Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].[Br:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([CH2:32][CH:33]3[CH2:35][O:34]3)[C:23]3[C:28]([C:29]=2[CH:30]=1)=[CH:27][C:26]([Br:31])=[CH:25][CH:24]=3>C1COCC1.CCOC(C)=O>[Br:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([CH2:32][CH:33]([OH:34])[CH2:35][O:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[C:9]4[C:8](=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:7]3=[O:16])[C:23]3[C:28]([C:29]=2[CH:30]=1)=[CH:27][C:26]([Br:31])=[CH:25][CH:24]=3
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1n2CC1CO1
Reactant: O=C1c2ccccc2C(=O)N1CCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCOCC(O)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 44 %

Procedure:
Sodium hydride dispersion (31.6 mg, 0.79 mmol) was added to a solution of N-(2-hydroxyethyl)-phthalimide (153.7 mg, 0.80 mmol) in anhydrous THF (1.2 ml, 0.67 M). The suspension is stirred for 15 minutes before the addition of carbazole epoxide 2-A. The reaction was stirred at room temperature for five minutes and then at 60° C. for 1 hour. The cooled reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted and the combined organics were filtered over a celite pad. The Crude product was used without further purification. Yield=44%
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:28]4[O:32][CH2:31][C:30]5([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]5)[N:29]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:28]4[O:32][CH2:31][C:30]5([CH2:37][CH2:36][N:35]([C:38](=[O:40])[CH3:39])[CH2:34][CH2:33]5)[N:29]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC5=NC6(CCNCC6)CO5)cc34)cc2C)cn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCC2(CC1)COC(Nc1ccc3ncnc(Nc4ccc(Oc5ccc(C)nc5)c(C)c4)c3c1)=N2

Procedure:
1-(2-{4-[3-Methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-ylamino}-3-oxa-1,8-diaza-spiro[4.5]dec-1-en-8-yl)-ethanone is prepared from N4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-N6-(3-oxa-1,8-diaza-spiro[4.5]dec-1-en-2-yl)-quinazoline-4,6-diamine by standard acetylation methods using acetic anhydride in a mixture of pyridine and methylene chloride.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](O)=[O:13])=[C:5]2[O:15][CH3:16].[CH3:17][NH:18][CH3:19].O1CCCC1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:17][N:18]([CH3:19])[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[O:15][CH3:16])=[CH:3][C:2]([I:1])=[CH:11][CH:10]=2)=[O:13]
Reactant: COc1c(C(=O)O)cnc2ccc(I)cc12
Reactant: CNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C(=O)N(C)C)cnc2ccc(I)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To the mixture of 6-iodo-4-methoxy-quinoline-3-carboxylic acid (example 1b) (1.5 g, 4.56 mmol), 2 M dimethylamine in THF (tetrahydrofuran) (9.11 mL, 18.2 mmol), HOBt (0.74 g, 5.5 mmol) and DIEA (diisopropylethylamine) (2.38 mL, 13.7 mmol) in DMF (N,N-dimethylformamide) (40 mL) was slowly added the solution of O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (2.08 g, 5.47 mmol) in DMF (10 mL). After stirring at room temperature for 3 hours, the product was extracted with methylene chloride (2×100 mL). The combined organic layers were successively washed with a saturated aqueous sodium bicarbonate solution (3×50 mL) and water (3×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, using ethyl acetate as eluant) afforded 6-iodo-4-methoxy-quinoline-3-carboxylic acid dimethylamide (1.27 g, 78%) as a solid. LC-MS m/e 357 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][C:8]([C:13]([OH:15])=[O:14])=[CH:7]2.O=S(Cl)Cl.[CH3:20]O>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][C:8]([C:13]([O:15][CH3:20])=[O:14])=[CH:7]2
Reactant: O=C(O)c1cc2cccc(F)c2c(=O)[nH]1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2cccc(F)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of 8-fluoro-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid (4 g, 19.3 mmol) in MeOH (100 mL) was added SOCl2 (20 mL) at 0° C. The reaction mixture was stirred at RT for 30 minutes and then heated to reflux for 5 hours. The reaction mixture was subsequently concentrated in vacuo. The crude product was purified by column chromatography eluting with petroleum ether and ethyl acetate (PE/EtOAc=1:1-1:2 gradient) to give a second batch of the title compound (3 g, 80%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.19 (s, 1H), 7.79-7.71 (m, 2H), 7.42-7.38 (m, 2H), 3.89 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.O[C:13]1C=CC([N+]([O-])=O)=CN=1.[Na].C(C(CC)(C([O-])=O)C([O-])=O)C>>[Br:1][C:2]1[C:3]([CH3:13])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(O)nc1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Agent: CCC(CC)(C(=O)[O-])C(=O)[O-]
Agent: [Na]
Product: Cc1ncc([N+](=O)[O-])cc1Br
Yield: 75 %

