Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](CC)=[CH:4][CH:3]=1.CCCCC.C([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=O)=[CH:19][C:18]=1O)=O.[Cl-].[NH4+]>O1CCCC1.O>[C:2]1([CH:21]([C:20]2[CH:19]=[CH:18][CH:17]=[CH:26][CH:25]=2)[OH:23])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1ccc(Br)cc1
Reactant: COC(=O)c1ccc(C=O)c(O)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-bromo-4-ethylbenzene (0.41 mL) in tetrahydrofuran (15 mL) was added 1.45 mol/L tert-buthyllithium n-pentane solution (2.3 mL) under an argon atmosphere at −78° C. After the mixture was stirred at −78° C. for 10 minutes, a solution of methyl 4-formyl-3-hydroxybenzoate (0.18 g) in tetrahydrofuran (5 mL) was added to the reaction mixture. After the mixture was stirred under ice-cooling for 45 minutes, a saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1) to give a diphenylmethanol compound (0.27 g). The obtained diphenylmethanol compound (0.27 g) was dissolved in methanol (5 mL), and concentrated hydrochloric acid (0.08 mL) and 10% palladium-carbon powder (54 mg) were added to the solution. After the mixture was stirred under a hydrogen atmosphere at room temperature for 18 hours, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1) to give methyl 4-(4-ethylbenzyl)-3-hydroxybenzoate (0.20 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]([OH:20])=O)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.C(OP(C#N)(OCC)=O)C.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)CC)C>COCCOC.O>[NH2:1][C:2]1[C:3]([C:18]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:20])=[N:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:12][CH:13]=2)=[CH:6][N:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2cnc(N)c(C(=O)O)n2)cc1
Reactant: Nc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: COCCOC
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cnc(N)c(C(=O)Nc3ccccc3)n2)cc1
Yield: 70.9 %

Procedure:
A mixture of 3-amino-6-(4-methylsulfonylphenyl)pyrazine-2-carboxylic acid (1.5 g, 5.114 mmol), diethoxyphosphorylformonitrile (926.8 mg, 849.5 μL, 5.114 mmol), aniline (476.2 mg, 465.9 μL, 5.114 mmol) and triethylamine (1.035 g, 1.426 mL, 10.23 mmol) were stirred in DME (18.75 mL) at 120° C. for 18 hours. After this time water was added and the resultant solid collected by filtration. The solid was triturated with acetone and dried to give the desired product (1.335 g, 71% Yield). 1H NMR (400.0 MHz, DMSO) d 3.28 (s, 3H), 7.18 (t, J=7.3 Hz, 1H), 7.41 (t, J=7.8 Hz, 2H), 7.82 (d, J=7.9 Hz, 2H), 7.89 (s, 2H), 8.01 (d, J=8.4 Hz, 2H), 8.51 (d, J=8.4 Hz, 2H), 9.04 (s, 1H) and 10.47 (s, 1H) ppm; MS (ES+) 369
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=O)Nc2cc(O)ccc21
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(=O)Nc2cc(OCCCCBr)ccc21
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a solution (20 ml) of 7-hydroxy-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (0.4 g) in DMF were added 1,4-dibromobutane (0.75 ml) and potassium carbonate (0.35 g) and the mixture was stirred at 60° C. for 6 hr. After cooling to room temperature, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1→50:1) to give the title compound (0.6 g) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][CH3:10])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].O>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:18](=[O:19])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[CH2:9][CH3:10])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCc1cc(Br)ccc1N
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cc(Br)ccc1NC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
4-Bromo-2-ethylaniline (500 mg, 2.50 mmol) was dissolved in toluene (25 mL), sodium carbonate (397 mg, 3.75 mmol) and benzyl chloroformate (0.428 mL, 3.00 mmol) were added and the mixture stirred under nitrogen at room temperature. After 20 hours water (25 mL) was added, the aqueous phase separated and washed with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated. Chromatography (40 g silica cartridge, 0-100% ethyl acetate/petroleum benzine 40-60° C.) gave the title compound (I38) (708 mg, 85%) as a pink solid; 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.44-7.28 (m, 7H), 6.43 (s, 1H), 5.20 (s, 2H), 2.54 (q, J=7.6 Hz, 2H), 1.21 (t, J=7.6 Hz, 3H). LCMS Method C: rt 6.46 min; 258.0 [M-PhCH2O+CH3OH]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.Br[CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(N(CC)CC)C.O>ClCCl>[OH:7][CH:4]1[CH2:5][CH2:6][N:1]([CH2:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:2][CH2:3]1
Reactant: OC1CCNCC1
Reactant: O=C(CBr)OCc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CN1CCC(O)CC1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 50.7 %

