Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C@H:5]1[C@H:14]2[CH2:15][CH2:16][N:17]([C:18]([C@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]3[NH:26][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:19])[C@H:13]2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6]1.CI.[C:37](=O)([O-])O.[Na+]>O1CCCC1>[CH3:37][O:3][CH2:4][C@H:5]1[C@H:14]2[CH2:15][CH2:16][N:17]([C:18]([C@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]3[NH:26][C:27](=[O:34])[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:19])[C@H:13]2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6]1
Reactant: O=C([O-])O
Reactant: O=C(N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](CO)Nc3ccccc3[C@@H]21)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)[C@H]1CCCC[C@H]1NC(=O)c1ccccc1
Reaction time: 1 h
Yield: 84 %

Procedure:
Sodium hydride (60% in oil, 14 mg, 0.1 mmol) was suspended in tetrahydrofuran (1 ml), the compound (35 mg, 0.08 mmol) synthesized in Example 50 was added under ice-cooling, and the suspension was stirred for 1 hr. Methyl iodide (14 mg, 0.1 mmol) was added thereto, and the mixture was stirred under ice-cooling for 30 min., and then at room temperature for 2 hrs. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried (over anhydrous Na2SO4), and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (10 g) and eluted with hexane-ethyl acetate (4:1, v/v) to give the title compound (30 mg, 84%) as an amorphous form.
Reaction SMILES: O=[C:2]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[CH2:3][C:4](OCC)=[O:5].[CH3:15][NH:16][C:17]([NH2:19])=[S:18].C1CCN2C(=NCCC2)CC1.CS(O)(=O)=O>O>[SH:18][C:17]1[N:16]([CH3:15])[C:4](=[O:5])[CH:3]=[C:2]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:19]=1
Reactant: CNC(N)=S
Reactant: CCOC(=O)CC(=O)c1ccncc1
Agent: CS(=O)(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: Cn1c(S)nc(-c2ccncc2)cc1=O
Temperature: 0 °C
Yield: 72.1 %

Procedure:
A solution of ethyl 3-oxo-3-(4-pyridyl)propionate (29.0 g, 150 mmol), N-methyl thiourea (40.6 g, 450 mmol) and 1,8-diazabicyclo[5,4,0]-7-undecene (22.4 ml, 150 mmol) was refluxed for 4 hours and the solution of methanesulfonic acid (14.4 g, 150 mmol) in water (50 ml) was added after cooling by ice-water. The precipitate was washed with water, filtered and dried to give the title compound (23.7 g, 72%).
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.C([O-])(O)=O.[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>CCOC(C)=O>[CH2:19]([O:18][C:16](=[O:17])[N:2]([C@H:3]1[CH2:8][CH2:7][C@@H:6]([OH:9])[CH2:5][CH2:4]1)[CH3:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CN[C@H]1CC[C@@H](O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN(C(=O)OCc1ccccc1)[C@H]1CC[C@@H](O)CC1

Procedure:
A well stirred solution of 100 g (774 mmol) of cis-4-Methylamino-cyclohexanol [Schut, Robert N. Analgesic 3-(methylamino)-1,2,3,4-tetrahydrocarbazole from 4-(methylamino)cyclohexanone. Fr. (1968), 3 pp. FR 1515629 19680301] in 775 ml EtOAc was treated with 1.55 l of aqueous 1M NaHCO3 and with 110 ml (774 mmol) of benzyl chloroformate (30 min, Tmax 30° C.). The phases were separated after 2 h at RT. The aqueous phase was extracted (EtOAc), the organic phases were dried (Na2SO4), filtered and evaporated. Purification by column chromatography on silica gel (hexane/EtOAc 2:1) gave 139 g (68%) of cis-(4-Hydroxy-cyclohexyl)-methyl-carbamic acid benzyl ester, MS: 263 (M).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([F:9])=[C:7]([F:10])[N:6]=[C:5](F)[C:4]=1[F:12].[CH3:13][O-:14].[Na+].O>CO>[OH:1][CH2:2][C:3]1[C:8]([F:9])=[C:7]([F:10])[N:6]=[C:5]([O:14][CH3:13])[C:4]=1[F:12]
Reactant: OCc1c(F)c(F)nc(F)c1F
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc(F)c(F)c(CO)c1F
Yield: 80 %