Procedure:
3-Bromo-2-chloro-5-nitropyridine (25 g, 105 mmol; prepared from 2-hydroxy-5-nitropyridine according to the procedure of V. Koch and S. Schnatterer, Synthesis 1990, 499-501) was treated with the sodium salt of diethylmalonate (17.6 mL, 116 mmol) according to the procedure of Odashima et al Bull Chem Soc Jpn 1993, 66, 797-803) to provide 17.1 g (78.8 mmol, 75%) of dark red oil: TLC Rf 0.5 (4:1 hexanes/EtOAc); 1H NMR (CDCl3, 300 MHz) δ 2.81 (s, 3H), 8.61 (d, 1H, J=2.0 Hz), 9.26 (d, 1H, J=2.0 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:19]([Mg]Br)[CH2:20][CH3:21]>C1COCC1.CCOCC>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[CH:4][N:3]=[C:2]3[CH2:19][CH2:20][CH3:21])=[CH:13][CH:14]=1
Reactant: Fc1ccc(-c2ccc3ncnc(Cl)c3c2)cc1
Reactant: CCC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCc1ncnc2ccc(-c3ccc(F)cc3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of 4-chloro-6-(4-fluorophenyl)-quinazoline (258 mg, 1 mmol) and Fe(acac)3 (17 mg, 0.05 mmol) in THF (5 ml) was added n-propyl magnesium bromide (600 ul of 2M THF solution). The reaction was stirred at RT for 1 hour at RT then diluted with ether (5 ml) and quenched with 3 drops 2N HCl. The mixture was further diluted with ether and extracted with H2O. The aqueous layer was neutralized with a saturated aqueous NaHCO3 solution and extracted 3× with ether. The combined organics were washed once with NaHCO3 and once with a saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by column chromatography on SiO2 using EtOAc/hex (10-30% EtOAc) to give the title compound (115 mg, 43% yield) which was characterized by mass spectrum as follows: (m/z): 267 ([M+H]) 100).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O.C(N(CC)CC)C.C(Cl)CCl.[NH2:25][C@@H:26]([CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[C@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[OH:28]>C(Cl)Cl>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH:25][C@@H:26]([CH2:35][N:36]1[CH2:37][CH2:38][O:39][CH2:40][CH2:41]1)[C@H:27]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[OH:28])=[O:13]
Reactant: O=C(O)CCCCCCCCCO
Reactant: N[C@@H](CN1CCOCC1)[C@@H](O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(CCCCCCCCCO)N[C@@H](CN1CCOCC1)[C@@H](O)c1ccccc1
Reaction time: 8 h
Yield: 62.5 %

Procedure:
Methylene chloride (20 ml), 10-hydroxydecanoic acid (377 mg, 2.0 mmol), triethylamine (0.70 ml, 5.0 mmol) and EDC (580 mg, 3.0 mmol) were added to (1S,2S)-2-amino-3-morpholino-1-phenyl-1-propanol (472.0 mg, 2.0 mmol), followed by stirring overnight. Methylene chloride (100 ml) was added to the reaction solution. After washed with a saturated sodium hydrogen carbonate solution (50 ml), water (50 ml) and saturated brine (50 ml) successively, the organic layer was dried over sodium sulfate and filtered, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform:ethanol=20:1) to obtain the title compound (508 mg, yield 62%) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([OH:13])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20](I)[CH3:21]>C(#N)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([O:13][CH2:20][CH3:21])=[CH:4][N:3]=1
Reactant: Oc1cnc(Cl)c2cc(F)ccc12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1cnc(Cl)c2cc(F)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution of 1-chloro-7-fluoroisoquinolin-4-ol (0.5 g, 2.53 mmol) in acetonitrile (10 ml) was added K2CO3 (700 mg, 5.06 mmol) followed by ethyl iodide (475 mg, 3.04 mmol) at room temperature. The reaction mixture was stirred at room temperature for overnight. The solvent was evaporated under reduced pressure and the residue was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get 1-chloro-7-fluoro-4-ethoxyisoquinoline (400 mg 70%) as off-white solid.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][CH:6]([C:9]3[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=3)[CH2:5][CH2:4]2)[CH2:2]1.B(F)(F)F.CCOCC.O>ClCCl>[CH:2]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:10]=[CH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:18][CH:19]=2)[CH2:5][CH2:4]1)=[O:1]
Reactant: CCOC(=O)c1ccc(C2CCC3(CC2)CO3)cc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Reaction time: 2 h

