Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)C1C=CC=C(N[C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])C=1.[CH2:40]([O:42]C(=O)CSC1C=CC=C(N)C=1)[CH3:41]>>[CH2:40]([O:42][C:11](=[O:38])[CH2:12][N:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C:14]1=[O:37])[CH3:41]
Reactant: CCOC(=O)CSc1cccc(N)c1
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that (3-amino-phenylsulfanyl)-acetic acid ethyl ester (S. Hagishita et al. Bioorg. Med. Chem. (1997), 5, 1433) was used instead of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester (Example 1, step c), according to the method of Example 1, step d. 1H NMR (DMSO-d6) 12.60 (1H, br s), 9.81 (1H, s), 7.50 (3H, m), 7.27-7.21 (4H, m), 6.97 (1H, m), 4.78 (2H, m), 4.27 (1H, d), 3.96 (1H, d), 3.72 (2H, s), 2.86 (1H, m), 1.83-1.65 (6H, m), 1.29-1.17 (13H, m). The compound was further characterised as the N-methyl-D-glucamine salt. Found C, 54.50; H, 7.36; N, 8.44; C30H36N4O5S.C7H17NO5.3.0H2O requires C, 54.59; H, 7.30; N, 8.60%.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)(=O)=[O:13])[C:6]=1[CH3:24])(=[O:4])=[O:3].C([C@@](C([O-])=O)(O)[C@@](CC)(O)C([O-])=O)C.C(N(C(C)C)CC)(C)C.[O-]O.C1(C(C)C)C=CC=CC=1.N>O.O1CCCC1>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S@:12]([C:15]2[NH:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[O:13])[C:6]=1[CH3:24])(=[O:3])=[O:4]
Reactant: Cc1c(S(C)(=O)=O)ccnc1CS(=O)(=O)c1nc2ccccc2[nH]1
Agent: CC[C@](O)(C(=O)[O-])[C@](O)(CC)C(=O)[O-]
Agent: N
Agent: [O-]O
Solvent: CC(C)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(S(C)(=O)=O)ccnc1C[S@@](=O)c1nc2ccccc2[nH]1
Temperature: 55 °C
Yield: 75.3 %

Procedure:
To a mixture of 2-(4-methanesulfonyl-3-methyl-pyridineylmethylsulfonyl)-1-H-benzimidazole (25 g), tetrahydrofuran (625 ml) and water (0.08 gm) was added (+)-diethyl-L-tartrate (31 gm) under nitrogen atmosphere and heated to 50 to 60° C. Subsequently, Ti(IV)isopropoxide (21.3 gm) was added to the reaction mixture at 50 to 60° C. and maintained at the same temperature for about 45-60 min. The reaction mixture was cooled to 20-25° C. and diisopropylethylamine (9.7 g) was added and maintained at the same temperature for 10-15 min. Cumene hydroperoxide (80% 15 ml) was then added to the reaction mixture and maintained at the same temperature for 2 hours. To the reaction mixture was added 10-12% aq. ammonia solution (100 ml) and maintained for 15 min. The layers were separated and 10-12% aq. ammonia solution (100 ml) was added to the organic layer at 20-25° C., maintained for 15 min and the steps repeated for two or three times. Combined all the aq. ammonia solution layers and cooled to 0-10° C. Adjusted the pH of the reaction mixture to 7.0 to 7.5 with acetic acid (125 ml) at 0 to 10° C. Distilled off the tetrahydrofuran traces at 40° C. under reduced pressure. Cooled the reaction mixture to 0 to 10° C. and maintained at the same temperature for about one to two hours. Filtered the solid and washed with DM water (50 ml) and dried to give 18 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([OH:14])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.[CH2:21](I)[CH3:22]>>[F:20][C:2]([F:19])([F:1])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:14][CH2:21][CH3:22])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1
Reactant: CCOC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Reactant: CCI
Product: CCOC(=O)c1c(OCC)cc(C(F)(F)F)nc1C(F)(F)F
Yield: 77 %

Procedure:
This material was prepared following the procedure of Example 8 in 77% yield from product of Example 3 and ethyl iodide as a white solid; mp 57°-59° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[H+].[B-](F)(F)(F)F.[N:16]([O-])=O.[Na+].CC([O-])=O.[K+]>O.C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]2[C:3]=1[CH:9]=[N:16][NH:5]2
Reactant: Cc1c(N)cccc1Br
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Brc1cccc2[nH]ncc12
Temperature: 25 °C
Yield: 28.5 %

