Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[C:14]([N:15]2[CH2:19][CH:18]([C:20]([OH:22])=O)[N:17]([CH3:23])[C:16]2=[O:24])=[CH:13][CH:12]=[CH:11][N:10]=1.C(N1CCOCC1)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl:56][C:57]1[CH:62]=[C:61]([Cl:63])[CH:60]=[CH:59][C:58]=1[CH2:64][NH2:65]>ClCCl>[Cl:56][C:57]1[CH:62]=[C:61]([Cl:63])[CH:60]=[CH:59][C:58]=1[CH2:64][NH:65][C:20]([CH:18]1[CH2:19][N:15]([C:14]2[C:9]([F:8])=[N:10][CH:11]=[CH:12][CH:13]=2)[C:16](=[O:24])[N:17]1[CH3:23])=[O:22]
Reactant: CN1C(=O)N(c2cccnc2F)CC1C(=O)O
Reactant: NCc1ccc(Cl)cc1Cl
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)N(c2cccnc2F)CC1C(=O)NCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.4 %

Procedure:
To a solution of 1-(2-fluoro-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylic acid TFA salt (182 mg, 0.761 mmol) and N-ethylmorpholine (0.578 ml, 4.57 mmol) in dichloromethane (5 ml) was added 1-hydroxybenzotriazole hydrate (117 mg, 0.761 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (146 mg, 0.761 mmol) and the reaction mixture was stirred for 10 minutes at room temperature. 1-(2,4-Dichlorophenyl)methanamine (134 mg, 0.761 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and the solution was washed with saturated sodium hydrogen carbonate solution, water and brine, separated through a hydrophobic frit and the organic layer was reduced under vacuum. The residue was purified by SP4 automated silica gel chromatography eluting with 10-100% ethyl acetate in isohexane to give N-[(2,4-dichlorophenyl)methyl]-1-(2-fluoro-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxamide (125 mg, 40.5% yield)
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH3:27][O:28][C:29]1[CH:30]=[N:31][CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1.C(=O)(O)[O-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O.COCCOC>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:33]2[CH:32]=[N:31][CH:30]=[C:29]([O:28][CH3:27])[CH:34]=2)[CH:3]=1)=[O:15]
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: COc1cncc(-c2cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c3cnn(C(C)C)c3n2)c1
Temperature: 25 °C

Procedure:
To a 20 mL microwave vial were sequentially added 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (100 mg, 0.267 mmol, 3-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (69.2 mg, 0.294 mmol), PdCl2(dppf)-CH2Cl2 adduct (21.84 mg, 0.027 mmol), (DME) (5 mL), and water (2 mL). The reaction mixture was degassed with nitrogen for 5 min. Sodium bicarbonate (67.4 mg, 0.802 mmol) was added and the contents sealed and irradiated (microwave) at 140° C. The reaction mixture was cooled to room temperature and poured on a silica column (through Na2SO4) and purified by silica gel chromatography (eluent: 5% MeOH/CH2Cl2) which provided the desired product as an off-white solid after preciptation from EtOAc/MeOH. The final product was collected as 0.090 g (76%). LCMS E-S (M+H) 447.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.57 (s., 1H), 9.06 (d, J=1.52 Hz, 1H), 8.92-9.00 (m, 1H), 8.39-8.48 (m, 2H), 8.24 (s, 1H), 8.14 (d, J=1.77 Hz, 1H), 5.91 (s, 1H), 5.30-5.45 (m, 1H), 4.42 (d, J=4.80 Hz, 2H), 3.97 (s, 3H), 2.24 (s, 3H), 2.13 (s, 3H), 1.55 (d, J=6.82 Hz, 6H).
Reaction SMILES: [NH:1]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C@H:2]([C:18]([O:20]N1C(=O)CCC1=O)=O)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[NH2:38][C@H:39]([C:42]([O:44][CH3:45])=[O:43])[CH2:40][OH:41].Cl.C(N(CC)CC)C>O1CCCC1.CN(C=O)C>[NH:1]([C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:29])[C@H:2]([C:18]([NH:38][C@H:39]([C:42]([O:44][CH3:45])=[O:43])[CH2:40][OH:41])=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=C(NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O)OCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CO)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 78.8 %

