Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Mg].I[CH3:15].[Cl-].[NH4+]>C(OCC)C.O>[CH:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]([OH:10])[CH3:15])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(C=O)cc1
Reactant: CI
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CC(C)Oc1ccc(C(C)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
A solution of 4-isopropyloxy benzaldehyde of formula 5 (5 g, 30 mmol) in dry diethyl ether is slowly added to an ethereal solution of Grignard reagent prepared from magnesium metal (0.84 g, 35 mmol) and iodomethane (2.6 ml, 40 mmol) and the contents stirred for 1 hour at room temperature. After the completion of the reaction, the mixture is worked up by adding saturated aqueous solution of ammonium chloride (10 ml), followed by dilution with water (100 ml), separating the organic layer and extracting the aqueous layer with solvent ether (2×100 ml). The combined organic layer is washed with water (2×20 ml), dried over anhydrous sodium sulphate and concentrated in vacuo to yield 1-(4-isopropyloxy phenyl) ethanol, in a semisolid of general formula 4 in 92.5% yield.
Reaction SMILES: [C:1]([O:5][C:6](=O)[CH2:7][CH3:8])(=[O:4])[CH2:2][CH3:3].[CH2:10](N(CC)CC)C.[C:17]([OH:21])(=[O:20])[CH2:18][CH3:19].O1CC1C=C>COCCOCCOC>[C:17]([O:21][CH:7]([CH2:6][O:5][C:1](=[O:4])[CH2:2][CH3:3])[CH:8]=[CH2:10])(=[O:20])[CH2:18][CH3:19]
Reactant: CCN(CC)CC
Reactant: CCC(=O)OC(=O)CC
Reactant: CCC(=O)O
Agent: C=CC1CO1
Solvent: COCCOCCOC
Product: C=CC(COC(=O)CC)OC(=O)CC
Temperature: 125 °C
Reaction time: 0.02 h
Yield: 90 %

Procedure:
A 100-mL autoclave was charged with 57.2 g (0.44 mol) propionic anhydride, 1.62 g (0.016 mol) of triethylamine, 1.2 g (0.016 mol) of propionic acid and 3.44 g of diglyme. The autoclave was purged with helium twice, then the vessel was pressurized to 6.2 bars (75 psig) with helium followed by agitation. The reaction mixture was heated to 125° C., then 31.35 mL (0.40 mol) of 3,4-epoxy-1-butene was introduced to the reactor via syringe pump over 10 seconds. A first sample was taken at 1 min, then sequential samples were obtained every 15 min during the course of 2 hrs for analysis by GC. GC analysis of the crude mixture after 2 hrs revealed a 90% yield of 3,4-dipropionyloxy-1-butene with a 91% selectivity and 6% 3,4-epoxy-1-butene. The reaction was observed to be first order in 3,4-epoxy-1-butene with a first order rate constant of 0.017 min-1 (Table A). This example shows the use of another carboxylic anhydride with its conjugate carboxylic acid.
