Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([O:13][C:14]([F:17])([F:16])[F:15])[CH:7]=1.[FH:18].N1C=CC=CC=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C>[F:18][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([O:13][C:14]([F:17])([F:16])[F:15])[CH:7]=1
Reactant: Nc1ccc(O)c(OC(F)(F)F)c1
Reactant: F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=N[O-]
Agent: [F-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1ccc(F)cc1OC(F)(F)F
Temperature: 100 °C
Yield: 17.9 %

Procedure:
33 mg (0.48 mmol) of sodium nitrite was added to a solution of 77 mg (0.4 mmol) of 4-amino-2-trifluoromethoxyphenol in 0.8 mL of 65% (w/w) hydrofluoric acid/pyridine under argon atmosphere with stirring at an outer bath temperature of 0˜5° C. The outer bath was heated to 5˜10° C. and the mixture was stirred for 30 min until the solution turned brownish red. To the above solution were successively added 90 mg (0.4 mmol) of stannous chloride dihydrate and 105 mg (0.4 mmol) of tetrabutylammonium fluoride trihydrate. The solution was slowly heated to—100° C., allowed to react at this temperature for 3.0 h until it was dark brown. The reaction was stopped, naturally cooled, poured into ice water, and 15 mL of ethyl acetate was added. The organic layer was isolated, and the water layer was extracted with 15 mL×2 of ethyl acetate. The organic layers were combined, successively washed with 30 mL of water and 30 mL of saturated saline, dried over anh. MgSO4, filtered and concentrated. The residue was purified by preparative silica gel thin layer chromatography (mobile phase: petroleum ether: ethyl acetate=2:1) to obtain 14 mg of a pale yellow oil. Yield 17.9%.
Reaction SMILES: C(=O)=O.CC(C)=O.C(NC(C)C)(C)C.C([Li])CCC.Cl[Si](C)(C)C.[F:25][C:26]1[CH:35]=[C:34]2[C:29]([CH2:30][CH2:31][CH2:32][CH:33]2[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:28][CH:27]=1.[Br:42]N1C(=O)CCC1=O.Cl>O1CCCC1.CCCCCC>[Br:42][CH:36]([CH:33]1[C:34]2[C:29](=[CH:28][CH:27]=[C:26]([F:25])[CH:35]=2)[CH2:30][CH2:31][CH2:32]1)[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: CCOC(=O)CC1CCCc2ccc(F)cc21
Reactant: O=C1CCC(=O)N1Br
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(Br)C1CCCc2ccc(F)cc21
Temperature: 25 °C

Procedure:
To a stirred, chilled (dry ice-acetone bath) solution of diisopropylamine (0.3 mL, 1.9 mmol, Aldrich) in tetrahydrofuran (3 mL) under nitrogen was successively added 2.5N n-butyl lithium in hexane (0.8 mL, Aldrich), chlorotrimethylsilane (0.2 mL, 1.8 mmol, Aldrich) and ethyl 2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthyl)acetate (236 mg, 1.0 mmol). The resulting clear solution was stirred for 1h, treated with N-bromosuccinimide (180 mg, 1.0 mmol, Aldrich) and stirred for an additional 0.5h before the dry ice-acetone bath was removed. The reddish cloudy solution was stirred for 2h at room temperature, treated with dilute aq hydrochloric acid (4 meq) and extracted with diethyl ether (30 mL). The ether layer was dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and chromatographed on Silica Gel 60 using dichloromethane-hexane (1:9) as eluent. Fractions containing only ethyl 2-bromo-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthyl)acetate as a 1:4 isomeric mixture were combined and concentrated in vacuo to a clear oil (171 mg, 54%); NMR (DMSO-d6): d 7.00-7.18 (m, 3H, Ar), 5.20 (d, J=6.2 Hz, 0.8H, BrCHCO), 5.17 (d, J=6.2 Hz, 0.2H, BrCHCO), 4.19 (q, 1.6H, CH2OOC), 4.14 (q, 0.4H, CH2OOC), 3.49 (m, 1H, ArCH), 2.69 (m, 2H, ArCH2), 1.81-1.97 (m, 3H, CH, CH2), 1.61-1.67 (m, 1H, CH), 1.21 (t, 2.4H, CH3), 1.07 (t, 0.6H, CH3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[CH:6][CH:5]=1.C1(C)C=CC(S(O[CH2:24][CH2:25][Cl:26])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:24][CH2:25][Cl:26])=[CH:6][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(OCCCl)c(OC)c1
Yield: 88.6 %