Procedure:
1.4 g of ethyl 4-(1-oxaspiro[2.5]oct-6-yl)benzoate (5.38 mmol, 1.4 eq.) are placed in 40 mL of dichloromethane at 4° C. 0.229 g of boron trifluoride etherate (1.61 mmol, 0.3 eq.) is added with stirring. After 2 hours, 0.153 g of boron trifluoride etherate (1.07 mmol, 0.2 eq.) is added. After 1 hour, water is added and the reaction medium is extracted three times with dichloromethane. The organic phases are combined and washed successively with saturated aqueous sodium hydrogen carbonate solution and water. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel with an 88/10/2 mixture of heptane/ethyl acetate/methanol. 0.64 g of ethyl trans-4-(4-formylcyclohexyl)benzoate is obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([CH3:14])[NH:11][CH2:10][C@@H:9]1[CH3:15])=O)(C)(C)C.[Cl:16][S:17]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22]([CH3:30])=[CH:23][N:24]=[CH:25]2)(=[O:19])=[O:18]>>[ClH:16].[ClH:16].[CH3:15][C@H:9]1[CH2:10][NH:11][C@@H:12]([CH3:14])[CH2:13][N:8]1[S:17]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22]([CH3:30])=[CH:23][N:24]=[CH:25]2)(=[O:18])=[O:19]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1
Reactant: Cc1cncc2cccc(S(=O)(=O)Cl)c12
Product: Cc1cncc2cccc(S(=O)(=O)N3C[C@H](C)NC[C@@H]3C)c12
Product: Cl
Yield: 51.3 %

Procedure:
Using 0.43 g of cis-1-(tert-butoxycarbonyl)-2,5-dimethylpiperazine and 0.48 g of 5-chlorosulfonyl-4-methylisoquinoline, the procedure of Example 1 was otherwise repeated to provide 0.2 g of the objective compound (white crystals).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][C:6]=1[NH2:17])[CH3:2].N1C=CC=CC=1.CO[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1OC)[C:30](Cl)=[O:31].[CH2:38]([Cl:40])Cl>>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][C:6]=1[NH:17][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][CH:35]=[C:27]([CH2:38][Cl:40])[CH:28]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(N2CCCCC2)ccc1N
Reactant: ClCCl
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(N2CCCCC2)ccc1NC(=O)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Amino-5-piperidin-1-yl-benzoic acid ethyl ester (compound A) (1.6 g) synthesized by the above process was dissolved in anhydrous methylene chloride (20 ml). Pyridine (1.0 ml) and 3-(chloromethyl)benzoyl chloride (compound B) (1.2 ml) were added dropwise to the solution at 0° C., and the mixture was then stirred at room temperature for one hr. After the completion of the reaction, the reaction solution was concentrated under the reduced pressure. Distilled water was added to the residue, and the mixture was subjected to separatory extraction with ethyl acetate. The organic layer was dried over sodium sulfate and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a chloroform-methanol system to give 2-(3-chloromethyl-benzoylamino)-5-piperidin-1-yl-benzoic acid ethyl ester as a useful intermediate (1.7 g, yield 63%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=1[Cl:28].[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][NH:35][CH3:36]>>[Cl:27][C:26]1[CH:25]=[N:24][CH:23]=[C:22]([Cl:28])[C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:35]([CH2:34][CH2:33][N:32]([CH3:37])[CH3:31])[CH3:36])[C:10]([O:29][CH3:30])=[CH:11][CH:12]=2)[NH:17][C:16](=[O:19])[CH:15]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Reactant: CNCCN(C)C
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCN(C)CCN(C)C

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 4) and N1,N1,N2-trimethylethane-1,2-diamine following the procedure outlined in Example 18, Step 2 (modifications: 40° C., 24 h then 60° C., 4 h). 1H NMR (400 MHz, DMSO-d6, bis HCl salt): δ 10.91 (br, 2H), 10.26 (s, 1H), 9.11 (s, 1H), 8.81 (s, 2H), 7.98 (d, 1H), 7.14 (d, 1H), 4.90 (s, 1H), 4.01 (t, 2H), 3.94 (s, 3H), 3.63-3.42 (br m, 4H), 3.25-3.00 (br m, 2H), 2.90-2.78 (m, 9H), 1.85-1.69 (m, 4H), 1.52-1.32 (m, 4H); MS (ESI): 536.4.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([NH:12][C:13]([C:15]23[CH2:22][CH:21]4[CH2:23][CH:17]([CH2:18][CH:19]2[CH2:20]4)[CH2:16]3)=[O:14])=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5])C.[OH-].[K+].Cl>C(O)C.O.C(OCC)(=O)C>[CH2:18]1[CH:19]2[C:15]3([C:13]([NH:12][C:11]4[C:6]([C:4]([OH:5])=[O:3])=[N:7][CH:8]=[CH:9][CH:10]=4)=[O:14])[CH2:22][CH:21]([CH2:23][CH:17]1[CH2:16]3)[CH2:20]2
Reactant: CCOC(=O)c1ncccc1NC(=O)C12CC3CC(CC1C3)C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ncccc1NC(=O)C12CC3CC(CC1C3)C2

