Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:14][C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29](O)=[O:30])[N:20]2[C:19]1=[O:32])=[O:16])([CH3:13])([CH3:12])[CH3:11].[S:33]1[CH:37]=[CH:36][N:35]=[C:34]1[NH2:38].ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C>[O:32]=[C:19]1[C@@H:18]([NH:17][C:15](=[O:16])[O:14][C:10]([CH3:11])([CH3:12])[CH3:13])[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29](=[O:30])[NH:38][C:34]3[S:33][CH:37]=[CH:36][N:35]=3)[N:20]12
Reactant: Nc1nccs1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(=O)O)N2C1=O
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(=O)Nc3nccs3)N2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.2 %

Procedure:
DIPEA (0.036 mL, 0.21 mmol) was added to a cold (0° C.) mixture of (4S,7S,10aS)-4-(tert-butoxycarbonylamino)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylic acid (55 mg, 0.16 mmol), thiazol-2-amine (19.2 mg, 0.192 mmol) and 1-hydroxy-7-azabenzotriazole (26.1 mg, 0.192 mmol) in DMF (0.6 mL). Then EDC (36.7 mg, 0.192 mmol) was added. The reaction was stirred at rt for 8 hr. The crude mixture was purified by RP prep-HPLC (Method B) to give tert-butyl (4S,7S,10aS)-5-oxo-7-(thiazol-2-ylcarbamoyl)octahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (35 mg, 0.082 mmol, 51% yield) as a white solid. Anal. Calcd. for C18H26N4O4S2 m/z 426.5. found: 427.1 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.45 (s, 1H), 6.98 (s, 1H), 5.96 (m, 1H), 5.37 (br s, 1H), 5.28 (br s, 1H), 3.35 (m, 2H), 2.94 (m, 2H), 2.36 (m, 1H), 2.45 (m, 1H), 2.05 (m, 2H), 1.53-1.50 (m, 4H), 1.50 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:21][CH2:20][CH:19]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:18]2)=[CH:13][CH:12]=1>>[Br:1][C:2]1[O:6][C:5]([C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH2:20][CH:19]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:18]3)=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2ccc(N)cc2)C1
Reactant: O=C(O)c1ccc(Br)o1
Product: CC(C)(C)OC(=O)NCC1CCN(c2ccc(NC(=O)c3ccc(Br)o3)cc2)C1

Procedure:
5-Bromofuran-2-carboxylic acid was reacted with tert-butyl [1-(4-aminophenyl)pyrrolidin-3-yl]methylcarbamate by method E. This resulted in the product with the molecular weight of 464.36 (C21H26BrN3O4); MS (ESI): 464 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[N:16]=[C:15]([C:17]([OH:19])=O)[CH:14]=[CH:13][C:12]=1[F:20].[NH2:21][C:22]1[C:23]([N:31]2[CH2:36][C@H:35]([CH3:37])[CH2:34][C@H:33]([NH:38]C(=O)OC(C)(C)C)[CH2:32]2)=[C:24]2[CH2:30][CH2:29][O:28][C:25]2=[N:26][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:38][C@H:33]1[CH2:34][C@@H:35]([CH3:37])[CH2:36][N:31]([C:23]2[C:22]([NH:21][C:17]([C:15]3[CH:14]=[CH:13][C:12]([F:20])=[C:11]([C:3]4[C:4]([F:10])=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=4[F:1])[N:16]=3)=[O:19])=[CH:27][N:26]=[C:25]3[O:28][CH2:29][CH2:30][C:24]=23)[CH2:32]1
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2c(N)cnc3c2CCO3)C1
Reactant: COc1ccc(F)c(-c2nc(C(=O)O)ccc2F)c1F
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: COc1ccc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@H](C)C[C@H](N)C3)CCO4)ccc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
To a mixture of 6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxylic acid (232 mg, 0.492 mmol), tert-butyl [(3S,5R)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (152 mg, 0.436 mmol), and HATU (513 mg, 1.35 mmol) in DMF (3.0 mL), DIPEA (298 mg, 2.30 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure. To the resulting residue, DCM (2.0 mL) was added followed by TFA (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (65.9 mg, 29%) LCMS calc. for C26H27F3N5O3 (M+H)+: m/z=514.2. found 514.0. 1H NMR (500 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.90 (s, 1H), 8.34 (dd, J=8.7, 4.0 Hz, 1H), 8.20 (t, J=8.8 Hz, 1H), 7.50-7.41 (m, 1H), 7.33-7.26 (m, 1H), 4.55-4.43 (m, 2H), 3.93 (s, 3H), 3.35 (t, J=8.5 Hz, 2H), 3.05-2.95 (m, 1H), 2.90-2.82 (m, 1H), 2.64-2.54 (m, 1H), 2.39 (t, J=10.4 Hz, 1H), 2.26 (t, J=11.2 Hz, 1H), 1.64-1.51 (m, 1H), 1.41-1.17 (m, 3H), 0.64-0.55 (m, 4H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]([CH3:16])[C:5]([O:6][CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([CH3:17])[CH:3]=1.BrC1C=C(C)C(O)=C(C)C=1.[N+:28]([O-])([OH:30])=[O:29]>S(=O)(=O)(O)O.O>[Br:1][C:2]1[CH:15]=[C:14]([CH3:16])[C:5]([O:6][CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([CH3:17])[C:3]=1[N+:28]([O-:30])=[O:29]
Reactant: CCOC(=O)C(C)Oc1c(C)cc(Br)cc1C
Reactant: O=[N+]([O-])O
Agent: Cc1cc(Br)cc(C)c1O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)C(C)Oc1c(C)cc(Br)c([N+](=O)[O-])c1C

