Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[SH:14][CH2:15][C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(CCO)ccc1F
Reactant: O=C(O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CSc1ccc(CCO)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 59.6 %

Procedure:
A mixture of 2-(4-fluoro-3-nitro-phenyl)ethanol [RN20274-69-5](1.1 g, 6 mmol), mercaptoacetic acid (0.61 g, 6.6 mmol), potassium carbonate (2.8 g, 20 mmol) and N,N-dimethylformamide (12 ml) was heated at 70° C. for 4 hours. The mixture was poured onto water (200 ml) and the aqueous phase was washed with ethyl acetate. The aqueous phase was then acidified with 1M aqueous hydrochloric acid and extracted three times with dichloromethane. The extracts were dried and evaporated to give an oil (0.92 g, 60%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC.Cl.[CH3:30][O:31][NH:32][CH3:33]>C(Cl)Cl>[CH3:30][O:31][N:32]([CH3:33])[C:13]([C@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: CNOC
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
To a solution of (R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (11.93 g, 55.42 mmol) and DCM (70 mL) cooled to −15° C. was added a solution of NMM (5.79 g, 57.3 mmol), ethyl carbonochloridate (12.03 g, 110.8 mmol) and DCM (50 mL) and the mixture was stirred for 15 min. Additional NMM (11.59 g, 114.5 mmol) was added followed by portion wise addition of O,N-dimethylhydroxylamine hydrochloride (10.81 g, 110.8 mmol). The reaction was stirred at RT for 18 h. The reaction was poured onto water and extracted with DCM. The organic layer was dried, filtered, and concentrated and the crude residue was purified by SiO2 chromatography eluting with EtOAc/hexane (1:1) to afford 9.74 g (68.03%) of (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (74).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:23])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH3:15])[C:10](=[O:16])[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:8]2)=[O:4].[Br:24]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:23])=[C:7]2[C:12](=[C:13]([Br:24])[N:14]=1)[N:11]([CH3:15])[C:10](=[O:16])[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2C)c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2C)c1O
Yield: 82.1 %

Procedure:
A mixture of 5-hydroxy-1-methyl-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (67 mg, 0.216 mmol) and N-bromosuccinimide (42 mg, 0.238 mmol) in CH2Cl2 (1 mL) was refluxed for 3 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (5-40% EtOAc/hexanes+1% AcOH) to give 69 mg of the title compound as a yellow solid. MS: (−) m/z 387.13, 389.15 (M-1, 79/81Br).
Reaction SMILES: [N:1]1([CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:20][CH:21]([F:25])[C:22](F)=[O:23]>C1(C)C=CC=CC=1>[F:20][CH:21]([F:25])[C:22](=[O:23])[C:8](=[CH:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C=CN1CCOCC1
Reactant: O=C(F)C(F)F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)C(=CN1CCOCC1)C(=O)C(F)F
Temperature: -30 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
Methyl 3-morpholin-4-ylacrylate (96.3%, 8.5 g, 50 mmol) and triethylamine (5.2 g, 50 mmol) were initially charged in toluene (250 ml) and cooled to −30° C. At this temperature, difluoroacetyl fluoride (5.0 g, 50 mmol) was introduced. The reaction mixture was stirred at −30° C. for 3 h and then, over a period of 1 hour, warmed to room temperature. Under reduced pressure, the reaction mixture was freed from the solvent. The residue obtained was 15.5 g of an orange solid which, according to quant. 1H-NMR, consisted to 66.4% of methyl 4,4-difluoro-3-oxo-2-(morpholin-4-ylmethylidene)butyrate (yield: 82%). 1H-NMR (CDCl3): δ=3.4 (m, 2H), 3.7 (m, 2H), 3.75 (s, 3H), 3.85 (m, 2H), 6.6 (t, 1H), 7.85 ppm (s, 1H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]4[CH2:23][CH2:22]4)[CH:20]=3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:27])[N:11]3[C:24](=[O:26])[CH3:25])[CH2:2]1.[CH3:28][C:29]([CH3:31])=O>>[CH:21]1([N:19]2[CH:20]=[C:16]([C:15]3[C:6]([O:5][CH:3]4[CH2:2][N:1]([CH:29]([CH3:31])[CH3:28])[CH2:4]4)=[C:7]4[C:12](=[CH:13][CH:14]=3)[N:11]([C:24](=[O:26])[CH3:25])[C@@H:10]([CH3:27])[CH2:9][CH2:8]4)[CH:17]=[N:18]2)[CH2:23][CH2:22]1
Reactant: CC(C)=O
Reactant: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)c(OC3CNC3)c2CC[C@@H]1C
Product: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)c(OC3CN(C(C)C)C3)c2CC[C@@H]1C