Procedure:
A mixture of 1.0 g (0.0055 mole) of 4-hydroxymethyl-2,3,5,6-tetrafluoropyridine (from Example 5) and 0.30 g (0.0055 mole) of sodium methoxide in 25 ml of methanol was refluxed for approximately twenty hours. After being cooled, the reaction mixture was poured into water. The aqueous solution was extracted with diethyl ether. The diethyl ether extract was dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated under reduced pressure, yielding 0.85 g of 4-hydroxymethyl-2-methoxy-3,5,6-trifluoropyridine as a yellow oil. The structure and nmr spectra are set forth in Table 1C below.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=[O:9])[NH2:8])=[C:4]([NH:10][C:11]([C@@H:13]2[CH2:17][CH:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:15][N:14]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=O)[CH:3]=1.[OH-].[Na+].Cl>C(O)C>[Br:1][C:2]1[S:6][C:5]2[C:7](=[O:9])[NH:8][C:11]([C@@H:13]3[CH2:17][CH:16]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[CH2:15][N:14]3[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:10][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCCCC2)C[C@H]1C(=O)Nc1cc(Br)sc1C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(N2CCCCC2)C[C@H]1c1nc2cc(Br)sc2c(=O)[nH]1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
In the same manner as in Example 11, step A, tert-butyl (2S)-2-[(5-bromo-2-carbamoylthiophen-3-yl)carbamoyl]-4-piperidin-1-ylpyrrolidine-1-carboxylate was obtained as a pale-brown amorphous solid (132 mg) from 3-amino-5-bromothiophene-2-carboxamide (200 mg) produced in Example 1, step D and 1-(tert-butoxycarbonyl)-4-piperidin-1-yl-L-proline (270 mg) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (413 mg) and N-ethyl-N-(1-methylethyl)propan-2-amine (0.316 mL) and N,N-dimethylformamide (5.0 mL). To tert-butyl (2S)-2-[(5-bromo-2-carbamoylthiophen-3-yl)carbamoyl]-4-piperidin-1-ylpyrrolidine-1-carboxylate produced above were added 2M aqueous sodium hydroxide solution (0.52 mL) and ethanol (1.0 mL), and the mixture was stirred at 70° C. for 2 hr. The reaction system was neutralized with 1M hydrochloric acid at 0° C. The mixture was extracted with ethyl acetate, and the mixture was washed with brine, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (63 mg) as a pale-brown amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[C:32]([O:36][C:37]([N:39]1[CH2:43][CH2:42][CH:41]([NH:44][CH3:45])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([N:39]1[CH2:43][CH2:42][CH:41]([N:44]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:30])([F:31])[F:29])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH3:45])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CNC1CCN(C(=O)OC(C)(C)C)C1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1)C1CCN(C(=O)OC(C)(C)C)C1

Procedure:
3-({5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-methyl-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 3-Methylamino-pyrrolidine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20]>C1COCC1>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)(=[O:21])=[O:20])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: Cc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc2ccn(S(=O)(=O)c3ccccn3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.7 %

Procedure:
6-Methylindole (42) (7.34 g, 56.0 mmol) was added in portions to a mixture of sodium hydride (3.36 g, 84.0 mmol) in THF (80 mL) at 0° C. After 15 min, pyridine-2-sulfonyl chloride (43) (10.0 g, 56.0 mmol) was added, and the reaction was allowed to warm to rt and stirred overnight under N2. The reaction mixture was then quenched with ice water and extracted with EtOAc. The organic layers were combined, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with a linear gradient ranging from 0 to 40% EtOAc-hexanes to provide 8.8 g (57%) of product 44 as a brown gum. 1H NMR (300 MHz, CDCl3) δ 2.44 (s, 3H), 6.62 (dd, J=1, 4 Hz, 1H), 7.03-7.06 (m, 1H), 7.41 (d, J=8 Hz, 1H), 7.41-7.45 (m, 1H), 7.59 (d, J=4 Hz, 1H), 7.79-7.81 (m, 1H), 7.84-7.90 (m, 1H), 8.10 (dt, J=1, 8 Hz, 1H), 8.58-8.60 (m, 1H). LC-MS (CI): m/z 273.0 [(M+H)+ C14H12N2O2S requires 272.06].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([CH3:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[C:4]([CH3:26])[N:3]=1.[CH:27]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28]1>>[CH:27]1([C:31]([NH:1][C:2]2[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]3[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:24])([F:25])[F:23])=[C:17]([CH3:19])[CH:18]=3)[CH3:12])=[O:9])[CH:5]=[C:4]([CH3:26])[N:3]=2)=[O:32])[CH2:30][CH2:29][CH2:28]1
Reactant: O=C(Cl)C1CCC1
Reactant: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(C)c2)nc(N)n1
Product: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(C)c2)nc(NC(=O)C2CCC2)n1

