Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Br)=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)=[O:16].[F-].[Cs+]>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>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:21]3[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=3)[C:15]([O:14][CH3:13])=[O:16])[N:5]=2)[CH:10]=[CH:11][C:2]=1[C:21]1[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=1)[C:15]([O:14][CH3:13])=[O:16]
Reactant: Brc1ccc2ccc(Br)nc2n1
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Product: COC(=O)c1cccc(-c2ccc3ccc(-c4cccc(C(=O)OC)c4)nc3n2)c1
Yield: 83 %

Procedure:
To a 250 mL Schlenk flask, 2,7-dibromo-1,8-naphthyridine (2.00 g, 6.94 mmol), 3-(methoxycarbonyl)phenylboronic acid (3.13 g, 17.40 mmol), CsF (4.00 g), and Pd(PPh3)4 (200 mg) were added. The flask was connected to a Schlenk line and evacuated of air then refilled with nitrogen gas. 130 mL of 1,2-dimethoxyethane (DME) was degassed (two hours) and added to the flask through a canula. The flask was equipped with a water condenser and refluxed under nitrogen gas atmosphere for 3 days. The solvent was removed on rotary evaporator. 100 mL of H2O was added and then extracted with CHCl3. The organic phase was dried with MgSO4. After removal of the CHCl3 solvent, the crude product was purified by column chromatography (silica, ethyl acetate/hexane, 20%) to give a white solid product with a yield of 83% (2.30 g) based on 2,7-dibromo-1,8-naphthyridine. 1H NMR (300 MHz, CD3Cl): δ 3.97 (s, 6H), 7.62 (t, 2H), 8.03 (d, 2H), 8.17 (d, 2H), 8.30 (d, 2H), 8.57 (d, 2H), 8.88 (s, 2H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]1[N:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[CH:21][C:20]([CH2:23][N:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)=[CH:19][C:18]=2[C:37]2[N:45]=[C:44]([CH3:46])[N:43]=[C:42]3[C:38]=2[N:39]=[CH:40][N:41]3C2CCCCO2)=[CH:12][CH:11]=1.C(Cl)Cl>>[CH3:8][O:9][C:10]1[N:15]=[CH:14][C:13]([NH:16][C:17]2[C:18]([C:37]3[N:45]=[C:44]([CH3:46])[N:43]=[C:42]4[C:38]=3[N:39]=[CH:40][NH:41]4)=[CH:19][C:20]([CH2:23][N:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]3)=[CH:21][N:22]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(Nc2ncc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Nc2ncc(CN3CCNCC3)cc2-c2nc(C)nc3[nH]cnc23)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (3.00 mL, 38.9 mmol) was added to a stirred mixture of tert-butyl 4-((6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)methyl)piperazine-1-carboxylate (155 mg, 0.252 mmol) in DCM (3 mL, 46.6 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated and then diluted with DCM, NaHCO3(aq) and water (10 mL each). The separated aqueous layer was extracted with DCM (3×10 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give crude N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)-5-(piperazin-1-ylmethyl)pyridin-2-amine
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH:22]=[C:21]([CH2:24][CH2:25][OH:26])[C:20]([CH3:28])([CH3:27])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH:22]=[C:21]([CH2:24][CH:25]=[O:26])[C:20]([CH3:28])([CH3:27])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC=C(CCO)C(C)(C)C1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC=C(CC=O)C(C)(C)C1
Reaction time: 0.17 h
Yield: 41.6 %

