Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[OH:3][CH2:4][C:5]([NH:7][NH:8][C:9]1[N:10]=[N:11][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:13]([CH3:15])[N:14]=1)=[O:6]>CO>[OH:3][CH2:4][C:5]([NH:7][NH:8][C:9]1[NH:10][N:11]=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]([CH3:15])[N:14]=1)=[O:6]
Reactant: Cc1nc(NNC(=O)CO)nnc1-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1N=C(NNC(=O)CO)NN=C1c1ccccc1
Reaction time: 1.5 h
Yield: 37.9 %

Procedure:
Sodium borohydride (0.494 ) was added portionwise to a stirred solution of 3-(2-hydroxyacetylhydrazino)-5-methyl-6-phenyl-1,2,4-triazine (1.684 g) in methanol (30 ml) under ice cooling in 10 minutes and the stirring was continued for 1.5 hours at the same temperature. The reaction mixture was evaporated and the residue was dissolved in water. The solution was passed through a column of DIAION HP-20 (Trademark, manufactured by Mitsubishi Chemical Industries Ltd.) (80 ml) and eluted with water and then with methanol. The methanol eluate was evaporated under reduced pressure and the residual solid was recrystallized from methanol to give colorless crystals of 3-(2-hydroxyacetylhydrazino)-5-methyl-6-phenyl-2,5-dihydro-1,2,4-triazine (0.644 g), m.p. 167°~168° C. (decomp.)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[CH:10]([O:18][N:19]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CCO.CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:30])[CH:10]([O:18][NH2:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)C(Cc1ccccc1)ON1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: NOC(Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
To a solution of the compound from Step 6b (10.00 g, 24.94 mmol) in EtOH (150 mL) was added hydrazine monohydrate (2.50 mL, 49.88 mmol) at room temperature. The resulting mixture was stirred for 1 hour at room temperature, diluted with EtOAc (450 mL), washed with saturated NaHCO3, water (300 mL×2) and brine, dried (Na2SO4), filtered and concentrated to afford 6.73 g of crude product, which was purified by flash chromatography (silica gel, CH2Cl2/Hexane=15/1) to provide 5.37 g (80%) of the title compound. 13C NMR (CDCl3): δ171.9, 136.6, 135.4, 129.3, 129.2, 129.1, 128.4, 128.3, 128.2, 128.1, 128.0, 126.6, 83.8, 66.4, 37.3. Step 6d. Preparation of: N-Boc-2-Aminooxy-3-phenyl-propionic acid benzyl ester
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:20][CH:19]=1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: Nc1ccc(F)cc1
Product: O=c1[nH]c2nccc(Nc3ccc(F)cc3)c2c2ccccc12
Yield: 70.8 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 4-fluoroaniline (96 mg, 0.87 mmol) to provide 202 (93 mg, 70% yield) as a white solid. LC-MS (M+H=306, obsd.=306).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:28])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2[N:22]([CH3:27])[CH2:23][C:24]([NH2:26])=O)[CH2:5][CH2:4]1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.C(Cl)Cl.C1COCC1>C([O-])(O)=O.[Na+]>[F:1][C:2]([F:29])([F:30])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:28])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2[N:22]([CH3:27])[CH2:23][C:24]#[N:26])[CH2:5][CH2:4]1
