Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:23]([C:27]([CH2:29][C:30](OCC)=[O:31])=[O:28])([F:26])([F:25])[F:24]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:30](=[O:31])[CH2:29][C:27](=[O:28])[C:23]([F:26])([F:25])[F:24])=[CH:19][CH:20]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cc2ccc(N)cc2)cc1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1ccc(Cc2ccc(NC(=O)CC(=O)C(F)(F)F)cc2)cc1
Temperature: -15 °C
Yield: 88.4 %

Procedure:
A solution of [4-(4-aminobenzyl)phenyl]carbamic acid tert-butyl ester (1.26 g, 4.2 mmol) in PhMe (15 mL) was treated with a PhMe (10 mL) solution of CF3COCH2CO2Et (0.79 g, 4.3 mmol), before being heated under reflux for 1 h. More CF3COCH2CO2Et (0.40 g, 2.2 mmol) was added, & the mixture was heated under reflux for 1.5 h. The precipitate generated when the mixture was cooled to −15° C. was collected to give {4-[4-(4,4,4-trifluoro-3-oxobutyrylamino)benzyl]phenyl}carbamic acid tert-butyl ester (1.62 g, 90%): m/z (ES−)=435.3 [M−H]−. This compound (1.00 g, 2.3 mmol) was added portionwise with stirring to cold H2SO4 (5 mL) to generate a brown solution. This solution was heated at 90° C. for 1 h, then the cooled mixture was poured onto crushed ice. The aqueous phase was treated with solid NaOH until basic, & the mixture was extracted with Et2O (200 mL). The Et2O extracts were dried (MgSO4), concentrated to a small volume, & triturated with PE to furnish the title compound (0.66 g, 91%): δH ((CD3)2SO)=3.80 (s, 2H), 4.85 (s, 2H), 6.45 (d, 2H), 6.85 (d, 2H), 6.95 (s, 1H), 7.35 (d, 1H), 7.40–7.50 (m, 2H); m/z (ES+)=319.1
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][NH:6][C:7](=[O:10])[O:8][CH3:9].C(=O)([O-])[O-].[Na+].[Na+].[Cl:20][C:21]1[CH:22]=[C:23](OB(O)O)[CH:24]=[CH:25][C:26]=1[Cl:27].[Cl-].[Na+]>C(O)C.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.C1(C)C=CC=CC=1>[Cl:20][C:21]1[CH:22]=[C:23]([C:2]2[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=2)[CH2:5][NH:6][C:7](=[O:10])[O:8][CH3:9])[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: COC(=O)NCc1cccc(Br)c1
Reactant: OB(O)Oc1ccc(Cl)c(Cl)c1
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: [Cl-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)NCc1cccc(-c2ccc(Cl)c(Cl)c2)c1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
1.30 g of methyl N-(3-bromobenzyl)carbamate, 0.56 g of sodium carbonate in aqueous solution (20 ml) and 0.13 g of tetrakis(triphenylphosphine)palladium (0) were added to toluene (40 ml) under a nitrogen atmosphere. The resulting solution was mixed with 1.02 g of 3,4-dichlorophenylboric acid in ethanol (20 ml) at room temperature with stirring and refluxed under heating for 2 hours. After the reaction, the reaction solution was cooled to room temperature, poured into saturated aqueous sodium chloride and extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure for removal of the solvent. The residue was purified by silica gel column chromatography to give 1.45 g of methyl N-[3-(3,4-dichlorophenyl)benzyl]carbamate as a yellow transparent viscous liquid.