Procedure:
(S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(1-isopropylazetidin-3-yloxy)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone was synthesized from (S)-1-(5-(azetidin-3-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone and acetone according to the procedure outlined above for Example 40. 1H NMR (400 MHz, CD3OD) δ ppm 0.89-1.01 (m, 6H), 1.01-1.15 (m, 7H), 1.21-1.35 (m, 1H), 2.16 (s, 3H), 2.25-2.45 (m, 3H), 2.85-2.95 (m, 1H), 3.06 (t, J=7.20 Hz, 1H), 3.15 (t, J=7.20 Hz, 1H), 3.41-3.55 (m, 2H), 3.68-3.73 (m, 1H), 4.21-4.29 (m, 1H), 4.65-4.81 (m, 1H), 7.01-7.12 (m, 1H), 7.36 (d, J=8.00 Hz, 1H), 7.81 (s, 1H), 8.03 (s, 1H). MS (ESI, pos. ion) m/z 409 [M+H]+.
Reaction SMILES: [OH-].[Na+].[S:3]1[CH2:8][CH2:7][CH2:6][S:5][C:4]1=[C:9]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[CH2:24][C:25]([OH:27])=[O:26].Cl>O>[C:25]([CH2:24][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:9](=[C:4]2[S:5][CH2:6][CH2:7][CH2:8][S:3]2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:21][CH:20]=1)([OH:27])=[O:26]
Reactant: Oc1ccc(C(=C2SCCCS2)c2ccccc2)cc1
Reactant: O=C(O)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)COc1ccc(C(=C2SCCCS2)c2ccccc2)cc1

Procedure:
To a solution of sodium hydroxide (1.3 g) in water (30 ml), (1,3-dithian-2-ylidene)-(4-hydroxyphenyl)-phenylmethane (3.0 g) and chloroacetic acid (1.4 g) are added. The mixture is refluxed for 3 hours. The water is slowly acidified with concentrated hydrochloric acid to pH 3. The aqueous phase is extracted with water (3×20 ml). The combined organic phases are washed with water (2×10 ml) and dried over magnesium sulphate. The solvent is evaporated in vacuo. The residue is purified by column chromatography on silicagel using dichloromethane/formic acid (99:1) as eluant. The fractions containing the pure product are washed with water to neutrality, dried over magnesium sulphate and evaporated. The residue is dried in vacuo to constant weight to give (4-carboxymethoxyphenyl)-(1,3-dithian-2-ylidene)-phenylmethane, m.p. 176°-177°.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([OH:17])=O)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.ON1C2C=CC=CC=2N=N1.[C@@H:28]1([NH2:37])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1.Cl.C(N=C=NCCCN(C)C)C>O1CCOCC1>[Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([NH:37][C@@H:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][CH2:29]2)=[O:17])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=C(O)C1COCCN1c1nc(Cl)ncc1Br
Reactant: N[C@H]1CCc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Product: O=C(N[C@H]1CCc2ccccc21)C1COCCN1c1nc(Cl)ncc1Br