Reactant: CNc1cc(N(C)CC(N)=O)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNc1cc(N(C)CC#N)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-2-[N-methyl-N-aminocarbonylmethyl-amino]-4-methylamino-5-nitro-benzoic acid amide (compound IIIa, 45 mg, 0.104 mmol), Burgess reagent (27 mg, 0.11 mmol, +20 mg after 0.5 h, +15 mg after 2.5 h, +20 mg after 16 h), DCM (2 mL) and THF (2 mL) is stirred for 2.5 h at rt, then for 13.5 h at 40° C. and then for 2 h at reflux. The mixture is diluted with sat aq NaHCO3, extracted with EtOAc and the combined organic phases are dried with Na2SO4, filtered and concentrated and directly used in the next step. Yield: 80 mg. HPLC Rt=1.36 min (method A). MS m/z: 414 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:41])[CH2:13][C:12]2[CH:11]=[C:10]3[N:5]([CH2:6][CH2:7][N:8]([C:15]4[C:20]([CH:21]=[O:22])=[C:19]([C:23]5[N:24]=[C:25]([NH:31][C:32]6[CH:37]=[CH:36][N:35]7[CH:38]=[CH:39][N:40]=[C:34]7[CH:33]=6)[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=5)[CH:18]=[CH:17][N:16]=4)[C:9]3=[O:14])[C:4]=2[CH2:3]1.[BH4-].[Na+]>CO>[OH:22][CH2:21][C:20]1[C:15]([N:8]2[CH2:7][CH2:6][N:5]3[C:4]4[CH2:3][C:2]([CH3:1])([CH3:41])[CH2:13][C:12]=4[CH:11]=[C:10]3[C:9]2=[O:14])=[N:16][CH:17]=[CH:18][C:19]=1[C:23]1[N:24]=[C:25]([NH:31][C:32]2[CH:37]=[CH:36][N:35]3[CH:38]=[CH:39][N:40]=[C:34]3[CH:33]=2)[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=1
Reactant: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CC(C)(C)C5)C3=O)c2C=O)nc(Nc2ccn3ccnc3c2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CC(C)(C)C5)C3=O)c2CO)nc(Nc2ccn3ccnc3c2)c1=O
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 185c (80 mg, 0.146 mmol) in methanol (5 mL) was added NaBH4 (34 mg, 0.90 mmol) at room temperature. After the reaction was stirred for 1 h, LCMS indicated the reaction was complete. The reaction mixture was quenched with water (3 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (3×10 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 185 (49 mg, 61%) as light yellow solid. MS-ESI: [M+H]+ 551. 1H NMR (500 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.57 (d, J=10.5 Hz, 1H), 8.51 (s, 1H), 8.41 (d, J=7.0 Hz, 1H), 7.77 (s, 1H), 7.75 (s, 1H), 7.63 (s, 1H), 7.46 (d, J=6.0 Hz, 1H), 7.42 (s, 1H), 6.59 (s, 1H), 5.04-5.02 (m, 1H), 4.67-4.64 (m, 1H), 4.519-4.481 (m, 1H), 4.31-4.20 (m, 3H), 3.88 (d, J=7.0 Hz, 1H), 3.58 (s, 3H), 2.63-2.55 (m, 2H), 2.44-2.42 (m, 2H), 1.23 (s, 6H).
Reaction SMILES: C([NH:4][C:5]1[C:6]([N+:17]([O-:19])=[O:18])=[C:7]([CH:13]=[CH:14][C:15]=1[Cl:16])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=O)C.S(=O)(=O)(O)O>C(O)C>[NH2:4][C:5]1[C:6]([N+:17]([O-:19])=[O:18])=[C:7]([CH:13]=[CH:14][C:15]=1[Cl:16])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1ccc(Cl)c(NC(C)=O)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)c1ccc(Cl)c(N)c1[N+](=O)[O-]

Procedure:
138.63 g of the mixture from step 3 were dissolved in 1.4 l of ethanol and 60 ml of concentrated sulfuric acid and the solution was boiled at reflux for 25 h. Then 1.3 l of ethanol were removed on a rotary evaporator and the residue was admixed with 1 l of ice-water, rendered basic using saturated NaHCO3 solution, and then extracted with three times 500 ml of dichloromethane. The combined organic phases were dried over MgSO4, filtered with suction over silica gel, and concentrated. The product was then subjected to chromatographic separation (silica gel, heptane/ethyl acetate 9:1).