Procedure:
3-bromo-2-methylaniline (1.70 ml, 13.8 mmol) was added to water (6 ml) in a corning, conical reaction vessel cooled in an ice water bath, and HBF4 (6.5 ml, 49.7 mmol) was added. Then, NaNO2 (0.99 g, 14.3 mmol) in water (2 ml), cooled in an ice water bath, was added via syringe, and the thick suspension was stirred while being warmed to room temperature over 45 minutes. It was then recooled in an ice water bath and filtered via a Buchner funnel. The solid was washed with 5% aqueous HBF4 (100 ml), the filtrate was filtered again, and the solid from both filtrations was washed with precooled (0 C) MeOH (4×25 ml) and precooled (0 C) diethyl ether (2×25 ml). The solid was then dried on a Buchner funnel for 30 minutes and then added to a flask containing KOAc (2.90 g, 29.5 mmol) and 18-c-6 (203 mg, 0.768 mmol) suspended in chloroform (100 ml). The reaction was stirred at room temperature for 2 hours and 20 minutes and then filtered, and the solid was washed with chloroform. The filtrate was washed with water (50 ml) and brine (50 ml), dried over sodium sulfate, filtered, concentrated, and diluted with water (150 ml). The suspension was filtered, and the solid was washed with hexanes, collected, and put under vacuum overnight to give title compound (773.6 mg, 28%). MS (ESI pos. ion) m/z: 197 (M+H). Calc'd Exact Mass for C7H5BrN2: 196.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][C:13]=1[CH:20]=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:7])(C)(C)C.Cl.[N:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][CH:37](C(O)=O)[CH2:36][CH2:35]2)=[CH:30][CH:29]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)CC)C>Cl.O1CCOCC1>[C:18]([C:16]1[CH:15]=[CH:14][C:13]([CH:20]=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:12]([O:11][CH2:10][CH2:9][NH:8][C:6]([CH:37]2[CH2:36][CH2:35][N:34]([C:31]3[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=3)[CH2:39][CH2:38]2)=[O:7])[CH:17]=1)#[N:19]
Reactant: CCOC(=O)C=Cc1ccc(C#N)cc1OCCNC(=O)OC(C)(C)C
Reactant: O=C(O)C1CCN(c2ccncc2)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)C=Cc1ccc(C#N)cc1OCCNC(=O)C1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3.0 g (8.33 mmol) of ethyl 3-[2-(2-(t-butoxycarbonylamino)ethoxy)-4-cyanophenyl]acrylate was dissolved in a mixture of 20 ml of 4 N solution of hydrogen chloride in dioxane and 10 ml of dioxane. The obtained solution was stirred at room temperature for 4 hours. The solvent was evaporated and the residue was dissolved in 50 ml of DMF. 2.22 g (9.17 mmol) of 1-(4-pyridyl)-4-piperidinecarboxyic acid hydrochloride, 4.27 g (9.17 mmol) of bromotripyrrolidinophosphonium hexafluorophosphate and 3.48 ml (25.0 mmol) of triethylamine were added to the obtained solution, and they were stirred at room temperature for 3 days. The solvent was evaporated, and the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[F:13][C:14]1[CH:15]=[C:16]([CH:34]=[CH:35][CH:36]=1)[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](=[O:30])[CH2:28][C@H:27]([C:31](O)=[O:32])[CH2:26]2)=[CH:21][CH:20]=1>O1CCCC1>[F:13][C:14]1[CH:15]=[C:16]([CH:34]=[CH:35][CH:36]=1)[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](=[O:30])[CH2:28][C@H:27]([C:31]([NH2:3])=[O:32])[CH2:26]2)=[CH:21][CH:20]=1
Reactant: O=C(O)[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: NC(=O)[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 18 °C
Reaction time: 0.25 h
Yield: 96.7 %

