Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C1COCC1.[Li]C(C)(C)C.Br[C:19]1[S:23][C:22]([C:24]2[N:28]3[N:29]=[C:30]([CH3:38])[CH:31]=[C:32]([CH:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[C:27]3=[N:26][C:25]=2[CH3:39])=[C:21]([O:40][CH3:41])[CH:20]=1>CCOC(C)=O.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:34]([CH:33]([C:32]1[C:27]2[N:28]([C:24]([C:22]3[S:23][C:19]([C:2]4[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=4)=[CH:20][C:21]=3[O:40][CH3:41])=[C:25]([CH3:39])[N:26]=2)[N:29]=[C:30]([CH3:38])[CH:31]=1)[CH2:36][CH3:37])[CH3:35]
Reactant: Ic1cccnc1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3OC)c(C)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4cccnc4)cc3OC)c(C)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
To a −78° C. solution of 3-iodo-pyridine (0.32 g, 1.56 mmol) and 0.5 M ZnCl2 in THF (3.20 mL, 1.59 mmol) is added t-BuLi (2.27 mL, 3.85 mmol). The solution is warmed to ambient temperature and stirred for 30 minutes. 3-(5-bromo-3-methoxy-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.26 g, 0.64 mmol) and Pd(PPh3)4 (0.037 g, 0.032 mmol) are added and the solution heated at 50° C. for 1 hour, cooled to ambient temperature and stirred overnight. The solution is diluted with EtOAc (30 mL), washed with sat. NH4Cl (2×30 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (20%-50% EtOAc/hexane gradient), furnish the title compound (0.16 g, 0.39 mmol, 61%). 1H NMR (CDCl3) δ 0.87 (t, J=7.5 Hz, 6H), 1.74-1.91 (m, 4H), 2.52 (s, 3H), 2.55 (s, 3H), 3.28-3.38 (m, 1H), 3.93, (3H), 6.67 (s, 1H), 7.26 (d, J=3.5 Hz, 1H), 7.31-7.36 (m, 1H), 7.88-7.92 (m, 1H), 8.55 (d, J=4.5 Hz, 1H), 8.92 (d, J=1.8 Hz, 1H). LC/MS (m/z): calcd. for C23H26N4OS (M+H)+: 407.6; found: 407.4.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:27]=[CH:26][C:6]2[C:7](=[O:25])[CH2:8][CH2:9][CH2:10][N:11]([C:16]([CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:24])[CH3:23])=[O:17])[C:12](=[O:15])[CH2:13][CH2:14][C:5]=2[CH:4]=1.[CH2:28]([OH:30])[CH3:29]>C(Cl)Cl>[C:22]([NH:21][CH2:20][CH2:19][CH2:18][C:16]([NH:11][CH2:10][CH2:9][CH2:8][C:7]([C:6]1[CH:26]=[CH:27][C:3]([Cl:2])=[CH:4][C:5]=1[CH2:14][CH2:13][C:12]([O:30][CH2:28][CH3:29])=[O:15])=[O:25])=[O:17])(=[O:24])[CH3:23]
Reactant: CC(=O)NCCCC(=O)N1CCCC(=O)c2ccc(Cl)cc2CCC1=O
Reactant: CCO
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CCc1cc(Cl)ccc1C(=O)CCCNC(=O)CCCNC(C)=O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
1 ml of concentrated hydrochloric acid is added to a solution of 2.66 g (0.007 mol) of N-[3-[(11-chloro-2,3,5,6,7,8-hexahydro-3,8-dioxo-4-benzazecin-4-(1H)-yl)carbonyl]propyl]acetamide in 100 ml of ethanol and 30 ml of methylene chloride and the mixture is stirred at room temperature for 5 days. The solution is concentrated, extracted with methylene chloride/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Chromatography on aluminum oxide with ethyl acetate/ethanol (19:1) and crystallization from methylene chloride/ether gives ethyl 2-[4-(4-acetamidobutyramido)butyryl]-5-chlorohydrocinnamate as white crystals with melting point 95°.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:33]2([CH3:36])[CH2:35][CH2:34]2)[N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([NH:17]C(=O)OC(C)(C)C)[CH3:16])[N:8]=1>Cl.CO>[Br:1][C:2]1[N:3]=[C:4]([C:33]2([CH3:36])[CH2:35][CH2:34]2)[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([NH2:17])[CH3:16])[N:8]=1
Reactant: C[C@@H](CNc1nccc(-c2c(Br)nc(C3(C)CC3)n2COCC[Si](C)(C)C)n1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: C[C@H](N)CNc1nccc(-c2[nH]c(C3(C)CC3)nc2Br)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 136 %

Procedure:
A mixture of (S)-tert-butyl 1-(4-(4-bromo-2-(1-methylcyclopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (2.46 g, 4.23 mmol) in concentrated HCl (1.3 mL) and MeOH (20 mL) was stirred at room temperature overnight. LCMS indicated only 30% conversion; the reaction was then heated at 60° C. for 4 hours and stirred overnight at room temperature. LCMS indicated complete conversion and the reaction mixture was concentrated to a yellow solid to afford the crude (S)—N1-(4-(4-bromo-2-(1-methylcyclopropyl)-1H-imidazol-5-yl)pyrimidin-2-yl)propane-1,2-diamine (2.02 g) as the HCl salt which is used in next step without purification: LCMS (m/z) 351.1 (MH+), tR=0.45 minute.