Reaction SMILES: [NH2:1]/[C:2](/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:3]1\[C:4](=[O:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[S:7]\1.OO.S([O-])([O-])=[O:22].[Na+].[Na+]>C(O)(=O)C>[NH2:1]/[C:2](/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:3]1\[C:4](=[O:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[S:7]\1=[O:22]
Reactant: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: N/C(=C1\C(=O)c2ccccc2S1=O)c1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 30.0 gm (0.118 mol) of (E)-2-[(amino)-phenylmethylene]-benzo[b]thiophen-3(2H)-one, 200 ml of glacial acetic acid and 13.5 gm (0.119 mol) of an aqueous 30% hydrogen peroxide solution was heated at 50° C. for four hours while stirring, and was then allowed to stand overnight at room temperature. After the addition of 100 ml of a 10% sodium sulfite solution, the solvent was largely distilled off in vacuo, and the residue was mixed with 300 ml of water. The solid precipitated thereby was suction-filtered off and recrystallized from ethanol/ethyl acetate (1:1 v/v) using activated charcoal. 23.0 gm (72% of theory) of light yellow crystals were obtained, m.p. 246°-247° C. (decomposition).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([CH3:18])[CH2:16][C:15]2[C:14](=O)[NH:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:40]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH:17]([CH3:18])[CH2:16][C:15]2[C:14]([Cl:40])=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1Cc2c(nc[nH]c2=O)CN1C(=O)OC(C)(C)C
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: CC1Cc2c(Cl)ncnc2CN1C(=O)OC(C)(C)C

Procedure:
A solution of (±)-6-methyl-4-oxo-4,5,6,8-tetrahydro-3H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester, (7.5 g, 28.3 mmol), triphenylphosphine (14.8 g, 56.5 mmol) and carbon tetrachloride (8.2 mL, 85 mmol) in 1,2-DCE (100 mL) is heated at 80° C. for 6 h. At that time the solution is concentrated in vacuo and the residue is separated via FCC (5-60% EtOAc/heptane) to give the title compound. MS (ESI) m/z 284.1 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[C:5]([C:17]([NH2:19])=[O:18])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]([N:30]2[CH2:34][CH:33]=[CH:32][CH2:31]2)=[O:29])[CH:24]=[CH:25][CH:26]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[N:30]1([C:28]([NH:27][C:23]2[CH:22]=[C:21]([NH:20][C:2]3[N:7]=[C:6]([NH:8][C@@H:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH3:10])[C:5]([C:17]([NH2:19])=[O:18])=[CH:4][N:3]=3)[CH:26]=[CH:25][CH:24]=2)=[O:29])[CH2:34][CH:33]=[CH:32][CH2:31]1
Reactant: Nc1cccc(NC(=O)N2CC=CC2)c1
Reactant: CC(Nc1nc(Cl)ncc1C(N)=O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C[C@@H](Nc1nc(Nc2cccc(NC(=O)N3CC=CC3)c2)ncc1C(N)=O)c1ccccc1
Yield: 22.5 %

Procedure:
A mixture of 2-chloro-4-(1-phenylethylamino)pyrimidine-5-carboxamide (2, 27 mg, 0.1 mmoles), N-(3-aminophenyl)-2,5-dihydro-1H-pyrrole-1-carboxamide (3, 34 mg, 0.15 mmoles), Pd(OAc)2 (2 mg). BINAP (15 mg), Cs2CO3 (100 mg) in dioxane (1 mL) was heated at 120° C. under microwave for 60 min. Purification with reversed phase HPLC, (R)-2-(3-(2,5-dihydro-1H-pyrrole-1-carboxamido)phenylamino)-4-(1-phenylethylamino)pyrimidine-5-carboxamide (4, 10 mg) was obtained. MS found for C24H25N7O2 as (M+H)+ 444. UV: λ=248 nm. 1H NMR: (CD3OD) δ 8.35 (s, 1H), 7.85 (s, 1H), 7.3 (m, 4H), 7.2 (m, 3H), 7.05 (d, 1H), 5.95 (s, 2H), 5.4 (dd, 1H), 4.25 (s, 4H), 1.48 (d, 3H).