Procedure:
The title compound is prepared from 2-amino-6-methyl-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carboxamide (20 mg, 0.05 mmol, Step-1, single enantiomer) and cyclobutanecarbonyl chloride (28 mg, 0.27 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [F:1][C:2]([F:56])([F:55])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13](COCC[Si](C)(C)C)[C:12]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:24][CH2:23]3)=[N:11][C:10]=2[C:38]([NH:40][CH2:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][N:43]2C(OC(C)(C)C)=O)=[O:39])=[CH:5][CH:4]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:43]1[CH2:44][CH2:45][CH2:46][CH2:47][CH:42]1[CH2:41][NH:40][C:38]([C:10]1[N:11]=[C:12]([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[C:33]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:31]=[CH:30][N:29]=3)[CH2:24][CH2:23]2)[NH:13][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:56])([F:1])[F:55])=[CH:4][CH:5]=1)=[O:39]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CNC(=O)c1nc(N2CCN(c3ncccc3C(F)(F)F)CC2)n(COCC[Si](C)(C)C)c1-c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC1CCCCN1)c1nc(N2CCN(c3ncccc3C(F)(F)F)CC2)[nH]c1-c1ccc(C(F)(F)F)cc1

Procedure:
A solution of tert-butyl 2-((5-(4-(trifluoromethyl)phenyl)-2-(4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxamido)methyl)piperidine-1-carboxylate from step (a) above (200. mg, 0.247 mmol) in TFA:DCM (4:1) was stirred at RT for 7 min. The solvent was removed and the residue was added H2O (0.5 mL). Then, saturated NaHCO3 was added at 0° C. until pH ˜7 and the solvents were removed. The residue was purified on silica gel using ISCO Combiflash® system with DCM/2M methanolic ammonia gradient to give the title compound as a light yellow solid. MS (ESI, positive ion) m/z: 582 (M+1).
Reaction SMILES: [CH2:1]([C:3]([C:17]1[CH:30]=[CH:29][C:20]([O:21][CH2:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[C:19]([CH3:31])[CH:18]=1)([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].[BH4-].[Na+]>CCO>[CH2:1]([C:3]([C:17]1[CH:30]=[CH:29][C:20]([O:21][CH2:22][CH:23]([OH:28])[C:24]([CH3:25])([CH3:27])[CH3:26])=[C:19]([CH3:31])[CH:18]=1)([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(c1ccc(-c2nnn[nH]2)cc1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCC(CC)(c1ccc(-c2nnn[nH]2)cc1)c1ccc(OCC(O)C(C)(C)C)c(C)c1
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a mixture of 1-(4-{1-Ethyl-1-[4-(1H-tetrazol-5-yl)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-one (0.37 g, 0.88 mmol) and EtOH (5 mL) was added NaBH4 (0.037 g, 0.97 mmol) and the solution stirred for 1 hour. The solids were removed by filtration and the solution concentrated. The residue was purified by ISCO (10-30 [89% EtOAc:10% MeOH:1% AcOH] gradient) to furnish the title compound (0.32 g, 0.76 mmol, 86%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH:13]([Mg]Br)=[CH2:14]>C1COCC1>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([OH:12])[CH:13]=[CH2:14])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=CC1CCC2(CC1)OCCO2
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)C1CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 8 h

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decane-8-carbaldehyde (860 mg, 5.05 mmol, prepared as described in Pearson, et al. in J. Org. Chem. 1997, 62(16), 5284-5292) in THF (6 mL) cooled to −78° C. under argon was added a vinylmagnesium bromide (20 mL, 20 mmol, 1 M in THF) dropwise. After the complete addition, the reaction mixture was allowed to reach room temperature overnight. It was then re-cooled to −78° C. and quenched with saturated NaHCO3 solution and warmed to room temperature. After extraction with ether, the organic layer was concentrated in vacuo and the residue purified by flash chromatography (silica gel, 0-100% ether/hexanes) to afford the product.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:22])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:21])[C@H:17]([CH2:19][OH:20])[NH2:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[CH2:2]([O:9][C:10](=[O:22])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:21])[C@H:17]([CH2:19][OH:20])[NH:18][S:36]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:38])=[O:37])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)[C@H](CO)NS(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 90.6 %

