Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16]O)[CH2:10][CH:9]1[C:18](=[O:35])[NH:19][CH:20]([CH:24]1[CH:29]([OH:30])[CH:28]([OH:31])[CH:27]([OH:32])[CH:26]([S:33][CH3:34])[O:25]1)[CH:21]([CH3:23])[CH3:22])=O)(C)(C)C.[C-:36]#[N:37].[Na+]>>[CH3:22][CH:21]([CH3:23])[CH:20]([NH:19][C:18]([CH:9]1[CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][C:36]#[N:37])[CH2:12][CH2:13][NH:8]1)=[O:35])[CH:24]1[CH:29]([OH:30])[CH:28]([OH:31])[CH:27]([OH:32])[CH:26]([S:33][CH3:34])[O:25]1
Reactant: CSC1OC(C(NC(=O)C2CC(CCCO)CCN2C(=O)OC(C)(C)C)C(C)C)C(O)C(O)C1O
Reactant: [C-]#N
Agent: [Na+]
Product: CSC1OC(C(NC(=O)C2CC(CCCC#N)CCN2)C(C)C)C(O)C(O)C1O

Procedure:
The title compound of example 23 was prepared from protected tosylate intermediate prepared in example 19, 11h according to the procedure used in examples 19–21 using sodium cyanide nucleophile in the displacement step; MS (ESPOS): 430.3 [M+H]+.
Reaction SMILES: [H-].[Na+].[O:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH:4]1[CH2:13][OH:14].O>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:6]([O:14][CH2:13][CH:4]1[CH2:5][CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:3]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCC1CCc2ccccc2O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COCC2CCc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A suspension of 60% sodium hydride dispersion in mineral oil (0.711 g, 17.8 mmol, previously washed with dry petroleum ether) in dry N,N-dimethylformamide (30 ml) was added; under inert atmosphere, with 2-chromanemethanol (1.218 g, 7.43 mmol) dissolved in N,N-dimethylformamide (15 ml) and the mixture was left under stirring at room temperature for 1 h. After that a solution of benzyl hbromide (2.12 ml, 17.8 mmol) in N,N-dimethylformamide (20 ml) and some crystals of tetrabutylammonium iodide were added stirring at room temperature for 18 h. Afterwards, water (10 ml) was added and the solvent was evaporated off under reduced pressure. The obtained residue was partitioned in a mixture of water (70 ml) and ethyl ether (70 ml), the phases were separated and the aqueous one was extracted with ethyl ether (3×70 ml). The combined organic phases were dried and the solvent was evaporated off under reduced pressure, to obtain a crude which was purified by flash chromatography through a silica gel column. Eluting with petroleum ether:ethyl ether, 9:1, 1.569 g of the title product were recovered (83% yield).
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([N+:22]([O-:24])=[O:23])=[C:14]([N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)[CH:15]=2)[NH:10][C:9](=[O:25])[C:8]1=[O:26])(=O)C.[ClH:27]>>[ClH:27].[OH:4][CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([N+:22]([O-:24])=[O:23])=[C:14]([N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)[CH:15]=2)[NH:10][C:9](=[O:25])[C:8]1=[O:26]
Reactant: CC(=O)OCCn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(-n3ccnc3)cc21
Agent: Cl
Product: O=c1[nH]c2cc([N+](=O)[O-])c(-n3ccnc3)cc2n(CCO)c1=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
In 5 ml of 4N-hydrochloric acid was dissolved 250 mg of 1-(2-acetoxyethyl)-7-(1-imidazolyl)-6-nitroquinoxaline-2,3-(1H,4H)-dione of Example 17-14 and the solution was stirred at 100° C. for 3 hours. The reaction mixture was concentrated, followed by addition of methanol, whereupon crystals separated out. The crystals were recovered by filtration to provide 200 mg of 1-(2-hydroxyethyl)-7-(1-imidazolyl)-6-nitroquinoxaline-2,3-(1H,4H)-dione hydrochloride.
Reaction SMILES: CN1C=CN=C1.[CH:7]1([CH2:12][C@H:13]([CH2:30][N:31]([CH:39]=[O:40])[O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[C:14]([N:16]2[CH:20]([C:21]([OH:23])=O)[CH2:19][CH2:18][N:17]2[C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1.S(Cl)(C)(=O)=O.[N:46]1[CH:51]=[CH:50][CH:49]=[N:48][C:47]=1[NH2:52]>CN(C)C=O>[CH:7]1([CH2:12][C@H:13]([CH2:30][N:31]([CH:39]=[O:40])[O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[C:14]([N:16]2[C@H:20]([C:21]([NH:52][C:47]3[N:48]=[CH:49][CH:50]=[CH:51][N:46]=3)=[O:23])[CH2:19][CH2:18][N:17]2[C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Nc1ncccn1
Reactant: C=CCOC(=O)N1CCC(C(=O)O)N1C(=O)[C@H](CC1CCCC1)CN(C=O)OC1CCCCO1
Agent: CS(=O)(=O)Cl
Agent: Cn1ccnc1
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1CC[C@@H](C(=O)Nc2ncccn2)N1C(=O)[C@H](CC1CCCC1)CN(C=O)OC1CCCCO1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 23.8 %