Procedure:
To a solution of Example 332A (0.23 g, 0.73 mmol) in ethanol/water (10/2) was added potassium hydroxide (0.2 g, 3.66 mmol). The solution was warmed to 65 degrees for 12 hours, cooled and diluted with ethyl acetate (50 mL). The solution was acidified with 0.5M HCl (10 mL), then washed with brine, dried over MgSO4, filtered, and concentrated to afford the title compound. MS (ESI) m/z 286 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][C:12]1[C:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=[CH:14][N:13]=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:20]1([CH2:19][O:18][C:17]2[C:12]([CH2:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:33][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCCCCCCOCCCc1ncccc1OCc1ccccc1
Reactant: NCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: c1ccc(CNCCCCCCOCCCc2ncccc2OCc2ccccc2)cc1
Reaction time: 2 h

Procedure:
2-[3-[(6-Bromohexyl)oxy]propyl]-3-(phenylmethoxy)pyridine (1.0 g) was added to benzylamine (3 ml) at 120° under nitrogen. After stirring for 2 h, the solution was cooled and added to water (10 ml) and 2N hydrochloric acid (10 ml). The aqueous mixture was basified with sodium carbonate and then extracted with ethyl acetate (3×50 ml). The ethyl acetate was evaporated and the excess benzylamine was removed by distillation at reduced pressure to leave the title compound as a red oil (810 mg), t.l.c. (ethyl acetate/triethylamine 99:1) Rf 0.13.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:13])[CH:6]=[C:7]2[C:11]=1[C:10](=O)[CH2:9][CH2:8]2.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:13])[CH:6]=[C:7]2[C:11]=1[C:10](=[N:15][OH:16])[CH2:9][CH2:8]2
Reactant: NO
Reactant: COc1cc(C)cc2c1C(=O)CC2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(C)cc2c1C(=NO)CC2
Yield: 98 %

Procedure:
7-Methoxy-5-methyl-1-indanon (CAS no: 62358-78-5) (7.70 g, 0.044 mol) was dissolved in ethanol (40 mL) and hydroxylamine hydrochloride (6.23 g, 0.09 mol) and sodium acetate (7.38 g, 0.09 mol) were added. The reaction mixture was heated to reflux for 3 h. Then water (100 mL) was added and a precipitation formed which was filtered. The precipitate was washed with water, isolated and dried under high vacuum to yield 7-methoxy-5-methyl-indan-1-one oxime (8.20 g, 98%) as a white solid; MS: m/e=192.4 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][C@@H:6]([CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[O:7][C@H:8]2[CH2:14][NH:15][CH:16]=[O:17].[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.ClC(Cl)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O.C(O)(=O)C>[CH2:24]([N:21]1[CH2:20][CH2:19][CH:18]([C@@H:6]2[CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:12]([CH3:13])[C:3]=3[O:2][CH3:1])[C@H:8]([CH2:14][NH:15][CH:16]=[O:17])[O:7]2)[CH2:23][CH2:22]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=Cc1ccccc1
Reactant: COc1c(C)ccc2c1C[C@@H](C1CCNCC1)O[C@H]2CNC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1c(C)ccc2c1C[C@@H](C1CCN(Cc3ccccc3)CC1)O[C@H]2CNC=O
Yield: 112.6 %

