c3ccccc3)cc2)c2ccccc21
Reaction time: 2 h

Procedure:
At -40°, 50 mg. of iron (III) nitrate and then, under agitation, 2.3 g. of Na are dissolved in 100 ml. of liquid ammonia. After two hours of agitation, 3.54 g. of 2-phenyl-2-[4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxy]-acetonitrile is added thereto, the mixture stirred for 30 minutes, and then 19.2 ml. of dimethyl sulfate is added dropwise within one hour. The mixture is further agitated overnight at -35° and then combined dropwise with another 10 ml. of dimethyl sulfate. After the ammonia has been evaporated, the residue is combined with water and extracted with ether. The crude 2-phenyl-2-[4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxy]-propionitrile obtained after the evaporation of the ether is refluxed for 40 hours with 3 g. of KOH in 30 ml. of ethanol and 3 ml. of water. The mixture is concentrated by evaporation, mixed with water, extracted with ether, hydrochloric acid is added to pH 5, and the acid Ih is thus produced.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5](Cl)=[O:6].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:37])=[C:17]([N:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH:26]=3)[N:21]=[CH:20]2)[CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:37])=[C:17]([N:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH:26]=3)[N:21]=[CH:20]2)[CH:18]=1)=[O:6]
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: Cc1ccc(N)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cc(F)cc(F)c2)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Yield: 97.1 %

Procedure:
3,5-Difluorobenzoyl chloride (0.91 g) was added to a stirred mixture of 3-(5-amino-2-methylphenyl)-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one (1.5 g), triethylamine (1.04 g) and methylene chloride (50 ml) and the resultant mixture was stirred at ambient temperature for 18 hours. The mixture was washed with a saturated aqueous sodium bicarbonate solution and the organic phase was evaporated. There was thus obtained the title compound (2.04 g); NMR Spectrum: (DMSOd6) 2.05 (s, 3H), 2.22 (s, 3H), 2.45-2.5 (m, 4H), 3.24-3.3 (m, 4H), 7.41-7.56 (m, 3H), 7.61-7.68 (m, 4H), 7.75-7.79 (m, 2H), 8.06 (s, 1H), 10.5 (s, 1H); Mass Spectrum: M+H+ 490.