Procedure:
1-Methylimidazole (38.1 μl, 0.478 mmol) was added into the solution of 2-((2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoyl)-1-[(2-propen-1-yloxy)carbonyl]-3-pyrazolidinecarboxylic acid (115 mg, 0.239 mmol) in N,N-dimethylformamide (DMF) (1.6 ml). The resulting solution was cooled to 0° C., and then mesyl chloride (19.41 μl, 0.251 mmol) was added dropwise at 0° C. To the reaction mixture was added 2-pyrimidinamine (34.1 mg, 0.358 mmol). After stirring for 3.5 hrs at ambient temperature, the reaction solution was purified by RP-HPLC to yield 2-propen-1-yl (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoyl)-3-[(2-pyrimidinylamino)carbonyl]-1-pyrazolidinecarboxylate (32 mg, 0.057 mmol, 24% yield). MS (ES+) m/z 559.0 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Reactant: C1CCNCC1
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
In THF (250 ml) was dissolved 3-nitrobenzyl chloride (25.0 g), and to the mixture was added piperidine (36 ml). The reaction mixture was stirred at room temperature for 20 hours. To the mixture was added water (500 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate) to give 1-(3-nitrobenzyl)piperidine (32.2 g) as pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:21][CH2:22][C@:23]([CH3:28])([CH:25]1[CH2:27][CH2:26]1)[OH:24]>>[Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([NH:21][CH2:22][C@:23]([CH:25]1[CH2:27][CH2:26]1)([OH:24])[CH3:28])=[O:9]
Reactant: O=C(O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Reactant: C[C@@](O)(CN)C1CC1
Product: C[C@@](O)(CNC(=O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 1c, using 5-bromo-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinic acid and (S)-α-(aminomethyl)-α-methyl-cyclopropanemethanol as starting materials, MS (ISP) 465.0, 467.1 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:8]1[CH:13]=[C:12](C)[CH:11]=[CH:10][N:9]=1)([OH:7])[CH2:4][CH2:5][CH3:6].[CH3:15]C1N=C(C#N)C=CC=1.C([Mg]Br)CC>>[NH2:1][CH2:2][C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:15])[N:9]=1)([OH:7])[CH2:4][CH2:5][CH3:6]
Reactant: Cc1cccc(C#N)n1
Reactant: CCCC(O)(CN)c1cc(C)ccn1
Agent: CCC[Mg]Br
Product: CCCC(O)(CN)c1cccc(C)n1