Procedure:
To piperidin-4-ol (HCl salt, 9.0 g) was added a solution of benzyl 2-bromoacetate (15.0 g, 65.7 mmol) in dichloromethane (100 mL). The mixture was cooled to 0° C. and triethylamine (27.6 mL, 0.200 mol) was added. The reaction mixture was allowed to warm to ambient temperature and stirred for 2 h. Water (100 mL) was added and the resulting mixture was extracted with dichloromethane (100 mL×3). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=20:1 to 10:1) to afford benzyl 2-(4-hydroxypiperidin-1-yl)acetate (8.3 g, 51% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7](C(F)(F)F)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][NH:13][C:14](=[O:28])[C@@H:15]1[CH2:19][CH2:18][C:17](=[O:20])[N:16]1[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.ClC1C=C([F:36])C=CC=1CN>>[Cl:1][C:2]1[CH:7]=[C:6]([F:36])[CH:5]=[CH:4][C:3]=1[CH2:12][NH:13][C:14](=[O:28])[C@@H:15]1[CH2:19][CH2:18][C:17](=[O:20])[N:16]1[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccc(F)cc1Cl
Reactant: O=C(NCc1cccc(C(F)(F)F)c1Cl)[C@@H]1CCC(=O)N1Cc1ccccc1
Product: O=C(NCc1ccc(F)cc1Cl)[C@@H]1CCC(=O)N1Cc1ccccc1

Procedure:
N-[(2-chloro-4-fluorophenyl)methyl]-5-oxo-1-(phenylmethyl)prolinamide was prepared in an analogous manner to that described for the synthesis of N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-5-oxo-1-(phenylmethyl)prolinamide (Example 92) above but using [(2-chloro-4-fluorophenyl)methyl]amine in the place of {[2-chloro-3-(trifluoromethyl)phenyl]methyl}amine.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11](OCC)=[O:12].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>CCOCC.CCOC(C)=O.[O-]S([O-])(=O)=O.[Mg+2]>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[CH2:10][CH2:11][OH:12]
Reactant: CCOC(=O)CC1Cc2ccccc2C1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: OCCC1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of ethyl 2,3-dihydro-1H-inden-2-ylacetate (285 mg, 1.39 mmol) in Et2O (5 mL) at 0° C. under N2 was added LAH (53 mg, 1.39 mmol). After stirring for 40 minutes at 0° C., 0.4 mL of H2O was added to quench the reaction. The reaction mixture was diluted with EtOAc (100 mL) and MgSO4 was added with stirring. The reaction mixture was then filtered and concentrated in vacuo to a clear oil. 2-(2,3-dihydro-1H-inden-2-yl)ethanol was isolated without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:12]2[CH2:21][CH2:20][CH:19]3[CH:14]([CH:15]([C:22]([O:24]CC)=[O:23])[CH2:16][CH2:17][CH2:18]3)[CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[OH-].[K+].Cl>O1CCCC1.O.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([N:12]2[CH2:21][CH2:20][CH:19]3[CH:14]([CH:15]([C:22]([OH:24])=[O:23])[CH2:16][CH2:17][CH2:18]3)[CH2:13]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCCC2CCN(C(=O)CCc3ccc(F)cc3)CC21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CCCC2CCN(C(=O)CCc3ccc(F)cc3)CC21
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
A solution of ethyl (4aSR,8SR,8aSR)-2-[3-(4-fluorophenyl)propanoyl]decahydroisoquinoline-8-carboxylate (385 mg, 1.07 mmol) in tetrahydrofuran (5 mL) was added to a solution of potassium hydroxide (168 mg, 3.0 mmol) in water (5 mL). The resulting solution was stirred at room temperature for 16 hours. Additional potassium hydroxide (385 mg, 1.07 mmol) dissolved in methanol (5 mL) was added, and stirring was continued for an additional 5 hours. The mixture was treated with concentrated aqueous hydrochloric acid until the pH was about 1. The mixture was concentrated to a volume of about 5 mL and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated to provide a white solid (350 mg, 98%). 1H NMR (300 MHz, CDCl3) δ7.11 (m, 2H), 6.90 (m, 2H), 4.66 (m, 1H), 3.80 (m, 1H), 2.85 (m, 2H), 2.7-2.4 (m, 3H), 2.1-1.9 (m, 2H), 1.80 (m, 1H), 1.7-0.9 (m, 9H). Mass spec (ES+) m/z 334.2 (M+H+, 100%).
Reaction SMILES: C1([Li])C=CC=CC=1.[Br-].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:34][O:35][C:36]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[C:40]([O:46][CH3:47])[C:37]=1[CH:38]=O.C(Cl)(Cl)Cl>O1CCCC1>[CH3:34][O:35][C:36]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[C:40]([O:46][CH3:47])[C:37]=1[CH:38]=[CH:14][C:10]1[S:9][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc([P+](Cc2cccs2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(OC)c(C=O)c(OC)c1
Agent: [Br-]
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1cc(OC)c(C=Cc2cccs2)c(OC)c1
Temperature: 0 °C
Yield: 92.8 %