Procedure:
To a solution of Z-Lys(Z)OSu (1.50 g, 2.93 mmole) (see Chladek et al. Collect. Czechr. Chem. Commun. 33: 4299 (1968)) in tetrahydrofuran (15 ml), a solution of H-Ser-OMe-HCl (0.46 g, 2.93 mmole) in N,N'-dimethylformamide (10 ml) containing triethylamine (0.41 ml) was added with stirring at 0° C. The mixture was stirred at 0° C. for 2 hr. and at room temperature for 15 hr. After removal of the solvent, the residue was dissolved in three portions of ethyl acetate, which were washed successively with 1N citric acid, sat. NaHCO3 solution and sat. NaCl solution, and dried over Na2SO4. After evaporating, the residue was solidified by addition of ether and reprecipitated from methanol-ether to yield (IV) (1.19 g, 78.8%). RfI 0.88, RfII 0.86 mp 120°-121° C., [α]D29 -7.8 (C=1.03 methanol)
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]=[C:6](S(C)(=O)=O)[N:5]=1)([CH3:3])[CH3:2].O1CCOCC1.[CH2:25]1[CH:29]2[CH2:30][CH:31]([NH2:32])[CH:27]([CH2:28]2)[CH2:26]1>O>[C@H:27]12[CH2:28][C@H:29]([CH2:25][CH2:26]1)[CH2:30][C@H:31]2[NH:32][C:6]1[N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]=1
Reactant: NC1CC2CCC1C2
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1C(C)C
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(N[C@@H]2C[C@H]3CC[C@@H]2C3)nc1C(C)C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
To a mixture of ethyl 4-isopropyl-2-(methylsulfonyl)pyrimidine-5-carboxylate (500 mg) and 1,4-dioxane (10 mL) was added exo-2-aminonorbornane (612 mg) at room temperature, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture was added water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain ethyl rac-2-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]-4-isopropylpyrimidine-5-carboxylate (470 mg) as a white solid.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][Br:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[CH2:32][O:33][CH3:34].Cl>C1COCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:20])[C@@H:15]([CH2:32][O:33][CH3:34])[CH2:16][CH2:17][CH2:18][Br:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCl
Reactant: O=C(CCCCBr)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@@H](CCCBr)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -10 °C
Reaction time: 48 h
Yield: 23.5 %

Procedure:
To a solution (S)-4-benzyl-3-(5-bromopentanoyl)oxazolidin-2-one (4.00 g, 1 eq.) and THF (100 ml) was added NaHMDS (1 M in THF, 53 ml, 4.5 eq.) at −78° C. After 30 min chloro(methoxy)methane (12.3 g, 13 eq.) was added dropwise. The reaction mixture was stirred at −10° C. for 2 days. Concentrated aqueous HCl solution was carefully added. The resulting mixture was concentrated and extracted with EtOAc. The organic layers were dried over MgSO4 and concentrated. Silica gel chromatography using 60-80% DCM-heptane yields the title compound (1.06 g, 23%).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:22][NH:23][C:24]([CH3:27])([CH3:26])[CH3:25]>>[C:24]([N:23]([CH3:22])[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)([CH3:27])([CH3:26])[CH3:25]
Reactant: CNC(C)(C)C
Reactant: O=C1NCCc2[nH]c(-c3cccc4ncc(F)nc34)cc21
Product: CN(c1cnc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1)C(C)(C)C
Temperature: 120 °C
Yield: 72 %

Procedure:
Prepared similarly to that described in Example 210 using 2-(3-fluoroquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 210i; 73 mg, 0.259 mmol) and N,2-dimethylpropan-2-amine (93 μl, 0.776 mmol, Fluka) and heating at 120° C. for 7 h. Purification by silica gel (100% DCM to 4% MeOH/DCM) provided 2-(3-(tert-butyl(methyl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (72% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56 (s, 9H) 2.87 (t, J=6.94 Hz, 2H) 3.26 (s, 3H) 3.44 (td, J=6.80, 2.45 Hz, 2H) 6.95 (br. s., 1H) 7.07 (d, J=2.35 Hz, 1 H) 7.44 (t, J=7.82 Hz, 1H) 7.70 (dd, J=8.02, 1.17 Hz, 1H) 7.90 (dd, J=7.43, 1.37 Hz, 1H) 8.75 (s, 1H) 11.78 (br. s., 1H). MS (ESI, pos. ion) m/z: 350.1 (M+1).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([CH3:25])[C:22]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:21][C:20]=2[CH3:31])=[CH:15][CH:14]=1.[CH3:32]I.[Cl-].[NH4+]>O1CCCC1>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[C:23]([CH3:25])[C:22]([CH:26]([CH3:32])[C:27]([O:29][CH3:30])=[O:28])=[CH:21][C:20]=2[CH3:31])=[CH:17][CH:18]=1
Reactant: COC(=O)Cc1cc(C)c(-c2ccc(OC)cc2)cc1C
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C)c1cc(C)c(-c2ccc(OC)cc2)cc1C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
After a lithium bis(trimethylsilyl)amide 1.0M-tetrahydrofuran solution (3.86 ml, 3.86 mmol) was added to a solution of methyl (4′-methoxy-2,5-dimethyl-1,1′-biphenyl-4-yl)acetate (730 mg, 2.57 mmol) obtained in Example (105-1) in tetrahydrofuran (6 ml) at −78° C., methyl iodide (800 μl, 12.9 mmol) was added dropwise thereto and the mixture was stirred for 1 hour. A saturated aqueous ammonium chloride solution was poured into the reaction mixture and the mixture was extracted with ethyl acetate (twice). The organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=95/5-15/1) to give methyl 2-(4′-methoxy-2,5-dimethyl-1,1′-biphenyl-4-yl)propanoate as a colorless oil (620 mg, 81%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([CH2:16][C:17]([OH:19])=[O:18])[CH2:15][O:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1)=[O:23].C(N(CC)CC)C>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1([CH2:16][C:17]([O:19][CH2:21][C:22](=[O:23])[C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([F:32])([F:33])[F:34])=[CH:26][CH:25]=2)=[O:18])[CH2:13][O:14][CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC1(NC(=O)OCc2ccccc2)COC1
Reactant: O=C(CBr)c1ccc(OC(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(CC1(NC(=O)OCc2ccccc2)COC1)OCC(=O)c1ccc(OC(F)(F)F)cc1
Yield: 106.9 %