Procedure:
The title material was prepared as described for the synthesis of 1-amino-2-(4-methylpyridin-2-yl)pentan-2-ol (Example L) in using 6-methylpicolinonitrile and propyl magnesium bromide. LC/MS (M+H)+: 195. HPLC ret. time (Condition E): 1.068 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[C:11](=[O:18])[C:10]([C:19](O)=[O:20])=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH:37]([NH2:40])([CH3:39])[CH3:38]>O1CCCC1>[CH:37]([NH:40][C:19]([C:10]1[C:11](=[O:18])[C:12]2[C:17](=[N:16][CH:15]=[CH:14][CH:13]=2)[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH:9]=1)=[O:20])([CH3:39])[CH3:38]
Reactant: O=C(O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Reactant: CC(C)N
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylic acid from Step 3 (26.3 g, 76 mmol) and triethylamine (23.2 g, 230 mmol) in tetrahydrofuran (1000 mL) at 0° C. was added isobutyl chloroformate (18.85 g, 138 mmol). After stirring at 0° C. for 2 hours, isopropylamine (23 g, 390 mmol) was added and the mixture was allowed to warm up to room temperature and stirred overnight. The mixture was then partitioned between ethyl acetate and water, the organic phase was dried and evaporated to a solid which was stirred in ether at room temperature for 3 hours and filtered to afford the N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[S:9][NH:8][C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.CN(C)C=O.S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[Cl:19][C:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:10]=2[S:9][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc2c(=O)[nH]sc12
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1cccc2c(Cl)nsc12
Reaction time: 1 h
Yield: 90 %

Procedure:
A 1 L four-neck flask equipped with a stirrer, a thermometer and a condenser tube was charged with 82.6 g (0.5 mol) of 7-methyl-1,2-benzisothiazol-3-one, 80.4 g (1.1 mol) of N,N-dimethylformamide and 200.0 g of toluene. While stirring, 83.3 g (0.7 mol) of thionyl chloride was added dropwise thereto at 70° to 80° C. over 1 hour, and the mixture was reacted at the same temperature for 3 hours. After terminating the reaction, the liquid reaction mixture was concentrated, and a crude product obtained was distillated under reduced pressure of 0.40 kPa at 110° C. to give 81.7 g (0.45 mol) of 3-chloro-7-methyl-1,2-benzisothiazole. The yield based on 7-methyl-1,2-benzisothiazol-3-one was 89%.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH2:21]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)[CH2:22][CH3:23]>>[CH2:19]([O:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][CH2:21][CH2:22][CH3:23])=[CH:26][CH:27]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1)[CH3:20]
Reactant: CCCOc1ccc(C=O)cc1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Product: CCCOc1ccc(CN2C(=O)C(C)CC2c2c(F)cccc2OCC)cc1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate with commercially available 4-propoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.97 min.; [M+H]+: 385.81 g/mol.
Reaction SMILES: [N+:1]([C:4]12[CH:11]3[CH:6]4[C:7]5([N+:12]([O-:14])=[O:13])C3C1[CH:8]5[CH:5]24)([O-:3])=[O:2].[C:15]([Cl:20])(=O)[C:16]([Cl:18])=O>>[Cl:18][C:16]12[CH:11]3[CH:6]4[CH:5]5[C:4]3([N+:1]([O-:3])=[O:2])[C:15]1([Cl:20])[CH:8]5[C:7]24[N+:12]([O-:14])=[O:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=[N+]([O-])C12C3C4C1C1C2C3C41[N+](=O)[O-]
Product: O=[N+]([O-])C12C3C4C1C1(Cl)C4([N+](=O)[O-])C3C21Cl
Yield: 68 %