Procedure:
To a 50 mL pear flask were added 4-(5-bromo-2-chloropyrimidin-4-yl)morpholine-3-carboxylic acid (PREPARATION x30, 300 mg, 0.930 mmol), 1-hydroxybenzotriazole (126 mg, 0.930 mmol), and (S)-2,3-dihydro-1H-inden-1-amine (0.119 mL, 0.930 mmol) in 1,4-dioxane (25 mL) to give a green solution. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (178 mg, 0.930 mmol) was added to the solution, which was allowed to reaction at room temperature for 6 hours. The reaction mixture was subsequently partitioned between aqueous saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound, which was used without further purification. ESI-MS m/z [M+H]+ calc'd for C18H18BrClN4O2, 437.03. found 437.2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[N+:6]([O-:9])([OH:8])=[O:7]>C(OC(=O)C)(=O)C>[N+:6]([O-:9])([OH:8])=[O:7].[N+:6]([O:5][CH2:4][CH2:3][CH2:2][NH2:1])([O-:8])=[O:7]
Reactant: NCCCO
Solvent: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: NCCCO[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
A solution of 3-amino-1-propanol (6.17 g, 82.2 mmol) was added, drop-wise, to an ice-cooled solution of fuming nitric acid (90%, 12 mL) in acetic anhydride (50 mL). The reaction was stirred in an ice-bath for 10 minutes and then at room temperature for 10 minutes. The solvent was evaporated under vacuum at 40° C. The residue was stirred in diethylether (200 mL) until the product precipitated. The mixture was filtered and the white crystalline solid was dried in vacuo to give the title compound (12.1 g, 80% yield). 1H NMR (300 MHz, DMSO-d6) δ 4.57 (br. t, 2 H), 2.8-3.0 (m, 2H), 1.98-1.93 (m, 2H). 13C NMR (75 MHz, DMSO-d6) δ 70.9, 36.1, 24.5. MS m/z 121 (M—NO3)+.
Reaction SMILES: [CH3:1][C:2]([S@:5](/[N:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:6])([CH3:4])[CH3:3].[CH2:25]([Li])[CH:26]([CH3:28])[CH3:27]>O1CCCC1>[CH3:4][C:2]([S@:5]([NH:7][C@@H:8]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:6])([CH3:1])[CH3:3]
Reactant: CC(C)(C)[S@@](=O)/N=C/c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: [Li]CC(C)C
Solvent: C1CCOC1
Product: CC(C)C[C@@H](N[S@](=O)C(C)(C)C)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A round bottom flask was charged with (R,E)-2-methyl-N-((4′-(trifluoromethyl) biphenyl-4-yl)methylene)propane-2-sulfinamide (25.0 g, 70.7 mmol) and tetrahydrofuran (140 mL) and cooled down to −78° C. To this solution was added isobutyllithium (1.6M in heptane; 50.8 mL) dropwise over 20 minutes. The reaction was allowed to stir at −78° C. for 30 minutes. LC-MS analysis showed complete conversion of the starting material and the formation of two product diastereomers (4.6:1). The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate twice. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (1-10% ethyl acetate/dichloromethane) allowed isolation of the major isomer (the less polar isomer), (R)-2-methyl-N-((R)-3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butyl)propane-2-sulfinamide (47.5 g, 74.2%) as a colorless gum. 1H NMR (400 MHz, CDCl3, δ): 0.91 (d, 3H) 0.96 (d, J=6.44 Hz, 3H) 1.24 (s, 9H) 1.49-1.59 (m, 1H) 1.63-1.72 (m, 1H) 1.84-1.94 (m, 1H) 3.38 (br. s., 1H) 4.46 (dd, J=8.19, 6.83 Hz, 1H) 7.43-7.46 (m, 2H) 7.56-7.60 (m, 2H) 7.68-7.70 (m, 4H). MS (M+1): 412.3.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH:8]=1)(=O)=O.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>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>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][CH:8]=1
Reactant: OB(O)c1cc(F)ccc1Cl
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
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: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(F)ccc2Cl)CC1
Temperature: 80 °C
Yield: 55.4 %