Procedure:
Ethyl 2-(4-bromo-2,6-dimethylphenoxy)propanoate (92.8 g, 307 mmole), prepared by the method of Example 1 from 4-bromo-2,6-dimethylphenol, was dissolved in 320 ml of cold (-10°) concentrated sulfuric acid. While maintaining the temperature below 0°, 22.4 ml of 70% nitric acid was added slowly. After fifteen minutes the reaction mixture was poured onto ice and diluted to 1.0 l with water, then extracted with two portions of diethyl ether. The organic portion was washed repeatedly with aqueous sodium bicarbonate and then with water. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to dryness. Chromatography on silica gel (ethyl acetate-hexane eluent) afforded the title compound. Structure assignment was supported by nmr and infrared spectra.
Reaction SMILES: O.[NH2:2][NH2:3].Cl.[NH2:5][CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15](=O)[CH2:16][CH2:17][C:18]([O:20]C)=O)[CH:12]=2)[CH2:7]1>C(O)(=O)C>[NH2:5][CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]3[CH2:16][CH2:17][C:18](=[O:20])[NH:2][N:3]=3)[CH:12]=2)[CH2:7]1
Reactant: NN
Reactant: COC(=O)CCC(=O)c1ccc2c(c1)CC(N)C2
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Reaction time: 0.5 h

Procedure:
8.5 g (0.17 mol) of 99% hydrazine hydrate are added to 10.0 g (0.035 mol) of methyl 4-(2-amino-indan-5-yl)-4-oxobutyrate hydrochloride in glacial acetic acid and the mixture is boiled for 30 minutes. The mixture is evaporated in vacuo, the residue is dissolved in water and the reaction product is precipitated by neutralisation with sodium hydroxide.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH:34]([CH3:36])[CH3:35])[C:27]([OH:29])=O.O[NH:38][C:39]([C:41]1[C:42]2[CH:43]=[CH:44][NH:45][C:46](=[O:51])[C:47]=2[CH:48]=[CH:49][CH:50]=1)=[NH:40]>CN(C=O)C>[Cl:23][C:24]1[CH:25]=[C:26]([C:27]2[O:29][N:40]=[C:39]([C:41]3[CH:50]=[CH:49][CH:48]=[C:47]4[C:42]=3[CH:43]=[CH:44][NH:45][C:46]4=[O:51])[N:38]=2)[CH:30]=[CH:31][C:32]=1[O:33][CH:34]([CH3:36])[CH3:35]
Reactant: N=C(NO)c1cccc2c(=O)[nH]ccc12
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(=O)[nH]ccc34)no2)cc1Cl
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 50.4 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI; 5.2 g) and hydroxybenzotriazole (HOBt; 3.6 g) were added to a solution of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (D3; 2.9 g) in DMF (200 ml) at room temperature, and the resulting solution was stirred for 30 minutes. N-hydroxy-1-oxo-1,2-dihydro-5-isoquinolinecarboximidamide (D37, 2.75 g) was added and the suspension was stirred at room temperature for 2 hours. The reaction mixture was heated to 140° C. and stirred for 1 hour. The solvent was evaporated and the residue was washed with water, followed by ethyl acetate to give the title compound (2.6 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4]Br.[S:6]([O-:9])([O-:8])=[O:7].[Na+:10].[Na+].C>O>[CH2:2]([S:6]([O-:9])(=[O:8])=[O:7])[CH2:3][CH2:4][S:6]([O-:9])(=[O:8])=[O:7].[Na+:10].[Na+:10]
Reactant: BrCCCBr
Reactant: O=S([O-])[O-]
Agent: C
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])CCCS(=O)(=O)[O-]
Yield: 85.6 %