Procedure:
A solution of 1,4-dinitrocubane (Eaton, P.E.; et al; J. Org. Chem.; 1984, 49, 185; Eaton, P.E.; Wicks, G.E.; J. Org. Chem.; 1988, 53, 5353) in oxalyl chloride was irradiated under a sunlamp for 12 h at room temperature. After removing oxalyl chloride under reduced pressure, the reaction mixture was hydrolyzed and partioned between ethyl acetate and 5% aqueous NaOH. From the organic phase was isolated 2-chloro-1,4-dinitrocubane,3, and 2,5-dichloro-1,4-dinitrocubane, 4. After acidification of the alkaline layer with HCl and extraction with ethyl acetate, 2-carboxy-1,4-dinitrocubane, 5, was obtained in 68% yield. ##STR1##
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[Cl:12][C:13]1[CH:14]=[C:15]([C:20](=[O:22])[CH3:21])[CH:16]=[CH:17][C:18]=1[Cl:19]>C1COCC1>[Cl:12][C:13]1[CH:14]=[C:15]([C:20]2([CH3:8])[CH2:21][O:22]2)[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC1(c2ccc(Cl)c(Cl)c2)CO1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents are stirred for 10 min. after which the solution of 1-(3,4-dichlorophenyl)ethanone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. After completion, the reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.
Reaction SMILES: [CH2:1]([CH:6]([CH:14](OCC)OCC)[CH:7](OCC)OCC)[CH2:2][CH2:3][CH2:4][CH3:5].S(O)(O)(=O)=O.[NH2:26][NH2:27].[OH-].[Na+]>Cl>[CH2:1]([C:6]1[CH:14]=[N:26][NH:27][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: NN
Reactant: CCCCCC(C(OCC)OCC)C(OCC)OCC
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCCCc1cn[nH]c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
4-Pentylpyrazole (4-PeP) was prepared by adding 2-Pentyl-1,1,3,3-tetraethoxypropane dropwise with stirring to a solution having a molar equivalent of hydrazine sulfate in 6M HCl at 40°-45° C. The mixture was kept at this temperature for 1 hour and the temperature then raised to 90° C. for 30 minutes. After the mixture cooled, 40% w/w 30 NaOH was added and the mixture thoroughly extracted with ether. Drying the ether solution over MgSO4 afforded 4-PeP. Stock solutions of 4-PeP (3 mM) were prepared by dissolution first in acetonitrile, followed by dilution with water to a final acetonitrile concentration of 8%.
Reaction SMILES: [CH3:1][C@:2]1([N:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[N+:21]([O-])=O)[N:12]=[C:11]2[CH3:24])[CH2:7][CH2:6][C:5](=[O:8])[NH:4][C:3]1=[O:9]>C(OCC)(=O)C.CO.[Pd].[O-2].[O-2].[Mn+4]>[NH2:21][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[C:19](=[O:20])[N:10]([C@@:2]1([CH3:1])[CH2:7][CH2:6][C:5](=[O:8])[NH:4][C:3]1=[O:9])[C:11]([CH3:24])=[N:12]2
Reactant: Cc1nc2cccc([N+](=O)[O-])c2c(=O)n1[C@@]1(C)CCC(=O)NC1=O
Agent: [Mn+4]
Agent: [Pd]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nc2cccc(N)c2c(=O)n1[C@@]1(C)CCC(=O)NC1=O
Reaction time: 16 h
Yield: 33.3 %

