Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:6][C:5]=1[NH2:17].Cl.[CH:20](N)=[NH:21]>C(O)C>[Cl:16][CH2:15][CH2:14][CH2:13][O:12][C:7]1[CH:6]=[C:5]2[C:4]([C:3]([OH:2])=[N:21][CH:20]=[N:17]2)=[CH:9][C:8]=1[O:10][CH3:11]
Reactant: N=CN
Reactant: COC(=O)c1cc(OC)c(OCCCCl)cc1N
Agent: Cl
Solvent: CCO
Product: COc1cc2c(O)ncnc2cc1OCCCCl
Temperature: 140 °C
Yield: 56.2 %

Procedure:
To a solution of the intermediate from Step 3 (4.2 g, 15.35 mmol) in ethanol was added formamidine hydrochloride (2.97 g, 36.96 mmol). The mixture was heated at 140° C. in sealed tube for 12h. Completion of the reaction was monitored by LCMS. The precipitate formed was filtered and washed with ethanol and dried to afford the pure compound 7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-ol (2.32 g, 56%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 11.93 (brs, 1H), 7.99 (s, 1H), 7.45 (s, 1H), 7.16 (s, 1H), 4.23 (t, 2H), 3.88 (s, 3H), 3.80 (t, 2H), 2.23 (t, 2H), LC-MS (ESI)m/z 269 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1.NN.[Ni]>[CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([NH2:13])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccn(Cc2ccccc2)n1
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Product: Nc1ccn(Cc2ccccc2)n1
Reaction time: 0.08 h

Procedure:
To a solution containing 1-benzyl-3-nitro-1H-pyrazole (86 mg, 0.42 mmol) in tetrahydrofuran (2 mL), anhydrous hydrazine (100 μL) was added to the clear solution. Raney nickel (˜100 mg washed 3 times with 5 mL of anhydrous tetrahydrofuran) was then added in tetrahydrofuran (300 μL). Gas evolved from the mixture and the reaction was allowed to proceed for 5 min, after which time the raney nickel was removed by filtration through a celite plug. The solvent was removed in vacuo to afford 1-benzyl-1H-pyrazol-3-ylamine as a yellow oil, which was used in the following step with no further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[S:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[C:28]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[N:27]1>CN(C)C=O>[S:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[C:28]([N:35]2[CH2:36][CH2:37][N:38]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:39][CH2:40]2)=[N:27]1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2nsc3ccccc23)CC1
Temperature: 20 °C
Yield: 24.3 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (11 g), triethylamine (11 cc) and 4-(1,2-benzisothiazole-3-yl)piperazine (8.6 g) in dimethylformamide (120 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure with ethyl acetate as eluant, and recrystallization from boiling methyl ethyl ketone (160 cc), 2-{3-[4-(1,2-benzisothiazole-3-yl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (4.4 g) is obtained, m.p. 172°-173° C.
Reaction SMILES: [F-].[K+].[O:3]=[S:4]1(=[O:38])[N:8](S(C2C=CC(C)=CC=2)(=O)=O)[C:7]2[CH:19]=[C:20]([CH2:23][N:24]([C:30]3[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=3)[N:25]3[CH:29]=[CH:28][N:27]=[CH:26]3)[CH:21]=[CH:22][C:6]=2[O:5]1>O.C(#N)C>[O:38]=[S:4]1(=[O:3])[NH:8][C:7]2[CH:19]=[C:20]([CH2:23][N:24]([C:30]3[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=3)[N:25]3[CH:29]=[CH:28][N:27]=[CH:26]3)[CH:21]=[CH:22][C:6]=2[O:5]1
Reactant: Cc1ccc(S(=O)(=O)N2c3cc(CN(c4ccc(C#N)cc4)n4ccnc4)ccc3OS2(=O)=O)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(N(Cc2ccc3c(c2)NS(=O)(=O)O3)n2ccnc2)cc1
Reaction time: 8 h
Yield: 15.1 %