Procedure:
A mixture of tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (2, 1.10 g, 3.3 mmol), 2-chloro-5-fluorophenyl boronic acid (0.58 g, 3.3 mmol), Pd(PPh3)4 (0.38 g, 0.33 mmol), and 2 M Na2CO3 (20 mL) in DME (50 mL) was heated at 80° C. for 6 h. The mixture cooled to ambient temperature, and the resulting solids were removed by filtration through a Celite pad. The filtrate was washed brine solution (4×50 mL) and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 40 g Redisep column, 0% to 80% EtOAc in hexanes) to provide tert-butyl 4-(2-chloro-5 fluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (15) as a clear oil (0.57 g, 55%): 1H NMR (300 MHz, DMSO-d6) δ 7.53-7.46 (m, 1H), 7.23-7.14 (m, 2H), 5.79-5.74 (m, 1H), 4.00-3.92 (m, 2H), 3.52 (t, J=5.7 Hz, 2H), 2.40-2.32 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].[CH2:21]([NH2:23])[CH3:22]>>[NH2:1][C:2]1[N:10]=[C:9]([NH:23][CH2:21][CH3:22])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: CCN
Agent: [Na+]
Agent: [OH-]
Product: CCNc1nc(N)c2ncn(Cc3ccccc3)c2n1
Yield: 71 %

Procedure:
6-Amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) and aqueous ethylamine (50 ml) were heated at 120° C. for 20 hours in autoclave. The reaction mixture was condensed in vacuo. To the residue was added 5N aqueous sodium hydroxide and the mixture was extracted with chloroform. The organic layer was dried on sodium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (147 mg, yield 71%).
Reaction SMILES: CCCCOCCOCCO[CH2:12][C:13]1[CH:14]=[C:15]2[O:24][CH2:23][O:22][C:16]2=[CH:17][C:18]=1[CH2:19][CH2:20][CH3:21].[ClH:25].O>C1C=CC=CC=1>[CH2:19]([C:18]1[C:13]([CH2:12][Cl:25])=[CH:14][C:15]2[O:24][CH2:23][O:22][C:16]=2[CH:17]=1)[CH2:20][CH3:21]
Reactant: CCCCOCCOCCOCc1cc2c(cc1CCC)OCO2
Reactant: Cl
Solvent: O
Solvent: c1ccccc1
Product: CCCc1cc2c(cc1CCl)OCO2
Temperature: 25 °C

Procedure:
15 g of piperonyl butoxide and 300 ml of concentrated hydrochloric acid were dissolved in 100 ml of benzene and the solution was heated under reflux for 3 h. The reaction mixture was cooled to room temperature and water was added thereto. After extraction with ethyl acetate, the extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to obtain 12 g of 6-propyl-5-chloromethyl-1,3-benzodioxole in the form of a faint brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N:11]([CH2:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21]([CH3:26])[NH:20][C:19]3=[O:27])[CH2:12][C:13]#[CH:14])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[N+:28]([C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][NH2:35])([O-:30])=[O:29]>>[NH2:1][C:2]1[CH:10]=[C:9]([N:11]([CH2:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21]([CH3:26])[NH:20][C:19]3=[O:27])[CH2:12][C:13]#[CH:14])[CH:8]=[CH:7][C:3]=1[C:4]([NH:35][CH2:34][C:33]1[CH:36]=[CH:37][CH:38]=[C:31]([N+:28]([O-:30])=[O:29])[CH:32]=1)=[O:5]
Reactant: C#CCN(Cc1ccc2nc(C)[nH]c(=O)c2c1)c1ccc(C(=O)O)c(N)c1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: C#CCN(Cc1ccc2nc(C)[nH]c(=O)c2c1)c1ccc(C(=O)NCc2cccc([N+](=O)[O-])c2)c(N)c1
Yield: 64 %

Procedure:
Using the procedure described in Example 1, o-amino-p-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]benzoic acid was reacted with 3-nitrobenzylamine to give o-amino-p-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]-N-(3-nitrobenzyl)benzamide in 64% yield, m.p. 86°-92° C.
Reaction SMILES: [C:1]1([S:7][C:8]2[N:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[S:24][C:23]([CH:25]([CH:29]([CH3:31])[CH3:30])[C:26](O)=[O:27])=[CH:22][C:21]=2[CH:32]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[S:24][C:23]([CH:25]([CH:29]([CH3:30])[CH3:31])[C:26]([O:15][CH2:14][C:12]3[CH:11]=[CH:10][CH:9]=[C:8]([S:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:13]=3)=[O:27])=[CH:22][C:21]=2[CH:32]=1
Reactant: CC(C)C(C(=O)O)c1cc2cc(Cl)ccc2s1
Reactant: OCc1cccc(Sc2ccccc2)n1
Product: CC(C)C(C(=O)OCc1cccc(Sc2ccccc2)n1)c1cc2cc(Cl)ccc2s1