Procedure:
L-seryl-L-proline benzylester hydrochloride (1.64 g, 5 mmole) was dissolved in methylene chloride (30 ml), and triethylamine (1.11 g, 11 mmole) was added thereto at -30° C. Methylene chloride (10 ml) solution of benzene sulfonyl chloride (0.86 g, 5 mmole) was added dropwise thereto. The mixture was stirred for 1 hour at less than 0° C. and then for 5 hours at room temperature, and methylene chloride (60 ml) was added thereto. The mixture was washed with 5% aqueous sodium bicarbonate (100 ml, twice), 1N aqueous hydrochloric acid (100 ml, twice) and water (100 ml) in the order given, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain N-benzenesulfonyl-L-seryl-L-proline benzylester (yield: 1.96 g, 90.6%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[N+:14]([C:17]1[CH:18]=[C:19]2[C:24](=O)[O:23][C:21](=[O:22])[C:20]2=[CH:26][CH:27]=1)([O-:16])=[O:15]>C(Cl)(Cl)Cl>[CH:8]1([N:5]2[CH2:6][CH2:7][CH:2]([N:1]3[C:24](=[O:23])[C:19]4=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:27][CH:26]=[C:20]4[C:21]3=[O:22])[CH2:3][CH2:4]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: NC1CCN(C2CCCCC2)CC1
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Solvent: ClC(Cl)Cl
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1C1CCN(C2CCCCC2)CC1