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5]([NH:29][C@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[N:4]=1.Br.CC#N>CC(O)=O>[CH3:33][O:32][CH2:31][C@H:30]([NH:29][C:5]1[NH:4][C:3](=[O:2])[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=1)[CH3:34]
Reactant: COC[C@@H](C)Nc1ncc(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(C)n2)c(OC)n1
Agent: Br
Solvent: CC(=O)O
Solvent: CC#N
Product: COC[C@@H](C)Nc1ncc(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(C)n2)c(=O)[nH]1
Temperature: 90 °C
Yield: 71.3 %

Procedure:
(R)-4-methoxy-N-(1-methoxypropan-2-yl)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine (98 mg, 0.21 mmol) was dissolved in AcOH (3 mL) and then hydrobromic acid (0.1 mL, 0.85 mmol) was added. The mixture was heated at 90° C. for 3.5 hours. The mixture was concentrated and the residue was treated with NaHCO3 solution. The solution was extracted with EtOAc (3×). The organic was washed with NaHCO3, dried over Na2SO4, filtered and concentrated to obtain the crude. The crude was treated with hot MeCN and kept at RT. The solid was filtered and washed with MeCN and dried under vacuum to obtain (R)-2-((1-methoxypropan-2-yl)amino)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one (67 mg, 59.2% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.85 (s, 1H), 8.67 (s, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.25 (m, 2H), 7.97 (s, 1H), 7.51 (d, J=8.6 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H), 6.75 (br s, 1H), 6.60 (dd, J=5.7, 2.4 Hz, 1H), 4.19 (m, 1H), 3.85 (s, 3H), 3.38 (m, 2H), 3.30 (s, 3H), 2.34 (s, 3H), 1.15 (d, J=6.7 Hz, 3H); MS (ESI) m/z: 448.2 (M+H+).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]=[C:11]=[O:12].[CH3:13][NH:14][CH2:15][CH:16]=[O:17]>C1C=CC=CC=1>[CH3:13][N:14]([CH2:15][CH:16]=[O:17])[C:11]([NH:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[O:12]
Reactant: O=C=Nc1nc2ccccc2s1
Reactant: CNCC=O
Solvent: c1ccccc1
Product: CN(CC=O)C(=O)Nc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzothiazol-2-yl isocyanate dimer prepared in Example 1, benzene (300 ml) and the dimethyl acetal of 2-methylaminoacetaldehyde (80 grams; 0.67 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at room temperature for a period of about one hour. After this time the mixture is filtered to remove a yellow solid that has formed. The filtrate is then stripped of solvent under reduced pressure to yield the desired product the dimethyl acetal of 2-(1-methyl-3-benzothiazol-2-ylureido)acetaldehyde as an oil.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[CH:22][S:23][C:16]=34)[CH:11]=[CH:10][C:5]=2[C:6]=1[C:7](Cl)=[O:8].[CH:24]([O:27][CH2:28][CH2:29][NH2:30])([CH3:26])[CH3:25]>>[CH:24]([O:27][CH2:28][CH2:29][NH:30][C:7]([C:6]1[C:5]2[CH:10]=[CH:11][C:12]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[CH:22][S:23][C:16]=34)=[CH:13][C:4]=2[O:3][C:2]=1[CH3:1])=[O:8])([CH3:26])[CH3:25]
Reactant: Cc1oc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)Cl
Reactant: CC(C)OCCN
Product: Cc1oc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)NCCOC(C)C

Procedure:
This material was prepared from 2-methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carbonyl chloride 101 and 2-(isopropoxy)ethylamine in a similar manner as that described for example 108. 1H NMR (CD3CN) δ8.49 (1H, d, J=5.6 Hz), 7.91 (1H, d, J=5.6 Hz), 7.82 (1H, d, J=8.6 Hz), 7.54 (1H, d, J=5.6 Hz), 7.41 (1H, d, J=2.3 Hz), 7.20 (1H, dd, J=8.6, 2.3 Hz), 6.67 (1H, bm), 6.63 (1H, d, J=5.3 Hz), 3.8-3.51 (5H, m), 2.66 (3H, s), 1.15 (6H, d, J=6.1 Hz). Anal. Calcd for C22H22N2O4S: C, 64.37; H, 5.40; N, 6.82; S, 7.81. Found: C, 64.35; H, 5.51; N, 6.76; S, 7.74.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([OH:8])=O.C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:29][C:30]1[CH:31]=[C:32]([CH:49]=[CH:50][CH:51]=1)[O:33][C:34]1[CH:35]=[CH:36][C:37]2[N:38]([CH:40]=[C:41]([NH:43][C:44]([CH:46]3[CH2:48][CH2:47]3)=[O:45])[N:42]=2)[N:39]=1>CN(C)C=O.CN1CCCC1=O>[CH:46]1([C:44]([NH:43][C:41]2[N:42]=[C:37]3[CH:36]=[CH:35][C:34]([O:33][C:32]4[CH:31]=[C:30]([NH:29][C:6](=[O:8])[C:5]5[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=[C:3]([C:2]([F:1])([F:17])[F:16])[CH:4]=5)[CH:51]=[CH:50][CH:49]=4)=[N:39][N:38]3[CH:40]=2)=[O:45])[CH2:47][CH2:48]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 31 %

Procedure:
Using 3,5-bis(trifluoromethyl)benzoic acid (120 mg, 0.45 mmol), oxalyl chloride (48 μL, 0.56 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (2.0 mL), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (120 mg, 0.37 mmol) and N-methylpyrrolidone (2.0 mL) as starting materials and in the same manner as in Example 335, the title compound (63 mg, 31%) was obtained as a white powder.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[C:2]1[C:12](O)=[O:13].S(Cl)(Cl)=O.[CH3:19][C:20]1[N:24]([CH2:25][CH2:26][OH:27])[C:23]([N+:28]([O-:30])=[O:29])=[CH:22][N:21]=1>>[CH3:19][C:20]1[NH:24][C:23]([N+:28]([O-:30])=[O:29])=[CH:22][N:21]=1.[O:11]=[C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[O:1][C:2]([C:12]([O:27][CH2:26][CH3:25])=[O:13])=[CH:3]1
Reactant: Cc1ncc([N+](=O)[O-])n1CCO
Reactant: O=C(O)c1cc(=O)c2ccccc2o1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(=O)c2ccccc2o1
Product: Cc1ncc([N+](=O)[O-])[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
The reaction mixture of chromone-2-carboxylic acid (190 mg, 1.0 mmol) and thionyl chloride (2 ml) was refluxed for 2 h. The excessive thionyl chloride was evaporated under vacuum. The residue was dissolved in 5 ml of dichloromethane. To this solution, metronidazole (162 mg, 0.95 mmol) was added. After the mixture was stirred at room temperature overnight some solid came out. The solid was filtered and was recrystallized from C2H5OH-CH3OH to give 102 mg 2-methyl-5-nitro-1H-imidazole-1-ethyl 4-oxo-4H-1-benzopyran-2-carboxylate. m.p.: 210-212° (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[CH:24]([NH2:26])[CH2:23][CH2:22]2.[CH3:27][N:28]1[C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([S:37](Cl)(=[O:39])=[O:38])[C:31]=2[CH:30]=[CH:29]1>>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[CH:24]([NH:26][C:8]1[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[NH:1][S:37]([C:32]3[C:31]4[CH:30]=[CH:29][N:28]([CH3:27])[C:36]=4[CH:35]=[CH:34][CH:33]=3)(=[O:38])=[O:39])[N:9]=1)[CH2:23][CH2:22]2
Reactant: Cn1ccc2c(S(=O)(=O)Cl)cccc21
Reactant: COc1cccc2c1C(N)CC2
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: COc1cccc2c1C(Nc1ccc3c(NS(=O)(=O)c4cccc5c4ccn5C)cccc3n1)CC2

Procedure:
The title compound, MS: m/e=499.0 (M+H+), was prepared in accordance with the general method of example 45 from 5-nitro-2-chloroquinoline, rac-7-methoxy-indane-1-ylamine and 1-methyl-1H-indole-4-sulfonylchloride.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:4]=1.[H][H]>CO.Cl.[Pt]=O>[ClH:1].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:4]=1