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([CH:2]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]([OH:5])=[O:4])=[CH:7][CH:8]=1
Reactant: O=C(O)C(Br)c1ccc(Cl)cc1
Reactant: Nc1ccccc1
Solvent: CC#N
Product: O=C(O)C(Nc1ccccc1)c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 99.8 %

Procedure:
2-Bromo-2-(4-chlorophenyl)acetic acid (1.2 g, 4.67 mmol) and aniline (0.85 mL, 9.33 mmol) are dissolved in acetonitrile (29 mL). The reaction is heated under microwave irradiation at 100° C. for 5 minutes. The solvent is evaporated and the residue is dissolved in EtOAc and washed with 3M HCl and then brine. The organic layer is dried over Na2SO4, filtered and evaporated to dryness to give intermediate I258 as a white solid (1.22 g, quantitative yield).
Reaction SMILES: C(Cl)Cl.[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([S:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])([CH2:30][O:31][CH2:32][O:33][CH3:34])[CH2:28][OH:29])=[C:21]([Cl:43])[CH:20]=2)[CH:15]=[CH:16][CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(Br)(Br)(Br)Br.[P:49]([O:54]C)([O:52][CH3:53])[O:50][CH3:51]>O.N1C=CC=CC=1>[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([S:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([NH:35][C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])([CH2:30][O:31][CH2:32][O:33][CH3:34])[CH2:28][O:29][P:49]([O:52][CH3:53])([O:50][CH3:51])=[O:54])=[C:21]([Cl:43])[CH:20]=2)[CH:15]=[CH:16][CH:17]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COP(OC)OC
Reactant: COCOCC(CO)(CCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl)NC(=O)OC(C)(C)C
Agent: BrC(Br)(Br)Br
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COCOCC(CCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl)(COP(=O)(OC)OC)NC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
To a methylene chloride solution (2 mL) containing the compound of Example 219 (860 mg), carbon tetrabromide (533 mg) and pyridine (2 mL), trimethyl phosphite (0.19 mL) was added while the mixture was stirred at 0° C. and the mixture was stirred for 5 hours until room temperature. Subsequently, water was added and the mixture was extracted with ethyl acetate. The extract was washed sequentially with water and a saturated aqueous solution of sodium chloride. The organic phase was then dried over anhydrous sodium sulfate. The solvent was removed by distillation and the residue was purified on a silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the desired product as a colorless oil (830 mg).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14](O)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=O)(C)(C)C.[F:17][C:18]([F:31])([F:30])[C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[NH2:22]>>[NH2:8][C@@H:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:14]([NH:22][C:21]1[CH:20]=[C:19]([C:18]([F:30])([F:31])[F:17])[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=1)=[O:15]
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC(C)C[C@H](N)C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 25.2 %

Procedure:
Using N-(tert-butoxycarbonyl)-L-leucine and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 302(1) gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:38][CH2:39][CH2:40][OH:41])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([NH:17][C@@H:18]([CH2:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:19][N:20]([CH3:30])[C:21](=[O:29])[O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.Cl[C:52]([O:54][C:55]1[CH:60]=[CH:59][C:58]([N+:61]([O-:63])=[O:62])=[CH:57][CH:56]=1)=[O:53]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:38][CH2:39][CH2:40][O:41][C:52]([O:54][C:55]2[CH:56]=[CH:57][C:58]([N+:61]([O-:63])=[O:62])=[CH:59][CH:60]=2)=[O:53])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([NH:17][C@@H:18]([CH2:31][CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]3)[CH2:19][N:20]([CH3:30])[C:21](=[O:29])[O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:28])[CH3:26])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C[C@H](CC1CCCCC1)NC(=O)N1CCC[C@@H]([C@@H](OCCO)c2cccc(Cl)c2)C1)C(=O)OCC[Si](C)(C)C
