Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:7][CH2:6][CH:5]([CH:8]=[CH:9][C:10]([C:12]2([C:15]([F:18])([F:17])[F:16])[CH2:14][CH2:13]2)=[O:11])[CH2:4][CH2:3]1>C(O)C.[Pd]>[F:1][C:2]1([F:19])[CH2:3][CH2:4][CH:5]([CH2:8][CH2:9][C:10]([C:12]2([C:15]([F:16])([F:17])[F:18])[CH2:13][CH2:14]2)=[O:11])[CH2:6][CH2:7]1
Reactant: O=C(C=CC1CCC(F)(F)CC1)C1(C(F)(F)F)CC1
Agent: [Pd]
Solvent: CCO
Product: O=C(CCC1CCC(F)(F)CC1)C1(C(F)(F)F)CC1
Yield: 95.3 %

Procedure:
3-(4,4-Difluorocyclohexyl)-1-(1-trifluoromethylcyclopropyl)propan-2-en-1-one (0.746 g, 2.64 mmol) obtained in step 2 was dissolved in ethanol (10 mL), and allowed to react at 25° C. in the full H2 mode of an H-cube (registered trademark) using 10% Pd/C CatCart (30 mm) (ThalesNano Technologies) to give 3-(4,4-difluorocyclohexyl)-1-(1-trifluoromethylcyclopropyl)propan-1-one (0.715 g, yield 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)[CH:7]=[CH:6][C:4]=1[NH2:5].C([Mg]Cl)C.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[CH:33]=[C:32]([C:34](OC)=[O:35])[N:31]([CH3:38])[C:28]2=[CH:29][N:30]=1>O1CCCC1>[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[CH:33]=[C:32]([C:34]([NH:5][C:4]3[CH:6]=[CH:7][C:8]([B:10]4[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]4)=[CH:9][C:3]=3[O:2][CH3:1])=[O:35])[N:31]([CH3:38])[C:28]2=[CH:29][N:30]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Reactant: COC(=O)c1cc2cc(OC)ncc2n1C
Agent: CC[Mg]Cl
Solvent: C1CCOC1
Product: COc1cc2cc(C(=O)Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3OC)n(C)c2cn1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
To 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.09 g, 8.37 mmol) in tetrahydrofuran (20 ml) under a nitrogen atmosphere was added ethylmagnesium chloride, 2.0 M in tetrahydrofuran (4.19 ml, 8.37 mmol) and the mixture was heated at reflux for one hour. To the warm reaction was added methyl 5-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (878 mg, 3.99 mmol) in tetrahydrofuran (10 ml) and the resulting mixture was heated overnight. Then the reaction mixture was cooled to room temperature and concentrated. The residue was taken up in ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was coated on hydromatrix and purified by flash chromatography (gradient of heptane to heptane/ethyl acetate 1/1) to give 5-methoxy-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (1.05 g).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].C([O-])([O-])=O.[K+].[K+].[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[SH:31])([CH3:24])[CH3:23].Cl>CN(C=O)C.O>[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14])([CH3:24])[CH3:23]
Reactant: O=C(O)C=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)c1ccccc1S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ccccc1Sc1ccc(/C=C/C(=O)O)cc1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
To a stirred mixture of 4-chloro-3-nitrocinnamic acid (500 mg, 2.2 mmol) in 5 mL of anhydrous DMF with K2CO3 (911 mg, 6.6 mmol) was added 2-isopropylbenzenethiol (372 mL, 2.2 mmol) in 1 mL of DMF dropwise. The resulting mixture was then heated at 70° C. under nitrogen atmosphere over night. Water (25 mL) was then added and the reaction mixture was acidified to pH=4 with 3N HCl. The cloudy mixture was extracted with EtOAc (2×20 mL). The combined organic layer was washed with brine, dried over Na2SO4, concentrated in vacuo to give the title compound as viscous light-yellow oil, which was used for coupling with further purification.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11](F)=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1.[F:19][C:20]([F:26])([F:25])[C:21]([OH:24])([CH3:23])[CH3:22]>CN1C(=O)N(C)CC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:24][C:21]([CH3:23])([CH3:22])[C:20]([F:26])([F:25])[F:19])=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1
Reactant: Fc1ccc(Br)cc1C(F)(F)F
Reactant: CC(C)(O)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCN(C)C1=O
Product: CC(C)(Oc1ccc(Br)cc1C(F)(F)F)C(F)(F)F
Temperature: 100 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