Reaction SMILES: [N:1]1[N:2]=[C:3]([SH:6])[NH:4][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][O:21][C:22]([C@:24]1([NH:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:29][C@H:28](OS(C2C=CC(C)=CC=2)(=O)=O)[C@@H:27]2[C@H:25]1[C@H:26]2[C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[F:51])=[O:42])=[O:23]>CN(C)C=O>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][O:21][C:22]([C@:24]1([NH:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:29][C@@H:28]([S:6][C:3]2[NH:4][CH:5]=[N:1][N:2]=2)[C@@H:27]2[C@H:25]1[C@H:26]2[C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[F:51])=[O:42])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2C[C@@](NC(=O)OC(C)(C)C)(C(=O)OCc3ccccc3F)[C@@H]3[C@@H](C(=O)OCc4ccccc4F)[C@@H]32)cc1
Reactant: Sc1nnc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@]1(C(=O)OCc2ccccc2F)C[C@@H](Sc2nnc[nH]2)[C@H]2[C@H](C(=O)OCc3ccccc3F)[C@H]21
Temperature: 70 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
Add 4H-1,2,4-triazole-3-thiol (0.59 g, 5.87 mmol) and potassium carbonate (0.81 g, 5.87 mmol) to a solution of bis[(2-fluorophenyl)methyl](1S,2S,4S,5R,6R)-2-(tert-butoxy carbonylamino)-4-(p-tolylsulfonyloxy)bicyclo[3.1.0]hexane-2,6-dicarboxylate (2.63 g, 3.92 mmol) in dry N,N-dimethylformamide (15.66 mL). Heat the resulting mixture at 70° C. under nitrogen in a sealed tube and maintain stirring overnight. Quench with water and dilute with ethyl acetate. Wash the organic layer with citric acid solution (10% in water), brine. Dry over sodium sulfate, filter and concentrate to give the crude material as a pale brown oil (2.3 g). Purify by flash chromatography eluting with ethyl acetate:hexane (30:70 to 70:30) to give the title product as a colorless oil (1.84 g, 3.06 mmol). MS (m/z): 601 (M+1), 623 (M+23).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)=[N:9][C:8]=2[CH:23]=1)([O-])=O.C([O-])=O.[NH4+]>C(O)C.[Pd]>[F:22][C:19]([F:20])([F:21])[O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[O:11][C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:23][C:8]=3[N:9]=2)=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccc2oc(-c3ccc(OC(F)(F)F)cc3)nc2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ccc2oc(-c3ccc(OC(F)(F)F)cc3)nc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 56.3 %

Procedure:
To 5-nitro-2-(4-(trifluoromethoxy)phenyl)benzo[d]oxazole (850 mg, 2.62 mmol) in ethanol (20 mL) was added ammonium formate (827 mg, 13.1 mmol) and palladium on carbon (85 mg). The mixture was stirred at room temperature for 20 min, then filtrated through a pad of Celite®, and washed with ethyl acetate. The organic solution was washed with water, followed by brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 434 mg (56%) of the title compound (LCMS RT=6.51 min, MH+ 294.9)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([N+]([O-])=O)[C:4]=1[C:5]#[N:6].[OH-:18].[K+]>FC(F)(F)CO.O>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([O:18][CH2:9][C:11]([F:14])([F:13])[F:12])[C:4]=1[C:5]#[N:6]
Reactant: COc1cc(C(F)(F)F)cc([N+](=O)[O-])c1C#N
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: OCC(F)(F)F
Product: COc1cc(C(F)(F)F)cc(OCC(F)(F)F)c1C#N
Temperature: 25 °C
Yield: 93.1 %

Procedure:
To a solution of 200 mg (0.804 mmol) 2-methoxy-6-nitro-4-trifluoromethyl-benzonitrile in 2.4 ml 2,2,2-trifluoroethanol under argon at 0° C. was added dropwise a solution of 81.3 mg (1.246 mmol) potassium hydroxide in 600 ul water. The mixture was refluxed for 2 days then cooled to room temperature and poured into ice/water. The resulting suspension was filtered and dried in vacuo to provide 112 mg (47%) of the title compound as a white solid. MS (m/e): 317.2 (M+H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)[CH2:6][NH:7][C:8]1[N:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1.[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[C:42]([CH:44]([CH3:46])[CH3:45])[CH:41]=[CH:40][C:39]=2[O:47][CH3:48])=[C:34]([CH2:49]Cl)[CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[H-].[Na+].[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[C:42]([CH:44]([CH3:46])[CH3:45])[CH:41]=[CH:40][C:39]=2[O:47][CH3:48])=[C:34]([CH2:49][N:7]([CH2:6][C:5]2[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=[C:3]([C:2]([F:1])([F:22])[F:23])[CH:4]=2)[C:8]2[N:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=2)[CH:33]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: FC(F)(F)c1cc(CNc2ncc(Br)cn2)cc(C(F)(F)F)c1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(OCc2ccccc2)cc1CCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C(C)C)cc1-c1ccc(OCc2ccccc2)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amine (315 mg) and 4-benzyloxy-2-chloromethyl-5′-isopropyl-2′-methoxy-biphenyl (300 mg) are dissolved in N,N-dimethylformamide (5 ml) and thereto is added sodium hydride (60%) (40.9 mg) under ice-cooling, and the mixture is stirred at room temperature overnight. Thereto are added a saturated aqueous ammonium chloride solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=1:0→97:3) to give (4-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-2-ylmethyl)-(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amine (458 mg). MS (m/z): 744/746 [M+H]+
Reaction SMILES: I[C:2]1[C:7]([NH2:8])=[C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[CH:4][N:3]=1.[C:16]([Si:20]([CH3:28])([CH3:27])[O:21][CH2:22]/[CH:23]=[CH:24]/[C:25]#[CH:26])([CH3:19])([CH3:18])[CH3:17]>C(#N)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Si:20]([O:21][CH2:22]/[CH:23]=[CH:24]/[C:25]#[C:26][C:2]1[C:7]([NH2:8])=[C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[CH:4][N:3]=1)([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:28])[CH3:27]
Reactant: Nc1c(I)ncnc1Oc1ccccc1
Reactant: C#C/C=C/CO[Si](C)(C)C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC/C=C/C#Cc1ncnc(Oc2ccccc2)c1N
Yield: 87.8 %

Procedure:
4-Iodo-6-phenoxypyrimidin-5-amine (1.0 g) was dissolved in a mixed solvent of acetonitrile (53 mL)/triethylamine (39 mL), and tert-butyl(dimethyl)[(2E)-2-penten-4-ynyloxy]silane (753 mg), trans-dichlorobis(triphenylphosphine)palladium(II) (112 mg) and copper(I) iodide (36.5 mg) were sequentially added. The title compound (1.07 g) was obtained as crystals by the reaction in the same manner as in Example 9 (iv).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.CN([CH:15]=[O:16])C.O=P(Cl)(Cl)Cl>>[Cl:1][C:2]1[C:3]([CH:15]=[O:16])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Cl)cc(OC)c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Cl)c(C=O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To a mixture of 5-chloro-1,3-dimethoxybenzene (25 g, 0.14 mol) in DMF (175 mL, 2.27 mol) at 0° C. was added POCl3 (42.5 mL, 0.46 mol) dropwise. The mixture was stirred at room temperature for 30 min and heated to reflux at 100° C. for an additional 2 h. The reaction mixture was poured onto ice and the yellow precipitate was collected by filtration, rinsed with cold water and dried under high vacuum to give a light yellow solid (22.7 g. Yield 78.3%). 1H NMR (400 MHz, CDCl3) δ0.43 (s, 1H), 6.59 (s, 1H), 6.42 (s, 1H), 3.92 (s, 3H), 3.89 (s, 3H); MS (ESI) m/z=201 [M+H]+.