Reaction SMILES: C([O:5][CH:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])N(C)C)(C)(C)C.[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([CH3:25])[N:24]=1)C(O)=O>C1(C)C=CC=CC=1>[C:11]([O:10][C:6](=[O:5])[C:18]1[CH:22]=[C:23]([CH3:25])[N:24]=[C:16]([Cl:15])[CH:17]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)OC(C)(C)C)cc(Cl)n1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
N,N-dimethylformamide-di-tert.-butyl-acetal (19 mL, 80 mmol) is added during 40 min to a hot (65° C., flask temperature) suspension of 2-chloro-6-methyl-isonicotinic acid (3.40 g, 19.8 mmol) in dry toluene (100 mL). The clear orange solution is stirred at 80° C. for 48 h, cooled to rt and diluted with toluene (100 mL). The solution is washed with water (2×40 mL), sat. aq. NaHCO3 (3×30 mL) and sat. aq. NaCl (25 mL), dried (Na2SO4), filtered and evaporated. The residue is purified by FC (SiO2, DCM-MeOH) to give 2-chloro-6-methyl-isonicotinic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([Cl:23])[CH:17]=4)[O:13][N:12]=3)[CH:9]=2)[N:4]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:37](I)([CH3:39])[CH3:38].CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH:37]([CH3:39])[CH3:38])=[C:18]([Cl:23])[CH:17]=4)[O:13][N:12]=3)[CH:9]=2)[N:4]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:3]=1
Reactant: CC(C)I
Reactant: CCOC(=O)CCn1cc(Cl)c2cc(-c3noc(-c4ccc(O)c(Cl)c4)n3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCn1cc(Cl)c2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc21
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To ethyl 3-{3-chloro-5-[5-(3-chloro-4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl]-1H-indol-1-yl}propanoate (D108) (180 mg, 0.40 mmol) and K2CO3 (138 mg, 1.0 mmol) in dry DMF (5 ml) was added isopropyl iodide (85 mg, 0.50 mmol) and the mixture stirred at 80° C. for 30 minutes. Cooled mixture and added EtOAc (50 ml). Washed with water (2×50 ml) and dried over MgSO4. Evaporated off the solvent and crystallised from ethanol to yield the title compound as 120 mg of white solid. δH (400 MHz, d6-DMSO) 1.12 (3H, t), 1.37 (6H, d), 2.91 (2H, t), 4.02 (2H, q), 4.50 (2H, t), 4.89-4.98 (1H, m), 7.72-7.85 (5H, m), 7.95-8.00 (1H, m), 8.24 (1H, d). MS (ES) C24H2335Cl2N3O4 requires 487; found 488 (MH+).
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[CH3:9][C:10]1[C:11]([S:16](Cl)(=[O:18])=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=1>>[C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][S:16]([C:11]2[C:10]([CH3:9])=[CH:15][CH:14]=[CH:13][N:12]=2)(=[O:18])=[O:17])[CH:2]=1
Reactant: Cc1cccnc1S(=O)(=O)Cl
Reactant: Cc1cccc(N)c1
Product: Cc1cccc(NS(=O)(=O)c2ncccc2C)c1

Procedure:
prepared by reaction of m-tolylamine with 3-methyl-pyridine-2-sulfonyl chloride
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[C:16]1[C:7](=[C:8]3[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([CH3:21])([CH3:20])[CH:10]=[C:9]3[CH3:22])[C:6](=[O:23])[O:5]2.C(=O)([O-])[O-].[K+].[K+].[C:30]([O:33][CH2:34]C)(=O)C.C(OCC)C>CN(C)C=O>[CH3:30][O:33][CH2:34][O:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[C:16]1[C:7](=[C:8]3[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([CH3:20])([CH3:21])[CH:10]=[C:9]3[CH3:22])[C:6](=[O:23])[O:5]2
Reactant: CCOC(C)=O
Reactant: CC1=CC(C)(C)Nc2ccc3c(c21)c(=O)oc1cc(O)ccc13
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COCOc1ccc2c(c1)oc(=O)c1c3c(ccc12)NC(C)(C)C=C3C
Temperature: 50 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
A mixture of 8-hydroxy-2,2,4-trimethyl-1,2-dihydro-6-oxa-1-azachrysen-5-one (Reference Compound No. 1-(4), 1.00 g, 3.25 mmol), chlorodimethylether (420 μL, 5.53 mmol) and potassium carbonate (1.35 g, 9.77 mmol) was suspended in anhydrous N,N-dimethylformamide (15 mL) and the suspension was stirred at 50° C. overnight. After cooling down, ethyl acetate (100 mL) and diethylether (100 mL) were added thereto. The whole was washed with water (150 mL, 100 mL) and saturated brine (100 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (747 mg) as a yellow solid. (Yield 66%)