Procedure:
In a stream of argon, to 30 ml of tetrahydrofuran was added 0.95 g of phenyllithium (19% solution in dibutylether) (2.15 mmol). To this mixture, 0.78 g (1.98 mmol) of thiophene-2-ylmethyltriphenylphosphonium bromide was added under cooling. After the mixture was well-stirred, 0.38 g (1.98 mmol) of 2,4,6-trimethoxybenzaldehyde dissolved in 3 ml of tetrahydrofuran was added dropwise. The mixture was reacted with stirring for 1.5 hours. After the reaction mixture was poured into 70 ml of ice water, extraction with 200 ml of chloroform, washing with a saturated saline solution, drying over anhydrous magnesium sulfate, and concentration were performed. The residue was purified by silica gel chromatography to give 508 mg (yield: 92%) of 2-[2-(2,4,6-trimethoxyphenyl)vinyl]thiophene as a colorless crystal.
Reaction SMILES: Br[C@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[C:9]([O-:17])(=[S:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cs+]>CN(C=O)C.CCOCC>[C:9]([S:16][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])(=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)[C@@H](Br)C(=O)O
Reactant: [O-]C(=S)c1ccccc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)[C@H](SC(=O)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 72.6 %

Procedure:
To a solution of (R)-(+)-2-bromo-3-methylbutyric acid (4.20 g, 23.2 mmol) in DMF (41 mL) was added cesium thiobenzoate (6.08 g, 22.5 mmol). The mixture was stirred at rt for 20 h. The resulting solution was diluted with ether (200 mL) and washed with H2O (4×40 mL). The ethereal layer was dried (Na2SO4), and concentrated. The crude residue was recrystallized from hexanes to afford (S)-2-benzoylthio-3-methylbutanoic acid as a pale yellow solid (3.89 g, 72%); 1H NMR (300 MHz, CDCl3) δ 1.09 (d, J=7.4 Hz, 3H), 1.11 (d, J=7.4 Hz, 3H), 2.40 (m, 1H), 4.37 (d, J=5.9 Hz, 1H), 7.45 (t, J=7.4 Hz, 2H), 7.57 (t, J=7.4 Hz, 1H), 7.97 (d, J=7.4 Hz, 2H), 12.0 (br s, 1H); 13C NMR (75 MHz, CDCl3) δ 19.8, 20.6, 30.5, 53.1, 127.6, 128.8, 133.9, 136.3, 177.9, 190.3; IR (neat) 3100, 2967, 1709, 1669 cm−1; [α]D22=−94.2 (c 1, CH2Cl2).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](O)([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1.O=S(Cl)Cl.[OH:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.CCOC(C)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:39]3[CH2:40][CH2:41][N:36]([CH2:35][CH2:34][OH:33])[CH2:37][CH2:38]3)([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2cc(C(C)(C)O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: OCCN1CCNCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC1(C)CC=C(c2cc(C(C)(C)N3CCN(CCO)CC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a suspension of 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-amide (as prepared in the previous step, 50.0 mg, 0.132 mmol) in 2 mL of DCM at −15° C. was added SOCl2 (29 μL, 0.40 mmol) under Ar. After stirring at RT for 1 h, the mixture was cooled back to −15° C. To the reaction was added 2-hydroxylethylpiperazine (162 μL, 1.32 mmol). After stirring at −15° C. for 1 h, the resulting mixture was warmed to RT and stirred for 16 h under Ar. Treated with EtOAc (30 mL), the mixture was washed with H2O (2×10 mL) and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (2-6% MeOH/DCM) to afford the title compound (37.5 mg, 58%) as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.12 (d, 1H, J=8.6 Hz), 7.93 (s, 1H), 7.42 (dd, 1H, J=8.6, 2.3 Hz), 7.34 (d, 1H, J=2.3 Hz), 5.72 (m, 1H), 3.70 (t, 2H, J=6.1 Hz), 2.52-2.77 (m, 10H), 2.25-2.32 (m, 2H), 2.04-2.10 (m, 2H), 1.59 (t, 2H, J=6.2 Hz), 1.38 (s, 6H), 1.08 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C28H38N6O2, 491.3 (M+H). found 491.0.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH3:13])[CH:7]=[C:6]([F:14])[C:3]=1[CH2:4][OH:5].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28](Cl)=[O:29])[C@H:24]([CH2:31][CH3:32])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH3:13])[CH:7]=[C:6]([F:14])[C:3]=1[CH2:4][O:5][C:28]([N:25]1[CH2:26][CH2:27][N:22]([C:20]([O:19][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:21])[CH2:23][C@H:24]1[CH2:31][CH3:32])=[O:29]
Reactant: CCCOc1cc(F)c(CO)c(Cl)c1
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Product: CCCOc1cc(F)c(COC(=O)N2CCN(C(=O)OC(C)(C)C)C[C@H]2CC)c(Cl)c1
Yield: 93 %