Procedure:
By using an identical method as in Example 46, 77 g of 4-hydroxy-5-methoxy-benzoic acid methyl ester, 99.2 g of 2-chloroethyl p-toluene sulfonate, 77.7 g of potassium carbonate, and 1.7 g (4.1 mmol) of methyl-tricapryl ammonium chloride was converted to 91.6 g of the title compound: mass spectrum (electrospray, m/e,): M+H 245.0
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:26](I)[CH3:27]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:26][CH3:27])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc(NCC2CCCC2)c1C
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCN(CC1CCCC1)c1cc(Cl)cc(C(=O)OC)c1C
Temperature: 80 °C
Yield: 91.2 %

Procedure:
To a stirred solution of methyl 5-chloro-3-((cyclopentylmethyl)amino)-2-methylbenzoate (1.0 g, 3.54 mmol) in DMF (10 mL), cesium carbonate (2.31 g, 7.09 mmol) and ethyl iodide (5.53 g, 35.4 mmol) were added. The resulting reaction mass was heated at 80° C. for 12 h. The mixture was cooled to room temperature and filtered. The residue was washed with ethyl acetate and the filtrate was concentrated to a residue which was purified by column chromatography to afford the title compound (1.0 g, 91%).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][CH:14]=2)[CH:4]=[C:3]1[C:24]([O:26]CC)=O.P(Cl)(Cl)(Cl)=O.[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=1[NH:42][NH2:43].C(=O)([O-])[O-].[K+].[K+]>>[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=1[N:42]1[C:24](=[O:26])[C:3]2=[CH:4][N:5]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:17][CH:18]=3)[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]2=[N:43]1
Reactant: CCOC(=O)c1cn(Cc2ccc(-n3cccn3)cc2)c2ccccc2c1=O
Reactant: NNc1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 4-oxo-1-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-1,4-dihydroquinoline-3-carboxylate (0.10 g, 0.27 mmol) was dissolved in phosphorus oxychloride (0.75 mL, 8.0 mmol, 30 equiv) and stirred vigorously for 1 hour at ambient temperature. The mixture was concentrated in vacuo and the residue was concentrated from toluene (3×10 mL). The resulting 4-chloro-3-[(ethyloxy)carbonyl]-1-{[4-(1H-pyrazol-1-yl)phenyl]methyl}quinolinium salt was dissolved in N,N-dimethylformamide (3 mL) and treated with (2,6-difluorophenyl)hydrazine (92 mg, 0.64 mmol, 2.5 equiv) and potassium carbonate (0.18 g, 1.3 mmol, 5 equiv). The mixture was placed into an oil bath preheated to 80° C. for 1 hour, cooled to ambient temperature and concentrated in vacuo. The residue was purified by preparative reverse phase HPLC (82:20 to 5:95; water containing 0.05% trifluoroacetic acid:acetonitrile containing 0.05% trifluoroacetic acid), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 9.18 (1H, s), 8.46 (1H, d, J=2.5 Hz), 8.18 (1H, dd, J=7.9, 1.3 Hz), 7.83 (2H, d, J=8.7 Hz), 7.78 (1H, d, J=9.0 Hz), 7.72 (1H, d, J=1.6 Hz), 7.66-7.57 (2H, m), 7.53 (1H, t, J=7.4 Hz), 7.48 (2H, d, J=8.5 Hz), 7.34 (2H, t, J=8.3 Hz), 6.53 (1H, dd, J=2.4, 1.8 Hz), 5.78 (2H, s) ppm; low resolution mass spectrometry (ES+) m/z 453.9 [(M+H)+; calculated for C26H18F2N5O: 454.1].
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:12][O:13][CH2:14][CH2:15][C:16]1[N:17]([CH2:29][CH2:30][CH2:31][CH2:32][C:33]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[O:34])[C:18]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:28]=1.[OH-].[NH4+:42].C1(S(Cl)(=O)=O)C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:12][O:13][CH2:14][CH2:15][C:16]1[N:17]([CH2:29][CH2:30][CH2:31][CH2:32][C:33]([N:35]2[CH2:36][CH2:37][O:38][CH2:39][CH2:40]2)=[O:34])[C:18]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[C:20]([NH2:42])[C:19]=2[N:28]=1
Reactant: [NH4+]
Reactant: COCCc1nc2cnc3ccccc3c2n1CCCCC(=O)N1CCOCC1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
mCPBA (6.60 g, 28.7 mmol) was added to a solution of 2-(2-methoxyethyl)-1-(5-morpholin-4-yl-5-oxopentyl)-1H-imidazo[4,5-c]quinoline (6.5 g, 17 mmol) in chloroform (100 mL); the reaction was stirred for two hours at ambient temperature. The reaction was cooled to 0° C., and ammonium hydroxide (50 mL) was added. A solution of benzenesulfonyl chloride (4.11 mL, 33.0 mmol) in chloroform (20 mL) was added over a period of 20 minutes, and the reaction was allowed to warm to ambient temperature and stirred for two hours. The work-up procedure and chromatographic purification was carried out as described in Part D of Example 8. The resulting product was triturated with 10% aqueous sodium hydroxide, isolated by filtration, washed with water, and dried overnight in a vacuum oven to provide 2-(2-methoxyethyl)-1-(5-morpholin-4-yl-5-oxopentyl)-1H-imidazo[4,5-c]quinolin-4-amine as an off-white powder, mp 128-129° C.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][NH:11][C:12](=[O:19])[CH2:13][CH2:14][NH:15][CH:16]([CH3:18])[CH3:17].CCN(CC)CC>CC#N>[Br:1][C:2]1[C:3]([N:15]([CH:16]([CH3:18])[CH3:17])[CH2:14][CH2:13][C:12]([NH:11][CH3:10])=[O:19])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CNC(=O)CCNC(C)C
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CNC(=O)CCN(c1nc(Cl)ncc1Br)C(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.5 %