Procedure:
Using the procedure of Example 10, (6-phenylthio-2-pyridyl)methanol is reacted with 2-(5-chloro-2-benzothienyl)-3-methylbutanoic acid to give (6-phenylthio-2-pyridyl)methyl 2-(5-chloro-2-benzothienyl)-3-methylbutanoate.
Reaction SMILES: O=C1[N:6]([C:7]2[CH:18]=[CH:17][C:10]([CH2:11][NH:12][C:13](=[O:16])[CH2:14][CH3:15])=[C:9]([C:19]([F:22])([F:21])[F:20])[CH:8]=2)[CH2:5][C:4]([C:27]2[CH:32]=[C:31]([Cl:33])[C:30]([Cl:34])=[C:29]([Cl:35])[CH:28]=2)([C:23]([F:26])([F:25])[F:24])[O:3]1.O.[OH-].[K+]>O1CCOCC1>[F:25][C:23]([F:24])([F:26])[C:4]([OH:3])([C:27]1[CH:28]=[C:29]([Cl:35])[C:30]([Cl:34])=[C:31]([Cl:33])[CH:32]=1)[CH2:5][NH:6][C:7]1[CH:18]=[CH:17][C:10]([CH2:11][NH:12][C:13](=[O:16])[CH2:14][CH3:15])=[C:9]([C:19]([F:20])([F:21])[F:22])[CH:8]=1
Reactant: CCC(=O)NCc1ccc(N2CC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)OC2=O)cc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCC(=O)NCc1ccc(NCC(O)(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C(F)(F)F
Temperature: 70 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
N-{4-[2-oxo-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-1,3-oxazolidin-3-yl]-2-(trifluoro-methyl)benzyl}propane amide (542 mg) was added to a solution of 1,4-dioxane (10 mL), water (10 mL) and potassium hydroxide (108 mg), and stirred at 70° C. for 1 hour. After the reaction, 1,4-dioxane was distilled off under reduced pressure, and conc. hydrochloric acid (70 mg) was added and stirred under ice cooling. The resultant was extracted with ethyl acetate, washed with water and saturated brine, and the organic layer is dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residues were purified by silica-gel column chromatography to give N-[4-{[3,3,3-trifluoro-2-hydroxy-2-(3,4,5-trichlorophenyl)propyl]amino}-2-(trifluoromethyl)benzyl]propane amide (503 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Cl)[N:3]=1.[OH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[Cl:1][C:2]1[N:3]=[C:4]([CH2:8][N:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]2=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1cccc(Cl)n1
Reactant: Oc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccccn1Cc1cccc(Cl)n1
Reaction time: 8 h