Procedure:
Potassium fluoride (0.36 g, 6.14 mmol) in water (5 ml) was added to 4[N-[(2,2-dioxido-3-tosyl-3H-1,2,3-benzoxathiazol-5-yl)methyl]-N-(1H-imidazol-1-yl)amino]benzonitrile (1.60 g, 3.07 mmol) in acetonitrile (15 ml) at room temperature. The solution was stirred overnight, concentrated, extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under vacuum. Flash chromatography on silica gel (toluene/dioxane: 5/5) yielded an oil and crystallization from ethanol yielded the expected product (0.17 g, 15%, mp: 230° C.).
Reaction SMILES: [O:1]([C:8]1[C:9]([NH2:21])=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([N:30]=[C:31]=[S:32])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[C:22]([NH:30][C:31]([NH:21][C:9]1[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][C:12]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:11][N:10]=1)=[S:32])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ncc(Sc2ccccn2)cc1Oc1ccccc1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: O=C(NC(=S)Nc1ncc(Sc2ccccn2)cc1Oc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
A 125 mL flask was charged with 3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-amine (Example 34, Step A, 1.15 g, 3.89 mmol) and benzoyl isothiocyanate (0.699 g, 4.28 mmol) in THF (50 mL) and stirred at ambient temperature for 18 hours. The THF was removed in vacuo and the residue was dissolved in CH2Cl2 (10 mL) and added dropwise to 100 mL of 9:1 hexanes:EtOAc. The solvent was decanted and the residue was dried to provide 1-benzoyl-3-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-yl)thiourea (1.57 g, 88.2% yield) as a yellow solid.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[C:8]2[C:9]3[N:10]([N:13]=[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:15]=3[C:16]([O:18][CH3:19])=[O:17])[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5]1)#[N:2]>N.C(O)C.[Co]>[NH2:2][CH2:1][CH2:3][CH:4]1[C:8]2[C:9]3[N:10]([N:13]=[C:14]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:15]=3[C:16]([O:18][CH3:19])=[O:17])[CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5]1
Reactant: COC(=O)c1c(-c2ccccc2)nn2ccc3c(c12)C(CC#N)CC3
Agent: [Co]
Agent: N
Solvent: CCO
Product: COC(=O)c1c(-c2ccccc2)nn2ccc3c(c12)C(CCN)CC3
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.2 %

Procedure:
Methyl 9-(cyanomethyl)-2-phenyl-8,9-dihydro-7H-cyclopenta[c]pyrazolo[1,5-a]pyridine-1-carboxylate (300 mg, 0.905 mmol) and Raney cobalt (3 g) were suspended in 2M ammonia/ethanol solution (15 mL), and the suspension was stirred under a hydrogen atmosphere at room temperature for 12 hr. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure to give the title compound (295 mg, yield 97%).
Reaction SMILES: [H-].[Na+].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH:4]=1.Br[CH2:13][C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1.CO>C1COCC1.C(OCC)(=O)C.O>[N:3]1([CH2:13][C:14]2[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[CH:4]1
Reactant: CCOC(=O)c1ccc(CBr)cc1
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(Cn2cnc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Sodium hydride (80% dispersion in oil) (0.61 g, 0.02 mol) was added to a stirred solution of benzimidazole (2.00 g, 0.017 mol) in dry THF (30 ml) under argon. After 90 m the mixture was cooled to 0° C. and treated with ethyl 4-bromomethylbenzoate (4.50 g, 0.019 mol) dissolved in dry THF (20 ml). The mixture was allowed to warm to ambient temperature and stirred overnight. Methanol (1 ml) was added, followed by water and the product extracted using ethyl acetate (3×75 ml). The combined organic layers were washed with water (2×50 ml), dried over K2CO3 and the solvent removed to give the crude product (4.87 g). Flash chromatography (flash silica, ethyl acetate) gave, after crystallisation from toluene, ethyl 4-[1H-benzimidazylmethyl]benzoate (1.61 g, 34%) as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22]>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: FC(F)(F)CCCBr
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)CCCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 102.5 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (250 mg) in N,N-dimethylformamide (1.6 mL) was added cesium carbonate (675 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added 4-bromo-1,1,1-trifluorobutane (466 mg), and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×3). The organic layer was washed with saturated brine (20 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=9/1→0/10). The object fraction was concentrated under reduced pressure and dried to give the title compound (440 mg) as a colorless transparent oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH:19]1[CH2:21][CH2:20]1>CN(C=O)C.C(OCC)(=O)C>[CH:19]1([CH2:18][O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:21][CH2:20]1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(OCC2CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.2 %

