Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1.B(F)(F)F.CCOCC.[CH:39](O)([CH3:41])[CH3:40]>>[F:1][C:2]([F:28])([F:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O:25][CH:39]([CH3:41])[CH3:40])=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Reactant: CC(C)O
Agent: FB(F)F
Solvent: CCOCC
Product: CC(C)OC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Temperature: 0 °C

Procedure:
A solution of 50.5 g of 4-[15-(trifluoromethyl)pentadecylamino]benzoic acid and 34.4 ml. of boron trifluoride etherate in 200 ml. of isopropyl alcohol is stirred under reflux for 44 hours, allowed to cool, and poured into 1.20 liters of ice cold 5% aqueous sodium carbonate solution. The white solid is collected by filtration and recrystallized from benzene-ethanol to yield the product as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][CH:17]([CH2:19]OS(C3C=CC(C)=CC=3)(=O)=O)[O:16][C:15]2=[O:31])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1.[N-:32]=[N+:33]=[N-:34].[Na+].CC#N.C(Cl)(Cl)Cl>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][N:32]=[N+:33]=[N-:34])[O:16][C:15]2=[O:31])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(c3ccc(N4CCSCC4)c(F)c3)C(=O)O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: [N-]=[N+]=NC[C@H]1CN(c2ccc(N3CCSCC3)c(F)c2)C(=O)O1
Temperature: 65 °C
Reaction time: 158 h
Yield: 100 %

Procedure:
The [[3-[3-fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-p-toluenesulfonate (2.0 g, 4.287 mmol) was dissolved in dry DMF (15 mL) and then treated with solid NaN3 (1.67 g, 25.722 mmol). The reaction was heated to 65° C. (external temperature) for 6 hours, after which the reaction was allowed to cool to ambient temperature, stirring over a long weekend (158 hours). At this point, the reaction was found to be complete by TLC (6% CH3CN/CHCl3, UV short wave). The reaction was diluted with EtOAc (300 mL) and then washed with water (3×250 mL). The aqueous portions were back-extracted with more EtOAc (2×150 mL). The EtOAc portions were combined, dried over Na2SO4, filtered and concentrated under reduced pressure to give 1.447 g (100%) of the title compound as an off-white solid with a melting point of 91.5°-93° C. and a HRMS (M+) calculated for C14H16N5O5FS 337.1009, found 337.1009.
Reaction SMILES: N(C(=CC1SC=C(F)C=1)C(OCC)=O)=[N+]=[N-].[N:17]([C:20](=[CH:26][C:27]1[S:28][C:29]([F:32])=[CH:30][CH:31]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N+]=[N-].CCOC(C)=O.CCCCCCC.COC1C=CC(C=O)=CC=1>C1(C)C=CC=C(C)C=1>[F:32][C:29]1[S:28][C:27]2[CH:26]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH:17][C:31]=2[CH:30]=1
Reactant: CCOC(=O)C(=Cc1ccc(F)s1)N=[N+]=[N-]
Agent: CCOC(=O)C(=Cc1cc(F)cs1)N=[N+]=[N-]
Agent: COc1ccc(C=O)cc1
Solvent: Cc1cccc(C)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2sc(F)cc2[nH]1
Temperature: 145 °C
Yield: 15 %

Procedure:
A mixture of ethyl 2-azido-3-(4-fluorothiophen-2-yl)acrylate and ethyl 2-azido-3-(5-fluorothiophen-2-yl)acrylate (0.37 g) was dissolved in m-xylene (˜10 mL) and heated at 145° C. for 20 min in a capped 40-mL vial. The m-xylene was evaporated in vacuo and the resulting residue was chromatographed over silica gel (0 to 40% EtOAc in heptane over 30 min) to give two products: (a) 0.15 g of an impure pale oil with an Rf=0.25 (10:90 EtOAc/heptane), which stained a bright violet color when developed using anisaldehyde and heat, which was further purified via preparative HPLC using a Chromeleon purification system (methanol/0.1% formic acid-1% acetonitrile mixture in water, 50 mm Dynamax C-18, 28 mL/min (initial gradient of 20% methanol and increasing to 100% over 7 min) to give ethyl 2-fluoro-4H-thieno[3,2-b]pyrrole-5-carboxylate (48.9 mg, 3%). tR of product: 4.2-4.4 min. 1H NMR (400 MHz, CD3CN) δ ppm 10.10 (s, 1H), 6.98-7.05 (m, 1H), 6.69 (dd, J=2.05, 0.49 Hz, 1H), 4.29 (q, J=7.09 Hz, 2H), 1.33 (t, J=7.13 Hz, 3H). 19F NMR (376 MHz, CD3CN) δ ppm −122.18 (d, J=2.29 Hz, 1F). (b) 10.5 mg of an impure pale oil with an Rf=0.30 (10:90 EtOAc/heptane), which stained a bright red color when developed using anisaldehyde and heat, was further purified via preparative HPLC as described above (40%-100% methanol over 7 min) to give ethyl 3-fluoro-4H-thieno[3,2-b]pyrrole-5-carboxylate (5.4 mg, 0.3%). tR of product: 3-3.4 min. 1H NMR (400 MHz, CD3CN) δ ppm 10.30 (s, 1H), 7.06 (t, J=2.05 Hz, 1H), 6.90 (d, J=2.54 Hz, 1H), 4.32 (q, J=7.09 Hz, 2H), 1.34 (t, J=7.10 Hz, 3H). 19F NMR (376 MHz, CD3CN) δ ppm −144.16 (t, J=2.29 Hz, 1F).
Reaction SMILES: Br[C:2]1[C:11]([C@H:12]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:23])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:25])=[N+:7]2[O-:24].[C:26]1(B(O)O)[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:19]([O:18][C@@H:12]([C:11]1[C:2]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)=[C:3]2[C:8](=[CH:9][C:10]=1[CH3:23])[N+:7]([O-:24])=[C:6]([CH3:25])[CH:5]=[CH:4]2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2c(ccc(C)[n+]2[O-])c1Br
Reactant: OB(O)C1=CCCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2c(ccc(C)[n+]2[O-])c1C1=CCCCC1
Temperature: 85 °C
Yield: 82.6 %

Procedure:
Pd(PPh3)4 (6 mg, 0.006 mmol) was added to a mixture (S)-5-bromo-6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-2,7-dimethylquinoline 1-oxide (compound of Example 20) (20 mg, 0.05 mmol), cyclohexenylboronic acid (12 mg, 0.1 mmol), K2CO3 (0.09 mL 2 M in water, 0.17 mmol) in 1,2-dimethoxyethane (1 mL). The reaction mixture was flushed with nitrogen, heated at 85° C. for overnight, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (30 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by HPLC to provide the desired product (17 mg, 68%). LCMS-ESI+ (m/z): 412.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26]>CN(C=O)C>[N:5]1[CH:6]=[CH:7][C:2]([O:1][CH:25]([OH:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])=[CH:3][CH:4]=1
Reactant: Oc1ccncc1
Reactant: OCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCC(O)Oc1ccncc1
Temperature: 90 °C
Yield: 21.9 %

Procedure:
The compound 4-pyridyloxyundecan-1-ol was prepared as follows: To a solution of 4-hydroxy-pyridine (5.71 g, 60 mmol) in DMF (150 cm3) was added cesium carbonate (19.56 g, 60 mmol). The mixture was heated to 90° C. for 5 mins then 11-bromoundecanol (12.56 g, 50 mmol) was added and the mixture heated to reflux temperature (125° C.) for 15 hours. After cooling, the contents of the flask were poured into rapidly stirring distilled water (800 cm3). A pale yellow precipitate formed which was filtered and dried (in air). Recrystallization from hexane gave white crystals of 4-pyridyloxyundecan-1-ol (2.9 g, 22%).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][CH3:17])[C:11]=2[C:18]#[C:19][C:20]2[C:21]([CH2:27][CH3:28])=[N:22][C:23]([NH2:26])=[CH:24][CH:25]=2)=[CH:6][C:5]=1[F:29].[OH-].[Na+]>C1COCC1.O>[NH2:26][C:23]1[N:22]=[C:21]([CH2:27][CH3:28])[C:20]([C:19]#[C:18][C:11]2[C:12]([CH2:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:30])=[O:2])=[C:5]([F:29])[CH:6]=2)=[CH:25][CH:24]=1
Reactant: CCc1nc(N)ccc1C#Cc1c(-c2ccc(C(=O)OC)c(F)c2)ccnc1CC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc(N)ccc1C#Cc1c(-c2ccc(C(=O)O)c(F)c2)ccnc1CC

Procedure:
The title compound is synthesized according to general procedure GP4 starting from 944 mg (2.34 mmol) 4-[3-(6-Amino-2-ethyl-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoic acid methyl ester (A-43) using 3.5 mL (3.5 mmoL) 1N NaOH in 25 mL THF. The reaction mixture is diluted with water and the product extracted with DCM. The organic phase is separated and the solvent removed under reduced pressure. The crude product is used without further purification. Yield: 945 mg (>100%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl-].[OH:19][NH3+:20].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[Cl:1][C:2]1[C:11]([CH:12]=[N:20][OH:19])=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=O)c1Cl
Reactant: [NH3+]O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C=NO)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.6 %

Procedure:
55.23 g (0.199 mol) of methyl 2-chloro-3-formyl-4-methylsulfonylbenzoate are suspended in 400 ml of methanol/100 ml of water and treated with 15.27 g (0.219 mol) of hydroxylammonium chloride. 11.56 g (0.11 mol) of sodium carbonate—dissolved in 100 ml of water—are then slowly added dropwise at room temperature. After stirring at room temperature for 4 hours, the methanol is removed in a rotary evaporator, the residue is diluted with water and the mixture is extracted three times with dichlormethane. 56.05 g (96% of theory) of methyl 2-chloro-3 hydroximinomethyl-4-methylsulfonylbenzoate having a melting point of 126-130° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])[N:21]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([C:22]4[N:21]=[C:20]([C:19]([F:35])([F:34])[F:18])[O:24][N:23]=4)[CH:26]=3)[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC(C)(CN)c1nc(-c2ccc(F)cc2)cs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1nc(-c2ccc(F)cc2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
2-(4-(4-Fluorophenyl)thiazol-2-yl)-2-methylpropan-1-amine (140 mg, 0.56 mmol), 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid (144.37 mg, 0.56 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) (214.42 mg, 1.12 mmol), and 1-hydroxybenzotriazole (HOBt) (120.91 mg, 0.89 mmol) were dissolved in dichloromethane (3 mL) at room temperature. Diisopropylethylamine (DIEA) (0.39 mL, 2.24 mmol) was then introduced at room temperature and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with dichloromethane (60 mL) and washed with water (1×20 mL) and brine (1×20 mL). The organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was then purified on Combiflash ISCO (0-30% Ethyl Acetate:Hexanes) to give the desired product (164 mg, 60% yield). 1H NMR (CDCl3) δ 8.52 (1H, t), 8.22 (1H, dt), 8.12 (1H, t), 8.03 (1H, dt), 7.85-7.81 (2H, m), 7.57 (1H, d), 7.35 (1H, s), 7.05-7.00 (2H, m), 3.80 (2H, d, J=4 Hz), 1.55 (6H, s); MS (ESI) m/z: Calculated for C23H18F4N4O2S: 490.11. found: 491.1 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:27]3[CH:28]=[N:29][C:30]4[C:35]([CH:36]=3)=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:10]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:11]([N:15](C(=O)C)[C:16](=[O:18])[CH3:17])[O:12]2)=[CH:7][CH:6]=1)(=O)C.O.NN>C(O)C>[C:16]([NH:15][C:11]1[O:12][C:13]2[C:8]([CH:9]([C:27]3[CH:28]=[N:29][C:30]4[C:35]([CH:36]=3)=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:10]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:7][CH:6]=[C:5]([OH:4])[CH:14]=2)(=[O:18])[CH3:17]
Reactant: CCOC(=O)C1=C(N(C(C)=O)C(C)=O)Oc2cc(OC(C)=O)ccc2C1c1cnc2ccccc2c1
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1=C(NC(C)=O)Oc2cc(O)ccc2C1c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.2 %

Procedure:
Ethyl 7-(acetyloxy)-2-(diacetylamino)-4-quinolin-3-yl-4H-chromene-3-carboxylate (268 mg, 0.55 mmol) was dissolved in absolute ethanol (1.7 mL). Hydrazine hydrate (35 μL, 0.72 mmol) was added and the mixture stirred at room temperature for 1 h. The reaction mixture was evaporated to dryness. 1H NMR analysis showed incomplete conversion of the starting material. The product was suspended in absolute ethanol (1.7 mL) and hydrazine hydrate (35 μL, 0.72 mmol) added. The mixture was stirred at room temperature for 2 h. The mixture was filtered. The residue was washed with ethanol (1.0 mL) and ethyl acetate (2.0 mL). The residue was dissolved in boiling ethanol (16 mL) and the volume reduced to half by heating under a stream of nitrogen. The mixture was cooled to 4° C. and filtered. The residue was dried at the pump to give the title compound (65 mg, 29% yield) as pale yellow needles.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11]C2C=C(N)N=CN=2)=[CH:7][C:6]=1[C:19]([F:22])([F:21])[F:20])[CH3:3].C([O-])([O-])=O.[K+].[K+]>CO>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[C:19]([F:20])([F:22])[F:21])[CH3:1]
Reactant: CN(C)Cc1ccc(Nc2cc(N)ncn2)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN(C)Cc1ccc(N)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
N-(4-Dimethylaminomethyl-3-trifluoromethyl-phenyl)-pyrimidine-4,6-diamine (359 mg, 1.2 mmol) is dissolved in MeOH (12 mL) and treated with K2CO3 (6 mL of a 1N aqueous solution) at RT. The reaction is heated to reflux for 1.5 h until completion, cooled back to RT and concentrated. The residual oil is taken up in EtOAc and washed with brine. The organic layers are dried over Na2SO4, filtered and concentrated under reduced pressure. Drying under high vacuum gives the title compound as a yellow oil. ESI-MS: 219 [MH]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:19]2[C:18](=O)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[O:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:11](=O)[C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>C(O)(C)C>[CH2:22]([O:21][C:16]1[C:17]2[C:12](=[CH:11][C:10]3[C:19]([CH:18]=2)=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]=[CH:8][CH:9]=3)[CH:13]=[CH:14][CH:15]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCOc1cccc2c1C(=O)c1c(OCCCC)cccc1C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CCCCOc1cccc2cc3cccc(OCCCC)c3cc12
Yield: 85.6 %

Procedure:
A mixture of 1,8-dibutoxyanthraquinone (38 g, 0.108 mol), sodium borohydride (20.5 g, 0.54 mol), and 800 mL of isopropanol was stirred at reflux for 18 hours, and then cooled. The excess borohydride was destroyed by the cautious addition of 20% aqueous HCl, and the product was extracted into dichloromethane. The extract was washed with water and dried with MgSO4, and the solvent was removed. The residue was recrystallized from ligroin to produce 29.8 grams of 1,8-dibutoxyanthracene, which has the structural formula: ##STR49##
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:15][NH:16][C:17]1[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C.O>[CH2:1]([O:15][NH:16][C:17]1[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1ccccc1NO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccccc1NOCc1ccccc1
Reaction time: 1 h
Yield: 72 %

Procedure:
To a stirring suspension of benzyl bromide (1.038 g, 6.07 mmol) and cesium carbonate (2.70 g, 8.28 mmol) in DMF (4 mL) was added ethyl 2-(hydroxyamino)benzoate (1.0 g, 5.52 mmol) dissolved in 2 mL DMF at RT and stirred for 1 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 0-3% EtOAC in hexane to get the titled compound in 72% yield.
Reaction SMILES: [CH2:1]([NH:18][C:19]([O:21][CH2:22][C@H:23]([OH:26])[CH2:24][OH:25])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[C:27]1([C:33](Cl)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[CH2:1]([NH:18][C:19]([O:21][CH2:22][C@H:23]([OH:26])[CH2:24][O:25][C:33]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCCCNC(=O)OC[C@H](O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCNC(=O)OC[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
A solution of 12.03 g of 3 -O-(N-heptadecylcarbamoyl)-sn-glycerol (prepared as described in Preparation 15), 10.77 g of triphenylmethyl chloride and 10.8 ml of triethylamine dissolved in 240 ml of toluene was heated under reflux for 1.5 hours. After cooling, the reaction mixture was poured into water (0.5 liter) and then extracted twice with ethyl acetate. The combined extracts were washed with water, dried and concentrated by evaporation under reduced pressure. The resulting residue was dissolved in 240 ml of tetrahydrofuran. To the resulting solution was added 120 ml of a saturated aqueous solution of sodium bicarbonate, and the mixture was stirred at room temperature for 1 hour. After pouring the reaction mixture into water followed by extracting twice with ethyl acetate, the combined extracts were washed with water, dried and concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through 400 g of silica gel and to medium pressure liquid chromatography using an NQ-3 Packed Column (Wako pure Chemical Industry Co.). 15.89 g of the title compound were obtained from the fractions eluted with mixtures of hexane and diethyl ether ranging from 3:2 to 2:3 by volume as a viscous liquid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=[O:4])=[O:3].[CH:19](Br)([CH3:21])[CH3:20]>>[CH:19]([N:16]1[CH2:15][CH2:14][N:13]([C:7]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)[CH2:18][CH2:17]1)([CH3:21])[CH3:20]
Reactant: COc1ccc(N2CCNCC2)cc1S(C)(=O)=O
Reactant: CC(C)Br
Product: COc1ccc(N2CCN(C(C)C)CC2)cc1S(C)(=O)=O

Procedure:
Beginning with 1-(3-Methanesulfonyl-4-methoxy-phenyl)-piperazine and isopropylbromide, the title compound was recovered by the procedure described in Example 2: MS m/z (rel. intensity, 70 eV)) 312 (M+, 43), 297 (bp), 84 (35), 71 (33), 56 (73).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(Br)c1ccccc1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(Oc1ccc(Cl)c([N+](=O)[O-])c1)c1ccccc1
Yield: 94.3 %

Procedure:
A solution of 4-chloro-3-nitro-phenol (2.0 g, 11.5 mmol), 1-bromoethyl-benzene (3.2 g, 17.3 mmol), sodium carbonate (1.80 g, 17.0 mmol) in acetone (20 ml) was heated at reflux for 18 hours. The reaction mixture was cooled, the solids filtered off and the filtrate concentrated to a thick syrup under vacuum. The residue was dissolved in ether (80 ml) and washed with water (20 ml) and 30% KOH solution (2×20 ml) and the solvent is concentrated under vacuum leaving an oily residue as the title compound (3.01 g, 94%).
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:22][CH:23]=[CH:24][C:25]#[C:26][C:27]([CH3:30])([CH3:29])[CH3:28]>>[CH3:28][C:27]([CH3:30])([CH3:29])[C:26]#[C:25]/[CH:24]=[CH:23]/[CH2:22][N:4]([CH2:5][C:6]1[CH:7]=[C:8]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1)[CH:1]([CH3:3])[CH3:2]
Reactant: CC(=O)c1cccc(CNC(C)C)c1
Reactant: CC(C)(C)C#CC=CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)c1cccc(CN(C/C=C/C#CC(C)(C)C)C(C)C)c1
Yield: 61.6 %

Procedure:
The procedure described in Example 13 was repeated, except that 3′-(N-isopropylaminomethyl)acetophenone (1.66 g; 8.7 mmol), sodium carbonate (925 mg; 8.7 mmol), and 1-bromo-6,6-dimethyl-2-hepten-4-yne (1.74 g; 8.7 mmol) were used, to thereby yield 1.67 g of the target compound (yield: 61.8%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:28]=[CH:27][C:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26][C:20]=4[CH:19]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11].CCN(C(C)C)C(C)C.Br[CH2:39][CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:28]=[CH:27][C:21]4[CH2:22][CH2:23][N:24]([CH2:39][CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:25][CH2:26][C:20]=4[CH:19]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCNCC4)no2)cc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN1CCc2ccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cc2CC1
Yield: 110.3 %

Procedure:
7-(5-{3-Chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (Example 17) (65 mg, 0.155 mmol), DIPEA (0.104 ml, 0.593 mmol) and ethyl 4-bromobutanoate (0.048 ml, 0.339 mmol) were stirred at 60° C. in DMF (10 ml) for 24 hours. The reaction mixture was partitioned between EtOAc (˜30 ml) and water (˜30 ml) and the aqueous layer extracted once more with EtOAc (˜40 ml). The combined organics were concentrated in vacuo to yield the crude title compound (100 mg, 0.171 mmol) as an orange solid. MS (ES): C27H3235ClN3O4 requires 497; found 498 [M+H]+.