Procedure:
1,1′-carbonyldiimidazole (8.27 g, 51.0 mmol) was suspended and partly dissolved in tetrahydrofuran (110 mL) at 18° C. (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid (14.0 g, 42.5 mmol; enantiomeric purity (S):(R)=99.5:0.5) was added as a solid together with tetrahydrofuran (30 mL) used for rinsing. The turbid solution, which turned into a white suspension after 15 min, was stirred 1 h at 16-20° C. and then transferred into a stirred 25% aqueous ammonia solution (7.95 mL) in tetrahydrofuran (80 mL). The last part of the white suspension was transferred with the aid of tetrahydrofuran (10 mL) for rinsing. After stirring for 0.5 h the reaction mixture was concentrated in vacuo to a volume of ˜70 mL and diluted with water (300 mL). Some ice was added to keep the temperature at 20-25° C. The white precipitate was collected by filtration, washed with water/tetrahydrofuran 80:20 and with heptane. Drying in vacuo at 20-45° C. afforded (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid amide (13.5 g, 96%) as a white solid. The purity of the material by HPLC was 96.9% (area) and the enantiomeric ratio (S):(R) was determined as 99.7:0.3.
Reaction SMILES: BrC1C=CC2C3C(=CC(Br)=CC=3)CC=2C=1.C(Br)C=C.[OH-].[Na+].[Br:22][C:23]1[CH:35]=[CH:34][C:33]2[C:32]3[C:27](=[CH:28][C:29]([Br:36])=[CH:30][CH:31]=3)[C:26]([CH2:43][CH2:44][CH2:45]CC=C)([CH2:37][CH2:38][CH2:39]CC=C)[C:25]=2[CH:24]=1>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].C1(C)C=CC=CC=1>[Br:22][C:23]1[CH:35]=[CH:34][C:33]2[C:32]3[C:27](=[CH:28][C:29]([Br:36])=[CH:30][CH:31]=3)[C:26]([CH2:43][CH:44]=[CH2:45])([CH2:37][CH:38]=[CH2:39])[C:25]=2[CH:24]=1
Reactant: C=CCCCCC1(CCCCC=C)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: C=CCBr
Solvent: Cc1ccccc1
Product: C=CCC1(CC=C)c2cc(Br)ccc2-c2ccc(Br)cc21

Procedure:
2,7-dibromofluorene (5 g, 15.4 mmol) was combined with allyl bromide (5.6 g, 46.2 mmol) and reacted with toluene, NaOH and Bu4NBr as above for 2,7-dibromo-9,9-dihex-5-enyl-fluorene. 7.1 g of a yellow solid was obtained.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].C(=O)([O-])[O-].[K+].[K+].[Br:11][CH:12]([CH:16](Br)[CH3:17])[C:13](Cl)=[O:14]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Br:11][CH:12]1[CH:16]([CH3:17])[O:4][N:3]([CH3:2])[C:13]1=[O:14]
Reactant: CNO
Reactant: CC(Br)C(Br)C(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CC1ON(C)C(=O)C1Br
Yield: 57.3 %

Procedure:
To a stirred mixture of 12.5 g (150 mmol) of N-methylhydroxylamine hydrochloride, 20.7 g (150 mmol) of potassium carbonate and 4.1 g (15 mmol) of tetrabutylammonium hydrogen sulfate in 250 ml of methylene chloride, there was added 2, 3-dibromobutyryl chloride (42 g,150 mmol) followed by the addition of 41.4 g (300 mmol) of potassium carbonate. After three days the mixture was filtered, the filtrate was concentrated and the concentrate was chromatographed on silica gel with 40% ethyl acetate-hexane to afford 16.8 g (86 mmol, 57%) of 4-bromo-2,5-dimethyl-3-isoxazolidinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C:8]2[C:9]([CH3:21])=[C:10]([CH3:20])[C:11]([CH:18]=C)=[C:12]([CH:17]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1.CC(C)=[O:26].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[CH:18]([C:11]1[C:10]([CH3:20])=[C:9]([CH3:21])[C:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:23][CH:22]=2)=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14])=[O:26]
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(OC)cc2)c(C)c1C
Reactant: CC(C)=O
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(Cc2ccc(OC)cc2)c(C)c(C)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(4-methoxybenzyl)-3,4-dimethyl-2-vinylbenzoate (13.6 g) in a mixed solvent of acetone (135 mL)-acetonitrile (135 mL)-water (135 mL) were added osmium oxide (fixed catalyst I) (5.57 g) and sodium periodate (46.9 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (13.5 g) as a crude product. This compound was used in the next step without an additional purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([O:12][CH2:13][O:14][CH3:15])[CH:7]([CH2:16][CH2:17][CH:18]([N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])[CH3:19])[CH2:6]2)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1.CO>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([O:12][CH2:13][O:14][CH3:15])[CH:7]([CH2:16][CH2:17][CH:18]([N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])[CH3:19])[CH2:6]2
Reactant: CCCN(CCC)C(C)CCC1Cc2cc(C#N)ccc2C1OCOC
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCN(CCC)C(C)CCC1Cc2cc(CN)ccc2C1OCOC
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.9 %