Procedure:
A solution of dimethylsulfoxide (1.1 mL, 15 mmol) in dichloromethane (5ml) was added to a cooled (−78° C.) solution of oxalyl chloride (0.67 mL, 7.5 mmol) in dichloromethane (50 mL) under an atmosphere of argon, and stirred for 10 minutes. Then a solution of 4-(2-hydroxyethyl)-3,3-dimethyl-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (0.96 g, 3.7 mmol) in dichloromethane (5 mL) was added thereto and stirred for 15 minutes at −78° C. and subsequently for 45 minutes at −40° C. Then triethylamine (3.7 mL, 26.4 mmol) was added thereto and stirred for 30 minutes at room temperature. After the reaction was completed, saturated aqueous ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic layer was washed with water three times and dried over anhydrous magnesium sulfate. After drying, it was filtered and the filtrate was concentrated under a reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent, hexane:ethyl acetate=10:1 to 7:1) to obtain 0.39 g (yield 41.1%) of 3,3-dimethyl-4-(2-oxoethyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (VII-152). Its physical property is shown below.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[Cl:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>O1CCCC1>[Cl:21][C:22]1[CH:23]=[C:24]([NH:28][C:29]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]([CH3:19])[C:3]2=[O:20])=[O:30])[CH:25]=[CH:26][CH:27]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)Nc2cccc(Cl)c2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 3-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 233°-234° C.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[C-:13]#[N:14].[K+]>CN(C=O)C.[I-].[K+]>[C:3]1([CH2:2][C:13]#[N:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: [C-]#N
Reactant: ClCc1cccc2ccccc12
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
1-Chloromethylnaphthalene (5.00 ml, 33 mmol) was dissolved in N,N'-dimethylformamide (50 ml) and potassium cyanide (4.31 g, 66 mmol) and potassium iodide (0.1 g) were added and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned between water (150 ml) and diethyl ether (2-100 ml). The combined organic phases were washed with water (100 ml), dried (MgSO4), filtered and concentrated in vacuo affording 5.41 g (98%) of 1-naphtylacetonitrile as an oil.
Reaction SMILES: [CH3:1][Mg+].[Br-].[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=3[CH2:30][N:31]3[C@@H:35]([CH3:36])[C@@H:34]([C:37]4[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[C:39]([C:47]([F:50])([F:49])[F:48])[CH:38]=4)[O:33][C:32]3=[O:51])[C:16]([Cl:19])=[CH:17][CH:18]=2)=[C:9]([CH3:52])[CH:8]=1)(=[O:6])[CH3:5].[Cl-].[NH4+]>C1COCC1>[F:44][C:43]([F:46])([F:45])[C:41]1[CH:42]=[C:37]([C@H:34]2[O:33][C:32](=[O:51])[N:31]([CH2:30][C:21]3[CH:22]=[C:23]([C:26]([F:27])([F:28])[F:29])[CH:24]=[CH:25][C:20]=3[C:15]3[C:16]([Cl:19])=[CH:17][CH:18]=[C:13]([C:10]4[CH:11]=[CH:12][C:7]([C:4]([OH:6])([CH3:1])[CH3:5])=[CH:8][C:9]=4[CH3:52])[CH:14]=3)[C@H:35]2[CH3:36])[CH:38]=[C:39]([C:47]([F:49])([F:50])[F:48])[CH:40]=1
Reactant: CC(=O)c1ccc(-c2ccc(Cl)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Reactant: C[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(C(C)(C)O)ccc1-c1ccc(Cl)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
MeMgBr (0.168 ml, 0.168 mmol, 1 M solution) was added to a solution of ketone from Example 52 (80 mg, 0.112 mmol) in THF (3 ml) at −78° C. The solution was stirred at −78° C. for 2 h. Saturated ammonium chloride solution was added. The mixture was extracted with EtOAc (3×10 ml). The combined EtOAc layers were washed with brine, and dried over sodium sulfate. The residue was purified by flash column on silica gel, eluting with EtOAc/hexane (30:70) to give the title compound as a colorless solid. 1H NMR (CDCl3, 500 MHz): δ a mixture of 1:1 atopoisomers 7.89 (s, 2H), 7.83 (d, J=8 Hz, 1H), 7.72 (m, 4H), 7.63 (d, J=8.5 Hz, 1H), 7.51 (d, J=8.0 Hz, 0.5H), 7.46 (d, J=8.0 Hz, 0.5H), 7.40-7.34 (m, 2H), 7.27 (d, J=2.0 Hz, 0.5H), 7.21 (d, J=2.5 Hz, 0.5H), 5.64 (d, J=8.0 Hz, 0.5H), 5.63 (d, J=8.0 Hz, 0.5H), 5.02 (d, J=16.0 Hz, 0.5H), 4.83 (d, J=16.0 Hz, 0.5H), 4.08 (d, J=16.0 Hz, 0.5H), 4.01 (d, J=15.5 Hz, 0.5H), 4.00 (m, 0.5H), 3.90(m, 0.5H), 2.41 (s, 1.5H), 2.39 (s, 1.5H), 1.60 (m, 3H), 1.28 (m, 3H), 0.64 (d, J=6.5 Hz, 1.5H), 0.62 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: [CH2:1]([NH:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:16]([Br:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CCOCC>[BrH:24].[CH2:16]([N:13]1[CH:14]=[CH:15][C:10](=[N:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:11]=[CH:12]1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCNc1ccncc1
Reactant: CCCCCCCCBr
Solvent: CCOCC
Product: Br
Product: CCCCCCCCN=c1ccn(CCCCCCCC)cc1
Temperature: 125 °C
Reaction time: 24 h
Yield: 62.3 %