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[NH2:12][NH2:13]>CO>[CH3:11][O:10][C:4]1[N:3]=[C:2]([NH:12][NH2:13])[C:7]([O:8][CH3:9])=[CH:6][N:5]=1
Reactant: COc1ncc(OC)c(Cl)n1
Reactant: NN
Solvent: CO
Product: COc1ncc(OC)c(NN)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
A slurry of 4-chloro-2,5-dimethoxypyrimidine (3.0 grams (g), 17.2 mmol) in methanol (15 milliliters (mL)) was treated with aqueous hydrazine (3.9 g of 35 wt. %, 42.5 mmol) in one portion causing a slow exotherm to 29° C. The reaction was then warmed to 50° C. and held at that temperature for 2 hours (h) at which time gas chromatography (GC) analysis indicated the reaction was complete. The clear solution was cooled to ambient temperature and allowed to stir overnight. The solvent was removed in vacuo and the resulting gummy solid was triturated with CH3CN (50 mL). The resulting mixture was filtered through a pad of silica gel (6 centimeter (cm)×6 cm). The pad was rinsed with CH3CN (550 mL). The filtrates were combined and the solvent removed in vacuo affording the title compound as a white solid (2.6 g, 89%): mp 115-117° C.; 1H NMR (300 MHz, DMSO-d6) 3.73 (s, 3H), 3.76 (s, 3H), 4.29 (bs, 2H), 7.51 (s, 1H), 8.23 (bs, 1H); MS(GC, 70eV) 170 (M+, 100%), 155(55%), 151 (40%).
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].[CH3:25][C:26]1[NH:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2.[CH2:35](Cl)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CCOCC.O>[CH2:35]([N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[C:26]1[CH3:25])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Cc1cc2ccccc2[nH]1
Reactant: ClCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc2ccccc2n1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 2.39 g (9.04 mmoles) of 18-crown-6 in 250 mL of dry ether was added 13.1 g (116.7 mmoles) of potassium tert-butoxide. The mixture was stirred while 13.11 g (100 mmoles) of 2-methylindole was added. The stirring was continued for 0.5 hour. Most of the solid dissolved. Then 20 g (116.9 mmoles) of benzyl chloride in 120 mL of ether was added during 45 minutes. The stirring was continued for 21.5 hours. Water (200 mL) was added. The layers were separated. The aqueous layer was extracted with ether (2×75 mL). The combined ether phases were washed with 50 mL of brine and dried over MgSO4. Evaporation of the solvent left 25.85 g of dark brown oil. The oil was chromatographed on a 1100 g column of silica gel. The column was eluted with 25% CH2Cl2 -Skellysolve B and 200 mL fractions were collected. The fractions were assayed by silica gel tlc (1×4") (25% CH2Cl2 -Skellysolve B). Fractions 22-25 were combined giving 2.28 g (10%) of slightly impure 1-benzyl-2-methylindole as a pale yellow oil which solidified upon standing. Fractions 26-35 were combined giving 8.42 g of 1-benzyl-2-methylindole and 1,3-dibenzyl-2-methylindole as a pale yellow oil. The 8.42 g was combined with the 7.50 g of a similar mixture from fractions 23-28, and chromatographed on a 1100 g column of silica gel. The column was eluted with 25% CH2Cl2 -Skellysolve B and 200 mL fractions were collected. The fractions were assayed as before. Fractions 21-24 were combined giving 3.59 g of 1-benzyl-2-methylindole as a pale yellow oil which solidified. Fractions 25-30 were combined giving 7.66 g of a mixture of 1-benzyl-2-methylindole and 1,3-dibenzyl-2-methylindole as an oil.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].C(=O)([O-])[O-].[K+].[K+].[Cl:11][C:12]1[CH:13]=[C:14]([CH:38]=[CH:39][C:40]=1[F:41])[NH:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([OH:37])=[CH:23][C:24]=2[O:26][CH2:27][C@H:28]2[CH2:32][CH2:31][CH2:30][N:29]2[C:33](=[O:36])[CH2:34][OH:35])[N:19]=[CH:18][N:17]=1.O>CN(C=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([CH:38]=[CH:39][C:40]=1[F:41])[NH:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:37][CH2:2][CH2:3][OH:4])=[CH:23][C:24]=2[O:26][CH2:27][C@H:28]2[CH2:32][CH2:31][CH2:30][N:29]2[C:33](=[O:36])[CH2:34][OH:35])[N:19]=[CH:18][N:17]=1