Procedure:
4-Nitrophenol (2.0 g, 14.4 mmol) was dissolved in DMF (50 mL) and potassium carbonate (6.0 g, 43 mmol) and bromomethylcyclopropane (1.51 mL, 16 mmol) were added and the resulting mixture was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate (50 mL) and washed with a saturated aqueous solution of sodium chloride (2×50 mL). Drying (MgSO4) and concentration afforded 2.23 g (75%) of 1-cyclopropylmethoxy-4-nitrobenzene as an oil.
Reaction SMILES: [C:1]([NH:22][C@H:23]([C:30]([OH:32])=[O:31])[CH2:24][O:25][P:26]([OH:29])([OH:28])=[O:27])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18]CC.[C:33](O)(=O)CCCCCCC/C=C\CC=CCC=CCC.Cl.COC(=O)[C@H]([C@@H](C)O)N>>[C:1]([NH:22][C@H:23]([C:30]([OH:32])=[O:31])[C@@H:24]([CH3:33])[O:25][P:26]([OH:29])([OH:28])=[O:27])(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH:12]=[CH:13][CH2:14][CH:15]=[CH:16][CH2:17][CH3:18]
Reactant: CCCCCC=CCC=CCC=CC/C=C\CCCC(=O)N[C@@H](COP(=O)(O)O)C(=O)O
Reactant: CCC=CCC=CC/C=C\CCCCCCCC(=O)O
Agent: COC(=O)[C@@H](N)[C@@H](C)O
Agent: Cl
Product: CCC=CCC=CC/C=C\CCCCCCCC(=O)N[C@H](C(=O)O)[C@@H](C)OP(=O)(O)O

Procedure:
This compound was prepared as described above for (6), using 0.5 mmol (139 mg) of cis-9,12,15-octadecatrienoic acid and 1 mmol (170 mg) of L-threonine methyl ester hydrochloride; yield 85 mg (37%); Rf 0.05-0.10 (system B); 1H-NMR (CD3SOCD3, 200 MHz) δ0.9-1.0 (t, 3H, ω-CH3); 1.3-1.5 (m, 13H, 5CH2 and CH3CHOP); 2.0-2.2 (m, 6H, CH2CO and 2CH2CH═CH); 2.7-2.9 (br s, 4H, 2HC═CH—CH2—CH═CH); 4.1-4.3 (m, 2H, 2CH); 5.2-5.4 (br s, 6H, 3HC═CH); 8.2-8.4 (m, 3H, NH and 2POH)
Reaction SMILES: C(O[C:4](=[O:25])/[C:5](=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]2)=[C:13]([O:23][CH3:24])[CH:12]=1)/[CH2:6][CH2:7][CH2:8]Cl)C.[NH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[N:29]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C.CN(C=O)C.O>[Cl:34][C:30]1[N:29]=[C:28]([CH2:27][N:26]2[CH2:8][CH2:7][CH2:6]/[C:5](=[CH:10]\[C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]4)=[C:13]([O:23][CH3:24])[CH:12]=3)/[C:4]2=[O:25])[CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)/C(=C/c1ccc(-n2cnc(C)c2)c(OC)c1)CCCCl
Reactant: NCc1cccc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1cc(/C=C2\CCCN(Cc3cccc(Cl)n3)C2=O)ccc1-n1cnc(C)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a suspension of (E)-5-chloro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl]benzylidene)valeric acid ethyl ester (200 mg) obtained in Example 417 and 2-(aminomethyl)-6-chloropyridine (CA 188637-75-4) hydrochloride (100 mg) in ethanol (3 mL) and DMF (3 mL), anhydrous potassium carbonate (100 mg) was added and the reaction mixture was agitated at 100° C. for 8 hours. After the reaction mixture was allowed to be cooled to room temperature, the reaction mixture was poured into iced water and the reaction solution was extracted with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, and concentrated under reduced pressure after dried over anhydrous magnesium sulfate. Ethanol (10 mL) and sodium hydroxide (1.0 g) aqueous solution (5 mL) were added to the residue, and the reaction solution was agitated at room temperature for 1 hour. The reaction solution was added to iced water and the reaction solution was extracted with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, and it concentrated under reduced pressure after dried over anhydrous magnesium sulfate. 23 mg of the title compound was obtained by the residue was purified by silica gel chromatography (elution solvent: heptane-ethyl acetate system).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:14]([NH:16][CH:17]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)[C:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:19])=[O:15])[CH3:2].[BH4-].[Na+].Cl>CO.[Cl-].[Mn+2].[Cl-]>[CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:14]([NH:16][CH:17]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:33]=1)[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[OH:19])=[O:15])[CH3:2]
Reactant: CCOc1ccc2ccccc2c1C(=O)NC(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(F)cc1
Agent: [Mn+2]
Agent: Cl
Agent: [BH4-]
Solvent: CO
Product: CCOc1ccc2ccccc2c1C(=O)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
To a solution of 2-(ethyloxy)-N-(2-(4-fluorophenyl)-2-oxo-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-1-naphthalenecarboxamide (400 mg, 0.79 mmol) in methanol (30 ml) was added manganese (II) chloride (198 mg, 1.57 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction solution was added sodium borohydride (30 mg, 0.79 mmol) under ice-cooling, and the mixture was stirred for 1 hr. The reaction solution was poured into 1N hydrochloric acid (30 ml), and extracted with ethyl acetate (50 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:1 and recrystallized from ethyl acetate-hexane to give the title compound (227 mg, 57%).
Reaction SMILES: [CH3:1][C:2](=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)[C:3](OCC)=[O:4]>C1(C)C=CC=CC=1>[CH3:1][C:2](=[CH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)[CH2:3][OH:4]
Reactant: CCOC(=O)C(C)=Cc1ccc(C)cc1
Solvent: Cc1ccccc1
Product: CC(=Cc1ccc(C)cc1)CO
Temperature: 3.5 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of ethyl 2-methyl-3-(4-methylphenyl)-2-propenoate (1002 g) in toluene (5371 ml) was added dropwise a 70% solution of dihydrobis(2-methoxyethoxy) sodium aluminate in toluene (2152 g) at 10° C. or below. The solution was stirred at 2 to 5° C. for 1 hr, a 10% solution of Rochel's salt (5968 ml) was added dropwise thereto at 20° C. or below and the solution was stirred at room temperature for 30 min. The toluene layer was fractionated, and washed with a 10% solution of Rochel's salt (2984 ml) and then washed with water. The solvent was distilled off to give the title compound as an oil (756 g, yield 93.9%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[O:26][C:25](=[O:27])[C:24]3[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=3[N:22]=2)[CH2:13][CH2:12]1.[CH:32]([NH2:35])([CH3:34])[CH3:33]>O1CCCC1>[CH:32]([NH:35][C:25](=[O:27])[C:24]1[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=1[NH:22][C:21](=[O:26])[CH2:20][CH2:19][CH2:18][CH2:17][N:14]1[CH2:13][CH2:12][N:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH2:16][CH2:15]1)([CH3:34])[CH3:33]
Reactant: CC(C)N
Reactant: O=c1oc(CCCCN2CCN(c3ccc4ccccc4n3)CC2)nc2ccccc12
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1ccccc1NC(=O)CCCCN1CCN(c2ccc3ccccc3n2)CC1
Temperature: 80 °C
Yield: 58.1 %