Procedure:
6.85 Grams of 4-amino-1-cyclohexylpiperidine were added to 7.26 grams of 4-nitrophthalic anhydride in 100 milliliters of chloroform and the solution was evaporated to dryness. 50 millilters of acetic anhydride were then added and the solution was heated on a steam bath for half an hour. The excess acetic anhydride was evaporated off and the residue dissolved in 40 millilters of isopropyl alcohol and the product crystallised out. This was filtered, dried and dissolved in the least amount of ethanol and ethereal hydrogen chloride added to give 2.85 grams of the title compound which was collected as the monohydrochloride. Melting Point: 265°-270° C.
Reaction SMILES: N1C=CN=C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[O:25]1[C:29]2([CH2:34][CH2:33][CH:32](O)[CH2:31][CH2:30]2)[O:28][CH2:27][CH2:26]1.[I:36]I>C1COCC1>[I:36][CH:32]1[CH2:33][CH2:34][C:29]2([O:28][CH2:27][CH2:26][O:25]2)[CH2:30][CH2:31]1
Reactant: II
Reactant: OC1CCC2(CC1)OCCO2
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: IC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
A mixture of imidazole (111 g, 1.63 mol, 1.2 eq.), PPh3 (428 g, 1.63 mol, 1.2 eq.) and 1,4-dioxaspiro[4.5]decan-8-ol (215 g, 1.36 mol, 1.0 eq.) in THF (1.5 L) was cooled using an ice bath under N2. To this reaction mixture was added slowly a solution of I2 (414 g, 1.63 mol, 1.2 eq.) in THF (1 L) keeping the internal temperature <12° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was partitioned between H2O (2 L), EtOAc (3 L), and brine (2 L). The aqueous layer was extracted with EtOAc (1 L×2). The combined organic layer was washed with 10% aqueous NaHSO3 (800 mL, organic layer turned light yellow), brine (1 L), dried over Na2SO4, filtered, and evaporated. The crude product was dissolved in diethyl ether (6 L), filtered, and the solid was washed with diethyl ether (300 mL×3). The filtrate was concentrated and purified by column chromatography (100% hexanes to 5% EtOAc in hexanes, Rf=0.3 in 5% EtOAc in hexanes) to give 340 g (93.4% yield) of 8-iodo-1,4-dioxaspiro[4.5]decane. GC-MS: 269 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:20])[C:9](N2[C@@H](C(C)C)COC2=O)=[O:10])=[CH:4][CH:3]=1.[OH:21]O.[Li+].[OH-]>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([CH3:20])[C:9]([OH:10])=[O:21])=[CH:6][CH:7]=1
Reactant: OO
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](C)c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](C(=O)O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
To a solution of (4S)-3-[(2S)-2-(4-fluorophenyl) propanoyl]-4-isopropyl-1,3-oxazolidin-2-one (2.40 g, 8.60 mmol) in 160 mL THF/H2O (3:1) at 0° C., was added 30% H2O2 (7.8 mL, 68.8 mmol) followed by LiOH (722 mg, 17.2 mmol). The resulting mixture was stirred at 0° C. for 2 h and the excess peroxide was quenched at 0° C. with 1.5 N aqueous Na2SO3 (51 mL). After buffering to pH 9–10 with aqueous NaHCO3 and evaporation of the THF, the oxazolidone chiral auxiliary was recovered by EtOAc extraction (50 mL×3). The aqueous layer was acidified with 3N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give 0.92 g (5.47 mmol, 64%) of (2S)-2-(4-fluorophenyl)propanoic acid; [α]D=+70° (C=1, MeOH): 1H NMR (400 MHz, CDCl3) δ 12.2–11.4 (br, 1 H), 7.31–7.24 (m, 2 H), 7.04–6.97 (m, 2 H), 3.72 (q, 1 H, J=7.3 Hz), 1.49 (d, 3 H, J=7.3 Hz); ESMS m/e: 167.2 (M−H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].C([Li])CCC.CN(C)[CH:17]=[O:18]>O1CCCC1.CCCCCC>[F:8][C:6]1[CH:5]=[CH:4][C:3]([CH3:9])=[C:2]([CH:7]=1)[CH:17]=[O:18]
Reactant: Cc1ccc(F)cc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(F)cc1C=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
To a solution of 2-bromo-4-fluorotoluene (16.0 g) in anhydrous tetrahydrofuran was added dropwise at −78° C. a solution of 1.6M butyllithium in hexane (55.5 ml), and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added dropwise a solution of dimethylformamide (6.8 g) in tetrahydrofuran (20 ml), and the mixture was allowed to stand to warm up to 0° C. To the reaction solution was added ice-water, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give oil of 5-fluoro-2-methylbenzaldehyde (11.5 g).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][N:16]=1)=O)(C)(C)C.[ClH:28]>C(OCC)C>[ClH:28].[CH2:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[N:16][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(Cc2ccccc2)cn1
Agent: Cl
Solvent: CCOCC
Product: c1ccc(Cc2ccc(OC[C@@H]3CCCN3)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To the product from step 3 (25 mg, 0.068 mmol) was added 2N HCl (3 mL) in diethyl ether. The resulting mixture was stirred at rt for 2 h. The solvent was removed to give the title compound (20 mg, 97%). MS; m/z 269 (M+H)>90% 1H NMR (DMSO-d6, 400 MHz) δ 1.59-2.12 (4H, m), 3.19 (2H, m), 3.88 (2H, s), 4.34 (1H, d, J=8.0 Hz), 4.48 (1H, dd, J1=4.0 Hz, J2=11.6 Hz), 6.80 (1H, d, J=8.4 Hz), 7.17-7.30 (5H, m), 7.58 (1H, dd, J1=2.4 Hz, J2=8.4 Hz), 8.09 (1H, d, J=2.4 Hz), 8.93 (1NH, s), 9.49 (1NH, s).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:32])[N:18]([CH2:28][C:29](O)=[O:30])[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[NH4+].O[N:35]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN(C)C=O>C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]2[C:17](=[O:32])[N:18]([CH2:28][C:29]([NH2:35])=[O:30])[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:13][CH:14]=1)#[N:2]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(=O)O)c2ncnn12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(N)=O)c2ncnn12
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.2 %

Procedure:
A mixture of {6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}acetic acid (0.5 g), 1-hydroxybenzotriazole ammonium salt (0.24 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.27 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.48 g, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([C:15]([NH2:17])=[O:16])=[C:13]([NH:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:20])[S:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O>[Pd].O1CCCC1.CCOCC>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([C:15]([NH2:17])=[O:16])=[C:13]([NH:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:20])[S:12][N:11]=2)=[CH:6][CH:5]=1
Reactant: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)nsc1NC(=O)NCCCN1CCCC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOCC
Product: NC(=O)c1c(-c2ccc(N)cc2)nsc1NC(=O)NCCCN1CCCC1
Yield: 92.9 %

Procedure:
3-(4-nitrophenyl)-5-({[(3-pyrrolidin-1-ylpropyl)amino]carbonyl}amino)isothiazole-4-carboxamide (16.0 g,) and 10% palladium on carbon (6 g) in tetrahydrofuran (1500 mL) was hydrogenated at 80 psi over 24 hr in metal bomb. Filter the catalyst on celite and washed with tetrahydrofuran. The filtrate was concentrated in vacuo to give off white solid, which was stirred in ether (200 mL) and filtered to give the title compound as a white solid (13.8 g, 93%).