Procedure:
The compound (436.8 mg) obtained in Example 127-9 was dissolved in THF (21.8 ml) and added with lithium aluminum hydride (138.7 mg), followed by stirring at room temperature for 24 hours. The reaction solution was added with ethyl acetate, methanol, and a 10% aqueous potassium sodium tartrate solution, and stirred for 1 hour, followed by separation/extraction with chloroform. The extract was washed with saturated saline solution and dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (189.7 mg) as a yellow oily substance.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[F:28]>>[Cl:21][C:22]1[CH:23]=[C:24]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:19])[CH2:3][C:2]3([CH3:1])[CH3:20])[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: CC1(C)CC(=O)c2ccc(-c3ccc(F)c(Cl)c3)cc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 3-chloro-4-fluorophenyl boronic acid according to the procedure described in example 21. MS m/z 289; HRMS: calcd for C17H14ClFO+H+, 289.07900; found (ESI, [M+H]+), 289.0785.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)=[O:24])[CH:17]=1)[C:10]([CH3:33])([CH3:32])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH3:32][C:10]1([CH3:33])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)=[O:24])[CH:17]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)N3CCN(C)CC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCN(C(=O)Nc2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)CC1
Temperature: 60 °C
Reaction time: 12 h
Yield: 15.7 %

Procedure:
A mixture of 3,3-dimethyl-2-{3-[(4-methyl-piperazine-1-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (612 mg, 1.36 mmol) in methanol (15 mL) and tetrahydrofuran (20 mL), 30% sodium hydroxide in water (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 3,3-dimethyl-2-{3-[(4-methyl-piperazine-1-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (90 mg, 22%) as a white solid: LC/MS m/e calcd for C24H30N4O3 (M+H)+: 423.53, observed: 423.2.
Reaction SMILES: [CH2:1]([C:5]1[NH:9][CH:8]=[N:7][C:6]=1[C:10](O)=[O:11])[CH2:2][CH2:3][CH3:4].CC1NC=NC=1C(O)=O>>[OH:11][CH2:10][C:6]1[N:7]=[CH:8][NH:9][C:5]=1[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1[nH]cnc1C(=O)O
Agent: Cc1[nH]cnc1C(=O)O
Product: CCCCc1[nH]cnc1CO

Procedure:
When 5-butyl-4-imidazolecarboxylic acid is substituted for 5-methyl-4-imidazolecarboxylic acid in the general procedure of Example 4, 4-hydroxymethyl-5-butylimidazole is produced.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][C:4]2([C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH2:8][C:7]2([CH3:15])[OH:14])[O:3]1.CN(C)C1C=CC=CC=1.[C:25](Cl)(=[O:29])[CH:26]([CH3:28])[CH3:27]>>[C:25]([O:14][C:7]1([CH3:15])[CH2:8][CH2:9][CH2:10][C:11]([CH3:13])([CH3:12])[C:4]21[O:3][CH:2]([CH3:1])[CH2:6][CH2:5]2)(=[O:29])[CH:26]([CH3:28])[CH3:27]
Reactant: CC1CCC2(O1)C(C)(C)CCCC2(C)O
Reactant: CC(C)C(=O)Cl
Solvent: CN(C)c1ccccc1
Product: CC1CCC2(O1)C(C)(C)CCCC2(C)OC(=O)C(C)C
Yield: 11 %

Procedure:
2.12 g (0.01 M) of 2,6,10,10-tetramethyl-1-oxa-spiro[4.5]decan-6-ol -- isomer A; see Example 1 -- were treated with a mixture of 12.1 g (0.1 M) of N,N-dimethylaniline and 5.3 g (0.05 M) pf isobutyryl chloride as indicated in Example 5 to give 0.3 g (ca. 11%) of the desired ester, b.p. 110°/0.5 Torr.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[O:18]C(=O)[NH:16][CH:15]2[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[NH2:16][CH:15]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=1)[CH:14]([C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1)[OH:18]
Reactant: O=C1NC(Cc2ccc(C(F)(F)F)cc2)C(c2ccc(Oc3ccccc3)cc2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Oc2ccccc2)cc1
Yield: 89.5 %

Procedure:
To a solution of (4RS,5SR)-5-(4-phenoxyphenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (6.0 g, 14.5 mmol) in ethanol (100 ml) was added 8N aqueous sodium hydroxide solution (9.0 ml, 72 mmol), and the mixture was heated under reflux for 4 hrs. The reaction solution was concentrated and diluted with water (300 ml). The mixture was extracted with ethyl acetate (300 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS,2SR)-2-amino-1-(4-phenoxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (5.03 g, 90%).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6].FC(F)(F)S([O:16][CH2:17][C:18]([F:29])([F:28])[CH2:19]OS(C(F)(F)F)(=O)=O)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[F:28][C:18]1([F:29])[CH2:17][O:16][C:9]2[CH:2]=[CH:3][C:4]([CH:5]=[O:6])=[CH:7][C:8]=2[O:10][CH2:19]1
Reactant: O=S(=O)(OCC(F)(F)COS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=Cc1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=Cc1ccc2c(c1)OCC(F)(F)CO2
Temperature: 50 °C

