Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:32])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=O)[CH2:10]CCCCCCCCCC/C=C\CCCCCCCC.[C:33]([OH:56])(=O)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]/[CH:45]=[CH:46]\[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54].[Cl-].N1C=CC(C2[NH:68][CH:67](C(O)=O)[CH2:66][S:65]2)=CC=1>N1C=CC=CC=1.C(Cl)Cl>[C:33]([N:68]1[CH:67]=[CH:66][S:65][C:4]1([C:8]1[CH:7]=[CH:6][N:5]=[CH:9][CH:10]=1)[C:3]([OH:2])=[O:32])(=[O:56])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]/[CH:45]=[CH:46]\[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)N1CCC[C@H]1C(=O)OC
Reactant: O=C(O)C1CSC(c2ccncc2)N1
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)O
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)N1C=CSC1(C(=O)O)c1ccncc1
Yield: 99 %

Procedure:
In a manner similar to (i), erucic acid (1 g) was converted to its chloride, to which was added 2-(4-pyridinyl)-4-thiazolidine carboxylic acid (618 mg). The mixture was stirred in pyridine (6 ml)-methylene chloride (2 ml) at room temperature for two hours. The solvent was concentrated, then the residue was washed with water. Resultant precipitates were dried and purified by means of a silica gel column chromatography (chloroform:methanol=10:1), followed by recrystallization from methanol to afford colorless crystals [1.58 g (yield 99%)], m.p. 156 to 158° C.
Reaction SMILES: [O:1]=[C:2]1[CH:11]2[CH2:12][CH2:13]O[C:10]2=[C:9]2[C:4]([C:5]([O:15][CH3:16])=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[CH3:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20]>C(O)COCCO.O>[CH3:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[N:20]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:15][CH3:16])[C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[CH2:12][CH2:13]1
Reactant: Cc1ccccc1N
Reactant: COc1cccc2c1=NC(=O)C1CCOC=21
Solvent: O
Solvent: OCCOCCO
Product: COc1cccc2c3c(c(=O)[nH]c12)CCN3c1ccccc1C
Temperature: 250 °C
Yield: 76.7 %

Procedure:
4-Oxo-6-methoxy-2,3-dihydrofuro[3,2-c]quinoline (217 mg, 1.0 mmol) was dissolved in 10 ml of diethylene glycol in a pressure tube and 2-methylaniline (267 μl, 2.5 mmol) was added under nitrogen. The reaction mixture was heated at 250° C. for 15 hours. The reaction mixture was diluted with 20 ml of salt water and the aqueous layer was extracted with methylene chloride (15 ml×3). After washing with water (15 ml×3), the organic layer was dried by anhydrous magnesium sulfate and filtered, amd concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent by silica gel chromatography to obtain 235 mg of desired compound as solid in 77% of yield.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH2:13][CH2:14][CH3:15])[CH2:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:16][CH3:17].[Br:18]Br.C1CCN2C(=NCCC2)CC1>CC#N>[C:9]1(=[O:12])[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:11]=2)[CH2:6][CH2:7][CH2:8]1.[Br:18][C:8]1[C:7]([CH2:13][CH2:14][CH3:15])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([F:1])=[C:3]([O:16][CH3:17])[CH:4]=2)[C:9]=1[OH:12]
Reactant: BrBr
Reactant: CCCC1CC(=O)c2cc(F)c(OC)cc2C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCc1cc2cc(OC)c(F)cc2c(O)c1Br
Product: O=C1CCCc2ccccc21

Procedure:
Treatment of 7-fluoro-6-(methyloxy)-3-propyl-3,4-dihydro-1(2H)-naphthalenone (133) (0.40 g, 1.69 mmol) with bromine followed by DBU in CH3CN gave 0.52 g (98% from tetralone) of the title compound (134) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 1.01 (t, J=7.3 Hz, 3H), 1.65-1.75 (m, 2H), 2.78 (t, J=7.7 Hz, 2H), 3.98 (s, 3H), 6.05 (s, 1H), 7.07 (d, J=8.2 Hz, 1H), 7.15 (s, 1H), 7.79 (d, J=12.3 Hz, 1H). LCMS (ESI): m/z 313 (M+H)+, m/z 311 (M−H)−.