Reaction SMILES: [OH:1][C:2]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][O:4][CH2:3]1.[CH:21]1([CH2:24][C:25]([NH2:33])([CH3:32])[C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH2:23][CH2:22]1>>[CH:21]1([CH2:24][C:25]([NH:33][C:12]([C:9]2[CH:8]=[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:6]([C:2]3([OH:1])[CH2:3][O:4][CH2:5]3)=[CH:11][N:10]=2)=[O:14])([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH3:32])[CH2:23][CH2:22]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2(O)COC2)cn1
Reactant: Cc1nc(C(C)(N)CC2CC2)no1
Product: Cc1nc(C(C)(CC2CC2)NC(=O)c2cc(OCC(F)(F)F)c(C3(O)COC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3-hydroxyoxetan-3-yl)-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (Example 112d) and 2-Cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (example 66e) as starting materials and isolated (37 mg, 47%); MS (ESI, m/z): 457.5 (M+H+).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@@H:19]([C:21]2[N:25]([CH2:26][CH3:27])[C:24](S(C)(=O)=O)=[N:23][N:22]=2)[CH3:20])(=[O:17])=[O:16])=[CH:11][CH:10]=1.[Cl-].[NH4+].[CH2:34]([OH:37])[CH2:35][CH3:36]>>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@@H:19]([C:21]2[N:25]([CH2:26][CH3:27])[C:24]([O:37][CH2:34][CH2:35][CH3:36])=[N:23][N:22]=2)[CH3:20])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: CCCO
Reactant: CCn1c([C@@H](C)NS(=O)(=O)c2ccc(Cl)cc2)nnc1S(C)(=O)=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCOc1nnc([C@@H](C)NS(=O)(=O)c2ccc(Cl)cc2)n1CC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (12 mg) was added, while cooled with ice, to a dimethylformamide (1.2 ml) solution of the 4-chloro-N-{(1R)-1-[4-ethyl-5-(methylsulfonyl)-4H-1,2,4-triazol-3-yl]ethyl}benzenesulfonamide (Compound 182) (47 mg) obtained in Example 5 and n-propanol (0.027 ml). The mixture was stirred for 30 minutes at room temperature, and then stirred for 2 hours at 100° C. After the reaction mixture was cooled to room temperature, it was added to a saturated aqueous solution (5 ml) of ammonium chloride. The mixture was extracted with ethyl acetate (20 ml×2) and washed with a saturated aqueous solution (20 ml) of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel flash column chromatography using a solvent mixture of methanol and chloroform to obtain Compound 183 (35 mg).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][CH:11]1[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:15][CH2:14][NH:13][C:12]1=[O:28])=[O:9])([CH3:6])([CH3:5])[CH3:4].ClC(Cl)(Cl)S(O[CH2:35][C:36]([F:39])([F:38])[F:37])(=O)=O.ClC(Cl)(Cl)S([O-])(=O)=O>CN(C)C=O>[C:3]([O:7][C:8]([NH:10][CH:11]1[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:15][CH2:14][N:13]([CH2:35][C:36]([F:39])([F:38])[F:37])[C:12]1=[O:28])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CCNC1=O
Agent: O=S(=O)([O-])C(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CCN(CC(F)(F)F)C1=O
Temperature: -35 °C
Reaction time: 0.25 h
Yield: 42 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 180 mg, 4.43 mmol) was added to a solution of benzyl 6-[(tert-butoxycarbonyl)amino]-5-oxo-1,4-diazepane-1-carboxylate (1.34 g, 3.69 mmol) in N,N-dimethylformamide (25 mL) at −35° C. After 15 min, 2,2,2-trifluoroethyl trichloromethanesulfonate (0.911 mL, 5.54 mmol) was added and the reaction was stirred at −35° C. After 2 h, an additional amount of sodium hydride (100 mg, 2.5 mmol) and trichloromethanesulfonate (0.500 mL, 3.04 mmol) were added. After 18 h, the reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was washed with water (3×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (hexanes→30% ethyl acetate/hexanes) gave the title compound (690 mg). MS 446 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH:17]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OC)(C)(C)C.C(O)(C)C>[NH2:17][C:10]1([C:14]([OH:16])=[O:15])[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCC(NC(=O)OCC2c3ccccc3-c3ccccc32)(C(=O)O)C1
Solvent: COC(C)(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCCC(N)(C(=O)O)C1

Procedure:
1-(tert-butoxycarbonyl)-3-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}piperidine-3-carboxylic acid was resolved by chiral HPLC resolution {Merck 50 mm 16 μm Kromasil Chirose 2 No. CT9014, tert-butylmethylether/iso-propanol (90/10). The second eluted enantiomer (800 mg, 1.71 mmol) 1-(tert-butoxycarbonyl)-3-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}piperidine-3-carboxylic acid (Isomer 2) was deprotected using an analogous procedure to that described for the equivalent step in Example 89 to give 3-amino-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (Isomer 2); 1H NMR Spectrum: (D2O) 1.44 (s, 9H); 1.63 (m, 1H); 1.79 (d, 1H); 1.97 (d, 1H); 2.10 (m, 1H); 2.88 (t, 1H); 3.33 (d, 1H); 4.09 (m, 2H).
