Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8]([C@@:10]23[CH2:25][C@H:24]2[CH2:23][C:22]([F:27])([F:26])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]([NH:28]C(=O)OC(C)(C)C)[C:15](=[O:36])[N:14]2[CH2:37][C@H:38]([O:40][C:41]4[CH:50]=[N:49][C:48]5[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=5)[N:42]=4)[CH2:39][C@H:13]2[C:12](=[O:51])[NH:11]3)=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[ClH:52]>C(OCC)(=O)C>[NH2:28][C@@H:16]1[C:15](=[O:36])[N:14]2[CH2:37][C@H:38]([O:40][C:41]3[CH:50]=[N:49][C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[N:42]=3)[CH2:39][C@H:13]2[C:12](=[O:51])[NH:11][C@:10]2([C:8]([NH:7][S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:6])=[O:5])=[O:9])[CH2:25][C@H:24]2[CH2:23][C:22]([F:26])([F:27])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[ClH:52]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCCC(F)(F)C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](Oc3cnc4ccccc4n3)CN2C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@H]1CCCCCC(F)(F)C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](Oc3cnc4ccccc4n3)CN2C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To tert-butyl (2R,6S,13aS,14aR,16aS)-14a-(cyclopropylsulfonylcarbamoyl)-12,12-difluoro-5,16-dioxo-2-(quinoxalin-2-yloxy)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate (Example 1, 8.81 mg, 0.012 mmol) was added ethyl acetate (60 μl) followed by HCl (4 N in dioxane, 60 μl, 0.240 mmol). The solution was stirred at room temperature for 4 hr (a solid appeared), and LC/MS showed completion. The reaction mixture was concentrated to give the title compound (2R,6S,13aS,14aR,16aS)-6-amino-N-(cyclopropylsulfonyl)-12,12-difluoro-5,16-dioxo-2-(quinoxalin-2-yloxy)octadecahydrocyclo propa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide, hydrochloric acid (8.05 mg, quantitative yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]([N:12]([CH2:30][CH:31]([CH3:33])[CH3:32])[C@@H:13]3[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][C@H:15]([C:26]([O:28]C)=[O:27])[CH2:14]3)=[O:11])[N:7]([CH2:34][CH2:35][CH2:36][CH2:37][O:38][CH3:39])[C:6]=2[CH:40]=1.[OH-].[Na+].Cl>C(O)C>[C:22]([O:21][C:19]([N:17]1[CH2:18][C@@H:13]([N:12]([C:10]([C:8]2[N:7]([CH2:34][CH2:35][CH2:36][CH2:37][O:38][CH3:39])[C:6]3[CH:40]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)=[O:11])[CH2:30][CH:31]([CH3:32])[CH3:33])[CH2:14][C@@H:15]([C:26]([OH:28])=[O:27])[CH2:16]1)=[O:20])([CH3:24])([CH3:25])[CH3:23]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C2)nc2ccc(F)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2ccc(F)cc21
Temperature: 50 °C
Reaction time: 5 h
Yield: 99.4 %

Procedure:
1-tert-Butyl 3-methyl(3R,5S)-5-[{[6-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (1.6 g) was dissolved in ethanol (100 ml), 2M aqueous sodium hydroxide solution (14.2 ml) was added, and the mixture was stirred at 50° C. for 5 hr. The reaction mixture was cooled to room temperature, adjusted to pH 7 with 1M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (1.55 g).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]([CH:22]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:23]([O:25]CC)=[O:24])[CH:13]=[C:14]([Cl:21])[C:15]=3[O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:7]=[CH:6][C:5]=12.CO.O.O[Li].O>C1COCC1>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]([CH:22]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:23]([OH:25])=[O:24])[CH:13]=[C:14]([Cl:21])[C:15]=3[O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:7]=[CH:6][C:5]=12
Reactant: CCOC(=O)C(CC(C)C)c1cc(Cl)c(OCC2CC2)c(-c2ccc3nonc3c2)c1
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC(C(=O)O)c1cc(Cl)c(OCC2CC2)c(-c2ccc3nonc3c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
To a stirred solution of ethyl 2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (0.25 g, 0.565 mmol) in a mixture of THF (10 mL), methanol (10 mL) and water (5 mL) was added LiOH.H2O (118.7 mg, 2.828 mmol) at room temperature and the mixture was stirred at RT for 2 h. After complete consumption of starting material as monitored by TLC, the reaction mixture was diluted with water (10 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×20 mL); combined organic extracts were washed with water (10 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material was purified by column chromatography to afford compound-2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoic acid (152 mg) as an off white solid. 1HNMR (500 MHz) (CDCl3): δ (ppm) 7.92 (s, 1H), 7.85 (m, 1H), 7.72 (m, 1H), 7.46 (s, 1H), 7.25 (s, 1H), 3.65 (t, 1H), 3.48 (d, 2H), 1.95 (m, 1H), 1.65 (m, 1H), 1.55 (m, 1H), 1.22 (m, 1H0, 0.93 (d, 6H), 0.39 (d, 2H), 0.0 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].C(N(CC)CC)C.P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH:16][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1]
Reactant: COc1cccc(N)c1
Reactant: Cc1ccccc1C(=O)O
Solvent: ClP(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cccc(NC(=O)c2ccccc2C)c1
Yield: 95 %