Procedure:
(3-{[(Benzyloxy)carbonyl]amino}oxetan-3-yl)acetic acid (Preparation 25, 1.011 Kg, 3.812 mol) was stirred in ethyl acetate (8 L). 2-Bromo-1-[4-(trifluoromethoxy)phenyl]-ethanone (1.08 Kg, 3.81 mol) was added, followed by triethylamine (585 mL, 4.19 mol). The reaction was initially fully solubilised, but a precipitate was then observed. The reaction was washed with water (2×4 L), then concentrated in vacuo to afford the title compound as a mobile orange oil (1.903 Kg, 107%, contains residual ethyl acetate).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3]1.Cl.[F:11][CH2:12][CH2:13][NH:14][CH3:15]>>[F:11][CH2:12][CH2:13][N:14]([CH3:15])[C:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:9]
Reactant: Cn1cc(C(=O)O)cn1
Reactant: CNCCF
Agent: Cl
Product: CN(CCF)C(=O)c1cnn(C)c1

Procedure:
From 1-methyl-1H-pyrazole-4-carboxylic acid (1.0 g, 7.93 mmol) and 2-fluoro-N-methylethanamine hydrochloride (991 mg, 8.72 mmol). Yellow oil (1.41 g, 92%).
Reaction SMILES: O[C@H](C(C)C)[C@@H](N([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)C(OC)=O)C(O)=O.O[C@@H:28]([CH:50]([CH3:52])[CH3:51])[C@@H:29]([N:33]([C:38]1C=CC(C2C=CC=CC=2)=CC=1)[C:34]([O:36]C)=[O:35])[C:30]([OH:32])=[O:31].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:18]1([C:15]2[CH:14]=[CH:13][C:12]([O:36][C:34](=[O:35])[N:33]([CH3:38])[C@H:29]3[C:30](=[O:32])[O:31][C@@H:28]3[CH:50]([CH3:52])[CH3:51])=[CH:17][CH:16]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)N(c1ccc(-c2ccccc2)cc1)[C@@H](C(=O)O)[C@H](O)C(C)C
Reactant: COC(=O)N(c1ccc(-c2ccccc2)cc1)[C@@H](C(=O)O)[C@@H](O)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@H]1OC(=O)[C@@H]1N(C)C(=O)Oc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 17 %