Procedure:
A mixture of 4-octylaminopyridine (10 g., 0.048 mole) and octyl bromide (8 ml., 0.048 mole) was heated at 125° C. for 8 hr. on one day and for 4 more hr. on the next day. The resulting solid was slurried, first in ether, then in ether-tetrahydrofuran (2:1) and finally in tetrahydrofuran, collected by filtration, washed with ether on the filter, and dried (70° C., 0.1 mm.) affording N-(1-octyl-4(1H)-pyridinylidene)octanamine monohydrobromide (11.95 g., 83% yield, m.r. 108°-112° C.), which is the monohydrobromide salt of the compound of Formula I wherein both R and R' are octyl.
Reaction SMILES: Cl.Cl[CH2:3][N:4]1[CH:8]=[N:7][C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[N:5]1.[CH2:13]([CH:16]([C:19]#[N:20])[C:17]#[N:18])[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:13]([C:16]([CH2:3][N:4]1[CH:8]=[N:7][C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[N:5]1)([C:19]#[N:20])[C:17]#[N:18])[CH:14]=[CH2:15]
Reactant: CC(C)(C)c1ncn(CCl)n1
Reactant: C=CCC(C#N)C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCC(C#N)(C#N)Cn1cnc(C(C)(C)C)n1
Yield: 10.8 %

Procedure:
1.28 g of 1-(chloromethyl)-3-t-butyl-1H-1,2,4-triazole hydrochloride and 0.77 g of allyl malononitrile were dissolved in 21 ml of N,N-dimethylformamide. 1.01 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for 4 hours. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexane-MTBE to obtain 0.16 g of allyl [(3-t-butyl-1H-1,2,4-triazole-1-yl)methyl]malononitrile (referred as the compound of the present invention (31), hereinafter) shown by below formula.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([O:17]C(=O)C(Cl)(Cl)Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-])=[O:2].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]([O:42]C(=O)C(Cl)(Cl)Cl)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[N+:39]([O-])=[O:40])[CH:29]=[CH:30][CH:31]=1>C(#N)C>[N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:17])=[O:2].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([C:32](=[O:42])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[N:39]=[O:40])[CH:29]=[CH:30][CH:31]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1[N+](=O)[O-])C(Cl)(Cl)Cl
Reactant: COc1cccc(C(OC(=O)C(Cl)(Cl)Cl)c2ccccc2[N+](=O)[O-])c1
Solvent: CC#N
Product: COc1cccc(C(=O)c2ccccc2N=O)c1
Product: O=Nc1ccccc1C(=O)c1ccccc1

Procedure:
A more powerful 100 W high pressure mercury arc lamp was initially used for the irradiation of α-phenyl-2-nitrobenzyltrichloroacetate (33) and α-(3-methoxyphenyl)-2-nitrobenzyl-trichloroacetate (35) at 365 nm (Scheme 3). The rate of photoconversion was monitored by HPLC, TLC and UV. Depending on the concentration of solution (0.002-2% in acetonitrile) and the length of light path used (1-10 mm) the rate of photoconversion varied between 20% and 90% for a 5 min irradiation. The products of photolysis, 2-nitrosobenzophenone (47) and 3′-methoxy-2-nitrosobenzophenone (48), were isolated by HPLC and showed by mass spectroscopy to be the same as those isolated previously during irradiations at 254 and 350 nm in the photoreactor described above. Secondary photoproducts were not observed under the conditions of relatively weak irradiation used in the photoreactor (4 W lamp), but were observed when the 100 W high pressure Hg arc lamp was used for extended time.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][CH:5]([CH3:12])[CH2:6][CH2:7][CH:8]=C(C)C.CC(=CCCC(CC=[O:25])C)C.O=[O+][O-].[BH4-].[Na+]>CO.CO.O>[CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][CH:5]([CH3:12])[CH2:6][CH2:7][CH2:8][OH:25]
Reactant: CC(C)=CCCC(C)CC=O
Reactant: COC(CC(C)CCC=C(C)C)OC
Agent: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(CC(C)CCCO)OC
Reaction time: 2 h
Yield: 85 %