Procedure:
A mixture of 2 g of 3,5-dihydroxybenzaldehyde, 6 g of 2,2-difluoropropane-1,3-diyl bis(trifluoromethanesulfonate) and 12 g of cesium carbonate in 100 mL of anhydrous acetonitrile was heated under nitrogen to 50° C. overnight. The mixture was allowed to cool, then filtered and concentrated under reduced pressure. The residue was partitioned between 250 mL of ethyl acetate and 100 mL of saturated sodium carbonate then dried over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography (0-25% ethyl acetate in hexanes) gave the product as colorless oil. MS (m+1)=215.1; 1H NMR (400 MHz, CDCl3) 9.85 (s, 1H), 7.6 (m, 2H), 7.1 (d, 1H), 4.48 (m, 4H).
Reaction SMILES: [CH2:1]([C:8]1([C:23]([O:25]CC)=[O:24])[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO>[CH2:1]([C:8]1([C:23]([OH:25])=[O:24])[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(Cc2ccccc2)CCCN1C(=O)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(OCc1ccccc1)N1CCCC1(Cc1ccccc1)C(=O)O
Temperature: 100 °C
Reaction time: 16 h
Yield: 81.1 %

Procedure:
To a stirred solution of compound 2 (8.0 g, 21.79 mmol) in CH3OH (20 mL) was added 2N aqueous KOH (20 mL) and heated up to 100° C. and stirred for 16 h. The volatiles were evaporated under reduced pressure. The residue obtained was diluted with ice cold water (50 mL) and washed with ether (50 mL). The aqueous layer was acidified to pH˜2 using HCl solution and extracted with EtOAc (2×100 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford compound 3 (6 g, 81%) as an off white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]=1[NH:15][C:16]1[CH:17]=[C:18]([C:22]([NH:24][CH2:25][C:26]([NH:28][CH:29]([C:36]2[CH:41]=[C:40]([Cl:42])[CH:39]=[C:38]([Cl:43])[CH:37]=2)[CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[O:23])[CH:19]=[CH:20][CH:21]=1.[Li+].[OH-].C(O)(C(F)(F)F)=O>O.CC#N>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]=1[NH:15][C:16]1[CH:17]=[C:18]([C:22]([NH:24][CH2:25][C:26]([NH:28][CH:29]([C:36]2[CH:37]=[C:38]([Cl:43])[CH:39]=[C:40]([Cl:42])[CH:41]=2)[CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[O:23])[CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC2=NCCCCC2)c1)c1cc(Cl)cc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: O=C(O)CC(NC(=O)CNC(=O)c1cccc(NC2=NCCCCC2)c1)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
To the product from Example 188 (370 mg, 0.00057 mole) in H2O (20 mL) and CH3CN (15 mL) was added LiOH (192 mg, 0.0046 mole). The reaction mixture was stirred at room temperature for 3 hours. The pH was lowered to ~2.5 with TFA and the product was isolated by RPHPLC to yield the title compound (280 mg after lyophilization) as a white solid.
Reaction SMILES: F[C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[C:22]1[S:26][CH:25]=[N:24][CH:23]=1.[CH3:27][C:28]1([OH:33])[CH2:32][CH2:31][NH:30][CH2:29]1>>[OH:33][C:28]1([CH3:27])[CH2:32][CH2:31][N:30]([C:2]2[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)=[O:7])=[CH:4][C:3]=2[C:22]2[S:26][CH:25]=[N:24][CH:23]=2)[CH2:29]1
Reactant: CC1(O)CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(F)c(-c2cncs2)c1
Product: CC1(O)CCN(c2ccc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncs2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 1 using 4-fluoro-3-(thiazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.1) and 3-methylpyrrolidin-3-ol to afford a yellow solid. UPLC-MS (Condition 1) tR=2.57 min, m/z=464.1 [M+H]+, m/z=462.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.09-1.30 (m, 3H) 1.63-1.85 (m, 2H) 2.88 (s, 1H) 2.95 (s, 1H) 3.02-3.15 (m, 1H) 3.26-3.30 (m, 1H) 4.72 (s, 1H) 6.94 (d, J=8.80 Hz, 1H) 7.33 (d, J=9.05 Hz, 2H) 7.78-8.00 (m, 6H) 9.15 (s, 1H) 10.14 (s, 1H).