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C[C@H](CC1CCCCC1)NC(=O)N1CCC[C@@H]([C@@H](OCCOC(=O)Oc2ccc([N+](=O)[O-])cc2)c2cccc(Cl)c2)C1)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2-(trimethylsilyl)ethyl (S)-2-((R)-3-((R)-(3-chlorophenyl)(2-hydroxyethoxy)methyl)piperidine-1-carboxamido)-3-cyclohexylpropyl(methyl)carbamate (0.1880 g, 0.3 mmol, 1.0 equiv), DMAP (0.150 g, 1.2 mmol, 4 equiv), DIEA (1 mL, 6 mmol, 20 equiv), and 4-nitrophenyl chloroformate (0.1346 g, 0.67 mmol, 2.2 equiv) in CH2Cl2 (6 mL) was stirred at rt for 24 h. The reaction mixture was directly used in the next step without further purification. LC-MS (3 min) tR=2.68 min, m/z 777, 775 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:24]=1[CH2:25]Br.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:25][C:24]3[C:23]([Cl:22])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:31])=[C:16]([Cl:21])[CH:15]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(Cl)c1CBr
Reactant: Oc1ccc(C2CN(Cc3ccccc3)CCO2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Clc1cc(C2CN(Cc3ccccc3)CCO2)ccc1OCc1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 102.5 %

Procedure:
A mixture of 4-(4-benzyl-morpholin-2-yl)-2-chloro-phenol (0.50 g; 1.56 mmol), 2,6-dichlorobenzyl bromide (0.39 g; 1.64 mmol) and Cs2CO3 (2.55 g; 7.82 mmol) in CH3CN (20 mL) was heated under reflux overnight. After cooling to RT the resulting mixture was partitioned between EtOAc and water. The layers were separated and the organic layer, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2:MeOH 98:2) to afford 4-benzyl-2-[3-chloro-4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine (0.74 g)
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:33][O:34][C:35]1[N:40]=[CH:39][C:38](B(O)O)=[CH:37][N:36]=1>>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:38]3[CH:37]=[N:36][C:35]([O:34][CH3:33])=[N:40][CH:39]=3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: COc1ncc(B(O)O)cn1
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Product: CCCCCCc1cccc(-c2nc(-c3cnc(OC)nc3)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 7, [2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 2) was reacted with 2-methoxy-pyrimidin-5-yl-boronic acid to give the title compound as yellow oil. MS: 531.5 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH:11]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])[CH:5]=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26][CH2:27][C:28]2[N:29]=[N:30][NH:31][CH:32]=2)=[CH:21][CH:20]=1.[BrH:33].C(O)(C)C>CO.ClCCl>[BrH:33].[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])[CH:5]=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26][CH2:27][C:28]2[NH:29][N:30]=[N:31][CH:32]=2)=[CH:21][CH:20]=1
Reactant: CC(=O)NCC1CN(c2ccc(-c3ccc(CNCc4c[nH]nn4)cc3)c(F)c2)C(=O)O1
Agent: Br
Solvent: CO
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(CNCc4cnn[nH]4)cc3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a suspension of N-[3-(2-Fluoro-4′-{[(1H-[1,2,3]triazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide (20 mg, 0.046 mmol) in 1:1 methanol/dichloromethane (0.6 mL) was added dropwise 0.5 M hydrobromic acid in isopropanol (0.28 mL, 0.14 mmol). The reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, acetonitrile (0.6 mL) was added and the resulting slurry stirred at room temperature overnight. The solid was filtered and dried to give the title compound (0.6 g, 98%) as a solid which was characterized by XRPD. FIG. 3 shows a characteristic X-ray powder diffraction (XRPD) pattern of amorphous N-{[(5S)-3-(2-fluoro-4′-{[(1H-1,2,3-triazol-5-ylmethyl)amino]methyl}biphenyl-4-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide monohydrobromide.