Reaction SMILES: C([NH:4][CH2:5][CH2:6][N:7]1[C:11]2[N:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[OH:17])(=O)C>Cl>[NH2:4][CH2:5][CH2:6][N:7]1[C:11]2[N:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[OH:17]
Reactant: CC(=O)NCCn1c(O)nc2ccc(Cl)nc21
Agent: Cl
Product: NCCn1c(O)nc2ccc(Cl)nc21
Reaction time: 8 h

Procedure:
11 grams of 1-(2-acetylaminoethyl)-2-hydroxy-6-chloro-7-aza-benzimidazole were stirred for 4 hours with 40 ml of concentrated hydrochloric acid at 80° C. and then allowed to stand overnight at 0° C., the substance crystallized out was recrystallized from methanol. Yield: 5 grams; M.P. of the hydrochloride 310°-312° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[O:24]1[C:28]2=[CH:29][CH:30]=[CH:31][C:32]([C:33](O)=[O:34])=[C:27]2[CH2:26][CH2:25]1>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:33]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]4[O:24][CH2:25][CH2:26][C:27]=34)=[O:34])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cccc2c1CCO2
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3cccc4c3CCO4)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 2,3-dihydro-benzofuran-4-carboxylic acid (WO99/33460). LC-MS (basic): tR=0.88 min; [M+H]+=478.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.C1(N=C=NC2CCCCC2)CCCCC1.[OH:25][C:26]1[C:27]([N+:36]([O-:38])=[O:37])=[C:28]([CH3:35])[CH:29]=[CH:30][C:31]=1C(O)=O.ClCCl>CN(C=O)C>[CH3:1][O:2][C:3](=[O:9])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:31]1[CH:30]=[CH:29][C:28]([CH3:35])=[C:27]([N+:36]([O-:38])=[O:37])[C:26]=1[OH:25]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: Cc1ccc(C(=O)O)c(O)c1[N+](=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCCN1c1ccc(C)c([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
16.5 g of L-proline methyl ester and 27.2 g of N,N'-dicyclohexylcarbodiimide were successively added to an ice-cooled and constantly stirred solution of 25.2 g of 3-hydroxy-2-nitro-p-toluic acid dissolved in a mixture consisting of 480 ml of dichloromethane and 43 ml of N,N'-dimethylformamide. The whole mixture was stirred at ice-cooled temperature for 1 hour and then at room temperature for 1 hour. After the reaction, the separated crystalline precipitate was filtered off, and the filtrate was washed with 10% aqueous hydrochloric acid, 5% aqueous solution of sodium hydrogen carbonate and 5% aqueous solution of sodium carbonate. The layer of 5% aqueous solution of sodium carbonate was acidified with hydrochloric acid and extracted with chloroform. The chloroform layer was dehydrated and concentrated. The residue was recrystallized from 50% ethanol, and there was obtained 32.7 g of 1-(3-hydroxy-2-nitro-p-toluyl)-L-proline methyl ester as yellow-colored prismatic crystal having a melting point of 111° to 113.5° C.
Reaction SMILES: FC1C=CC(CBr)=CC=1.[F:10][C:11]([F:21])([F:20])[C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1.[CH3:22][C:23]1[CH:27]=[C:26]([N:28]2[C:32](=[O:33])[NH:31][N:30]=[CH:29]2)[S:25][C:24]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH3:22][C:23]1[CH:27]=[C:26]([N:28]2[C:32](=[O:33])[N:31]([CH2:16][C:15]3[CH:18]=[CH:19][C:12]([C:11]([F:21])([F:20])[F:10])=[CH:13][CH:14]=3)[N:30]=[CH:29]2)[S:25][C:24]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)cc1C
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: Fc1ccc(CBr)cc1
Product: CCOC(=O)c1sc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)cc1C
Yield: 94 %

Procedure:
Following the procedure as described in Example 29, making variations as required to replace 4-fluorobenzyl bromide with 4-(trifluoromethyl)benzyl bromide to react with ethyl 3-methyl-5-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiophene-2-carboxylate, the title compound was obtained as a yellowish solid in 94% yield: 1H NMR (300 MHz, CDCl3) δ 7.75 (s, 1H), 7.62 (d, J=8.1 Hz, 2H), 7.51 (d, J=8.1 Hz, 2H), 6.95 (s, 1H), 5.07 (s, 2H), 4.32 (q, J=7.1 Hz, 2H), 2.55 (s, 3H), 1.36 (t, J=7.1 Hz, 3H); MS (ES+) m/z 412.2 (M+1).