Reactant: NC1=NC(c2ccncc2)Cc2ccccc21
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: NC1=NC(C2CCNCC2)Cc2ccccc21
Yield: 82 %

Procedure:
A slurry of platinum oxide (8 mg, 10 moll) in methanol (1 ml) was added to a solution of 1-amino-3-(4-pyridyl)-3,4-dihydroisoquinoline hydrochloride (Example 28) (150 mg, 0.578 mmol) in methanol and concentrated hydrochloric acid (0.4 ml), and stirred under 3 atmospheres of hydrogen for 16 h. The mixture was filtered through celite and evaporated. The residue was purified by RP-HPLC to yield a white hygroscope solid (126 mg). [M+H]+ 230; 360 MHz 1H n.m.r (d6 -DMSO) 10.30 (1H, s), 9.43 (1H, s), 9.03 (1H, s), 8.80 (1H, br.s), 8.56 (1H, br.s), 8.05 (1H, d, J 7.8 Hz), 7.71 (1H, t, J 7.5 Hz), 7.54-7.50 (2H, m), 3.72-3.68 (1H, m), 3.27 (2H, d, J 13.2 Hz), 3.15 (1H, dd, J 17, 4 Hz), 2.99 (1H, dd, J 17.2, 6.9 Hz), 2.80-2.74 (2H, m), 1.95-1.63 (3H, m), 1.48-1.38 (2H, m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([NH2:15])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.Cl[C:27]1[N:32]=[C:31]([S:33][C:34]#[N:35])[C:30]([N+:36]([O-:38])=[O:37])=[CH:29][N:28]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[N+:36]([C:30]1[C:31]([S:33][C:34]#[N:35])=[N:32][C:27]([NH:15][C:10]2[CH:9]=[C:8]([NH:7][C:6](=[O:16])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:13]=[CH:12][C:11]=2[CH3:14])=[N:28][CH:29]=1)([O-:38])=[O:37]
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1Nc1ncc([N+](=O)[O-])c(SC#N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl(3-amino-4-methylphenyl)carbamate (8.82 g, 39.7 mmol) in tetrahydrofuran (200 mL) were added N-ethyl-N-isopropylpropane-2-amine (10.4 mL, 59.8 mmol) and 2-chloro-5-nitropyrimidin-4-yl thiocyanate (9.49 g, 43.8 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (200 mL), and the mixture was extracted with ethyl acetate (150 mL, 2×30 mL). The combined organic layer was washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give tert-butyl {3-[(5-nitro-4-thiocyanatopyrimidin-2-yl)amino]-4-methylphenyl}carbamate as a yellow amorphous solid. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH2:5][NH:6][NH2:7].C(O[CH:17]=[CH:18][C:19](=O)[C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH2:5][N:6]1[C:19]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])=[CH:18][CH:17]=[N:7]1.[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH2:5][N:6]1[CH:17]=[CH:18][C:19]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])=[N:7]1
Reactant: Cc1cc(CNN)ccc1[N+](=O)[O-]
Reactant: CCOC=CC(=O)C(F)(F)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1cc(Cn2ccc(C(F)(F)C(F)(F)F)n2)ccc1[N+](=O)[O-]
Product: Cc1cc(Cn2nccc2C(F)(F)C(F)(F)F)ccc1[N+](=O)[O-]

Procedure:
(3-Methyl-4-nitrobenzyl)-hydrazine (1.81 g) and 5-ethoxy-1,1,1,2,2-pentafluoro-4-penten-3-one (2.18 g) were refluxed in ethanol (60 ml) for 8 hours, and p-toluenesulfonic acid (0.10 g) was added thereto and the mixture was further refluxed for 6 hours. After finishing the reaction, the solvent was distilled off and the obtained residue was purified by silica gel column chromatography (mixed solvent of n-hexane and ethyl acetate) to obtain 1-(3-methyl-4-nitrobenzyl)-5-pentafluoroethyl-1H-pyrazole (0.96 g) as the first elution portion and 1-(3-methyl-4-nitrobenzyl)-3-pentafluoroethyl-1H-pyrazole (0.50 g) as the second elution portion.