Procedure:
This compound was prepared by a modification of the method described in Stone, G. C. H. (1936) J. Am. Chem. Soc., 58:488. 1,3-Dibromopropane (40.4 g, 0.20 mol) was treated with sodium sulfite (60.3 g, 0.50 mol) in water at reflux temperature for 48 h. Inorganic salts (sodium bromide and sodium sulfite) were removed by successive treatment of the resultant reaction mixture with barium hydroxide and silver(I) oxide. The solution was then neutralized with Amberlite-120 (acid form) and decolorized with Norit-A. Barium ions were removed by treatment of the aqueous solution with Amberlite-120 (sodium form) ion-exchange resin. The solvent was removed on a rotary evaporator, and the crude product was recrystallized from water-ethanol several times to give the title compound (42.5 g). The small amount of trapped ethanol was removed by dissolving the crystals in a minimum amount of water and then concentrating the solution to dryness. The pure product was further dried under high vacuum at 56° C. for 24 h: mp>300° C.; 1H NMR (D2O) δ: 3.06-3.13 (m, 4H, H-1 and H-3), 2.13-2.29 (m, 2H, H-2); 13C NMR (D2O) δ: 52.3 (C-1 and C-3), 23.8 (C-2).
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:6][C:7]([N:10]([CH3:14])[C:11](Cl)=[O:12])=[N:8][N:9]=1)(=[O:4])=[O:3].[O:15]1[CH2:20][CH2:19][CH2:18][O:17][CH:16]1[CH2:21][NH2:22].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][S:2]([C:5]1[S:6][C:7]([N:10]([CH3:14])[C:11]([NH:22][CH2:21][CH:16]2[O:17][CH2:18][CH2:19][CH2:20][O:15]2)=[O:12])=[N:8][N:9]=1)(=[O:4])=[O:3]
Reactant: CN(C(=O)Cl)c1nnc(S(C)(=O)=O)s1
Reactant: NCC1OCCCO1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN(C(=O)NCC1OCCCO1)c1nnc(S(C)(=O)=O)s1
Temperature: 25 °C

Procedure:
N-(2-Methylsulfonyl-1,3,4-thiadiazol-5-yl)-N-methylcarbamoyl chloride (0.05 mole), N-(1,3-dioxan-2-ylmethyl)amine (0.05 mole), triethylamine (0.07 mole) and benzene (200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is then heated at reflux for a period of about 4 hours. After this time the mixture is cooled to room temperature and is filtered. The filtrate is washed with water and is dried over anhydrous magnesium sulfate. The dried solution is then stripped of solvent under reduced pressure to yield the desired product N-(2-methylsulfonyl-1,3,4-thiadiazol-5-yl)-N-methyl-N'-(1,3-dioxan-2-ylmethyl)urea.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[NH:34][C@H:35]([CH2:38][OH:39])[CH2:36][CH3:37])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][N:9]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O1CCCC1>[F:48][C:2]([F:1])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:42]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[NH:34][C@H:35]([CH2:38][OH:39])[CH2:36][CH3:37])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2N[C@@H](CC)CO)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@@H](CO)Nc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.8 %

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-((S)-1-hydroxymethyl-propylamino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (40 mg) is dissolved in a mixed solvent of methanol (0.3 ml) and tetrahydrofuran (1 ml) and thereto is added a 1M-aqueous sodium hydroxide solution (0.5 ml), and the mixture is stirred at room temperature for 30 minutes. To reaction mixture are added a 10% aqueous citric acid solution and a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-((S)-1-hydroxymethyl-propylamino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (41 mg). MS (m/z): 669 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[F:16])[CH:12]1[CH2:17][CH:10]([CH2:11]1)[N:9]1[C:5]2=[N:6][C:7]([C:18]([OH:20])=O)=[CH:8]1.C[N:22](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N.O>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[F:16])[CH:12]1[CH2:17][CH:10]([CH2:11]1)[N:9]1[C:5]2=[N:6][C:7]([C:18]([NH2:22])=[O:20])=[CH:8]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.9 %