Procedure:
A solution of citronellal dimethyl acetal [55.0 g, 275 mmole, prepared from racemic citronellal, according to the process described by V. R. Mamdapur et al. in Tetrahedron 20, 2601 (1964)] in methanol (550 ml) was treated at -75° with a stream of ozone for 3.5 h (4.5 g of O3 per hour, 328 mmole of O3). The excess of ozone was purged with argon, the solution was allowed to warm to 0° and then treated with a solution of NaBH4 (5.22 g, 137.5 mmole) in MeOH--H2O (1:1, 154 ml). After 2 h, the reaction mixture was concentrated at reduced pressure, then extracted with ether, and the organic phase was washed to neutrality, dried over MgSO4 and concentrated at reduced pressure. 60.2 g of the desired hexanol (ca. 85% pure) were thus obtained and this product was used as such in the next preparation step. An analytical sample, obtained by preparative GLC (gas-liquid chromatography) gave the following data:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2.[OH-].[Na+].[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl>CO>[O:19]1[CH2:18][CH:17]1[CH2:15][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2
Reactant: O=C1CCc2c(O)cccc2N1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CCc2c(cccc2OCC2CO2)N1
Reaction time: 3 h

Procedure:
16.4 Grams of 5-hydroxy-3,4-dihydrocarbostyril and 3.7 g of sodium hydroxide were added into 100 ml of methanol and stirred at 40°-50° C. for 3 hours, then 150 ml of epichlorohydrin was added thereto and heated under refluxing condition for 5 hours. The reaction mixture was concentrated under a reduced pressure to dryness and the residue thus obtained was recrystallized from methanol-water (1:1) to obtain 18.5 g of 5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril having the melting of 172°-173° C. as in the form of coloress amorphous crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:26][C:27]([F:38])([F:37])[O:28]OCCOS(C)(=O)=O.[I-].[Na+].[C:41](OCC)(=O)[CH3:42]>C(OCC)(=O)C.CCCCCC.CCCCCC.CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:41][CH2:42][O:28][C:27]([F:26])([F:37])[F:38])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Reactant: CCOC(C)=O
Reactant: CS(=O)(=O)OCCOOC(F)(F)F
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCOC(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (0.31 g, 1 mmol) and dimethylformamide (8 mL). Cool in an ice-bath. Add sodium hydride (0.024 g, 1 mmol). After 2 hours, add 2-(methanesulfonyloxy)ethyl trifluoromethoxy ether (0.31 g, 1.5 mmol) and sodium iodide (0.14 g, 1 mmol). Heat to 80° C. After 6 hours, cool to ambient temperature. After 56 hours dilute the reaction mixture with ethyl acetate and extract brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with hexane, 30% ethyl acetate/hexane and then 50% ethyl acetate/hexane to give 1-(t-butoxycarbonyl)-4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane; Rf =0.24 (silica gel, 50% ethyl acetate/hexane).
Reaction SMILES: C([Li])(CC)C.Br[C:7]1[CH:8]=[C:9]([CH:17]=[C:18]([Br:20])[CH:19]=1)[O:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.CN(C)[CH:23]=[O:24].C(O)(=O)C>CCCCCC.CCOCC>[Br:20][C:18]1[CH:19]=[C:7]([CH:8]=[C:9]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:17]=1)[CH:23]=[O:24]
Reactant: CN(C)C=O
Reactant: Brc1cc(Br)cc(Oc2cccnc2)c1
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CCCCCC
Product: O=Cc1cc(Br)cc(Oc2cccnc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.7 %

Procedure:
A 1.3M solution of s-butyllithium in hexane (9.2 ml) was added dropwise to a stirred solution of 3-(3,5-dibromophenoxy)pyridine (Preparation 6; 3.29 g) in dry ether (100 ml) at -78° C., and the resulting mixture was stirred at this temperature for 15 minutes. N,N-dimethylformamide (2.2 g) was then added dropwise and this mixture stirred at the same temperature for 1 hour. Glacial acetic acid (1.6 ml) was next added and the reaction solution was allowed to warm to room temperature, washed sequentially with saturated aqueous sodium bicarbonate solution and water, then dried (MgSO4). Evaporation under vacuum of the solvent gave an oil which was chromatographed on silica gel. Elution with dichloromethane first gave impurity which was followed by pure product. The product fractions were combined and evaporated under vacuum to give the title compound as an oil (1.80 g); δ (CDCl3): 7.36-7.43(4H,m), 7.76(1H,s), 8.45-8.50(2H,m), 9.90(1H,s). Found: C,51.76; H,2.89; N,5.04. C12H8BrNO2 requires C,51.82; H,2.90; N,5.04%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21]([NH2:23])=[O:22].CCN(C(C)C)C(C)C.[O:33]1[CH2:38][CH2:37][CH:36]([CH2:39][NH2:40])[CH2:35][CH2:34]1>CN1C(=O)CCC1>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:40][CH2:39][CH:36]4[CH2:37][CH2:38][O:33][CH2:34][CH2:35]4)=[C:3]([C:21]([NH2:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: COc1cc2c(Cl)c(C(N)=O)cnc2cc1-c1c(C)noc1C
Reactant: NCC1CCOCC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(NCC3CCOCC3)c(C(N)=O)cnc2cc1-c1c(C)noc1C
Temperature: 120 °C
Yield: 54.1 %