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:3]=1[NH:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1B1OC(C)(C)C(C)(C)O1.Br[C:32]1[N:37]=[C:36]([C:38]([NH:41][C:42]2[C:47]([CH3:48])=[CH:46][C:45]([CH3:49])=[CH:44][C:43]=2[CH3:50])([CH3:40])[CH3:39])[CH:35]=[CH:34][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].O>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.C1(C)C=CC=CC=1.CO>[C:43]1([CH3:50])[CH:44]=[C:45]([CH3:49])[CH:46]=[C:47]([CH3:48])[C:42]=1[NH:41][C:38]([C:36]1[N:37]=[C:32]([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[CH:15][C:6]=2[CH2:5][NH:4][C:3]2[C:2]([CH3:1])=[CH:28][C:27]([CH3:29])=[CH:26][C:25]=2[CH3:30])[CH:33]=[CH:34][CH:35]=1)([CH3:40])[CH3:39]
Reactant: Cc1cc(C)c(NCc2ccc3ccccc3c2B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: Cc1cc(C)c(NC(C)(C)c2cccc(Br)n2)c(C)c1
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: CO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C)c(NCc2ccc3ccccc3c2-c2cccc(C(C)(C)Nc3c(C)cc(C)cc3C)n2)c(C)c1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 1.70 g (4.20 mmol) of 2,4,6-trimethyl-N-{[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthyl]methyl}aniline, 1.40 g (4.20 mmol) of N-[1-(6-bromopyridin-2-yl)-1-methylethyl]-2,4,6-trimethylaniline, 3.00 g (10.50 mmol) of Na2CO3×10H2O, 48 ml of water, 13 ml of methanol, and 56 ml of toluene was purged with argon for 30 min. To this solution 0.24 g (0.21 mmol) of Pd(PPh3)4 was added. The resulting mixture was stirred for 12 h at 80° C. and then cooled to room temperature. The organic layer was separated, the aqueous layer was extracted with 3×200 ml of ethyl acetate. The combined organic extract was washed with brine, dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel 60 (40-63 um, eluent: dichloromethane-ethyl acetate=20:1, vol.). Yield 1.25 g (56%) of yellow oil. Anal. calc. for C37H41N3: C, 84.21; H, 7.83; N, 7.96. Found: C, 84.38; H, 7.69; N, 8.02. 1H NMR (CDCl3): δ 7.90 (m, 1H, 8-H in naphthalene), 7.86 (d, J=8.4 Hz, 1H, 4-H in naphthalene), 7.77-7.82 (m, 2H, 4, 5-H in pyridine), 7.37-7.50 (m, 4H, 3, 5, 6, 7-H in naphthalene), 7.23 (dd, J=6.1 Hz, J=2.3 Hz, 1H, 3-H in pyridine), 6.79 (s, 2H, 3, 5-H in mesityl), 6.78 (s, 2H, 3, 5-H in mesityl), 3.99 (m, 2H, CH2N), 3.66 (br.s, 2H, NH), 2.24 (s, 3H, 4-Me in mesityl), 2.23 (s, 3H, 4-Me in mesityl), 2.06 (s, 6H, 2, 6-Me in mesityl), 2.05 (s, 6H, 2, 6-Me in mesityl), 1.57 (s, 3H, CMeMe′), 1.54 (s, 3H, CMeMe′).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:19][C:20](OCC)=[O:21])[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH2:25]([N:27]([CH2:32][CH3:33])[CH2:28][CH2:29][CH2:30][NH2:31])[CH3:26]>>[CH2:25]([N:27]([CH2:32][CH3:33])[CH2:28][CH2:29][CH2:30][NH:31][C:20](=[O:21])[CH2:19][N:11]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:9]=[N:10]1)[CH3:26]
Reactant: CCN(CC)CCCN
Reactant: CCOC(=O)Cn1ncc(-c2ccc(F)cc2)c1-c1ccccc1
Product: CCN(CC)CCCNC(=O)Cn1ncc(-c2ccc(F)cc2)c1-c1ccccc1

Procedure:
A solution of 8.73 g (0.027 mol) of ethyl 4-(4-fluorophenyl)-5-phenyl-1H-pyrazole-1-acetate of example 6 in 30 mL of 3-(diethyl-amino)propanamine was heated at reflux for 3 hr. The excess amine was stripped under vacuum and the residue triturated in 1:1 hexane/methyl t-butyl ether. The solid was recrystallized from triethylamine to yield 8.4 g of product, mp 82°-83° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]1[CH:16]=[C:15](Br)[S:14][C:13]=1[Br:18])[N:7]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:6][CH2:5]2.[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1.O>>[Br:18][C:13]1[S:14][C:15]([C:29]2[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=2)=[CH:16][C:12]=1[CH:8]1[C:9]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)[CH2:5][CH2:6][N:7]1[C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20]
Reactant: OB(O)c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Cl)ccc2C1c1cc(Br)sc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2cc(Cl)ccc2C1c1cc(-c2ccncc2)sc1Br