Procedure:
This compound was prepared from 2-chloro-6-fluoro-4-propoxy-benzylalcohol and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester according to the procedure described in Example 179 to give the product as a colorless oil (499 mg; 93%); MS (ISP): 476.3 (M+NH4)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1)=[O:11].[CH3:38][O:39][CH2:40][CH2:41][CH2:42]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.O>[CH3:38][O:39][CH2:40][CH2:41][CH2:42][N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:36])[CH3:37])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:16][NH:15][CH2:14]1)=[O:11]
Reactant: COCCCO
Reactant: CC(C)CN(C(=O)c1nc2ccccc2[nH]1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCOCC3)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 60 h
Yield: 27.2 %

Procedure:
tert-Butyl (3S,5R)-3-{(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (700 mg), 3-methoxypropan-1-ol (123 mg) and triphenylphosphine (465 mg) were dissolved in THF (20 ml), diisopropyl azodicarboxylate (40% toluene solution: 896 mg) was added, and the mixture was stirred at room temperature for 60 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was saturated aqueous sodium hydrogen carbonate and saturated washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:9-1:3) was concentrated under reduced pressure. The obtained substance was dissolved in ethyl acetate (3 ml), 4M hydrogen chloride-ethyl acetate (3 ml) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was basified with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:9-1:0) and ethyl acetate-methanol (93:7) was concentrated under reduced pressure. The obtained substance was dissolved in ethyl acetate (10 ml), sulfuric acid (42 mg) was added, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethanol (10 ml), and the solvent was evaporated under reduced pressure. The residue was crystallized from ethyl acetate-methanol to give the object product (180 mg) as crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:17][C:18]1[NH:19][CH:20]=[CH:21][N:22]=1.OC1C=CC=C2C=1N=CC=C2>CN(C=O)C.C(=O)(O)[O-].C([N+](CC)(CC)CC)C.[Cu]I>[CH3:17][C:18]1[N:19]([C:2]2[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=2)[C:5]([OH:7])=[O:6])[CH:20]=[CH:21][N:22]=1
Reactant: O=C(O)c1cc(Br)cc(S(F)(F)(F)(F)F)c1
Reactant: Cc1ncc[nH]1
Agent: [Cu]I
Agent: CC[N+](CC)(CC)CC
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Cc1nccn1-c1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Temperature: 160 °C

Procedure:
1.0 g (3.06 mmol) of the compound of Example 15A and 276 mg (3.36 mmol) of 2-methylimidazole were dissolved in 20 ml of DMF and 2 ml of water, and the mixture was degassed with argon. 2.06 g (6.42 mmol) of tetraethylammonium bicarbonate were added carefully, followed by 232 mg (1.22 mmol) of copper(I) iodide and 177 mg (1.22 mmol) of 8-hydroxyquinoline. The mixture was heated in a microwave oven (Biotage Initiator, with Dynamic Field Tuning) at 160° C. for 60 min. The reaction was then filtered, and the filtrate was adjusted at pH 1 with concentrated hydrochloric acid and concentrated under reduced pressure. The residue was separated into its components by preparative HPLC (Method 17). Evaporation of the product fractions and drying of the residue under high vacuum gave 238 mg (94% pure, 22% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]2([C:15](=[N:16][O:17][CH3:18])[CH2:14][N:13](CC3C=CC=CC=3)[CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]2([C:15](=[N:16][O:17][CH3:18])[CH2:14][NH:13][CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CON=C1CN(Cc2ccccc2)CC12CN(C(=O)OC(C)(C)C)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CON=C1CNCC12CN(C(=O)OC(C)(C)C)C2
Yield: 87.9 %