Procedure:
5-Bromo-2,4-dichloropyrimidine (1.83 g, 8.00 mmol), N-methyl-3-(propan-2-ylamino)propanamide (Intermediate 14, 1.16 g, 8.00 mmol) and Et3N (1.2 mL, 8.16 mmol) were combined in MeCN (50 mL) and shaken at ambient temperature for 3 days before the solvent was removed under reduced pressure. Purification by column chromatography (SiO2, eluent gradient 2-10% MeOH to DCM) to afford the title compound (2.08 g, 78%) as a gum.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:28])=[C:4]([NH:10][C@H:11]([C@@H:25]([OH:27])[CH3:26])[C:12]([NH:14][NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:29][C:30]([Si:33](Cl)([CH3:35])[CH3:34])([CH3:32])[CH3:31].N1C=CN=C1>>[Si:33]([O:27][C@@H:25]([CH3:26])[C@@H:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:28])[C:12]([NH:14][NH:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:13])([C:30]([CH3:32])([CH3:31])[CH3:29])([CH3:35])[CH3:34]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(F)cc2)[C@H](C)O)ccc(C#N)c1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(F)cc2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl

Procedure:
N′-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-4-fluoro benzohydrazide (15.2 g, 38.0 mmol) was protected using TBDMSCl (11.32 g, 75.0 mmol) and imidazole (10.23 g, 150 mmol) in a manner analogous to that described for the preparation of intermediate 7b. Purification of the compound was accomplished by pouring the reaction mixture into ice-cold water (1.6 L) and filtering off the solid precipitate. This was taken up in methylene chloride (700 mL) and sequentially washed with water (2×200 mL) and brine (1×200 mL). This was then dried over sodium sulfate, filtered and concentrated down to give a yellow solid. After column chromatography (50% EtOAc/hexanes) the title compound was isolated as a white solid (20 g, quant.). 1H NMR (400 MHz, CDCl3, δ in ppm) 9.32 (m, 2H), 7.77 (dd, J=5.3, 8.8 Hz, 2H), 7.27 (d, J=8.7 Hz, 1H), 7.05 (t, J=8.6 Hz, 2H), 6.54 (d, J=8.7 Hz, 1H), 4.94 (d, J=6.0 Hz, 1H), 4.36 (m, 1H), 4.01 (t, J=5.3 Hz, 1H), 2.26 (s, 3H), 1.35 (d, J=6.4 Hz, 3H), 0.89 (s, 9H), 0.14 (s, 3H), 0.09 (s, 3H).