Procedure:
Under nitrogen atmosphere, to a stirred mixture of (2R*,3R*)-3-hydroxy-4-methyl-2-[(4-phenylphenyl)-methoxy-carbonylamino]-pentanoic acid and (2R*,3S*)-3-hydroxy-4-methyl-2-[(4-phenylphenyl)-methoxy-carbonylamino]-pentanoic acid (0.059 g, 0.17 mmol) in dry CH2Cl2 (7.0 mL), at 0° C., Et3N (0.07 mL, 0.5 mmol) and subsequently TBTU (0.065 g, 0.2 mmol) were added. The mixture was left stirring at 0° C. for 1 h and at rt for 15 h. The organics were then removed under reduced pressure, and the resulting crude product purified by column chromatography, using a Teledyne ISCO apparatus, eluting with Cy:AcOEt (from 90:10 to 80:20) to afford the pure title compound (0.01 g, 17%), as pure anti diastereoisomer, as white solid. MS (ESI) m/z: 357 [M−NH4]+; (ESI) m/z: 338 [M−H]−. 1H NMR (DMSO-d6) δ 0.89 (d, J=6.79 Hz, 3H), 0.97 (d, J=6.57 Hz, 3H), 1.81-2.12 (m, 1H), 4.26 (dd, J=4.38, 9.11 Hz, 1H), 4.80 (dd, J=4.39, 8.16 Hz, 1H), 5.12 (s, 2H), 7.29-7.54 (m, 5H), 7.63-7.77 (m, 4H), 8.26 (d, J=8.21 Hz, 1H).
Reaction SMILES: [Si]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][C@@:25]([CH:44]2[CH2:46][CH:45]2[C:47]([OH:49])=[O:48])([CH3:43])[C:24]1=[O:50])[CH2:21][CH3:22])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:42][C:38]1[CH:37]=[C:36]([C@@H:27]2[C@@H:28]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[N:23]([C@@H:20]([CH2:21][CH3:22])[CH2:19][OH:18])[C:24](=[O:50])[C@:25]([CH:44]3[CH2:46][CH:45]3[C:47]([OH:49])=[O:48])([CH3:43])[CH2:26]2)[CH:41]=[CH:40][CH:39]=1
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)[C@@](C)(C2CC2C(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC[C@@H](CO)N1C(=O)[C@@](C)(C2CC2C(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of the acid from Example 248, Step F (10 mg, 0.014 mmol) in THF (0.2 mL) was added TBAF (0.1 mL, 1.0 M solution in THF). After 30 minutes more TBAF (0.1 mL, 1.0 M solution in THF) was added and the reaction was stirred at rt for 3 hours. After this time the reaction was partitioned between EtOAc (30 mL) and 1M aqueous HCl (5 mL). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo. The resulting residue was purified by reverse phase HPLC (Sunfire Prep C18 OBD 10 μm column, gradient elution of 20% MeCN in water to 80% MeCN in water over a 30 min period, where both solvents contain 0.1% TFA) to give the title compound.
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]([OH:17])[C@@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.C1C=CC2N(O)N=NC=2C=1.[NH:28]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:29]([C:31]([NH:33][C@H:34]([C:38](O)=[O:39])[CH:35]([CH3:37])[CH3:36])=[O:32])[CH3:30]>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]([OH:17])[C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:38](=[O:39])[C@H:34]([CH:35]([CH3:37])[CH3:36])[NH:33][C:31](=[O:32])[C@H:29]([CH3:30])[NH:28][C:41]([O:43][C:44]([CH3:47])([CH3:45])[CH3:46])=[O:42]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)O
Reactant: OC(c1nc2ccccc2s1)[C@@H]1CCCN1
Agent: Cl
Agent: On1nnc2ccccc21
Product: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(O)c1nc2ccccc2s1