Procedure:
In a glass tube, 414 mg of 2-[4-(4-quinolin-2-ylpiperazin-1-yl)butyl]-3,1-benzoxazin-4-one as synthesized in above Step 7-15-B, 590 mg of isopropylamine and 5 ml of tetrahydrofuran were hermetically sealed and stirred for an hour at the exterior temperature of 80° C. Cooling the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting residue was purified on silica gel column chromatography (dichloromethane:methanol=10:1) to provide 275 mg (58%) of N-isopropyl-2-[5-(4-quinolin-2-ylpiperazin-1-yl)pentanoylamino]benzamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([OH:14])=[O:13])[CH2:6][CH2:5]2.C(Cl)(=O)C(Cl)=O.ClCCl.[N+:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O-:26])=[O:25]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([O:14][C:30]1[CH:31]=[CH:32][C:27]([N+:24]([O-:26])=[O:25])=[CH:28][CH:29]=1)=[O:13])[CH2:6][CH2:5]2
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)C1CCc2cc(F)ccc2O1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)C1CCc2cc(F)ccc2O1
Temperature: 25 °C
Reaction time: 17 h
Yield: 40.5 %

Procedure:
A 50 ml rbf was charged with 6-fluoro-3,4-dihydro-2H-chromen-2-carboxylic acid (10.0 g, 51.0 mmol), oxalyl chloride (9.71 g, 76.5 mmol) and dichloromethane (24.9 g) under nitrogen atmosphere at room temperature. The mixture was stirred for 17 h at room temperature and then concentrated in vacuo at 30° C. The residue was dissolved in toluene (75 ml) and stirred at rt. 4-nitrophenol (7.05 g, 51.02 mmol) was added to the reaction mixture, followed by pyridine (5 ml) over the period of 5 min. The slurry was heated to 80° C., stirred for 3 h at this temperature and then cooled to 25° C. The solid was separated by filtration and the filtered solution washed with 2M aqueous sodium hydroxide (65 g), with a saturated solution of sodium bicarbonate (2×51 g), and with demi water (53 g). The separated organic phase was concentrated in vacuo and dried via azeotropic distillation to furnish 4-nitrophenyl 6-fluoro-3,4-dihydro-2H-chromen-2-carboxylate as a vetrous oil (7.71 g, 40.5% yield, 85.0 A %).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=O>CC(O)C>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCCOc1ccccc1
Reactant: O=CN1CCNCC1
Solvent: CC(C)O
Product: c1ccc(OCCCCN2CCNCC2)cc1
Yield: 71.3 %