Procedure:
t-butyl-6-benzyl-8-(methoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate was dissolved in 40 ml of methanol and thereto 4.0 g of 10% Pd-C was added. The resulting mixture was stirred for 2 hours under the pressure of hydrogen at 5° C., filtered and concentrated under the reduce pressure to give 1.3 g of the titled compound (yield: 87.9%).
Reaction SMILES: [CH2:1]([C@H:3]1[C:8](=[O:9])[N:7]([CH:10]([CH3:12])[CH3:11])[C:6]2[CH:13]=[CH:14][C:15]([C:17]([OH:19])=O)=[CH:16][C:5]=2[O:4]1)[CH3:2].S(Cl)([Cl:22])=O>>[CH2:1]([C@H:3]1[C:8](=[O:9])[N:7]([CH:10]([CH3:12])[CH3:11])[C:6]2[CH:13]=[CH:14][C:15]([C:17]([Cl:22])=[O:19])=[CH:16][C:5]=2[O:4]1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC[C@@H]1Oc2cc(C(=O)O)ccc2N(C(C)C)C1=O
Product: CC[C@@H]1Oc2cc(C(=O)Cl)ccc2N(C(C)C)C1=O

Procedure:
A mixture of (S)-2-ethyl-4-(2-propyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-carboxylic acid (0.70 g) in thionyl chloride (15 ml) was stirred under reflux for 2 hours. Thionyl chloride was distilled off under reduced pressure to give (S)-2-ethyl-4-(2-propyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-carbonyl chloride (0.70 g).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[C@@H:12]1[CH2:14][O:13]1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][C:16]1=[O:21]>C(Cl)Cl>[OH:13][C@H:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])[CH2:14][N:18]1[CH2:19][CH2:20][NH:15][C:16](=[O:21])[CH2:17]1
Reactant: O=C1CNCCN1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Solvent: ClCCl
Product: Cc1c([C@@H](O)CN2CCNC(=O)C2)ccc2c1COC2=O
Temperature: 145 °C

Procedure:
A mixture of 4-Methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (0.46 g, 2.4 mmol) and piperazin-2-one (0.20 g, 2.0 mmol) was heated to 145° C. in a microwave tube for 1 hour. The crude reaction was diluted with DCM, adsorbed onto silica gel, and purified by silica gel chromatography to provide the title product. LC-MS (IE, m/z): 291 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[C:4]([S:16][CH2:17][CH2:18][NH:19][CH2:20][C@H:21]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:22][CH:23]=[CH2:24])=[C:5]([C:13]([OH:15])=O)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].C(N(C(C)C)CC)(C)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>C(#N)C.C(OCC)(=O)C>[Cl:32][C:27]1[CH:26]=[C:25]([C@H:21]([CH2:22][CH:23]=[CH2:24])[CH2:20][N:19]2[C:13](=[O:15])[C:5]3[C:6]4[C:11]([CH:12]=[C:3]([C:1]#[N:2])[C:4]=3[S:16][CH2:17][CH2:18]2)=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: C=CC[C@H](CNCCSc1c(C#N)cc2ccccc2c1C(=O)O)c1ccc(Cl)c(Cl)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C=CC[C@H](CN1CCSc2c(C#N)cc3ccccc3c2C1=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 26.7 %

Procedure:
To a solution of 3-cyano-2-[(2-{[(2S)-2-(3,4-Dichlorophenyl)pent-4-enyl]amino}ethyl)thio]-1-naphthoic acid (Intermediate 6, 135 mg, 0.28 mmol) in dry acetonitrile (6 mL) under nitrogen at 0° C. was added diisopropylethyl amine (146 μL, 0.84 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl, 86 mg, 0.34 mmol). Stirring was continued for 45 min as the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was diluted with ethyl acetate (50 mL), washed with 0.5 N HCl and brine, dried (Na2SO4), and evaporated to a residue which was chromatographed on silica gel in 25–40% EtOAc/Hexanes to give 85 mg of partially purified material. A portion (50 mg) of this material was chromatographed on silica gel in 20% EtOAc/Hexanes to give 35 mg of the title compound.