Procedure:
Into a 5000-mL 4-necked round-bottom flask was placed a solution of 9-bromo-10-fluoro-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene-4-carboxylic acid (280 g, 830.51 mmol, 1.00 equiv) in N,N-dimethylformamide (2500 mL), HBTU (315 g, 830.61 mmol, 1.00 equiv), and DIEA (139 g, 1.08 mol, 1.30 equiv). The resulting solution was stirred at room temperature for 1.5 h. This was followed by the addition of amine hydrate (300 mL). The resulting solution was stirred at room temperature for 0.5 h and diluted with 2000 mL of H2O. The solids were collected by filtration, washed with 3×1000 mL of water and dried to afford 150.6 g (54%) of 9-bromo-10-fluoro-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene-4-carboxamide as a white solid. LC-MS: [M+H]+336 1H-NMR (DMSO, 300 MHz, ppm) □ 1.66-1.70 (2H, m), 3.08-3.12 (2H, m), 3.70-3.71 (1H, m), 4.88-4.94 (1H, m), 7.14 (1H, s), 7.36-7.39 (1H, m), 7.60 (1H, s), 7.83 (1H, s), 8.84-8.86 (1H, m).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].CC1(C)C(C)(C)OB([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[C:26]([NH:31][C:32]([C:34]2[CH:38]=[CH:37][S:36][CH:35]=2)=[O:33])[CH:25]=[CH:24]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[C:7]([C:6]1[CH:10]=[C:2]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[C:26]([NH:31][C:32]([C:34]2[CH:38]=[CH:37][S:36][CH:35]=2)=[O:33])[CH:25]=[CH:24]3)[CH:3]=[CH:4][C:5]=1[O:11][CH3:12])(=[O:8])[NH2:9]
Reactant: COc1ccc(I)cc1C(N)=O
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)cc1C(N)=O
Temperature: 25 °C
Yield: 15.2 %

Procedure:
5-iodo-2-methoxybenzamide (47.9 mg, 0.173 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (140.4 mg, 0.370 mmol), Fibercat palladium catalyst (Johnson-Matthey, 70.1 mg), and K2CO3 (2 M in water, 0.65 ml, 1.3 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (1.8 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 85 C for 20 minutes. The reaction was then cooled to room temperature, diluted with water (5 ml), and extracted with EtOAc (4×10 ml). The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified via silica gel (Biotage instrument, 13%->100% EtOAc/hexanes). This crude material was then purified via HPLC (10%->95% MeCN/water with 0.1% TFA) to afford title compound (10.6 mg, 15%). MS (ESI pos. ion) m/z: 403 (M+H). Calc'd Exact Mass for C23H18N2O3S: 402.
Reaction SMILES: [H-].[Na+].O[C:4]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:5]=1[C:6](=[O:17])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[C:26]1(=[O:33])[O:32][C:30](=[O:31])[CH2:29][CH2:28][CH2:27]1.[O:34]1CCCC1>>[C:30]([CH2:29][CH2:28][CH2:27][C:26]([O:32][C:4]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[C:5]=1[C:6](=[O:17])[CH:7]=[CH:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)=[O:33])([OH:31])=[O:34]
Reactant: C1CCOC1
Reactant: COc1ccc(C=CC(=O)c2c(O)cc(OC)cc2OC)cc1
Reactant: O=C1CCCC(=O)O1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(C=CC(=O)c2c(OC)cc(OC)cc2OC(=O)CCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 11 %

Procedure:
Sodium hydride (76 mg of 60% purity) was added with stirring to an ice-cooled solution of 2'-hydroxy-4,4',6'-trimethoxychalcone (500 mg) in 20 ml of tetrahydrofuran. After 10 minutes, a solution of glutaric anhydride (218 mg) in 3 ml of tetrahydrofuran was added. The mixture was stirred at room temperature for 2 hours and evaporated under reduced pressure. The residue was dissolved in 50 ml of ethyl acetate, which was then extracted with 50 ml of 10% aqueous sodium carbonate. The extract was acidified with hydrochloric acid and shaken with 50 ml of chloroform. The chloroform extract was washed with water, dried over Na2SO4 and evaporated under reduced pressure. Crystallization of the residue from benzene gave 75 mg (11% yield) of 2'-(4-carboxybutanoyloxy)-4,4',6'-trimethoxychalcone as pale yellow crystals; m.p. 131°-132° C.
Reaction SMILES: N[C@H:2]([C:8]([OH:10])=O)[CH2:3][CH2:4][C:5](=O)[NH2:6].CC1(C)S[C@@H]2[C@H](NC(CC3C=CC=CC=3)=O)C(=O)N2[C@H]1C([O-])=O.[K+].C[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H:45]([NH:50][C:51]([NH2:53])=N)[C@@H:44](O)[C@@H:43]2[NH:55][C:56]([NH2:58])=N)[C@H](O[C@@H]2O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]2NC)[C@@]1(O)C=O>>[CH:2]1[CH:3]=[C:4]([CH2:5][NH:6][C:45]2[N:50]=[CH:51][N:53]=[C:43]3[N:55]=[CH:56][NH:58][C:44]=23)[O:10][CH:8]=1
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](NC(=N)N)[C@@H](O)[C@@H]3NC(=N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: [K+]
Product: c1coc(CNc2ncnc3nc[nH]c23)c1