Reaction SMILES: C(C1C=C2C(=CC=1)N(OC(OC(C)(C)C)=O)C(=O)[C@@H](NC(=O)OC(C)(C)C)C2)C1C=CC=CC=1.[CH2:35]([C:42]1[CH:43]=[C:44]([C:68]([N+:71]([O-:73])=[O:72])=[CH:69][CH:70]=1)[CH2:45][C@@H:46]([C:61]([O:63]C(C)(C)C)=[O:62])[N:47]=C(C1C=CC=CC=1)C1C=CC=CC=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:35]([C:42]1[CH:43]=[C:44]([C:68]([N+:71]([O-:73])=[O:72])=[CH:69][CH:70]=1)[CH2:45][C@@H:46]([C:61]([OH:63])=[O:62])[NH2:47])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1cc(Cc2ccccc2)ccc1[N+](=O)[O-])N=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)OC(=O)N[C@H]1Cc2cc(Cc3ccccc3)ccc2N(OC(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1cc(Cc2ccccc2)ccc1[N+](=O)[O-])C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.2 %

Procedure:
tert-Butyl {(3S)-6-benzyl-1-[(tert-butoxycarbonyl)oxy]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}carbamate (81) To a solution of tert-butyl 3-benzyl-N-(diphenylmethylene)-6-nitro-L-phenylalaninate (79) (150 mg, 0.288 mmol) in dichloromethane was added trifluoroacetic acid in equal volume at 0° C., and the reaction was allowed to stir at RT for 18 h. Solvents were removed under reduced pressure, and the residue was taken in water (50 mL), and washed with EtOAc (3×50 mL). The aqueous layer was concentrated under reduced pressure to provide 3-benzyl-6-nitro-L-phenylalanine (80) as a solid (70.2 mg, 59%). LCMS m/z 301.0 (M+1). This crude product (70.2 mg, 0.234 mmol) was dissolved in a 1:1 mixture of THF and MeOH and treated with sodium acetate (325 mg, 2.34 mmol) and tin(II) chloride dihydrate (269 mg, 1.17 mmol) and stirred for 4 h at 0° C. To the reaction mixture was added triethylamine (0.33 mL, 2.4 mmol) and (BOC)2O (132 mg, 0.585 mmol), and the reaction was allowed to warm to RT and stir for 18 h. The reaction mixture was filtered, and the filtrate was washed with water (3×100 mL), washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 80% EtOAc in heptane) yielded the product as a solid (40 mg, 36%). 1H NMR (500 MHz, CDCl3) δ 1.47 (br s, 9H), 1.56 (br s, 9H), 2.86-3.00 (m, 1H), 3.33-3.43 (m, 1H), 3.94 (s, 2H), 4.47-4.55 (m, 1H), 5.57 (br s, 1H), 6.9-7.1 (v br s, 1H), 7.04 (s, 1H), 7.11 (br d, J=8 Hz, 1H), 7.18 (d, J=7.6 Hz, 2H), 7.21-7.25 (m, 1H), 7.31 (dd, J=7.8, 7.3 Hz, 2H).
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:8])[CH2:4][CH2:5][CH2:6][CH3:7].N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].[NH4+].[Cl-]>CN(C=O)C.C(OCC)(=O)C>[C:17]([Si:14]([O:8][CH:3]([CH2:4][CH2:5][CH2:6][CH3:7])[C:2]#[CH:1])([CH3:16])[CH3:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: C#CC(O)CCCC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#CC(CCCC)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.8 %

Procedure:
To a solution of hept-1-yn-3-ol (5.0 g, 0.0446 mol) in dry DMF (50 mL) were added imidazole (3.64 g, 0.054 mol) and tert-butyldimethylsilyl chloride (6.06 g, 0.054 mol). The resulting mixture was stirred at RT for 18 h and then treated with saturated NH4Cl (25 mL) and ethyl acetate (250 mL). The organic layer was washed with saturated NH4Cl (50 mL), water (4×100 mL), brine (2×100 mL), dried over sodium sulfate, and concentrated in vacuo to afford the crude product (9.57 g, 95%), as a yellow oil, which was used in the next step without further purification. Rf 0.9 (EtOAc/hexanes 1/9); 1H NMR (CDCl3) δ 0.09 (s, 3H), 0.12 (s, 3H), 0.89 (s, 9H), 1.31-1.38 (m, 4H), 1.65-1.67 (m, 2H), 3.35 (s, 1H), 4.32-4.33 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Ca+2].[I:17]Cl.S([O-])([O-])(=O)=S.[Na+].[Na+]>CO.O>[NH2:1][C:2]1[C:10]([I:17])=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: ClI
Reactant: Nc1ccc2c(c1)C(=O)CC2
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Ca+2]
Solvent: O
Solvent: CO
Product: Nc1ccc2c(c1I)C(=O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
6-Amino-1-indanone (5.00 g, 34.0 mmol) was dissolved in a mixed solvent of methanol (200 mL) and water (50 ml), calcium carbonate (6.81 g, 68.0 mmol) and iodine(I) chloride (2.22 mL, 44.2 mmol) were added, and the mixture was stirred at room temperature for 2 hr. To the reaction solution was added saturated aqueous sodium thiosulfate solution, and the organic solvent was evaporated under reduced pressure. To the mixture was added saturated aqueous sodium hydrogencarbonate solution. The mixture was extracted with ethyl acetate and washed with saturated brine. The solvent was evaporated under reduced pressure. The residue was washed with methanol and ethyl acetate to give the title compound (7.95 g, yield 86%).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[H-].[Na+].C([O-])([O-])=O.[Cs+].[Cs+].BrC(C)(C)C([NH2:24])=O>O1CCOCC1.C(Cl)(Cl)Cl.CO.CN1C(=O)N(C)CCC1.CN1C(=O)CCC1>[NH2:24][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Oc1ccnc2ccccc12
Reactant: CC(C)(Br)C(N)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [H-]
Solvent: CN1CCCN(C)C1=O
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Nc1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.2 %

Procedure:
To a solution of 4-hydroxyquinoline (537 mg, 3.70 mmol) in dioxane (20 mL) was added NaH (Aldrich, dry, 300 mg, 12.2 mmol) and Cs2CO3 (4.00 g, 12.2 mmol). The resulting mixture was stirred at room temperature for about 30 minutes, then 2-bromo-2-methyl-propanamide (2.03 g, 12.2 mmol) was added and the resulting mixture was stirred at reflux for 16 h. After the reflux period, NMP (20 mL), DMPU (2 mL), and NaH (Aldrich, dry, 100 mg, 4.07 mmol) were added. The resulting mixture was stirred at 150° C. for 72 h. The reaction was cooled to room temp., and partitioned between water (50 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (100 mL) and the combined organics washed with water (2×50 mL), dried (Na2SO4), and concentrated to about 3 g of material. The brown oil was distilled by Kugelrohr to remove residual NMP and DMPU, then chromatographed on silica (200 mL, 4 cm diam. column), eluting with 9:1 CHCl3 /MeOH then 7:3 CHCl3 /MeOH to obtain 4-aminoquinoline as an off-white solid (140 mg, 0.97 mmol, 26.2% yield).: mp 146-148° C. (lit. 154-155° C., Suzuki, Y., J. Pharm. Soc. Jpn., 1961, 81, 1146); 1H NMR (300 MHz, CDCl3) δ8.30 (d, 1 H, J=6.20 Hz), 8.22 (d, 1 H, J=8.39 Hz), 7.78 (d, 1 H, J=8.89 Hz), 7.68-7.62 (m, 1 H), 7.49-7.38 (m, 3 H), 6.59 (d, 1 H, J=5.99 Hz); MS (EI) 144.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]([CH3:11])=O>>[CH:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:11])[CH3:8]
Reactant: CC(C)=O
Reactant: Nc1ccccc1
Product: CC(C)Nc1ccccc1

Procedure:
N-Isopropylaniline [NMR (200 MHz, DMSO-d6): δ 1.13 (d, J=6.3 Hz, 6H); 3.58 (m, 1H); 5.30 (d, J=8.0 Hz, 1H); 6.49 (t, J=7.2 Hz, 1H); 6.55 (d, J=7.8 Hz, 2H); 7.06 (t, J=7.6 Hz, 2H)] was prepared from aniline and acetone via reductive amination using the general method described by Schellenberg (Schellenberg, K. A. J. Org. Chem. 1963, 28, 3259).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:14][CH3:15])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH2:14][CH3:15])[C:11]([O:13][CH2:21][CH3:22])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(CC)c1ccc([N+](=O)[O-])cc1
Yield: 48 %

Procedure:
In 250 ml of ethanol was dissolved 16.71 g (0.08 mole) of 2-(4-nitrophenyl)-n-butyric acid and 15 ml of conc. sulfuric acid was then added and heated under reflux for 3.5 hours on an oil bath. After the ethanol was distilled off in vacuo, the residue was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated sodium chloride solution and dried over sodium sulfate. After the ethyl acetate was distilled off in vacuo, the residue was subjected to silica gel chromatography eluting with a mixture of benzene and n-hexane (1:1) to give 9.13 g (0.0385 mole, 48% yield) of ethyl 2-(4-nitrophenyl)-n-butyrate.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CN(C)C(CCCC1C=C2C(=CC=1)N(CCC)C=C2C[C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][C:34]=1[O:42][CH3:43])=O.CI>O1CCCC1>[CH3:43][O:42][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:33]=1)[C:37]([OH:39])=[O:38]
Reactant: CCCn1cc(Cc2ccc(C(=O)O)cc2OC)c2cc(CCCC(=O)N(C)C)ccc21
Agent: [Li]CCCC
Solvent: CI
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cccc(C(=O)O)c1
Reaction time: 0.25 h
Yield: 222.7 %

Procedure:
To a mixture of diisopropylamine (2.92 ml) and tetrahydrofuran (17.5 ml), at -78°, under nitrogen, was added 1.17 M n-butyllithium (16.3 ml). After stirring for 15 min, a solution of 4-[5-[3-(dimethylcarbamoyl)propyl]-1-propylindol-3-ylmethyl]-3-methoxybenzoic acid (3.8 g) in tetrahydrofuran (50 ml) was added. The reaction was allowed to warmed to -30° and stirred for 45 min. Methyl iodide (2.71 ml) was added and the mixture stirred for 90 min. The reaction was quenched with saturated ammonium chloride (100 ml) and the organic layer was partitioned between ethyl acetate and saturated ammonium chloride. The organic phase was washed (saturated ammonium chloride, water), dried (MgSO4), and evaporated. The residue was dissolved in saturated sodium bicarbonate. The solution was washed with diethyl ether and acidified to pH 2 with 6N hydrochloric acid. The product was extracted into ethyl acetate, and the organic layer was dried (MgSO4) The solvent was evaporated and the residue was triturated with hexane, powderized and vacuum dried at 40° for 18 hr to afford 4-[5-[3-dimethylcarbamoyl)butyl]1-propylindol-3-ylmethyl]-3methoxybenzoic acid (2.95 g, 75%) as a pale pink solid; mp 60.0°-64.0°.
Reaction SMILES: [CH3:1][C:2]([O:9][CH2:10][CH3:11])([O:6]CC)OCC.C1N=CN(C([N:19]2[CH:23]=NC=C2)=O)C=1>CC(OC(C)=O)=O>[CH2:10]([O:9][C:2](=[O:6])/[C:1](/[C:23]#[N:19])=[C:2](\[O:9][CH2:10][CH3:11])/[CH3:1])[CH3:11]
Reactant: CCOC(C)(OCC)OCC
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)/C(C#N)=C(/C)OCC
Temperature: 140 °C
Reaction time: 8 h

Procedure:
To a 2000 mL round-bottom flask was added CH3C(OEt)3 (583.2 g, 3.6 mol, 1.00 eq.) and Compound [CDI] (407.2 g, 3.6 mol, 1.00 eq.) in Ac2O (1000 mL). The mixture was heated to reflux at 130-150° C. for 3 hours. The reaction mixture was concentrated to a small volume and then allowed to cool to room temperature. The mixture was allowed to sit in refrigerate overnight. The precipitated solid was filtered and dried in vacuo to give Compound [CDII] as yellow solid: LCMS (m/e) 184 (M+H).
Reaction SMILES: COC1C=C(C=C(OC)C=1OC)C=O.COC1C=C(C=C(OC)C=1OC)C(CCC(O)=O)=O.N1CCC[C@H]1C(O)=O.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([CH:61]=[C:62]([O:66][CH3:67])[C:63]=1[O:64][CH3:65])[C:47]([CH2:49][CH2:50][C:51]([N:53]1[CH2:60][CH2:59][CH2:58][C@H:54]1[C:55]([OH:57])=[O:56])=[O:52])=[O:48].[Br:68]Br>C(O)(=O)C>[Br:68][CH:49]([C:47](=[O:48])[C:46]1[CH:61]=[C:62]([O:66][CH3:67])[C:63]([O:64][CH3:65])=[C:44]([O:43][CH3:42])[CH:45]=1)[CH2:50][C:51]([N:53]1[CH2:60][CH2:59][CH2:58][C@H:54]1[C:55]([OH:57])=[O:56])=[O:52]
Reactant: BrBr
Reactant: COc1cc(C(=O)CCC(=O)N2CCC[C@H]2C(=O)O)cc(OC)c1OC
Agent: COc1cc(C(=O)CCC(=O)O)cc(OC)c1OC
Agent: COc1cc(C=O)cc(OC)c1OC
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CC(=O)O
Product: COc1cc(C(=O)C(Br)CC(=O)N2CCC[C@H]2C(=O)O)cc(OC)c1OC

Procedure:
As described in Example 52, 3,4,5-trimethoxybenzaldehyde is converted to 3-(3,4,5-trimethoxybenzoyl)propionic acid. The preceding compound is converted to the hydroxysuccinimide ester as described in Example 15 and coupled to L-proline as described in Example 16. The 1-[3-(3,4,5-trimethoxybenzoyl)propionyl]-L-proline is reacted with bromine in acetic acid as in Example 20 to give 1-[3-bromo-3-(3,4,5-trimethoxybenzoyl)propionyl]-L-proline. The preciding compound is reacted with potassium thioacetate in ethanol-water as in Example 21 to give the product of the Example as a glass.