Procedure:
A 13.6 g (0.1 mol) portion of o-methylbenzoic acid, 10.9 g (0.1 mol) of m-methoxyaniline and 10.1 g (0.1 mol) of triethylamine were dissolved in 250 ml of toluene. A 4.6 g (0.033 mol) amount of phosphorus trichloride was added dropwise to the above solution with stirring at 20°-60° C. After the addition, the reaction mixture was stirred at 80°-90° C for 3 hours. The reaction mixture was cooled and washed with water to remove the triethylamine hydrochloride, and the product was dried over anhydrous sodium sulfate. The toluene was removed to give 22.8 g (95%) of fine white prismatic crystals having a melting point of 142°-143° C.
Reaction SMILES: C(O[CH:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:18])[CH3:17])=[C:11]([O:19][CH2:20][CH3:21])[CH:10]=1)[C:6]([OH:8])=[O:7])(=O)C.O>CO.[OH-].[OH-].[Pd+2]>[C:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:5][C:6]([OH:8])=[O:7])=[CH:10][C:11]=1[O:19][CH2:20][CH3:21])(=[O:18])[CH3:17]
Reactant: CCOc1cc(C(OC(C)=O)C(=O)O)ccc1OC(C)=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOc1cc(CC(=O)O)ccc1OC(C)=O
Yield: 88.8 %

Procedure:
Intermediate 3 (30.9 g, 0.104 mol) was dissolved in methanol (500 mL), Pd(OH)2 (5.0 g) wet with distilled water was added, and the mixture was placed under hydrogen at 30 psi with shaking. After 48 hr Pd(OH)2 was removed by filtration and solvent was removed under vacuum giving 22 g of intermediate 4 as a yellow oil.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:8]([C:9]2[CH:10]=[C:11]([NH:23]C(=O)C)[CH:12]=[CH:13][C:14]=2[O:15][CH2:16][C:17]([CH3:22])([N+:19]([O-:21])=[O:20])[CH3:18])=[CH:7][CH:6]=[N:5]1>O.CO>[CH3:3][N:4]1[C:8]([C:9]2[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=2[O:15][CH2:16][C:17]([CH3:22])([N+:19]([O-:21])=[O:20])[CH3:18])[NH2:23])=[CH:7][CH:6]=[N:5]1
Reactant: CC(=O)Nc1ccc(OCC(C)(C)[N+](=O)[O-])c(-c2ccnn2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1nccc1-c1cc(N)ccc1OCC(C)(C)[N+](=O)[O-]
Temperature: 140 °C
Yield: 72.4 %

Procedure:
A solution of sodium hydroxide (70 mg, 1.74 mmol) in water (0.15 mL) was added to a suspension of N-(3-(2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)phenyl)acetamide (84 mg, 0.29 mmol) in methanol (1 mL) and the mixture was stirred at 140° C. in a screw capped vial for 90 min. The mixture was allowed to cool to room temperature, and the solvent was removed under reduced pressure. The residue was partitioned between dichloromethane and water, the organic layer was dried with sodium sulfate, filtered and evaporated to dryness to afford the title compound (62 mg, 0.21 mmol, 74%) as a yellow oil which was used without further purification. LCMS m/z (%)=291.3 (M+H 98%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[CH:16]=[C:15](Br)[CH:14]=[CH:13][C:12]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([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].COCCOC>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[CH:16]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:12]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1ccc(Br)cn1CCOCc1ccccc1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: O=c1ccc(-c2ccccc2)cn1CCOCc1ccccc1
Temperature: 85 °C