Reactant: OCCBr
Reactant: O=C(CO)N1CCC[C@@H]1COc1cc(O)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CO)N1CCC[C@@H]1COc1cc(OCCO)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Temperature: 70 °C
Yield: 45 %

Procedure:
2-Bromoethanol (51 μl) and potassium carbonate (86 mg) were added to a mixture of 4-[3-chloro-4-fluoroanilino]-5-{[(2R)-1-glycoloylpyrrolidin-2-yl]methoxy}-quinazolin-7-ol (70 mg) in DMF and the reaction mixture was heated at 70° C. for 16 hours. The reaction mixture was cooled to room temperature and then water (5 ml) was added to leave a white precipitate. The precipitate was filtered, washed with water and then purified by column chromatography using 2-5% methanol in DCM as eluent. The product was purified further by acidic reverse phase HPLC, and then the combined fractions were reduced to a third of the initial concentration, basified with sodium carbonate and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and concentrated in vacuo to give the title compound as a white solid (35 mg, 45%); NMR Spectrum (DMSO-d6 at 373 K) 9.80 (br s, 1H), 8.40 (s, 1H), 8.15 (m, 1H), 7.65 (m, 1M, 7.33 (m, 1H), 6.80 (m, 2H), 4.60 (m, 1H), 4.50 (m, 1H), 4.30-4.10 (m, 4H), 4.0 (m, 2H), 3.75 (m, 2H), 3.60 (m, 1H), 3.50-3.37 (m, 2H), 2.10-1.85 (m, 4H); Mass spectrum MH+ 491.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:48]=[CH:47][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:44]=[CH:45][CH:46]=2)[O:30][CH2:31][CH:32]2[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33]2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCOCC1>[CH2:1]([N:8]([CH2:21][C:22]1[CH:48]=[CH:47][C:25]([O:26][C:27]2[CH:46]=[CH:45][CH:44]=[C:29]([O:30][CH2:31][CH:32]3[CH2:36][CH2:35][NH:34][CH2:33]3)[CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCC3CCN(C(=O)OC(C)(C)C)C3)c2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCC3CCNC3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from Example 93C (0.108 g, 0.161 mmoles) was treated with 4 N HCl (2.0 mL/8.00 mmoles) in dioxane and stirred at room temperature for one hour. Reaction quenched with saturated NaHCO3 and extracted with CH2Cl2. Extracts dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure to provide the title compound with no further purification.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[O:12][CH:13]1[CH2:16][CH2:15][CH2:14]1.O1CCOCC1.CO.[Li+].[OH-]>CO.C(Cl)Cl.O>[Br:10][C:8]1[CH:7]=[C:6]([CH3:11])[C:5]([O:12][CH:13]2[CH2:14][CH2:15][CH2:16]2)=[C:4]([CH:9]=1)[C:3]([OH:17])=[O:2]
Reactant: COC(=O)c1cc(Br)cc(C)c1OC1CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Cc1cc(Br)cc(C(=O)O)c1OC1CCC1
Reaction time: 18 h
Yield: 88 %

Procedure:
A 100 mL flask containing 5-bromo-2-cyclobutoxy-3-methyl-benzoic acid methyl ester (2.07 g, 7.25 mmol) as prepared above is charged with 1,4-dioxane (12 mL) and MeOH (12 mL). A stirring bar is added and stirring is initiated. After dissolution, water (6 mL) is added followed by the LiOH (768 mg, 18.3 μmol). After 18 h, tlc analysis (silica, 10% MeOH/DCM) indicates that the starting material is completely consumed. The pH of the reaction mixture is carefully adjusted to pH 2 by slowly adding dilute aqueous HCl (3%, ˜11 mL). The contents of the flask are poured into a separatory funnel which contains EtOAc (50 mL). The layers are separated. The aqueous layer is extracted with EtOAc (40 mL). The combined organic phases are washed with water (40 mL) and brine (40 mL), dried over MgSO4, filtered and concentrated by pumping to constant weight to give a white solid (1.82 g, 88%).