Procedure:
36 (0.43 g, 1.23 mmol), HOBt (0.183 g, 1.35 mmol), WSCD (0.259 g, 1.35 mmol), Boc-Ala-Val-OH (0.35 g, 1.23 mmol), TEA (0.172 ml, 1.54 mmol)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH2:10])=[O:4].[O:17]1[CH2:21][CH2:20][C@H:19]([O:22][CH:23]2[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]2)[CH2:18]1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH:10][C@H:26]1[CH2:25][CH2:24][C@H:23]([O:22][CH:19]2[CH2:20][CH2:21][O:17][CH2:18]2)[CH2:28][CH2:27]1)=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N
Reactant: O=C1CCC(O[C@H]2CCOC2)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N[C@H]1CC[C@H](OC2CCOC2)CC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 3-amino-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (2.41 g, 10.2 mmol), 4-(tetrahydro-furan-3(S)-yloxy)-cyclohexanone (1.6 g, 8.5 mmol), TFA (2.6 mL, 34 mmol) and triethylsilane (2.7 mL, 17 mmol) in CH2Cl2 (12 mL) was stirred for 22 h at room temperature. The reaction was concentrated in vacuo and the crude oil was dissolved in toluene (50 mL) and concentrated (repeat) to give a yellow solid. The crude solid was purified by column chromatography (10-25% ethyl acetate/hexanes) to give 5-(3,3-dimethyl-but-1-ynyl)-3-[4-(tetrahydro-furan-3-yloxy)-trans-cyclohexylamino]-thiophene-2-carboxylic acid methyl ester (1.09 g, 2.69 mmol) as a single isomer.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Br[C:26]1[C:31]([F:32])=[CH:30][C:29]([F:33])=[CH:28][N:27]=1>>[F:32][C:31]1[C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[O:11])=[N:27][CH:28]=[C:29]([F:33])[CH:30]=1
Reactant: Fc1cnc(Br)c(F)c1
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(F)cc2F)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone and 2-bromo-3,5-difluoropyridine. MS (ESI) 438 (M+H).
Reaction SMILES: [N:1]1([C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22](O)=[O:23])=[CH:16][CH:15]=2)=[O:13])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.S(Cl)(Cl)=O.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>ClCCl>[CH2:29]([NH:36][C:22](=[O:23])[CH2:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]([N:1]2[CH2:7][CH2:6][CH2:5][CH2:4][C:11]3[CH:10]=[CH:9][CH:8]=[CH:3][C:2]2=3)=[O:13])=[CH:19][CH:18]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)CCc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(CCc1ccc(C(=O)N2CCCCc3ccccc32)cc1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
A mixture of 3-[4-(2,3,4,5-tetrahydro-benzo[b]azepine-1-carbonyl)-phenyl]-propionic acid from Example E65.4 (57 mg, 0.18 mmol) and thionyl chloride (0.2 ml, 2.74 mmol) in dichloromethane (6 ml) was heated at reflux for 2 h then volatiles were removed in vacuo. The residue was dissolved in dichloromethane (8 ml) then benzylamine (0.022 ml, 0.20 mmol) and triethylamine (0.05 ml, 0.36 mmol) were added. The mixture was stirred for 3 h at room temperature then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 30% pet. ether:70% EtOAc) to give a white fluffy solid identified as the title compound (36.5 mg, 50%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][C:10]#[N:11])[CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:17]>C(Cl)Cl>[CH3:1][S:2]([C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][C:10]#[N:11])[CH:4]=1)=[O:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cc(CC#N)ncn1
Solvent: ClCCl
Product: CS(=O)c1cc(CC#N)ncn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.8 %

Procedure:
To a suspension of [6-(methylthio)-4-pyrimidinyl]acetonitrile (Intermediate 15, 292 mg, 1.767 mmol) in DCM (15 mL) was added 3-chloroperoxybenzoic acid (457 mg, 2.65 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and kept stirring for 3 hours. The reaction mixture was quenched with saturated sodium thiosulfate solution (10 mL) and vigorously stirred for 30 minutes, then treated with DCM (75 mL). The reaction mixture was partitioned between DCM and water. The organic layer was washed with saturated ammonium carbonate solution, water and brine sequentially, then dried over sodium sulfate, concentrated under pressure to give the title compound as a brown solid (150 mg);
Reaction SMILES: FC1C=C(F)C=CC=1C1C=C(COS(C)(=O)=O)C(=O)N(CC(C)C)N=1.[F:26][C:27]1[CH:28]=[C:29]([C:35]2[CH:36]=[C:37]([C:52]([O:54]C)=[O:53])[C:38](=[O:51])[N:39]([CH2:41][CH2:42][CH2:43][C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=3)[N:40]=2)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34]>>[C:52]([C:37]1[C:38](=[O:51])[N:39]([CH2:41][CH2:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)[N:40]=[C:35]([C:29]2[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:27]([F:26])[CH:28]=2)[CH:36]=1)([OH:54])=[O:53]
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(CCCc2ccc(F)cc2)c1=O
Agent: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(COS(C)(=O)=O)c1=O
Product: COc1ccc(-c2cc(C(=O)O)c(=O)n(CCCc3ccc(F)cc3)n2)cc1F
Yield: 89.2 %

Procedure:
Following the procedure of Example 1 (7), 6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-methoxycarbonyl-2H-pyridazin-3-one was reacted to yield the title compound as a yellow powder (yield: 89.2%).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C1COCC1>[CH3:14][S:15]([O:4][CH2:3][C@@H:2]([CH3:1])[CH2:5][CH3:6])(=[O:17])=[O:16]
Reactant: CC[C@H](C)CO
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@H](C)COS(C)(=O)=O
Temperature: -10 °C
Reaction time: 2 h

Procedure:
To a −25° C. cooled solution of (2S)-2-methylbutan-1-ol (8.8 g) and triethylamine (30 ml) in THF (50 ml), a solution of methanesulfonyl chloride (1.14 g) in THF (10 ml) was drop wise added. After complete addition (15 min) the reaction mixture was further stirred for 2 h at −10° C. then for 30 min at 0° C. It was then filtered over celite and evaporated to dryness to give nearly pure (2S)-2-methylbutyl methanesulfonate as yellowish oil.