Procedure:
A mixture of (S)-3-methyl-3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione (0.30 g, 1.0 mmol) and 10% Pd—C (0.2 g, 50% wet), in 200 mL of 3:1 ethyl acetate-methanol was shaken under 50 psi H2 for 45 minutes. The mixture was filtered through Celite, and the solvent was evaporated. The residue was redissolved in 200 mL of 4:1 dichloromethane-acetone, and manganese dioxide (0.20 g, 2.2 mmol) was added. This mixture was stirred for 16 hours. The mixture was filtered through Celite, and the filtrate was evaporated. The residue was chromatographed on silica gel using a dichloromethane-acetonitrile gradient, eluting (S)-3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-3-methylpiperidine-2,6-dione as a beige solid (0.10 g, 37% yield): HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 20/80 CH3CN/0.1% H3PO4, 1.63 (99.20%); mp 297-299° C.; 1H NMR (DMSO-d6) δ 1.88 (s, 3H, CH3), 2.31-2.36 (m, 1H, CHH), 2.53-2.59 (m, 2H, 2CHH), 2.62 (s, 3H, CH3), 2.71-2.84 (m, 1H, CHH), 6.53-6.56 (m, 2H, Ar), 6.95 (br, 2H, NH2), 7.35 (t, J=8 Hz, 1H, Ar), 10.72 (s, 1H, NH); 13C NMR (DMSO-d6) δ 24.5, 26.3, 28.3, 29.0, 62.2, 104.2, 110.5, 110.8, 135.0, 147.4, 150.4, 152.9, 164.9, 171.5, 173.0; Anal. Calcd for C15H16N4O3: C, 59.99; H, 5.37; N, 18.66. Found: C, 59.61; H, 5.43; N, 18.59.
Reaction SMILES: [CH:1]1([N:7]([CH3:30])[C:8](=[O:29])[CH2:9][CH2:10][CH:11]([C:27]#[N:28])[CH2:12][C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=[CH:15][C:14]=2[NH2:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[NH2:28][C:27]1[CH:11]([CH2:10][CH2:9][C:8]([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH3:30])=[O:29])[CH2:12][C:13]2[C:14](=[CH:15][CH:16]=[C:17]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:18]=2)[N:26]=1
Reactant: CN(C(=O)CCC(C#N)Cc1cc(Oc2ccccc2)ccc1N)C1CCCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CN(C(=O)CCC1Cc2cc(Oc3ccccc3)ccc2N=C1N)C1CCCCC1
Temperature: 25 °C

Procedure:
5-(2-amino-5-phenoxy-phenyl)-4-cyano-pentanoic acid cyclohexyl-methyl-amide (0.20 g, 0.46 mmol) was dissolved in toluene (5 mL), followed by addition of aluminum chloride (0.184 g, 1.38 mmol). The reaction mixture was heated to reflux for 10 minutes and then allowed to cool to room temperature. The crude reaction mixture was poured into a separatory funnel and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic layer was washed 2 more times with 10% Na2CO3 solution and one time with saturated brine solution. The organic layer was dried with anhydrous sodium sulfate and the solvent was removed under reduced pressure to yield a residue which was purified by flash chromatography using chloroform:methanol:triethylamine as the mobile phase to yield the title compound as a residue.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([C:27]#[C:28][C:29]([CH3:32])([OH:31])[CH3:30])=[CH:10][CH:11]=3)[N:6]=1.[CH3:33]S(O)(=O)=O.C(=O)(O)[O-].[Na+]>CO>[CH3:33][O:31][C:29]([CH3:32])([CH3:30])[C:28]#[C:27][C:9]1[CH:8]=[C:7]2[C@@:5]3([CH2:4][O:3][C:2]([NH2:1])=[N:6]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)[CH:18]=3)[O:13][C:12]2=[CH:11][CH:10]=1
Reactant: Cc1ccc(-c2cnc3c(c2)[C@]2(COC(N)=N2)c2cc(C#CC(C)(C)O)ccc2O3)cc1
Reactant: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(C)(C)C#Cc1ccc2c(c1)[C@@]1(COC(N)=N1)c1cc(-c3ccc(C)cc3)cnc1O2

Procedure:
A vial was charged with (S)-4-(2′-amino-3-p-tolyl-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl)-2-methylbut-3-yn-2-ol (134.5 mg, 0.316 mmol), MeOH (3161 μL), and methanesulfonic acid (103 μL, 1.581 mmol). The vial was sealed and placed in a 70° C. oil bath for 4 hours. The mixture was poured into saturated aq. sodium bicarbonate solution (30 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on a 40-g Redi-Sep column to give a impure material that was dissolved in methanol and purified by reverse-phase HPLC (10-90% CH3CN/H2O with 0.1% TFA). The fractions containing product were combined in saturated aq. sodium bicarbonate solution with the aid of methanol, and the mixture was extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to give (S)-7-(3-methoxy-3-methylbut-1-ynyl)-3-p-tolyl-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O>C1(=O)OC(C)CO1>[Br:14][C:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: O=C1CCC(=O)N1Br
Solvent: CC1COC(=O)O1
Product: Brc1cccc2c1Cc1ccccc1-2
Temperature: 80 °C
Reaction time: 10 h
Yield: 68 %