Potassium tert-butoxide (236 mg, 2.1 mmol) was added to a solution of 5-bromo-2-fluorobenzotrifluoride (485 mg, 2.0 mmol) and 2-trifluoromethyl-2-propanol (0.24 mL, 2.2 mmol) in DMI (0.5 mL) at room temperature, and the mixture was stirred at 100° C. for two hours. The reaction solution was purified by silica gel column chromatography to give 4-bromo-1-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-2-trifluoromethyl-benzene (349 mg, 50%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3C=C(C(O)=O)[N:13]=[C:12]3[C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCCC1.O.CO>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)=[NH:13])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(-c2nc(C(=O)O)cn2-c2ccc3c(c2)OCCO3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=N)Nc2ccc3c(c2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.61 g (4.0 mmol) of 1,4-benzodioxan-6-amine in 5 mL of tetrahydrofuran at ambient temperature was added 2.2 mL (4.4 mmol) of 2.0 M (in tetrahydrofuran) sodium bis(trimethylsilyl)amide and the resulting solution was stirred for 20 min. To this reaction mixture was slowly added a solution of 0.47 g (4.0 mmol) of p-tolunitrile in 2 mL of tetrahydrofuran. The resulting mixture was stirred at ambient temperature for 5 hrs and then poured into brine (25 mL) and dichloromethane (50 mL). The organic layer was separated and the aqueous layer was extracted with 25 mL of dichloromethane (25 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as brown crystalline solid, which was used without further purification. LC/MS 269.2 (M+1). Step B: Ethyl 1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazole-4-carboxylate. To a mixture of the compound from Step A and 0.80 g (9.5 mmol) of sodium bicarbonate in 10 mL of 1,4-dioxane was added 0.60 mL (4.8 mmol) of ethyl bromopyruvate. The reaction mixture was refluxed overnight. After cooling to room temperature, the solid was filtered off and the filtrate was concentrated in vacuo. Flash chromatography on a Biotage Horizon® system (silica gel, 0 to 50% ethyl acetate in hexanes gradient) gave the title compound as a yellow foam. LC/MS 365.3 (M+1). Step C: 1-(2,3-Dihydro-1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazole-4-carboxylic acid. To a solution of 0.62 g (1.7 mmol) of the compound from Step B in 10 mL of tetrahydrofuran, 5 mL of water and 5 mL of methanol was added 0.80 mL (4.0 mmol) of 5.0 M NaOH solution. The reaction mixture was stirred at ambient temperature overnight. Hydrochloric acid (2.0 M) was then added to neutralize the reaction mixture. After removal of the organic solvents in vacuo, dichloromethane (20 mL) was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane (10 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as a yellow foam. LC/MS 337.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:28](=[O:29])[N:27]([CH3:30])[C:11]3[N:12]([CH3:26])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19](=O)[CH:20]=[CH:21][N:22](C)C)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.O.[NH2:32]N>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:28](=[O:29])[N:27]([CH3:30])[C:11]3[N:12]([CH3:26])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[NH:32][N:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=4)=[CH:6][CH:7]=1
Reactant: NN
Reactant: CN(C)C=CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Br)cc3)c(=O)n(C)c1n2C
Solvent: O
Product: Cn1c(=O)c(-c2ccc(Br)cc2)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21

Procedure:
The process is carried out as indicated in Example 36 above, with compound 3-(4-bromophenyl)-6-(3-dimethylaminoacryloyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and hydrazine monohydrate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.Br[CH2:17][CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:20]([O:19][CH2:18][CH2:17][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCCOCc1ccccc1
Reactant: Nc1ccccc1
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc(COCCNc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