Procedure:
To the solution of 2-chloro-6-chloromethylpyridine (1.62 g g, 10 mmol) in DMF (10 mL) was added 2-hydroxypyridine (0.95 g, 10 mmol) and Cs2CO3 (6.52 g, 20 mmol). The mixture was stirred overnight, then diluted with water and extracted with CH2Cl2. The combined organic layer was dried, filtered, and concentrated to give a solid. The solid was purified by silica gel chromatography (2-4% MeOH in CH2Cl2) to give 1-[(6-chloropyridin-2-yl)methyl]pyridin-2(1H)-one. 1H-NMR (500 MHz, CDCl3) δ 7.62 (t, 1H, J=7.8), 7.51 (dd, 1H, J=6.8, 2.0), 7.31-7.37 (m, 2H), 7.25 (d, 1H, 3=8.3), 6.59 (d, 1H, J=9.2), 6.21 (td, 1H, J=6.6, 1.3), 5.19 (s, 2H). LRMS m/z (M+H) Calcd: 221.7. found: 221.0.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:30])[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[N+:31]([C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH:36]=[O:37])([O-:33])=[O:32]>O1CCCC1>[C:26]([O:25][C:23]([N:20]1[CH2:19][CH2:18][CH:17]([CH:16]([C:15]([O:14][CH3:13])=[O:30])[CH:36]([OH:37])[C:35]2[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=2[N+:31]([O-:33])=[O:32])[CH2:22][CH2:21]1)=[O:24])([CH3:27])([CH3:29])[CH3:28]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: COC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C1CCN(C(=O)OC(C)(C)C)CC1)C(O)c1ccccc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
N,N-diisopropylamine (4.40 mL, 31.3 mmoles) was dissolved in tetrahydrofuran (50 mL). The mixture was cooled to −78° C. Butyllithium (2.5 M in hexanes, 12.4 mL, 31 mmoles) was added dropwise to the stirred solution. After stirring at −78° C. for 30 min, a solution of tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (6.65 g, 25.8 mmoles) in tetrahydrofuran (15 mL) was added dropwise to the mixture. Stirring was continued at −78° C. for 1 h. A solution of 2-nitrobenzaldehyde (3.90 g, 25.8 mmoles) in tetrahydrofuran (20 mL) was then added to the mixture dropwise, and then stirring was continued at −78° C. for a further 2.5 h. The reaction was quenched with cold aqueous ammonium chloride and then diluted with water. The mixture was extracted twice with ethyl acetate and the aqueous phase was discarded. The material was dried (magnesium sulfate) filtered, and concentrated to dryness. Silica gel chromatography afforded the desired product in 94% yield as light yellow foam. MS m/e (M-C4H8+H)+=353.1.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:26])=[N:8][N:9]2[C:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[F:24])=[CH:13][C:12]([CH3:25])=[CH:11][C:10]=12)=[O:5])C.[OH-].[Na+].CS(C)=O>O1CCOCC1>[F:24][C:18]1[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][O:15][C:14]1[N:9]2[N:8]=[C:7]([CH3:26])[C:6]([C:4]([OH:5])=[O:3])=[C:10]2[CH:11]=[C:12]([CH3:25])[CH:13]=1
Reactant: CCOC(=O)c1c(C)nn2c(OCc3cccc(F)c3F)cc(C)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: Cc1cc(OCc2cccc(F)c2F)n2nc(C)c(C(=O)O)c2c1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
A solution of 190 mg (0.527 mmol) of 7-[(2,3-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester from Example 116A in 5 ml of dioxane was admixed with 2.1 ml of 2 N sodium hydroxide solution. The resulting mixture was stirred at 90° C. for 15 h. Owing to incomplete mixing, 1 ml of dimethyl sulphoxide was added, followed by further 2 N sodium hydroxide solution (1 ml). The resulting mixture was stirred for a further 2 h. After the reaction had ended, the solvent was removed under reduced pressure. The residue was admixed with acetonitrile (5 ml), followed by the dropwise addition of trifluoroacetic acid (2 ml). The resulting precipitate was filtered off and dried under reduced pressure, which gave 130 mg (71% of theory, 93% pure) of the target compound.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[C:10]1(=O)[O:15][C:13](=[O:14])[CH2:12][CH2:11]1>>[C:13]([CH2:12][CH:11]=[C:10]1[C:7]2[CH:8]=[C:2]([CH3:1])[C:3]([OH:9])=[CH:4][C:5]=2[O:6][C:5]2[C:7]1=[CH:8][C:2]([CH3:1])=[C:3]([OH:9])[CH:4]=2)([OH:15])=[O:14]
Reactant: O=C1CCC(=O)O1
Reactant: Cc1ccc(O)cc1O
Product: Cc1cc2c(cc1O)Oc1cc(O)c(C)cc1C2=CCC(=O)O
Temperature: 65 °C
Yield: 74.2 %

Procedure:
4-Methylresorcinol (25.8 g, 0.208 mol) and succinic anhydride (20.8 g, 0.208 g) were placed in a round bottom flask and the flask was purged with nitrogen. Methanesulfonic acid (150 mL) was added and the solution heated under nitrogen to 65° C. for 2 hours. The solution was added dropwise to 1 L of rapidly stirred, ice-cooled water with the simultaneous addition of 50% aq sodium hydroxide to maintain the pH at 2.25±0.25. The product was collected by centrifugation and washed with water (3×) and acetone (2×). The solid was air-dried, then vacuum-dried at 110° C. to afford a brick-red powder (24.1 g, 74%).