Procedure:
1.2 litters of propylene carbonate and 160 g (0.96 mol) of fluorene were put into a 2 litter 3-neck round-bottom flask equipped with a stirrer, a thermometer and a reflux condenser under an argon atmosphere, and the resulting mixture was heated to 80° C. so as to make completely dissolved. 179.9 g (1.01 mol) of N-bromosuccinimide was added portionwise to the reaction mixture, and the resultant was stirred at 80° C. for 10 hours. The reaction mixture was cooled down to room temperature to precipitate white solid. The solid was filtered, thoroughly washed with methanol, dried and then recrystallized from ethanol, to obtain white crystal, which was filtered and then sufficiently dried in a vacuum oven at 40° C. to give 160 g (yield: 60%) of the desired product, and its melting point was 102° C.–103° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@H:9]2[O:10][C@H:8]2[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH2:29][C:30]2[NH:31][CH:32]=[CH:33][N:34]=2)=[CH:24][CH:23]=1>>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@@:4]1([CH3:18])[C@@H:9]([OH:10])[C@H:8]([N:28]([C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)[CH2:29][C:30]2[NH:31][CH:32]=[CH:33][N:34]=2)[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H]2O[C@@H]21
Reactant: Clc1ccc(NCc2ncc[nH]2)cc1
Product: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H](N(Cc2ncc[nH]2)c2ccc(Cl)cc2)[C@@H]1O
Yield: 119.6 %

Procedure:
The title compound (269 mg, 63%) was prepared using (2S,3S,4S)-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-6-nitro-2H-1-benzopyran (129 mg, 0.46 mmol) and 4-chlorophenyl-1H-imidazol-2-ylmethylamine (183 mg, 0.88 mmol), according to the same procedure used for the preparation of example 1 above.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].Cl.Cl[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: ClCCNCCCl
Reactant: Nc1cc(F)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: Fc1cc(N2CCNCC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 30.3 %

Procedure:
To 60 ml of n-butanol were added 5.0 g of 3-fluoro-5-(trifluoromethyl)aniline and 5.0 g of bis(2-chloroethyl)amine hydrochloride, and the mixture was heated under reflux for 47 hours. To the reaction mixture was added 3.85 g of potassium carbonate, followed by heating under reflux for 24 hours. After cooling to room temperature, the solvent was removed by evaporation. The residue was dissolved in an 1N sodium hydroxide aqueous solution and extracted with chloroform-methanol (19:1 by volume). The extract was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was removed by evaporation, and the residue was subjected to silica gel column chromatography using a 9:1 (by volume) mixed solvent of chloroform and methanol as a developing solvent. The fraction containing the desired compound was concentrated to yield 2.1 g of the title compound.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][N:8]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:14]1(C)C=CC=C[C:15]=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.C=C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[C:1]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:14]=[CH2:15])=[CH:9][N:8]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)Nc1ccc(Br)cn1
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Pd+2]
Agent: C=C
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=Cc1ccc(NC(=O)C(C)C)nc1
Temperature: 80 °C

Procedure:
A mixture of 9.72 g of 2 isobutyramido-5-bromopyridine, 0.49 g of tris-(0-tolyl)phosphine, 110 mg of palladium acetate, 10 ml of triethylamine and 30 ml of acetonitrile was heated at 80° C. in a glass lined vessel at 200 psi of ethylene for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue chromatographed on el (0-25% ethyl acetate/methylene chloride) to give 6.67 g of pure product, m.p. 77°-8° C.; Analysis: Calc'd for C11H14N2O: