Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:24])=[C:14]([C:20](OC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.[NH2:29][CH2:30][CH2:31][CH2:32][OH:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:24])=[C:14]([C:20]([NH:29][CH2:30][CH2:31][CH2:32][OH:33])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[C:4]([C:25]([F:26])([F:28])[F:27])[CH:3]=1
Reactant: COC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3C(F)(F)F)cc2[nH]c1=O
Reactant: NCCCO
Product: O=C(NCCCO)c1c(O)c2ncc(Cc3ccc(F)cc3C(F)(F)F)cc2[nH]c1=O

Procedure:
This compound was prepared from methyl 7-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-amino-1-propanol employing methods similar to those described in Example 245 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.74 (1H, br), 10.26 (1H, m), 8.49 (1H, s), 7.70 (1H, d, J=9 Hz), 7.56 (2H, m), 7.32 (1H, s), 4.58 (1H, t, J=5 Hz), 4.32 (2H, s), 3.51-3.40 (4H, m), 1.70 (2H, m, J=6 Hz); HRMS calcd for C20H17F4N3O4+H+: 440.1233. Found: 440.1241.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH2:12][C:13]2[N:14]([CH3:40])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH:37]([CH3:39])[CH3:38])[N:16]=3)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:9][CH:10]([CH2:12][C:13]2[N:14]([CH3:40])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH:37]([CH3:38])[CH3:39])[N:16]=3)[CH2:11]1
Reactant: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[2-(2-isopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]azetidine-1-carboxylic acid tert-butyl ester (256 mg, 0.47 mmol) in DCM (5 mL) was added TFA (5 mL) and the resulting mixture stirred for 2 h at r.t. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording the title compound as an orange foam (205 mg, 97%). LCMS (method H): RT 1.91 min [M+H]+ 447.4
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)=O)=[CH:4][CH:3]=1.[C:20]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)(=[O:22])[CH3:21].[OH-].[K+].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2ccc(Cl)cc2)cc1OC
Reactant: CC(=O)N1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C(=CC(=O)N2CCOCC2)c2ccc(Cl)cc2)cc1OC
Reaction time: 0.5 h
Yield: 8.3 %

Procedure:
6.92 g (25 mmol) 4-chloro-3',4'-dimethoxybenzophenone, 12.9 g (100 mmol) N-acetylmorpholine and 11.2 g (170 mmol) powdered potassium hydroxide (85%) were mixed well and allowed to stand at room temperature for 30 minutes, with occasional stirring. The viscous mass so obtained was then added to a vigorously stirred mixture of 100 ml water and 50 ml toluene. The toluene phase was dried and separated over a column containing 50 g silica gel using 150 ml each of 95:5, 90:10 and 80:20 toluene-acetone mixture as eluant. The fractions with an Rf value of 0.37 (Toluene/Acetone 7:3) were evaporated in a rotary evaporator, after which 0.8 g of the title compound were obtained by trituration with a little diisopropyl ether.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[N:23]=[N:24][N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:9]([C:22]2[N:23]=[N:24][N:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[N:26]=2)[OH:8])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1nnn(-c2ccccn2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC(CCCCCCc1ccccc1)c1nnn(-c2ccccn2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
2-(5-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)-2H-tetrazol-2-yl)-pyridine (4.4 mg, 0.009 mmol) was dissolved in THF (122 μL), treated with Bu4NF (1 M in THF, 0.013 mL, 0.013 mmol) and stirred at room temperature for 2 h under Ar. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaCl and dried over Na2SO4. Evaporation in vacuo yielded the crude alcohol that was purified by flash chromatography (SiO2, 0.5×4 cm, 20-50% EtOAc-hexanes) to afford 7-phenyl-1-(2-(pyridin-2-yl)-2H-tetrazol-5-yl)-heptan-1-ol (2.7 mg, 79%) as a white solid: 1H NMR (CDCl3, 600 MHz) δ 8.69 (dd, 1H, J=1.1, 4.7 Hz), 8.18 (d, 1H, J=8.1 Hz), 8.00 (m, 1H), 7.50 (ddd, 1H, J=0.7, 4.8, 7.4 Hz), 7.26 (m, 2H), 7.16 (m, 3H), 5.16 (m, 1H), 2.59 (t, 2H, J=7.7 Hz), 2.48 (d, 1H(—OH), J=6.1 Hz), 2.07 (m, 2H), 1.61 (m, 2H), 1.52 (m, 2H), 1.40 (m, 4H); 13C NMR (CDCl3, 150 MHz) δ 169.5, 149.6, 148.8, 142.9, 139.6, 128.5, 128.4, 125.7, 125.3, 115.3, 67.0, 36.7, 36.1, 31.5, 29.3 (2C), 25.2; HRMS-ESI-TOF m/z 338.1966 ([M+H]+, C19H23N5O requires 338.1975).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[P:61]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])([O:63][CH2:64][C:65]([NH2:73])([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[CH3:66])=[O:62].C(N(CC)C(C)C)(C)C>CS(C)=O.O>[C:80]([O:79][P:61]([O:63][CH2:64][C:65]([NH:73][C:20]([C:19]1[CH:23]=[CH:24][C:16]([S:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:10][CH:11]=2)=[C:17]([NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)[CH:18]=1)=[O:21])([C:67]1[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=1)[CH3:66])([O:74][C:75]([CH3:78])([CH3:76])[CH3:77])=[O:62])([CH3:81])([CH3:82])[CH3:83]
Reactant: CC(C)(C)OP(=O)(OCC(C)(N)c1ccccc1)OC(C)(C)C
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NC(C)(COP(=O)(OC(C)(C)C)OC(C)(C)C)c4ccccc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Reaction time: 2 h
Yield: 68.8 %

Procedure:
The product of Example 385E (100 mg, 0.19 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate [TBTU] (79 mg, 0.24 mmol) and the product of Example 442C (90 mg., 0.26 mmol) in DMSO (1.0 mL) were treated with N,N-diisopropylethylamine (100 μL, 0.57 mmol) dropwise at room temperature and stirred under N2 for 2 hours. The reaction was diluted with WATER (10 mL) with stirring. The resulting precipitate was extracted with ethyl acetate (50 mL). The organic layer was washed with WATER (3×), saturated aqueous NaHCO3, then brine, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:chloroform=4:1) to give the title compound as a pale yellow amorphous solid (112 mg, 69%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=O)[CH:19]=3)=[O:17])[CH:9]=2)=[CH:4][C:3]=1[CH2:26][N:27]1[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[C@@H:29]([CH3:40])[CH2:28]1.[NH2:41][CH2:42][C:43]1[C:48]([CH2:49][CH3:50])=[N:47][C:46]2[N:51]([CH2:54][CH3:55])[N:52]=[CH:53][C:45]=2[C:44]=1[NH:56][CH:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCl.O>[CH2:54]([N:51]1[C:46]2=[N:47][C:48]([CH2:49][CH3:50])=[C:43]([CH2:42][NH:41][CH2:24][C:20]3[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=3)[C:16]([NH:15][CH2:14][C:10]3[CH:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH2:26][N:27]5[CH2:32][CH2:31][NH:30][C@@H:29]([CH3:40])[CH2:28]5)[CH:4]=4)[CH:13]=[CH:12][CH:11]=3)=[O:17])[C:44]([NH:56][CH:57]3[CH2:58][CH2:59][O:60][CH2:61][CH2:62]3)=[C:45]2[CH:53]=[N:52]1)[CH3:55]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: C[C@H]1CN(Cc2cc(-c3cccc(CNC(=O)c4cccc(C=O)c4)c3)ccc2F)CCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNCc1cccc(C(=O)NCc2cccc(-c3ccc(F)c(CN4CCN[C@@H](C)C4)c3)c2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1,1-dimethylethyl (2S)-4-{[4-fluoro-3′-({[(3-formylphenyl)-carbonyl]amino}methyl)-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (195 mg, 0.36 mmol) in dichloromethane (5 mL) was added 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine, and (110 mg, 0.36 mmol) and sodium triacetoxyborohydride (115 mg. 0.54 mmol) and the resulting solution was stirred at ambient temperature for 16 h and then treated with aqueous hydrochloric acid (2M, 2 mL) and stirred for a further 2 h. The mixture was treated with water (20 mL) and extracted with dichloromethane (25 mL). The organic phase was concentrated to dryness and the residue dissolved in methanol (5 mL), treated with aqueous hydrochloric acid (2M, 2 mL) and stirred at ambient temperature for 16 h. The mixture was then concentrated to dryness and the product purified by mass-directed automated preparative HPLC. Product-containing fractions were concentrated to dryness to afford 25 mg of the title compound. LC-MS m/z 733 (M+H)+, 0.79 min (ret time).
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(N(C(C)C)CC)(C)C.[CH2:25]([N:27]([CH2:38][CH3:39])[C:28](=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35]O)[CH3:26].C(OC([N:47]1[CH:51]=[C:50]([I:52])[N:49]=[CH:48]1)=O)(C)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:25]([N:27]([CH2:38][CH3:39])[C:28](=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][N:49]1[C:50]([I:52])=[CH:51][N:47]=[CH:48]1)[CH3:26]
Reactant: CC(C)(C)OC(=O)n1cnc(I)c1
Reactant: CCN(CC)C(=O)c1ccccc1CO
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccccc1Cn1cncc1I
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A flask is charged with dichloromethane (200 mL) and trifluoromethanesulfonic anhydride (19.34 g, 67.20 mmol) and cooled to −78° C. A solution of diisopropylethylamine (9.57 g, 73.30 mmol) and N,N-diethyl-2-hydroxymethyl-benzamide (12.92 g, 61.09 mmol) in dichloromethane (40 mL) is added over 10 min. After 30 min, a solution of 4-iodo-imidazole-1-carboxylic acid tert-butyl ester (12.83 g, 42.76 mmol) in dichloromethane (40 mL) is added. The mixture is allowed to gradually warm overnight and after 18 h, saturated aqueous sodium bicarbonate (100 mL) is added and the mixture is stirred vigorously for 30 min. The aqueous layer is extracted with dichloromethane. The combined organic phase is dried over MgSO4, filtered through a cotton plug and concentrated in vacuo. The residue is purified by silica gel flash chromatography (dichloromethane-methanol, 49:1) to afford N,N-diethyl-2-(5-iodo-imidazol-1-ylmethyl)-benzamide; MS (ESI) m/z 384.1 (M+H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([CH2:11][OH:12])=[N:7][CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:4][C:5]1[C:6]([CH:11]=[O:12])=[N:7][CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cccnc1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: C=CCOc1cccnc1C=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.2 %

Procedure:
To a solution of (3-allyloxy-pyridin-2-yl)-methanol (2.08 g, 12.6 mmol) (Chen, Y. L. Eur. Pat. Appl. (1985), EP 150984) in CH2Cl2 (60 mL) was added Dess-Martin Periodinane (5.82 g, 13.7 mmol), and stirred at room temperature for 24 hours. CH2Cl2 (40 mL), saturated NaHCO3 (30 mL), and aqueous sodium thiosulfate (30 mL) were added and stirred for 40 minutes. The layers were separated and the aqueous phase was extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed with brine (1×75 mL), dried (Na2SO4), and concentrated to provide 2.02 g (98%) of 3-allyloxy-pyridine-2-carbaldehyde as a brown oil. 1H NMR (CDCl3) δ 4.71 (d, 2H, J=6.0 Hz), 5.37 (d, 1H, J=12.0 Hz), 5.50 (d, 1H, J=18.0 Hz), 5.99-6.12 (m, 1H), 7.38-7.48 (m, 2H), 8.40 (d, 1H, J=3.0 Hz), 10.41 (s, 1H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].[O:10]=[CH:11][C:12]([Cl:15])([Cl:14])[Cl:13]>C(CC(C)(C)C)(C)C.CC1C=C(OC)C=C(C)C=1.C(CC(C)(C)C)(C)C.Cl[Ti](Cl)(Cl)Cl>[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][O:5][CH:11]([OH:10])[C:12]([Cl:15])([Cl:14])[Cl:13])[CH3:2]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: CCCCC(CC)CO
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: COc1cc(C)cc(C)c1
Solvent: CC(C)CC(C)(C)C
Product: CCCCC(CC)COC(O)C(Cl)(Cl)Cl
Temperature: -15 °C
Reaction time: 4.5 h

Procedure:
In a separate reaction vessel, the chloral 2-ethylhexyl hemiacetal was prepared from 1.05 g 2-ethyl-1-hexanol and 1.19 g (0.00807 mole) chloral substantially as described in Example 3. This material was dispersed in 1 ml of iso-octane and was added dropwise over twenty minutes to the 3,5-dimethylanisole/iso-octane/TiCl4 mixture. A sticky material precipitated, but the reaction solution was stirred at -15° C. for 4.5 hours before being with quenched with water, treated with NaOH, and worked-up substantially as described in Example 1.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][CH2:7][C:8]#[N:9].C(N(CC)CC)C.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23](SC)=[S:24])[CH:18]=1>CO>[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[S:24][C:7]([NH2:6])=[CH:8][N:9]=2)[CH:18]=1
Reactant: CSC(=S)c1cccnc1
Reactant: N#CCN
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: Nc1cnc(-c2cccnc2)s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 66.9 %

Procedure:
To a dry 500 ml round bottom flask equipped with magnetic stirrer, thermometer, bleach scrubber, and addition funnel was charged 27.6 g (179 mmoles) of aminoacetonitrile bisulfate, and 200 mLs of anhydrous methanol. The solution was cooled to ˜0° C. and 24.15 g (239 mmoles) of triethyl amine was added dropwise at a rate that maintained the temperature below 10° C. After 10 minutes, 20.2 g (119 mmoles) of methyl pyridine-3-carbodithioate was added dropwise in 50 mLs of anhydrous methanol. The reaction mixture was stirred at ambient temperature for 20 hours, after which, the solvent was removed under vacuum on a rotary evaporator. The residue was poured into 500 mLs of water and extracted with methylene chloride (4×100 mLs). The combined methylene chloride extracts were washed with 100 mLs of water, 100 mLs of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum on a rotary evaporator. The crude product was suspended in 100 mLs of ethyl ether, and the resulting yellow solid was collected by vacuum filtration to afford 14.1 g (66%) of a pale yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 8.97 (d, J=2.2 Hz, 1H), 8.53 (dd, J=4.8, 1.6 Hz, 1H), 8.12-8.03 (m, 1H), 7.45 (dd, J=7.9, 4.8 Hz, 1H), 6.99 (s, 1H), 6.28 (bs, 2H); 13C-NMR (101 MHz, CDCl3) δ 151.72, 148.55, 146.06, 145.40, 131.57, 130.18, 129.93, 122.20.
Reaction SMILES: [OH:1][CH:2]([C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1)[CH2:3][NH:4][C:5](=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH2:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[C:22]([CH3:27])[NH:21][C:20]3=[O:28])[CH2:13][C:14]#[CH:15])=[CH:8][CH:7]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>>[C:39]([O:1][CH:2]([C:30]1[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=1)[CH2:3][NH:4][C:5](=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH2:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[C:22]([CH3:27])[NH:21][C:20]3=[O:28])[CH2:13][C:14]#[CH:15])=[CH:8][CH:7]=1)(=[O:41])[CH3:40]
Reactant: C#CCN(Cc1ccc2nc(C)[nH]c(=O)c2c1)c1ccc(C(=O)NCC(O)c2ccc([N+](=O)[O-])cc2)cc1
Reactant: CC(=O)OC(C)=O
Product: C#CCN(Cc1ccc2nc(C)[nH]c(=O)c2c1)c1ccc(C(=O)NCC(OC(C)=O)c2ccc([N+](=O)[O-])cc2)cc1
Yield: 88 %

Procedure:
Using an analogous procedure to that described in Example 4, N-[2-hydroxy-2-(4-nitrophenyl)ethyl]-p-[N-(2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]benzamide was reacted with acetic anhydride to give N-[2-acetoxy-2-(4-nitrophenyl)ethyl]-p-[N-(2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]benzamide (containing 2.3 equivalents of water) in 88% yield, m.p. 198°-203° C.
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:19])=[C:7]([CH3:18])[C:8]([CH3:17])=[C:9]([CH2:11][CH2:12][C:13]([O:15]C)=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH2:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>CO>[CH2:20]([NH:38][C:13](=[O:15])[CH2:12][CH2:11][C:9]1[CH:10]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:6]([OH:19])=[C:7]([CH3:18])[C:8]=1[CH3:17])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C)c1C
Reactant: CCCCCCCCCCCCCCCCCCN
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCNC(=O)CCc1cc(C(C)(C)C)c(O)c(C)c1C
Reaction time: 4 h

Procedure:
A mixture consisting of 10.6 grams of methyl 3-(5-tert.-butyl-2,3-dimethyl-4-hydroxyphenyl)propionate and 11.9 grams of n-octadecylamine were heated together for 1 hour at 160° to 165° and then at 175° to 180° for four hours, the methanol of reaction being removed continuously by distillation. Crystallization from methanol yielded white crystals melting at 85° to 87° (Compound 35).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1[nH]c(=O)ccc1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 115 °C

Procedure:
A suspension of 6-methyl-5-nitro-1H-pyridin-2-one (Preparation 2, 3.53 g, 22.9 mmol) in phosphorous oxychloride (20 mL) was heated to 115° C. (oil bath temperature) for 3 h then allowed to cool to rt. The phosphorous oxychloride was removed in vacuo and the residue poured into iced water (100 mL). The mixture was quenched by addition of saturated sodium bicarbonate solution, then the aqueous mixture was extracted with ethyl acetate (3×100 mL). The combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to furnish the title compound as a brown solid. δH (CDCl3): 2.86 (3H, s), 7.36 (1H, d, 8.59 Hz), 8.27 (1H, d, 8.32 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([F:12])[C:3]=1[O:13][C:14]1[CH:18]=[C:17]([CH3:19])[N:16](C(OC)=O)[N:15]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[C:4]([F:12])[C:3]=1[O:13][C:14]1[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=1
Reactant: COC(=O)n1nc(Oc2c(F)cc(C(F)(F)F)cc2Cl)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Oc2c(F)cc(C(F)(F)F)cc2Cl)n[nH]1
Yield: 88.2 %

Procedure:
To an ethanol (10 mL) solution of methyl 3-(2-chloro-6-fluoro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxylate (0.53 g, 1.5 mmol) was added 5% sodium hydroxide (8 mL), and the mixture was refluxed under heating for 2 hours. After completion of the reaction, the solvent was distilled off the reaction mixture, and then water was added, followed by extraction with ethyl acetate. The organic layers combined were washed with water, and dried over anhydrous magnesium sulfate and the solvent was distilled off. The resultant residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:5) to give a white solid of 3-(2-chloro-6-fluoro-4-trifluoromethylphenyloxy)-5-methylpyrazole (0.39 g, yield: 88.2%).
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][C:33]([O:35]C(C)(C)C)=[O:34]>C(#N)C>[C:16]1([C@@H:14]2[CH2:15][C@H:13]2[NH:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:11][CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)CCBr
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(O)CCN1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 38.5 %

Procedure:
To a solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (300 mg, 0.919 mmol) in acetonitrile (10 mL) was added potassium carbonate (381 mg, 2.76 mmol) followed by tert-butyl 3-bromopropanoate (211 mg, 1.011 mmol) was heated in a seal tube at 80° C. for 4 hours. The reaction mixture was filtered, and the filtrate evaporated to dryness. The resulting oil was dissolved in 2 ml of EtOH and 2 ml of 1 M NaOH. The reaction mixture was stirred for 20 min. The solution injected on a preparatory HPLC (2 to 10% AcCN: H2O with 0.1% formic acid modifier). The fractions were collected. To each fraction was added 0.1 ml of 6 M HCl, and the fractions were evaporated to dryness. Acid was formed by deprotection of t-butyl during evaporation. 3-(4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)propanoic acid (140 mg, 0.354 mmol, 38.5% yield) was isolated as yellow oil. 1H NMR (400 MHz, METHANOL-d4) δ 7.29-7.37 (m, 2H), 7.11-7.29 (m, 3H), 3.65 (br. s., 2H), 3.45 (t, J=7.07 Hz, 2H), 3.23 (d, J=5.81 Hz, 2H), 3.11 (br. s., 2H), 3.04 (dt, J=4.01, 7.89 Hz, 1H), 2.90 (t, J=7.07 Hz, 2H), 2.62 (ddd, J=3.54, 6.63, 10.29 Hz, 1H), 2.04-2.29 (m, 3H), 1.70 (dd, 2H), 1.62 (ddd, J=4.42, 6.51, 10.55 Hz, 1H), 1.42 (q, J=6.91 Hz, 1H); LC-MS Rt=0.42 min; MS (ESI): 303.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9]1.N1C=CC=CC=1.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38]>ClCCl>[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9]1)(=[O:39])=[O:38]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1N)N2
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1NS(=O)(=O)c1ccccc1F)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.6 %

Procedure:
To an ice-cold mixture of methyl 2-(2-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (60 mg, 0.19 mmol, 1.0 eq.) and pyridine (0.3 mL, 3.8 mmol, 20 eq.) in dichloro methane (5 mL) was added 2-fluorobenzene-1-sulfonyl chloride (51 mg, 0.29 mmol, 1.5 eq.) under nitrogen. Then the reaction mixture was stirred at room temperature for two hours. Thin layer chromatography and LC-MS indicated that the starting material was consumed completely. The reaction was quenched with 20 mL water extracted with ethyl acetate (20 mL×2). The combined organic layers were concentrated and the residue was purified by silica gel (petroleum ether/ethyl acetate=2:1) to afford 62 mg of methyl 2-(2-(2-fluorophenylsulfonamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a pale yellow solid; yield: 70%; MS (ESI+APCI) M+1=469.