Reaction SMILES: [CH3:1][N:2]1[C@H:8]([CH2:9][OH:10])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[CH3:18][S:19]([O:10][CH2:9][C@@H:8]1[CH2:7][CH2:6][C:3]2([CH2:5][CH2:4]2)[N:2]1[CH3:1])(=[O:21])=[O:20]
Reactant: CN1[C@H](CO)CCC12CC2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1[C@H](COS(C)(=O)=O)CCC12CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
A mixture of (5S)-4-methyl-5-(hydroxymethyl)-4-azaspiro[2.4]heptane (0.2 g, 1.42 mmol) and triethylamine (0.287 g, 2.84 mmol, Shantou Xilong chemical factory) in 5 mL of dichloromethane was stirred at 0° C. for 30 min. To the mixture was added methanesulfonyl chloride (0.325 g, 2.84 mmol, Shanghai Haiqu chemical. Ltd.) via a syringe. The reaction mixture was stirred at 0° C. for 4 hrs and quenched with a mixture of 5 mL of saturated Na2CO3 aqueous solution and 5 mL of water. The resulted mixture was extracted with dichloromethane (20 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo to give ((55)-4-methyl-4-azaspiro[2.4]heptane-5-yl)methyl methanesulfonate as yellow oil (150 mg, 48%).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][N:14]=[C:13]([NH:21][CH2:22][C:23]2[CH:24]=[N+:25]([O-:33])[CH:26]=[CH:27][C:28]=2[C:29]([F:32])([F:31])[F:30])[N:12]=1.[NH2:34][CH:35]1[C:38]([CH3:40])([CH3:39])[CH:37]([OH:41])[C:36]1([CH3:43])[CH3:42]>C(O)C>[OH:41][CH:37]1[C:38]([CH3:40])([CH3:39])[CH:35]([NH:34][C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][N:14]=[C:13]([NH:21][CH2:22][C:23]3[CH:24]=[N+:25]([O-:33])[CH:26]=[CH:27][C:28]=3[C:29]([F:32])([F:31])[F:30])[N:12]=2)[C:36]1([CH3:43])[CH3:42]
Reactant: [O-][n+]1ccc(C(F)(F)F)c(CNc2ncc(C(F)(F)F)c(Cl)n2)c1
Reactant: CC1(C)C(N)C(C)(C)C1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC1(C)C(O)C(C)(C)C1Nc1nc(NCc2c[n+]([O-])ccc2C(F)(F)F)ncc1C(F)(F)F
Temperature: 80 °C

Procedure:
DIEA (3.0 equiv.) was placed in a sealable flask with 3-(((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)-4-(trifluoromethyl)pyridine 1-oxide (1.0 equiv.), 3-amino-2,2,4,4-tetramethylcyclobutanol (2.0 equiv.)(See J. Med. Chem. 2011, 54, 7693-7704 for preparation), and ethanol. The flask was purged with nitrogen and sealed. The reaction mixture was heated to 80° C. for 9 h. Standard work-up afforded the following compounds. Stereochemistry was assigned based on similar activity as other compounds provided herein in the biochemical assays described herein.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][NH:11][C:12]([NH2:14])=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:16][C:17]1[CH:36]=[CH:35][C:20]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33]Cl)=[CH:29][CH:28]=2)=[CH:19][CH:18]=1.Cl>CN(C)C=O>[CH2:3]([O:10][N:11]([CH2:16][C:17]1[CH:36]=[CH:35][C:20]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][N:11]([O:10][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:12]([NH2:14])=[O:13])=[CH:29][CH:28]=2)=[CH:19][CH:18]=1)[C:12]([NH2:14])=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NC(=O)NOCc1ccccc1
Reactant: ClCc1ccc(OCCCCOc2ccc(CCl)cc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)N(Cc1ccc(OCCCCOc2ccc(CN(OCc3ccccc3)C(N)=O)cc2)cc1)OCc1ccccc1
Temperature: 80 °C
Reaction time: 7.5 h
Yield: 63.2 %

Procedure:
60% Sodium hydride (0.41 g) and 1.71 g of benzyloxyurea were added to 20 ml of dimethylformamide and the mixture was stirred at 80° C. for 7.5 hours. 1,4-Bis(4-chloromethylphenoxy)butane (1.74 g) was added to the reaction mixture at room temperature and the mixture was stirred at 95° C. for 0.5 hour. The reaction product was cooled to room temperature, poured into ice water, mixed with 1N hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride aqueous solution in that order and dried over anhydrous magnesium sulfate and then the solvent was evaporated under a reduced pressure. The resulting crude product was washed with ethyl acetate to obtain 1.94 g of 1,4-bis[4-[(1-benzyloxyureido)methyl]phenoxy]butane.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3OC)[C:16]3[S:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[C:35]([CH3:42])[CH:34]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]4[S:20][N:19]=[CH:18][N:17]=4)(=[O:13])=[O:14])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[C:35]([CH3:42])[CH:34]=1
Reactant: Cc1cc(Cl)ccc1B(O)O
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Cl)ccnc3c2)c(OC)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(Cl)ccc1-c1ccnc2cc(S(=O)(=O)Nc3ncns3)ccc12
Temperature: 90 °C
Reaction time: 1 h
Yield: 49.6 %

Procedure:
A vial was charged with 4-chloro-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)quinoline-7-sulfonamide (INTERMEDIATE QQQQ, 55.8 mg, 0.117 mmol), (4-chloro-2-methylphenyl)boronic acid (Indofine Chemical, Hillsborough, N.J., 21.93 mg, 0.129 mmol), Pd(AmPhos)2Cl2 (4.14 mg, 5.85 mmol), potassium phosphate (74.5 mg, 0.351 mmol), 1,4-dioxane (439 μl), and water (146 μl). The vial was flushed with Ar (g), then sealed and heated in a Biotage Initiator microwave reactor for 30 min h at 90° C. LCMS showed two peaks with mass of protected desired product. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The residue was dissolved in DCM (1 mL) and TFA (0.5 mL). After 1 h, triflic acid (0.05 mL) was added drop wise. Following an additional 1 h of stirring, the mixture was diluted with 2-PrOH, then concentrated. The residue was purified by chromatography on silica gel (25-g Interchim column, 0-60% EtOAc/Heptane, then with 100% EtOAc). The resulting material was further purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-6% MeOH/DCM) to give 4-(4-chloro-2-methylphenyl)-N-(1,2,4-thiadiazol-5-yl)quinoline-7-sulfonamide (24.08 mg, 0.058 mmol, 49.4% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=9.10 (d, J=4.4 Hz, 1H), 8.48 (d, J=1.8 Hz, 1H), 8.42 (s, 1H), 7.88 (dd, J=2.0, 8.8 Hz, 1H), 7.61-7.53 (m, 3H), 7.43 (dd, J=1.9, 8.1 Hz, 1H), 7.29 (d, J=8.1 Hz, 1H), 1.97 (s, 3H). m/z (ESI) 417.2 (M+H)+.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]2[O:11][CH2:12][O:13][C:7]=2[CH:6]=1)([CH3:3])[CH3:2].[N-:14]=[C:15]=[O:16].[Na+].[OH-].[Na+]>C(O)(=O)C>[CH:1]([N:4]([C:5]1[CH:10]=[CH:9][C:8]2[O:11][CH2:12][O:13][C:7]=2[CH:6]=1)[C:15]([NH2:14])=[O:16])([CH3:3])[CH3:2]
Reactant: CC(C)Nc1ccc2c(c1)OCO2
Reactant: [N-]=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)N(C(N)=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 14.7 gm. of N-isopropyl-3,4-methylenedioxyaniline, prepared as in Example A, in 200 ml. of glacial acetic acid, cooled to 10°-18°C., is added 4.9 gm. of sodium isocyanate (sodium cyanate) in several portions. The resulting mixture is then stirred at ambient temperature for 15 hours. At the end of this time, the solvent is stripped at reduced pressure and the solid residue treated with 300 ml. of 2N sodium hydroxide. The resulting mixture is extracted with chloroform, dried and evaporated. The gum thus obtained is recrystallized from cyclohexane to obtain N-isopropyl-N-(3,4-methylenedioxyphenyl)urea, m.p. 116°-119°C.
Reaction SMILES: [N:1]1([C:80]([O:82][CH2:83][C:84]2[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=2)=[O:81])[CH2:79][CH2:78][CH2:77][C@H:2]1[C:3]([NH:5][C@H:6]([C:17]([NH:19][C@H:20]([C:36]([NH:38][C@H:39]([C:50]([NH:52][C@H:53]([C:69]([NH:71][CH2:72][C:73]([O:75]C)=[O:74])=[O:70])[CH2:54][CH2:55][CH2:56][CH2:57][NH:58][C:59]([O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:60])=[O:51])[C@@H:40]([CH3:49])[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:37])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:18])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:16])[NH:12][N+:13]([O-:15])=[O:14])=[O:4].[OH-].[Na+]>CN(C=O)C.CO>[N:1]1([C:80]([O:82][CH2:83][C:84]2[CH:85]=[CH:86][CH:87]=[CH:88][CH:89]=2)=[O:81])[CH2:79][CH2:78][CH2:77][C@H:2]1[C:3]([NH:5][C@H:6]([C:17]([NH:19][C@H:20]([C:36]([NH:38][C@H:39]([C:50]([NH:52][C@H:53]([C:69]([NH:71][CH2:72][C:73]([OH:75])=[O:74])=[O:70])[CH2:54][CH2:55][CH2:56][CH2:57][NH:58][C:59]([O:61][CH2:62][C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1)=[O:60])=[O:51])[C@@H:40]([CH3:49])[O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:37])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])=[O:18])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:16])[NH:12][N+:13]([O-:15])=[O:14])=[O:4]
Reactant: COC(=O)CNC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@@H](NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)[C@@H](C)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
A solution of compound (i) (0.87 g, 0.0007 M) in 50% DMF/methanol (30 ml) was treated with 1 N NaOH solution (1.7 ml) and stirred at R.T. for 2 hours. Acidification precipitated the product (0.43 g) in 50% yield. T.L.C. 2:1 CHCl3 :MeOH (I2 stain) showed one spot at Rf 0.77. [α]D25° =-4.1° (C=1, AcOH). The NMR was consistent with structure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1.[N+:13]([CH:15](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:16])#[C-:14].C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:14]=[N:13][C:15]=2[CH3:16])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccc(-c2ocnc2C)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-formyl-benzoic acid methyl ester (2.50 g), 1-(1-isocyano-ethanesulfonyl)-4-methyl-benzene (3.19 g), and potassium carbonate (2.76 g) in methanol (50 mL) is heated to reflux for 2 h. After cooling to room temperature, the mixture is poured onto water and extracted with dichloromethane. The organic phase is washed with water, dried over Na2SO4 and concentrated in vacuo. The residue is chromatographed on silica gel (dichloromethane/methanol 40:1) to afford the title compound. LC (method 6): tR=2.68 min; Mass spectrum (ESI+): m/z=218 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH:15]=[O:16].FC(F)(F)S(O[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[Si](C)(C)C)(=O)=O.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1>[Cl:11][C:12]1[CH:13]=[C:14]([CH:15]2[O:16][CH:2]3[CH:3]=[CH:4][C:5]4[C:10]([N:1]3[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]2=3)=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: c1ccc2ncccc2c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccc(C2OC3C=Cc4ccccc4N3c3ccccc32)cc1Cl
Yield: 67 %

Procedure:
Following the general procedure, treatment of quinoline (0.064 g, 59 μL, 0.50 mmol) and 3,4-dichlorobenzaldehyde (0.130 g, 0.75 mmol) with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.179 g, 146 μL, 0.60 mmol) in the presence of KF (0.070 g, 1.2 mmol) and 18-crown-6 (0.317 g, 1.2 mmol) in THF (2.0 mL) at −10° C. to room temperature for 12 hrs followed by flash column chromatography (Pet. ether/EtOAc=75/25) of the crude reaction mixture afforded 5-(3,4-dichlorophenyl)-5H,6aH-benzo[4,5][1,3]oxazino[3,2-a]quinoline as a yellow solid (0.127 g, 67% yield, dr determined by 1H NMR analysis of crude reaction mixture is >20:1).
Reaction SMILES: [N+:1](=[CH2:3])=[N-:2].[Br:4][C:5]1[CH:6]=[C:7]([CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH3:15])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].C(O)(=O)C>CCOCC.C(OCC)(=O)C>[Br:4][C:5]1[CH:6]=[C:7]([CH:13]2[CH2:3][N:1]=[N:2][C:14]2([CH3:15])[N+:16]([O-:18])=[O:17])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: C=[N+]=[N-]
Reactant: COc1ccc(C=C(C)[N+](=O)[O-])cc1Br
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1ccc(C2CN=NC2(C)[N+](=O)[O-])cc1Br
Reaction time: 28 h
Yield: 100.8 %

Procedure:
An ethereal solution of diazomethane (3.0 mL, 0.3M, 0.9 mmol) was added to 1-(3-bromo-4-methoxyphenyl)-2-nitropropene (250 mg, 0.92 mmol) dissolved in 2.5 mL of ether, and the solution was allowed to stand at room temperature for 28 h. Acetic acid (0.25 mL, 0.26 g, 4.4 mmol) was then added to the almost colorless solution, giving some gas evolution. After 15 min, the solution was diluted with 25 mL of ethyl acetate and washed with 10 mL of saturated aqueous sodium bicarbonate followed by 10 mL of saturated aqueous sodium chloride. The organic layer was dried (sodium sulfate), decanted, and evaporated to give 285 mg (99% yield) of a colorless oil which crystallized upon standing. 1H NMR (400 MHz, CDCl3): δ 7.17 (d, 1H, J=2 Hz), 6.89 (dd, 1H, J=8, 2 Hz), 6.84 (d, 1H, J=8 Hz), 5.21 (dd, 1H, J=18, 8 Hz), 4.97 (dd, 1H, J=18, 6 Hz), 3.90 (s, 3H), 3.77 (dd, 1H, J=8, 6 Hz), 1.60 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].C([O-])([O-])=O.[K+].[K+].[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.O>[N+:13]([C:5]1[CH:4]=[CH:3][C:2]([O:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O-:15])=[O:14]
Reactant: CCOC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 130 °C
Yield: 36 %

Procedure:
To a stirring suspension of ethyl 5-chloro-2-nitrobenzoate (15 g, 65.3 mmol) and K2CO3 (13.54 g, 98 mmol) in DMF (5 ml) was added phenol (6.76 g, 71.9 mmol). Reaction mixture was heated at 130° C. for 16 h. Reaction mixture was diluted with water and extracted with EtOAc. The organic layer was separated and distilled out to get crude product which was column purified using 10% EtOAC in hexane to get the titled compound in 36% yield.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[N:14](C(OC(C)(C)C)=O)[C:13]1=[O:26].[H-].[Na+].Cl([F:33])(=O)(=O)=O.Cl>CN(C)C=O.C(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1([F:33])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:26]
Reactant: CC(C)(C)OC(=O)N1C(=O)CCC(N2C(=O)c3ccccc3C2=O)C1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CCC(F)(N2C(=O)c3ccccc3C2=O)C(=O)N1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1,3-dioxo-2-(1-tert.-butoxycarbonyl-2,6-dioxopiperidin-3-yl)-isoindoline (1.0 g. 2.8 mmol) in dimethylformamide (10 mL) is added sodium hydride (112 mg, 2.8 mmol, 60%) at room temperature. After about 30 minutes, perchloryl fluoride (5 mmol) is bubbled into the mixture. The mixture is stirred with methylene chloride (10 mL) and 1N hydrochloric acid (10 mL) for one hour. The organic layer is separated and the solvent removed in vacuo to yield 1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidin-3-yl)isoindoline which can be further purified through chromatography.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][C:13]2([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])[CH2:16][CH:9]1[CH2:10][CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-:26].[K+].[K+].OO>CS(C)=O>[CH2:1]([N:8]1[CH2:15][CH2:14][C:13]2([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]([NH2:21])=[O:26])[CH2:16][CH:9]1[CH2:10][CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cccc(C23CCCC(C2)N(Cc2ccccc2)CC3)c1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1cccc(C23CCCC(C2)N(Cc2ccccc2)CC3)c1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
3-(2-Benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzonitrile (1.95 g, 6.16 mmol) in DMSO (55 ml) was charged with potassium carbonate (120 mg, 0.86 mmol) then 30% aqueous hydrogen peroxide (3.2 ml, 30.8 mmol). The reaction mixture was allowed to stir at room temperature for 23 h at which time it was determined not to have proceeded. Additional potassium carbonate (850 mg, 6.16 mmol) and 30% aqueous hydrogen peroxide (6.4 ml, 61.6 mmol) were introduced and stirred for 5.5 h. After a water quench (50 ml), the product was extracted with EtOAc (3×50 ml), washed with 50% saturated aqueous NaCl solution (5×50 ml), dried over Na2SO4, filtered and concentrated to a white solid which was triturated with hexanes and collected (1.0 g, 49%). (TLC 50% EtOAc/hexanes Rf 0.08); 1H NMR (400 MHz, CDCl3) δ 7.83–7.85 (m, 1H), 7.49–7.57 (m, 1H), 7.40–7.47 (m, 1H), 7.38–7.28 (m, 5H), 7.21–7.25 (m, 1H), 6.10 (brs, 1H), 5.63 (brs, 1H); 3.74–3.82 (m, 2H), 3.06–3.15 (m, 2H), 2.86–2.96 (m, 1H), 2.16–2.26 (m, 2H), 1.96–2.08 (m, 4H), 1.84–1.89 (m, 1H), 1.68–1.74 (m, 1H), 1.59–1.65 (m, 1H), 1.34–1.42 (m, 1H); APCI MS m/z 335.1 (M+1)+.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[C:19]([NH:22]C(=O)OC(C)(C)C)[CH:20]=5)[NH:15][C:14]4=[O:30])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:34][CH2:33]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:30])[C:13]12[CH2:12][CH:11]1[C:7]1[CH:6]=[C:5]2[C:10]([C:2]([C:41]3[CH:40]=[CH:39][C:38]([N:35]4[CH2:34][CH2:33][N:32]([CH3:31])[CH2:37][CH2:36]4)=[CH:43][CH:42]=3)=[N:3][NH:4]2)=[CH:9][CH:8]=1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)C1(CC1c1ccc3c(I)n[nH]c3c1)C(=O)N2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(c2ccc(-c3n[nH]c4cc(C5CC56C(=O)Nc5ccc(N)cc56)ccc34)cc2)CC1
Reaction time: 1 h
Yield: 5.1 %

Procedure:
The Suzuki coupling was executed according to the method in Example A45, except substituting tert-butyl 2-(3-iodo-1H-indazol-6-yl)-2′-oxospiro[cyclopropane-1,3′-indoline]-5′-ylcarbamate (70 mg, 0.136 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (57 mg, 0.190 mmol). The resulting product was dissolved into CH2Cl2 (1.0 mL) and TFA (50 uL) was added. After 1 h the reaction was complete, the solvent was removed and the residue purified by prep-HPLC to give a white powder (3.2 mg, 15%); 1H NMR (400 MHz, CD3OD) δ 7.94 (d, J=8.6 Hz, 1H), 7.87 (d, J=8.4 Hz, 2H), 7.53 (s, 1 H), 7.18 (d, J=8.8 Hz, 2H), 7.05-7.02 (m, 3H), 6.04 (s, 1H), 4.01-3.97 (bs, 2H), 3.75-3.65 (bs, 2H), 3.46 (t, J=8.4 Hz, 1H), 3.32-3.28 (bs, 2H), 3.18-3.08 (bs, 2H), 3.00 (s, 3H), 2.35-2.31 (m, 1H), 2.29-2.25 (m, 1H); MS ESI [M+H]+ 465.1, calcd for [C28H28N6O+H]+ 465.24.