In a round bottom flask aniline (2.0 g, 21.5 mmol, 2.0 mL), 2,6-lutidine (2.30 g, 21.5 mmol) and benzyl 2-bromoethyl ether (4.6 g, 21.5 mmol, 3.4 mL) were combined in DMF (10 mL) and stirred at 100° C. overnight. The reaction was allowed to cool and then diluted with ethyl acetate (50 mL). This was washed with water (3×20 mL) and the organics were dried and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (0-50% B, 100 g, 19.5 CV, 85 mL/min) to afford 2.22 g (37%) of (2-benzyloxy-ethyl)-phenyl-amine (21) as a yellow oil. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 43.6, 68.6, 73.2, 113.1, 117.5, 127.5, 127.7, 128.4, 129.1, 138.2, 148.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]2[N:11]([CH3:14])[CH:12]=[N:13][C:8]2=[C:7]([F:15])[C:6]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])=[O:4].C1C(=O)N([Br:31])C(=O)C1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]2[N:11]([CH3:14])[CH:12]=[N:13][C:8]2=[C:7]([F:15])[C:6]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([Br:31])=[CH:19][C:18]=1[F:23])=[O:4]
Reactant: COC(=O)c1nc2c(ncn2C)c(F)c1Nc1ccccc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc2c(ncn2C)c(F)c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 7-fluoro-6-(2-fluorophenylamino)-3-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (1.00 equivalent) in DMF is added NBS (1.20 equivalents) at room temperature. After stirring for 16 hours at room temperature, the reaction mixture is diluted with EtOAc and washed with water. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is purified by trituration or flash column chromatography to afford the desired product as necessary.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C@H:12]2[CH2:16][N:15]([C@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])[C:14](=[O:25])[CH2:13]2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:28](I)[CH3:29].[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([C:9]1([C@H:12]2[CH2:16][N:15]([C@H:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH3:18])[C:14](=[O:25])[CH2:13]2)[CH2:11][CH2:10]1)[CH2:28][CH3:29])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](c1ccccc1)N1C[C@H](C2(NC(=O)OC(C)(C)C)CC2)CC1=O
Reactant: CCI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(C(=O)OC(C)(C)C)C1([C@@H]2CC(=O)N([C@@H](C)c3ccccc3)C2)CC1
Reaction time: 0.17 h

Procedure:
4-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]-1-[1-(S)-phenylethyl]pyrrolidin-2-one (4.16 g, 12.1 mmol) was dissolved in dimethylformamide (50 ml). Under a nitrogen atmosphere and at room temperature, 60% oily sodium hydride (580 mg, 14.5 mmol) was added thereto and stirred for 10 minutes, and then ethyl iodide (4.87 ml, 60.5 mmol) was added dropwise. After completion of dripping, the reaction suspension was stirred at room temperature for 15 hours. After adding a saturated aqueous ammonium chloride solution (150 ml) to the reaction suspension while stirring and cooling with ice, extraction with ethyl acetate (150 ml×2) was performed. The combined organic layer was then washed with water (150 ml×2) and saturated saline solution (150 ml) in that order, and then dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, the residue obtained was applied to a silica gel chromatography, and 4.56 g (quantitative) of the title compound was obtained in the form of a colorless oily substance from an n-hexane:ethyl acetate=1:2 eluate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:18][CH:17]([C:19]([O:21]C)=[O:20])[CH2:16][CH2:15][N:14]2[C:23]([O:25][CH3:26])=[O:24])[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:11])([F:10])[F:9].[Br-].[Li+].C(N(CC)CC)C.CC(OC)(C)C>C(#N)C.O>[F:12][C:6]1[CH:5]=[C:4]([CH:13]2[CH2:18][CH:17]([C:19]([OH:21])=[O:20])[CH2:16][CH2:15][N:14]2[C:23]([O:25][CH3:26])=[O:24])[CH:3]=[C:2]([F:1])[C:7]=1[C:8]([F:9])([F:11])[F:10]
Reactant: COC(=O)C1CCN(C(=O)OC)C(c2cc(F)c(C(F)(F)F)c(F)c2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)N1CCC(C(=O)O)CC1c1cc(F)c(C(F)(F)F)c(F)c1
Yield: 86 %

Procedure:
Dimethyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)piperidine-1,4-dicarboxylate (2.851 g, 7.48 mmol) was dissolved in acetonitrile (25 mL) and water (2.5 mL), then lithium bromide (5.19 g, 59.82 mmol) was added followed by triethylamine (4.15 mL, 29.91 mmol). The reaction mixture was heated under reflux for 1 h. MTBE (150 mL) and water (150 mL) were added, shaken and the phases separated. The organic phase was extracted with water (2×150 mL). The combined aqueous phases were acidified with 3 M HCl to pH 1 and extracted with MTBE (2×450 mL). The combined organic phases were dried over Na2SO4, filtered and evaporated in vacuo yielding 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-1-(methoxy-carbonyl)piperidine-4-carboxylic acid (2.363 g, 86%). MS m/z 368 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:12][CH:13]=2)[C:8]([S:29]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[N:7]1.C1COCC1.Cl.[CH2:51]([NH2:53])[CH3:52]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][NH:53][CH2:51][CH3:52])=[CH:12][CH:13]=2)[C:8]([S:29]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[N:7]1
Reactant: CCN
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3Cc2cccc(Cl)c2)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCNCCOc1ccc2c(c1)c(S(=O)(=O)c1cccc3ccccc13)nn2Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A solution of toluene-4-sulfonic acid 2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.415 g, 0.641 mmol) in 2.0 M ethylamine in THF (8.0 mL, 16.0 mmol) was stirred at 70° C. for 3 hours and then at 80° C. for 19 hours. The reaction mixture was allowed to cool to ambient temperature and solvent evaporated. It was partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with brine, dried with magnesium sulfate, filtered and concentrated. Drying in vacuo at 80° C. for 20 minutes resulted in {2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-ethyl-amine as an orange semi-solid (0.270 g, 81.1%). This was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried in vacuo at 83° C. for 16 hours. The hydrochloride as a pale orange foam resulted (0.276 g); Mass Spectrum (+EI, [M+H]+) m/z 520. 1HNMR (500 MHz, DMSO-d6): δ8.71-8.77 (m, 3H), 8.55 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.29 Hz), 8.02-8.05 (m, 1H), 7.82 (d, 1H, J=9.15 Hz), 7.70-7.74 (m, 1H), 7.57-7.64 (m, 2H), 7.24-7.28 (m, 2H), 7.16-7.21 (m, 3H) 7.05 (d, 1H, J=7.56 Hz), 5.73 (s, 2H), 4.24-4.27 (m, 2H), 3.30-3.32 (m, 2H), 2.97-3.03 (m, 2H), 1.16-1.20 ppm (m, 3H). Elemental Analysis for C28H26ClN3O3S.1.00 HCl.0.60 mole H2O: Calcd: C, 59.28; H, 5.01; N, 7.41; Found: C, 58.95; H, 5.06; N, 7.14.
Reaction SMILES: [N:1]1([C:7](=[O:29])[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[ClH:30].O1CCOCC1>>[ClH:30].[ClH:30].[N:16]1([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[O:29])=[CH:11][CH:12]=2)[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(CCC(=O)N3CCOCC3)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CCc1ccc(N2CCNCC2)cc1)N1CCOCC1
Reaction time: 1 h

Procedure:
A mixture of Example 4C (317 mg, 0.787 mmol) in 4N HCl/dioxane was allowed to stand for 1 hour and concentrated to provide the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10](=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].[H-].[Na+].Br[C:22]([CH3:28])([CH3:27])[C:23](C#N)=[O:24]>C1COCC1>[CH3:27][C:22]1([CH3:28])[C:23](=[O:24])[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:4]2[CH:5]=[CH:6][C:7]([S:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[O:18]1
Reactant: CC(C)(Br)C(=O)C#N