Procedure:
A suspension of 1-(2-(benzyloxy)ethyl)-5-bromopyridin-2(1 H)-one (350 mg, 1.14 mmol), phenylboronic acid (277 mg, 2.27 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (83 mg, 114 μmol), Na2CO3 (1.70 mL, 3.41-mmol) [2M], and DME (3 mL) was sparged with argon for 10 min then heated to 85° C. for 60 min. The reaction mixture was partitioned between EtOAc and 5% NaHCO3. The organic residue was purified on 40 grams of silica eluting with 20-60% EtOAc/hexane to give a colorless oil. MS (ESI pos. ion) m/z (MH+): 306. Calc'd exact mass for C20H19NO2: 305. 1H NMR (400 MHz, Chloroform-d) δ ppm 3.77-3.89 (m, 2 H) 4.19-4.30 (m, 2 H) 4.50 (s, 2 H) 6.58-6.73 (m, 1 H) 7.17-7.45 (m, 10H) 7.59-7.71 (m, 2 H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:5]2[S:10][C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[N:34][NH:35]3)O1>>[NH:35]1[C:36]2[C:32](=[C:31]([C:2]3[N:3]=[C:4]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:5]4[S:10][C:9]([NH:11][C:12]([CH:14]5[CH2:16][CH2:15]5)=[O:13])=[CH:8][C:6]=4[N:7]=3)[CH:39]=[CH:38][CH:37]=2)[CH:33]=[N:34]1
Reactant: O=C(Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1)C1CC1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: O=C(Nc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)C1CC1

Procedure:
Crude N-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)cyclopropanecarboxamide (50 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A. The product was purified by reverse phase HPLC to yield 12.1 mg of 172. MS (Q1) 421 (M)+
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:5]([O:4][CH2:3][CH2:2][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1)[CH2:6][CH2:7][CH3:8]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCOCCOc1ccc(C=O)cc1
Yield: 64 %

Procedure:
Nine grams (0.05 mole) of 1-bromo-2-butoxy-ethane and 6.1 grams (0.05 mole) of 4-hydroxybenzaldehyde were dissolved in 75 mls. of acetonitrile. Into the mixture were added 13.8 grams (0.1 mole) of finely ground potassium carbonate and the resulting reaction mixture was stirred under reflux for ten hours. The reaction mixture was allowed to cool, was filtered, washed with acetonitrile and evaporated to an amber oily product. The product was passed through a silica gel chromatographic column for recovery of a colorless oil (64% yield) having the following structure: ##STR20##
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:22])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:8].[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:22][C:5]1[CH:4]=[CH:3][C:2](/[CH:25]=[CH:24]/[C:23]([O:27][CH3:28])=[O:26])=[CH:21][C:6]=1[C:7]([NH:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:8]
Reactant: C=CC(=O)OC
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Br)ccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 90 °C

Procedure:
5-Bromo-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (5 g), methyl acrylate (1.4 ml), triethylamine (2.1 ml), palladium acetate (0.070 g) and tri-orthotolyl phosphine (0.185 g) were combined in N,N-dimethylformamide (20 ml). The mixture was heated in a sealed tube under nitrogen at 90° C. for 24 h. After cooling, the reaction mixture was partitioned between dichloromethane and dilute hydrochloric acid, the mixed phases were filtered through celite and the phases separated. The organic layer was washed with dilute hydrochloric acid and brine, dried over magnesium sulfate and concentrated under reduced pressure to give a residue which was triturated with diethyl ether and filtered to yield the subtitled compound as an off white solid (4.1 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][CH2:17][N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH2:23]([SH:25])[CH3:24]>B(F)(F)F.CCOCC>[CH2:23]([S:25][CH:15]([C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=1)[CH2:16][CH2:17][N:18]1[CH:22]=[CH:21][CH:20]=[N:19]1)[CH3:24]
Reactant: C(=Cc1ccc(OCc2ccccc2)cc1)Cn1cccn1
Reactant: CCS
Agent: FB(F)F
Solvent: CCOCC
Product: CCSC(CCn1cccn1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 86 %