Procedure:
FD lymphoblast lines were grown in RPMI-1640 and primary fibroblast lines in Dulbecco's modified Eagle's media (DMEM) with Earle's balanced salts. Both media were supplemented with 2 mM L-glutamine and 1% penicillin/streptomycin and either 10% (lymphoblast) or 20% (fibroblast) fetal bovine serum (Invitrogen). Kinetin was obtained from both MicroSource Discovery Systems and Sigma and dissolved at 10 mM in either DMSO or water. FD cells were cultured in the presence of kinetin for 72 hours except where noted. Benzyladenine, zeatin, and 2iP were obtained from Sigma and dissolved in DMSO at 10 mM. These compounds were tested at concentrations of 1 μM, 10 μM, 50 μM, and 100 μM. Cycloheximide was obtained from Sigma and dissolved at 10 mg/ml in DMSO. Cells were treated with 100 μM kinetin for eight hours, then 50 μg/ml cycloheximide was added to the cultures for four hours16.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[OH:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:17][CH:18]=[N:19]2)=[CH:14][C:13]=1[O:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:30][O:29][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:12]=1[O:11][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[N:19]=[CH:18][N:17]=[C:16]2[O:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1O
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCN1CCCCC1
Temperature: 110 °C
Yield: 84.8 %

Procedure:
1-(2-Chloroethyl)piperidine hydrochloride (0.83 g, 4.5 mmol) was added to 7-hydroxy-6-methoxy-4-phenoxyquinazoline (1.0 g, 3.73mmol), (prepared as described for the starting material in Example 16), and potassium carbonate (2.6 g, 18.8 mmol) in DMF (30 ml), and the mixture heated at 110° C. for 2.5 hours and allowed to cool. The insolubles were removed by filtration, and the volatiles were removed from the filtrate by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (9/1) to give 6-methoxy-4-phenoxy-7-(2-piperidinoethoxy)quinazoline (1.2 g, 85%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[C:24](=[O:26])[CH3:25])=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:9]2[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[C:6]([O:27][CH3:28])[CH:7]=3)[N:12]=[CH:11][CH:10]=2)=[C:17]([C:24](=[O:26])[CH3:25])[CH:18]=1
Reactant: C1COCCN1
Reactant: COc1ccc(Oc2ccnc3cc(OCCCl)c(OC)cc23)c(C(C)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccnc3cc(OCCN4CCOCC4)c(OC)cc23)c(C(C)=O)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 23.9 %

Procedure:
1-(2-{[7-(2-Chloroethoxy)-6-methoxy-4-quinolyl]oxy}-5-methoxyphenyl)-1-ethanone (compound 119) (89 mg), morpholine (57 mg), and potassium carbonate (152 mg) were suspended in N,N-dimethylformamide (2 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (24 mg, yield 24%).
Reaction SMILES: [CH:1]1([N:7]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[C:30]([O:34][C:35](=[O:38])[CH2:36][NH2:37])([CH3:33])([CH3:32])[CH3:31].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH:1]1([N:7]([CH2:25][CH:26]2[CH2:27][CH2:28]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][NH:37][CH2:36][C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:38])=[CH:21][CH:22]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=Cc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)CNCc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.6 %

Procedure:
A solution of 6-[cyclohexyl(cyclopropylmethyl)amino]-N-(4-formylphenyl)pyrimidine-4-carboxamide (Intermediate 24, 80 mg; 0.18 mmol) in DCM (8 ml) was treated with Glycine tert-butyl ester hydrochloride (Sachem, 60.6 mg; 0.36 mmol) and triethylamine (50 μl; 0.36 mmol). After 2 minutes sodium triacetoxyborohydride (96 mg; 0.45 mmol) and acetic acid (2 μl; 0.04 mmol) were added and the reaction was stirred at room temperature for 20 hours. The solvent was removed under vacuum and the residue was redissolved in AcOEt. The organic phase was washed twice with an aqueous solution (1N) of NaOH and once with brine, dried (MgSO4) and the solvent removed under vacuum to afford the title compound as a colorless oil (62.7 mg, 70%) after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.