Temperature: 100 °C
Yield: 40.8 %

Procedure:
A mixture of tert-butyl 6-chloro-1-(2,5-dibromo-3-thienyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (177.0 mg, 0.3486 mmol), pyridine-4-boronic acid (51.43 mg, 0.4184 mmol) tetrakis(triphenylphosphine)palladium(0) (20.1 mg, 0.0174 mmol) and cesium carbonate (0.341 g, 1.04 mmol) in 1,4-dioxane (6.0 mL, 77 mmol) and water (2.0 mL, 110 mmol) was degassed and heated at 100° C. for 1 h. The mixture was extracted with EtOAc. The organic layer was separated and washed with water. The organic layer was dried and evaporated to leave a residue which was purified by chromatography to afford tert-butyl 1-(2-bromo-5-pyridin-4-yl-3-thienyl)-6-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate as a white solid (72 mg, 41%). LCMS AA ES+ 505.1, 507.1
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.C[Si]([C:30]#[CH:31])(C)C.CCN(CC)CC>CN(C=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>[C:30]([C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1)#[CH:31]
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Reactant: C#C[Si](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#Cc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Temperature: 120 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
To a solution of 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (1.0 g, 2.8 mmol) in DMF (10 mL) under nitrogen was added trimethylsilylacetylene (2.0 mL, 14 mmol), cupric iodide (0.11 g, 0.58 mmol) and Et3N (1.2 mL, 8.4 mmol). Upon completion of addition, the mixture was degassed with nitrogen for 15 min. Tetrakis(triphenylphosphine)palladium (0.20 g, 0.28 mmol) was then added and the resulting mixture was again degassed with nitrogen for 10 min. After this time, the reaction mixture was heated in a sealed tube to 120° C. where it stirred for 16 h. At the conclusion of this period, the reaction mixture was allowed to cool to room temperature. Once at the prescribed temperature, the reaction mixture was quenched by the addition of water. The resulting reaction mixture was extracted with ethyl acetate and the organic layer was washed successively with water and brine. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting concentrate was dissolved in methanol and saturated with ammonia gas. The saturated solution was stirred for 2 h at 0° C. and then concentrated under reduced pressure to yield a residue. The residue was purified by flash column chromatography using ethyl acetate and petroleum ether to afford 2-ethynyl-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (650 mg). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.15 (d, J=4.0 Hz, 1H), 7.86 (dd, J=8.4, 1.2 Hz, 1H), 7.69 (t, J=8.4 Hz, 1H), 7.56 (dt, J=3.6, 1.6 Hz, 1H), 7.49-7.42 (m, 5H), 7.26-7.23 (m, 1H), 7.13-7.08 (m, 2H), 6.94 (bs, 1H), 4.67 (d, J=10.0 Hz, 2H), 3.02 (s, 1H). LCMS Method O: retention time 1.35 min, [M+1]=337.0.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@H:26]4[CH2:30][CH2:29][CH2:28][N:27]4C(OC(C)(C)C)=O)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:38])[NH:6]2.Cl>O1CCOCC1.CO>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@H:26]4[CH2:30][CH2:29][CH2:28][NH:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:38])[NH:6]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@H]1CCCN1
Yield: 61.8 %

Procedure:
Using an analogous procedure to that described for the preparation of the starting material in Example 11, tert-butyl (2R)-2-[(4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-yloxy)methyl]pyrrolidine-1-carboxylate (960 mg, 1.84 mmol) was reacted with hydrogen chloride in dioxane. The solid was dissolved in methanol and absorbed onto an Isolute SCX column which was washed through with methanol and then the product was eluted with 7N ammonia in methanol to give 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2R)-pyrrolidin-2-ylmethoxy]quinazoline (480 mg, 62%).