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][CH2:20][NH:19][C:18]2=[O:22])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].Br[CH2:24][C:25]#[N:26].[H-].[Na+]>O1CCCC1>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][CH2:20][N:19]([CH2:24][C:25]#[N:26])[C:18]2=[O:22])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(C=C2SCNC2=O)cc(C(C)(C)C)c1O
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C=C2SCN(CC#N)C2=O)cc(C(C)(C)C)c1O
Yield: 40.7 %

Procedure:
7.03 g of 5-{[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-4-thiazolidinone and 2.64 g of bromoacetonitrile were reacted in the presence of 0.97 g of 60% sodium hydride in mineral oil and 330 ml of tetrahydrofuran. Work-up of the reaction mixture provided 3.21 g of the desired title product, m.p. 168°-188° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.[N+:31]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38])([O-:33])=[O:32]>ClCCl>[F:23][C:2]([F:22])([F:1])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]2[CH2:17][CH2:18][N:19]([C:37]([C:36]3[CH:40]=[CH:41][CH:42]=[C:34]([N+:31]([O-:33])=[O:32])[CH:35]=3)=[O:38])[CH2:20][CH2:21]2)=[CH:13][CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: OC(c1ccc(CN2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccc([N+](=O)[O-])c1)N1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 53.9 %

Procedure:
To a stirred mixture of 1,1,1,3,3,3-hexafluoro-2-(4-(piperazin-1-ylmethyl)phenyl)-propan-2-ol (3.21 mmol, 1.1 g) and triethylamine (3.21 mmol, 0.448 mL, 0.325 g) in dichloromethane at 0° C. was added 3-nitrobenzoyl chloride (3.21 mmol, 0.596 g). The reaction was stirred at 0° C. for 2 hours then was allowed to warm to room temperature and stir overnight. The reaction was purified by chromatography on silica (eluting dichloromethane to dichloromethane/methanol) and SCX column chromatography to give the title compound (850 mg). MS (ESI) m/z 492.3 [M+H]+
Reaction SMILES: C(OC[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13](C)C)=[C:8]([O:16]COCC)[C:7]=1C)C.Cl.O>CO>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][C:8]=1[OH:16]
Reactant: CCOCOc1ccc(OC(C)C)c(OCOCC)c1C
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1ccc(O)cc1O
Yield: 127.9 %

Procedure:
A solution of 5c (157 mg, 0.53 mmol) in MeOH (4.40 mL) at room temperature was treated dropwise with 3 M HCl (1.40 mL, 4.21 mmol), then heated to reflux for one hour. Water (5 mL) was added and the solution was extracted with EtOAc (3×10 mL). Combined organic fractions were washed with saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated to afford 6c as a red amorphous solid (95 mg, 99%): 1H NMR (CDCl3, 500 MHz) 6.54 (d, J=8.7 Hz, 1H), 6.21 (d, J=8.7 Hz, 1H), 5.78 (s, 1H), 4.37-4.32 (m, 1H), 2.09 (s, 3H), 1.25 (d, J=6.1 Hz, 6H); 13C NMR (CDCl3, 125 MHz) δ 147.7, 144.9, 137.5, 110.8, 109.8, 104.0, 71.7, 21.3 (2C); IR (film) νmax 3526, 2974, 2924, 2853, 1717, 1607, 1475, 1238, 1113, 1067, 928, 887, 791 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:14]=[C:15]([O:23][CH3:24])[C:16]4[N:17]([C:19]([CH3:22])=[N:20][N:21]=4)[CH:18]=3)[C:11](=[O:25])[C:10](=O)[CH:9]2[C:27](=O)[CH2:28][CH3:29])=[CH:4][CH:3]=1.Cl.[F:32][C:33]([F:41])([F:40])[CH2:34][O:35][CH2:36][CH2:37][NH:38][NH2:39]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:9]3[C:27]([CH2:28][CH3:29])=[N:39][N:38]([CH2:37][CH2:36][O:35][CH2:34][C:33]([F:41])([F:40])[F:32])[C:10]=3[C:11](=[O:25])[N:12]2[C:13]2[CH:14]=[C:15]([O:23][CH3:24])[C:16]3[N:17]([C:19]([CH3:22])=[N:20][N:21]=3)[CH:18]=2)=[CH:4][CH:3]=1
Reactant: NNCCOCC(F)(F)F