Reactant: CSc1ccc(C(=O)Cc2ccccc2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ccc(C2=C(c3ccccc3)C(=O)C(C)(C)O2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-{3-fluoro-4-(methylthio)phenyl}-2-phenyl-ethan-1-one (1.68 g) in 100 ml dry THF, was added portion-wise at 0° C. 60% oil dispersion of sodium hydride (270 mg). The reaction solution was stirred at the same temperature for 1 hour. Then 1.2 ml of α-bromo-isobutyryl cyanide diluted in 25 ml dry THF was added dropwise to the stirred solution at 0° C. The reaction mixture was stirred overnight while warming gradually to room temperature. The solution was concentrated in vacuo, to which was added 50 ml water. The aqueous solution was extracted with dichloromethane (50 ml×3). The organic layer was concentrated in vacuo and purified by column chromatography (hexane/ethylacetate=6:1) to give 1.21 g of 2,2-dimethyl-5-{3-fluoro-4-(methylthio)phenyl}-4-phenyl-3(2H)-furanone. NMR: δ1.55 (s, 6H), 2.48 (s, 3H), 7.26-7.39 (m, 7H), 7.67 (m, 1H), 7.81 (m, 1H). IR (cm−1): 1696, 1421, 1388, 1238.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH3:16][O:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1>>[CH3:16][O:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:13]([C:9]1[CH:10]=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)=[O:15]
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: COC[C@@H]1CCCN1
Product: COC[C@@H]1CCCN1C(=O)c1cnoc1-c1ccc(C)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and (S)-2-methoxymethyl-pyrrolidine (6.9 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (4.6 mg). Calcd for C17H20N2O3: 300.1474, found 300.1474.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=4[Cl:28])[C:22](O)=[O:23])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:29]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:60][CH2:61][CH2:62][OH:63]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:20]=[C:21]([C:22](=[O:23])[NH:60][CH2:61][CH2:62][OH:63])[CH:25]=[CH:26][C:27]=4[Cl:28])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:29]=1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1cc(C(=O)O)ccc1Cl
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1cc(C(=O)NCCO)ccc1Cl
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a mixture of 3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoic acid (3 g, 6.09 mmol) in THF (50 mL) was added EDCI (2.34 g, 12.18 mmol), HOBt (1.23 g, 9.13 mmol), DIPEA (5 mL) and 2-aminoethanol (0.56 g, 9.13 mmol) by sequence under nitrogen atmosphere at room temperature. The reaction mixture was stirred overnight, diluted with water. The resulting precipitate was washed with water and EtOAc to give 8-bromo-N-(2-chloro-5-(2-hydroxyethylcarbamoyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (2.52 g, yield 77%). LC-MS: (ESI, m/z)=535 [M+H]+
Reaction SMILES: [Br:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][C:21]([CH2:25][CH3:26])([CH3:24])[CH2:20][CH2:19]2)=[C:4]([C@H:10]([OH:17])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]>C(Cl)Cl>[Br:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][C:21]([CH2:25][CH3:26])([CH3:24])[CH2:20][CH2:19]2)=[C:4]([C@H:10]([O:17][C:4]([CH3:10])([CH3:5])[CH3:3])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]
Reactant: CCC1(C)CCN(c2c(Br)c(C)nc(C)c2[C@H](O)C(=O)OC(C)C)CC1
Solvent: ClCCl
Product: CCC1(C)CCN(c2c(Br)c(C)nc(C)c2[C@H](OC(C)(C)C)C(=O)OC(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 164.9 %

Procedure:
The isobutylene gas was bubbled into a nitrogen purged, cooled (0° C.) solution of (S)-isopropyl 2-(5-bromo-4-(4-ethyl-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (1.9 g, 4.19 mmol) and 0.6 mL of 70% HClO4 in DCM (15 mL) for 20 min. The reaction mixture was allowed to warm to rt and stirred for 18 h in a pressure sealed vessel, after which it was recooled, and an additional 0.4 mL of 70% HClO4 was added at 0° C., and the reaction was stirred for 24 h at rt. The reaction was diluted with DCM, washed with 1M Na2CO3 solution, and dried over MgSO4. The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient elution (5-12% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(5-bromo-4-(4-ethyl-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate 1.67 g (64%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) 6 (br. s, 1H), 4.94-4.89 (m, 1H), 3.98 (br. s, 1H), 3.45-3.39 (m, 2H), 2.82 (m, 1H), 2.53 (s, 3H), 2.42 (s, 3H), 1.53-1.43 (m, 4H), 1.32-1.26 (m, 2H), 1.14 (br. s, 12H), 1.07 (d, J=6.2 Hz, 3H), 0.99/0.91 (s, 3H), 0.8 (t, J=7.3 Hz, 3H). UPLC (M+H)=485.4.