Procedure:
A mixture of 45.8 g (0.2 moles) of 4-phenoxybutyl bromide and 45.6 g (0.4 moles) of 1-formylpiperazine in 500 ml of 2-propanol was heated at reflux for 18 hours. The mixture was cooled and filtered. The filter was washed with 2-propanol and the filtrate was evaporated to a paste in vacuo. Water was added and the mixture was extracted three times with 200 ml portions of chloroform. The extracts were combined and evaporated to dryness. Then 250 ml of 5N sodium hydroxide was added to the residue. The mixture was refluxed for 18 hours with stirring, cooled and extracted twice with 250 ml portions of chloroform. The extracts were combined, dried over magnisium sulfate and evaporated to an oil. The oil was distilled bp 153°-156° C./0.05 mm of mercury and gave 33.4 g of 1-(4-phenoxybutyl)piperazine as a colorless liquid which crystallized on standing, mp 35°-36° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[CH3:11][C@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.C([O-])([O-])=O.[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1
Reactant: C[C@H]1CCCN1
Reactant: O=[N+]([O-])c1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@H]1CCCN1c1cccc([N+](=O)[O-])c1
Yield: 58.2 %

Procedure:
To a solution of 1-bromo-3-nitrobenzene (2.02 g, 0.01 mol) and (S)-2-methylpyrrolidine (1.02 g, 0.012 mol) in 20 mL of 1,4-dioxane was added Cs2CO3 (6.5 g, 0.02 mol) followed by Pd(dba)2 (1.15 g, 0.002 mmol) and X-Phos (476 mg, 0.001 mol) under nitrogen with stirring. The mixture was refluxed for 16 hours under nitrogen. After cooled, the mixture was filtered, and then the filtrate was evaporated by rotary evaporation. The residue was diluted with water and extracted with EtOAc (3×30 mL). The organic layer was washed with brine and dried over Na2SO4. After filtration and concentration, the residue was purified by column chromatography on silica gel eluting with (petroleum ether:EtOAc=10:1) to give (S)-2-methyl-1-(3-nitrophenyl)pyrrolidine (1.2 g, 57%) as an oil. 1H NMR (300 MHz, CDCl3) δ 7.47-7.44 (m, 1H), 7.37-7.35 (m, 1H), 7.32-7.27 (m, 1H), 6.86-6.83 (m, 1H), 3.95-3.91 (m, 1H), 3.50-3.44 (m, 1H), 3.26-3.18 (m, 1H), 2.18-1.99 (m, 3H), 1.80-1.72 (m, 1H), 1.21 (d, 2H, J=6.3 Hz). LC-MS: 207 [M+H]+, tR=1.75 min.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](C)=[N:7][C:6]=2[CH:11]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2]>[O:9]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:11][C:6]=2[N:7]=[CH:8]1
Reactant: Cc1nc2cc(Cl)ccc2o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: c1ccc2ocnc2c1
Temperature: 100 °C

Procedure:
To form 5-vinyl-2-methylbenzoxazole (4aa), the general procedure was followed using 5-chloro-2-methylbenzoxazole (3d) (167 mg, 1.01 mmol), vinyl MIDA boronate (2g) (218 mg, 1.19 mmol), SPhos (42 mg, 0.10 mmol) and Pd(OAc)2 (11 mg, 0.050 mmol). The reaction time and temperature were modified so that the reaction mixture was heated to 100° C. for 2 h. Benzoxazole 4aa was isolated as a pale golden liquid (152 mg, 96%). TLC (hexanes:EtOAc 3:1) Rf=0.46, visualized by UV (254 nm). 1H-NMR (500 MHz, CDCl3 w/TMS) δ 7.67 (s, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 6.79 (dd, J=17.5, 11.0 Hz, 1H), 5.74 (d, J=17.5 Hz, 1H), 5.24 (d, J=11.0 Hz, 1H), 2.61 (s, 3H). 13C-NMR (125 MHz, CDCl3) δ 164.3, 150.6, 141.9, 136.5, 134.2, 122.9, 116.8, 113.4, 109.9, 14.5. HRMS (EI+) Calculated for C10H9NO (M)+: 159.0684, Found: 159.0685. IR (KBr, cm−1) 3087, 3006, 2984, 2928, 1623, 1622, 1578, 1477, 1433, 1381, 1335, 1262, 1179, 1114, 1040, 989, 918, 881, 840, 815.