Procedure:
4.51 g of 1-benzyloxy-4-[3-(1-pyrazolyl)prop-1-enyl]benzene were dissolved in a mixture of 25 ml of ethanethiol and 25 ml of boron trifluoride diethyl etherate, and the resulting mixture was stirred at 25° C. for 0.75 hours. The excess thiol was removed by evaporation, and the residue was partitioned between ethyl acetate and water. The organic phase was separated, dried over sodium sulfate, and filtered. The filtrate was evaporated, and the residue was chromatographed on silica gel using chloroform for the elution. The eluate was evaporated, whereby 3.5 g (86%) of 4-[1-ethylthio-3-(1-pyrazolyl)propyl]phenol in the form of an oil was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1.CCN(CC)CC.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C(Cl)Cl>[C:40]([N:17]1[CH2:18][CH2:19][CH:14]([CH:12]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[C:4]([O:20][CH3:21])[C:3]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:27][CH:28]=2)=[C:2]3[Cl:1])[OH:13])[CH2:15][CH2:16]1)(=[O:42])[CH3:41]
Reactant: COc1nc2ccc(C(O)C3CCNCC3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1nc2ccc(C(O)C3CCN(C(C)=O)CC3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(piperidin-4-yl)methanol (74 mg, 0.16 mmol, Intermediate 11: step b) in DCM (3 mL) was added Et3N (24 L, 0.18 mmol) and the resulting solution cooled to 0° C. Then acetic anhydride (16 μL, 0.17 mmol) was added dropwise and the reaction stirred at 0° C. for 30 minutes. The mixture was diluted with DCM and washed with saturated aqueous NaHCO3. The organic layer was dried (MgSO4), filtered, concentrated to dryness and purified by reverse-phase HPLC (acetonitrile/water+ TFA). The acidic fractions were neutralized by diluting with EtOAc and washing with saturated aqueous NaHCO3. The organics were concentrated to dryness, dissolved in 1/1 acetonitrile/water and lyophilized to provide the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.02-7.99 (m, 1H), 7.84-7.80 (m, 1H), 7.72-7.68 (m, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.43 (d, J=7.9 Hz, 2H), 5.49 (s, 1H), 4.57-4.50 (m, 1H), 4.43-4.30 (m, 3H), 4.01 (s, 3H), 3.83-3.71 (m, 1H), 2.94-2.84 (m, 1H), 2.40-2.33 (m, 1H), 1.94 (d, J=8.2 Hz, 3H), 1.84-1.72 (m, 2H), 1.32-1.19 (m, 2H), 1.16-1.03 (m, 1H). MS (ESI): mass calcd. for C26H26ClF3N2O3, 506.2; m/z found, 507.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([O:14]CC)=[O:13])[NH:9]2)=[CH:5][C:4]=1[C:17]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]3[CH3:34])=[C:24]([C:35]([F:38])([F:37])[F:36])[CH:23]=2)[O:19][N:18]=1.[OH-].[Li+].O>C1COCC1.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([OH:14])=[O:13])[NH:9]2)=[CH:5][C:4]=1[C:17]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]3[CH3:34])=[C:24]([C:35]([F:38])([F:37])[F:36])[CH:23]=2)[O:19][N:18]=1
Reactant: CCOC(=O)c1cc2cc(-c3noc(-c4ccc(N5CCCCC5C)c(C(F)(F)F)c4)n3)c(OC)cc2[nH]1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2[nH]c(C(=O)O)cc2cc1-c1noc(-c2ccc(N3CCCCC3C)c(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.1 %

Procedure:
To a solution of example 20 (71 mg; 0.13 mmol) in THF (4.5 mL) was added lithium hydroxide (16 mg; 0.67 mmol) (1.50 ml), followed by water (2 mL) and the resulting mixture was stirred at RT for 24 hours. The solution was diluted with NaOH (0.1 M) washed with Et2O and acidified to pH 1 with 1M HCl (1 M). The formed precipitate was filtered, washed with water and dried under high vacuum to give the title compound as an off-white solid (56 mg, 83%). 1H NMR (DMSO-d6) δ 12.97 (bs, 1H), 11.86 (bs, 1H), 8.45-8.41 (m, 1H), 8.37-8.36 (m, 1H), 8.31 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.20 (m, 1H), 7.06 (m, 1H), 3.90 (s, 1H), 3.15 (m, 1H), 2.97-2.93 (m, 1H), 2.64-2.57 (m, 1H), 1.80-1.76 (m, 2H), 1.63-1.29 (m, 4H), 0.78 (d, J=6 Hz, 3H). HPLC (Method A) Rt 5.43 min (Purity: 99.1%). LC/MS (method A): 501.3 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].C(OC(N([N+]([O-])=O)[C@H](C(O)=O)CCCNC(=N)N)=O)(C)(C)C.C(Cl)(=O)OCC(C)C.[NH2:43][CH2:44][C:45]([NH2:47])=[O:46]>CN(C)C=O.O1CCCC1.C(N(CC)CC)C>[NH2:1][C@H:2]([C:10]([NH:43][CH2:44][C:45]([NH2:47])=[O:46])=[O:12])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8]
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: NCC(N)=O
Agent: CC(C)(C)OC(=O)N([C@@H](CCCNC(=N)N)C(=O)O)[N+](=O)[O-]
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N=C(N)NCCC[C@H](N)C(=O)NCC(N)=O
Temperature: 25 °C