Reactant: CCC(=O)C1C(=O)C(=O)N(c2cc(OC)c3nnc(C)n3c2)C1c1ccc(Cl)cc1
Agent: Cl
Solvent: CO
Product: CCc1nn(CCOCC(F)(F)F)c2c1C(c1ccc(Cl)cc1)N(c1cc(OC)c3nnc(C)n3c1)C2=O

Procedure:
The tile compound was prepared in analogy to the procedure described in Example 68 using 5-(4-chlorophenyl)-1-(8-methoxy-3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-4-propionylpyrrolidine-2,3-dione (Step 84.5) and (2-(2,2,2-trifluoroethoxy)ethyl)hydrazine hydrochloride in MeOH and TEA. The crude material was first purified by silica gel chromatography (hexane/EtOAc/MeOH 75:25:5 to 5:1) followed by preparative achiral SFC (Propyl-pyridyl-urea, gradient 13-18% in 6 min_total 11 min). tR: 1.04 min (LC-MS 2); ESI-MS: 549 [M+H]+ (LC-MS 2).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:25]=[CH:24][C:12]([C:13]([NH:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])=[O:14])=[CH:11][C:10]=1[C:26]([CH3:29])([CH3:28])[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:25]=[CH:24][C:12]([C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])=[CH:11][C:10]=1[C:26]([CH3:29])([CH3:28])[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(OCc2ccccc2)c(C(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cc(C(=O)NCC(=O)O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 86.4 %

Procedure:
To a solution of tert-butyl 2-(4-(benzyloxy)-3-tert-butylbenzamido)acetate (3.37 g, 8.48 mmol) in CH2Cl2 (100 mL) at 0° C. was added TFA (10 mL) and the mixture was stirred at room temperature under nitrogen atmosphere for 10 h. The reaction mixture was concentrated in vacuo to dryness to give 2-(4-(benzyloxy)-3-tert-butylbenzamido)acetic acid (2.50 g, 86%) as a white powder: mp 172-174° C.; 1H NMR (300 MHz, CD3OD) δ 7.86 (s, 1H), 7.74-7.70 (m, 1H), 7.50-7.30 (m, 5H), 7.10-7.05 (m, 1H), 5.18 (s, 2H), 4.07 (s, 2H), 1.41 (s, 9H); IR (film) 3497, 3062, 3031, 2931, 2865, 1447, 1289, 1139, 1085, 1062 cm−1; MS found: (M+H)+=342.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[NH:4][C:5]([O:7][CH3:8])=[O:6].[CH3:13][C:14]1(O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.CCCCCC>S(=O)(=O)(O)O>[F:1][C:2]1[CH:12]=[C:11]([C:14]2([CH3:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:10]=[CH:9][C:3]=1[NH:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: CC1(O)CCCCC1
Reactant: COC(=O)Nc1ccccc1F
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Product: COC(=O)Nc1ccc(C2(C)CCCCC2)cc1F
Temperature: 70 °C

Procedure:
2-Fluoro-N-methoxycarbonylaniline (3.38 g, 20.0 mmol) prepared as described in Example 1 was dissolved in 77.6% sulfuric acid (20 g) to prepare a solution. 1-Methylcyclohexyl alcohol (2.28 g, 20.0 mol) was added dropwise to the solution under a nitrogen atmosphere over a period of 30 min while stirring and heating the solution at 70° C. After the completion of the dropwise addition, the reaction solution was vigorously stirred at the same temperature for 5 hr. Subsequently, the reaction solution was cooled to room temperature. n-Hexane (100 mL) was then added to the cooled reaction solution to carry out extraction for separation of the mixture into a sulfuric acid layer and an organic layer. n-Hexane (100 mL) was again added to the sulfuric acid layer to carry out extraction for separation of an organic layer. The organic layers thus obtained were combined, and the combined organic layer was washed with water and saturated brine in that order. The solvent was then removed from the organic layer by distillation to give 2-fluoro-4-(1-methylcyclohexyl)-N-methoxycarbonylaniline as an oil. The oil was further subjected to separation and purification by column chromatography on silica gel to give 843 mg of 2-fluoro-4-(1-methylcyclohexyl)-N-ethoxycarbonylaniline as a target compound (yield 15.8%, 4-substituted compound: 5-substituted compound=100:0).