Procedure:
4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 9) (1.890 g, 5.70 mmol) was dissolved in NMP (5 ml), DIPEA (2.487 ml, 14.24 mmol) was added followed by (tetrahydro-2H-pyran-4-yl)methanamine (0.82 g, 7.12 mmol) and the mixture was heated at 120° C. for 3 h, then cooled and the brown solution loaded onto a 70 g SCX-2 cartridge, the column washed with methanol (200 ml) and then eluted with 2M methanolic ammonia (100 ml) and methanol (100 ml). The eluant was evaporated in vacuo to give a brown solid. This was triturated with EtOAc (30 ml) and the solid collected by filtration to give 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-quinolinecarboxamide (1.58 g, 3.85 mmol, 54.1% yield) as brown solid. LCMS (formate) Rt 0.64, MH+ 411
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:29]=[CH:30][C:31]([O:34][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:32][CH:33]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Yield: 71.5 %

Procedure:
To a solution of 4-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol (100 mg, 0.22 mmol) in acetone (10 mL) was added ethyl α-bromoacetate (49 μL, 0.44 mmol) and potassium carbonate (304 mg, 2.2 mmol). The mixture was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature and water was added. The solution was extracted with ethyl acetate. The organics were dried (magnesium sulfate), filtered and concentrated, followed by purification with flash chromatography (1:1 ethyl acetate:hexanes) to give ethyl (4-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenoxy)acetate (85 mg, 71%) as a brown oil. 1H NMR (CDCl3): δ 7.94 (d, 1H), 7.70 (d, 1H), 7.55 (d, 2H), 7.23 (t, 1H), 6.95 (d, 2H), 6.25 (d, 1H), 5.98–5.95 (m, 2H), 5.13 (d, 1H), 4.62 (s, 2H), 4.31–4.21 (m, 3H), 3.94 (m, 1H), 2.07–1.99 (m, 4H), 1.75–1.46 (m, 12H), 1.28 (t, 3H); MS m/z 541 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH3:15])[N:7]=[C:6]2[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([C:34]2([C:37](O)=[O:38])[CH2:36][CH2:35]2)=[O:33])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[F:24][C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32]([C:34]2([C:37]([NH:23][C:20]3[CH:19]=[CH:18][C:17]([O:16][C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[C:8]([CH3:15])[N:7]=4)=[CH:22][CH:21]=3)=[O:38])[CH2:36][CH2:35]2)=[O:33])=[CH:29][CH:30]=1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: COc1cc2nc(C)nc(Oc3ccc(N)cc3)c2cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nc(C)nc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 1.9 %

Procedure:
To a mixture of 4-(6,7-dimethoxy-2-methyl-quinazolin-4-yloxy)-phenylamine (0.100 g, 0.321 mmol) and 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (0.056 g, 0.386 mmol) in DMF was added DIEA (0.168 mL, 0.963 mmol), followed by HATU (0.183 g, 0.482 mmol). The reaction mixture was stirred at RT for 15 hours. The mixture was diluted with EtOAc, washed with 5% LiCl aq solution three times, dried over Na2SO4, and concentrated in vacuo. The crude product was purified on preparative HPLC to give ′N-(4-fluorophenyl)-N′-(4-{[2-methyl-6,7-bis(methyloxy)quinazolin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide (3.2 mg) as a white solid. 1H NMR (DMSO-d6) 10.15 (bs, 1H), 10.01 (bs, 1H), 7.69-7.75 (m, 2H), 7.61-7.68 (m, 2H), 7.52 (s, 1H), 7.32 (s, 1H), 7.23-7.29 (m, 2H), 7.12-7.19 (m, 2H), 3.93 (d, 6H), 2.43 (s, 3H), 1.53 (s, 4H).