Reaction SMILES: [N+:1]([C:4]1[C:62]([CH3:63])=[CH:61][CH:60]=[CH:59][C:5]=1[CH2:6][N:7]1[CH2:11][CH2:10][N:9]([C@@H:12]([C:54]([CH3:57])([CH3:56])[CH3:55])[C:13]([NH:15][C@@H:16]([CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:17]([OH:46])[CH2:18][C@@H:19]([NH:33][C:34]([C@@H:36]([NH:41][C:42](=[O:45])[O:43][CH3:44])[C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[CH:23][CH:22]=2)=[O:14])[C:8]1=[O:58])([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[C:62]([CH3:63])=[CH:61][CH:60]=[CH:59][C:5]=1[CH2:6][N:7]1[CH2:11][CH2:10][N:9]([C@@H:12]([C:54]([CH3:55])([CH3:56])[CH3:57])[C:13]([NH:15][C@@H:16]([CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:17]([OH:46])[CH2:18][C@@H:19]([NH:33][C:34]([C@@H:36]([NH:41][C:42](=[O:45])[O:43][CH3:44])[C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[CH:23][CH:22]=2)=[O:14])[C:8]1=[O:58]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccc(C)c2[N+](=O)[O-])C1=O)C(C)(C)C)C(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccc(C)c2N)C1=O)C(C)(C)C)C(C)(C)C
Yield: 82.6 %

Procedure:
A solution of Example 141E (64 mg, 0.074 mmol) in ethanol (2 mL) was treated with 10% Pd/C (23.6 mg, 0.022 mmol) with a hydrogen balloon at 25° C. for 16 h. The catalyst was filtered through Celite®, rinsed with ethanol, and the solvents were evaporated. The crude residue was purified using reverse phase chromatography eluting with a gradient of 95% water (0.1% trifluoroacetic acid)/5% acetonitrile to 100% acetonitrile to give the title compound (0.051 g, 83%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.83(s, 9H), 0.87(s, 9H), 1.58-1.49(m, 2H), 2.12(s, 3H), 2.23-2.12(m, 1H), 2.61-2.54(m, 1H), 2.66-2.64(d, J=7.35 Hz, 2H), 2.88-2.81(m, 2H), 3.02-2.93(q, J=8.58 Hz, 1H), 3.18-3.12(m, 1H), 3.48(s, 3H), 3.69-3.65(m, 1H), 3.86-3.82(d, J=9.93 Hz, 1H), 4.05(s, 1H), 4.33-4.13(m, 4H), 6.65-6.58(m, 2H), 6.99-6.90(m, 4H), 7.08-7.05(d, J=7.72 Hz, 2H), 7.28-7.25(d, J=8.46 Hz, 2H), 7.37-7.33(d, J=9.93 H, 1H), 7.46-7.42(m, 1H), 7.90-7.83(m, 2H), 8.03-7.90(m, 2H), 8.69-8.67(d, J=4.78 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][O:20][CH3:21])[C:14]3=[O:22])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.Br[CH2:24]/[CH:25]=[CH:26]/[C:27]1[S:28][C:29]([Cl:32])=[CH:30][CH:31]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH2:24][CH:25]=[CH:26][C:27]4[S:28][C:29]([Cl:32])=[CH:30][CH:31]=4)[C@@H:15]([CH2:19][O:20][CH3:21])[C:14]3=[O:22])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COCC1NCCN(Cc2ccc3c(N)ncnc3c2)C1=O
Reactant: Clc1ccc(/C=C/CBr)s1
Product: COC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1CC=Cc1ccc(Cl)s1

Procedure:
The title compound is prepared as described in EXAMPLE 278 using 1-(4-amino-quinazoline-7-ylmethyl)-3-methoxymethyl-piperazine-2-one, EXAMPLE 75 and 2-(3-bromo-(E)-propenyl)-5-chloro-thiophene EXAMPLE 17. 1H NMR (d6-DMSO, 300 MHz) δ9.74 (bs, 2H), 8.80 (s, 1H), 8.38 (d, 1H), 7.69 (m, 2H), 7.02 (dd, 1H), 6.84 (d, 1H), 6.02 (m, 1H), 4.76 (AB, 2H), 3.86 (m, 4H), 3.30 (s, 3H), 3.23 (m, 2H), 3.02 (m, 2H). MS (ion spray), m/z, 458, 460, (M+H) (Cl pattern). Elemental analysis, cal C22H24ClN5O2S.2C2HF3O2.1.45H2O % C=43.85, % H=4.09, % N=9.83; found % C=43.92, % H=3.61, % N=9.63.