Procedure:
Stir a suspension of N-((1R,3S)-5-methoxy-6-methyl-3-(4-piperidinyl)-1-isochromanylmethyl)formamide (0.5 g, 1.6 mmol), benzaldehyde (0.16 g, 1.5 mmol), acetic acid (0.9 g and dichloroethane (13 mL) for 5 min. Add sodium triacetoxyborohydride (0.5 g, 2.3 mmol) and stir at room temperature for 4 h. Cool the reaction in an ice bath and and water (18 mL), and then make the make the mixture basic by the addition of 50% aqueous NaOH. Extract the mixture with dichloromethane, filter the biphasic mixture through Celite, separate the phases and reextract the aqueous with dichloromethane. Combine the extracts, wash with H2O, dry over MSO4, filter and concentrate under vacuum to obtain 0.69 g of a brown oil. Purify the crude oil by preparative HPLC on a silica gel cartridge (35 g) and use 2% diethylamine(Et2NH)-EtOAc followed by 10% Et2NH-EtOAc. Combine like fractions and concentrate to obtain 0.34 g of the title compound
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:18])=[N:6][CH:7]=1.[C:19]([C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[CH:22]=1)#[CH:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:30][O:29][C:23]1[CH:22]=[C:21]([C:19]#[C:20][C:2]2[CH:3]=[N:4][C:5]([NH:8][C:9]3[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=3[CH3:18])=[N:6][CH:7]=2)[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=1
Reactant: Cc1cccc([N+](=O)[O-])c1Nc1ncc(Br)cn1
Reactant: C#Cc1cc(OC)cc(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: COc1cc(C#Cc2cnc(Nc3c(C)cccc3[N+](=O)[O-])nc2)cc(OC)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 39.3 %

Procedure:
A mixture of 5-bromo-N-(2-methyl-6-nitrophenyl)pyrimidin-2-amine (573 mg, 3.0 mmol), 1-ethynyl-3,5-dimethoxybenzene (483 mg, 3.0 mmol), triphenylphosphine (157 mg, 0.60 mmol), bis(triphenylphosphine)palladium(II) chloride (210 mg, 0.30 mmol), copper(I) iodide (57 mg, 0.30 mmol) and diethylamine (1.50 ml, 15.0 mmol) in N,N-dimethylformamide (10 mL) was degassed with nitrogen three times, and then stirred at 80° C. for 2 hrs. LCMS showed the reaction was completed. The mixture was cooled to RT, quenched with water (20 mL) and extracted with ethyl acetate (3×80 mL). The combined organic layers were separated, washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=4:1) to afford the title compound as a yellow solid (460 mg, 39%). MS (ES+) C21H18N4O4 requires: 390. Found: 391 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[C:8](=[O:14])[CH2:7][CH2:6]2.C([O:19][N:20]=O)CCC.Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[C:8](=[O:14])[C:7](=[N:20][OH:19])[CH2:6]2
Reactant: CCCCON=O
Reactant: COc1cc2c(c(OC)c1)C(=O)CC2
Agent: Cl
Solvent: CO
Product: COc1cc2c(c(OC)c1)C(=O)C(=NO)C2
Temperature: 40 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of 5,7-Dimethoxy-indan-1-one (8.7 g, 45.26 mmol) in the methanol (80 ml) was added n-butylnitrite (6.13 ml, 49.78 mmol) followed by concentrated HCl (4.4 ml). The solution was stirred at 40° C. for one hour during which time a precipitate was formed. The precipitate was collected and dried to yield product as a yellow solid (10 g, 99%). LC-MS: m/e 222 (MH+).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])[CH:2]=[CH2:3].[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[N:18]=[C:19]=[S:20].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:4]([CH2:5][CH2:6][C:7]([OH:9])=[O:8])[C:19]([NH:18][C:12]1[C:11]([CH3:10])=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:17])=[S:20])[CH:2]=[CH2:3]
Reactant: C=CCNCCC(=O)O
Reactant: Cc1cccc(C)c1N=C=S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN(CCC(=O)O)C(=S)Nc1c(C)cccc1C
Yield: 39.7 %

Procedure:
A mixture of the 3-allylaminopropionic acid (21.9 g), 2,6-dimethylphenyl-isothiocyanate (19 g), triethylamine (20 g) and methylene chloride (200 mL) was heated at reflux for 3 hours. The cooled reaction mixture was extracted with 1N NaOH (150 mL). The aqueous layer was separated and acidified with 2N HCl. The solid was collected by filtration. 13.5 g of the title compound was obtained and used without further purification for the reaction in step 3.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([SH:14])=[CH:8][C:7]=1[CH3:15].Br[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1>>[CH3:13][O:12][C:10]1[C:9]([S:14][CH2:15][C:7]2[CH:8]=[CH:9][C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[CH:11][CH:6]=2)=[CH:8][C:7]([CH3:15])=[C:6]([CH:11]=1)[O:5][CH2:4][C:3]([OH:2])=[O:16]
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: COC(=O)COc1cc(OC)c(S)cc1C
Product: COc1cc(OCC(=O)O)c(C)cc1SCc1ccc(-c2cccc(C(F)(F)F)c2)cc1

Procedure:
The title compound was prepared in the manner analogous to Example 5A using 1D and 1-bromo-3-trifluoromethyl-benzene. MS m/z 477 (M+1).