Procedure:
Protected arginine, i.e., tert-butyloxycarbonylnitro-arginine is dissolved in a suitable solvent such as dimethylformamide and tetrahydrofuran. The dissolved protected amino acid is then cooled to a temperature slightly below the freezing point (0° C), whereupon isobutyl chlorocarbonate and triethylamine is added with stirring. After a short period, glycinamide dissolved in dimethylformamide is added. The mixture is then permitted to warm to room temperature and stirred for a period of several hours and then filtered. The filtrate is recovered and evaporated to dryness and then extracted with dimethylformamide. The dimethylformamide solution is precipitated with ethylacetate to yield the dipeptide, i.e., protected arginyl-glycinamide.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]([C:44](=[O:48])[N:45]([CH3:47])[CH3:46])[NH:13][C:14](=[O:43])[CH2:15][NH:16][C:17]([C:19]1[CH:42]=[CH:41][C:22]2[N:23]([CH3:40])[C:24]([NH:26][C:27]3[S:28][C:29]4[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:30]=4[N:31]=3)=[N:25][C:21]=2[CH:20]=1)=[O:18])(C)(C)C.[ClH:50]>O1CCOCC1.C(Cl)Cl>[ClH:50].[ClH:50].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:13][C:14]([CH2:15][NH:16][C:17]([C:19]1[CH:42]=[CH:41][C:22]2[N:23]([CH3:40])[C:24]([NH:26][C:27]3[S:28][C:29]4[CH:35]=[C:34]([C:36]([F:38])([F:39])[F:37])[CH:33]=[CH:32][C:30]=4[N:31]=3)=[N:25][C:21]=2[CH:20]=1)=[O:18])=[O:43])[C:44](=[O:48])[N:45]([CH3:46])[CH3:47]
Reactant: CN(C)C(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN(C)C(=O)[C@H](CCCCN)NC(=O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2C

Procedure:
1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [((S)-5-amino-1-dimethylcarbamoyl-pentylcarbamoyl)-methyl]-amide dihydrochloride (150 mg) was prepared by following General Procedure L starting from [((S)-5-dimethylcarbamoyl-5-(2-{[1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetylamino)-pentyl]-carbamic acid tert-butyl ester (200 mg) in 4M HCl in dioxane (1 mL) and DCM (2 mL). LC/MS: m/z 547.8.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH2:15]2)[CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O)([CH3:3])[CH3:2]>C(O)C.[Pd]>[NH2:11][C:10]1[CH:9]=[CH:8][C:7]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH2:15]2)=[CH:6][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc([N+](=O)[O-])c(OC(C)C)c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N1CCN(c2ccc(N)c(OC(C)C)c2)CC1
Reaction time: 2 h

Procedure:
The compound prepared in Step 2 was dissolved in ethanol, added with 10% Pd/C and stirred under hydrogen atmosphere for 2 hours. Upon completion of the reaction, the Pd/C in the reaction mixture was removed using celite and the solvent was removed under reduced pressure. The thus obtained compound was used in the subsequent reaction without further purification.
Reaction SMILES: [CH2:1]([C@H:8]1[C@@H:12]([CH2:13]OS(C2C=CC(C)=CC=2)(=O)=O)[O:11][C:10](=[O:25])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([NH:30][C:31]([C@@H:33]1[CH2:42][C@H:41]2[C@H:36]([CH2:37][CH2:38][CH2:39][CH2:40]2)[CH2:35][NH:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[CH2:1]([C@H:8]1[C@@H:12]([CH2:13][N:34]2[C@H:33]([C:31]([NH:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[CH2:42][C@H:41]3[C@H:36]([CH2:37][CH2:38][CH2:39][CH2:40]3)[CH2:35]2)[O:11][C:10](=[O:25])[NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2OC(=O)N[C@H]2Cc2ccccc2)cc1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@H]1OC(=O)N[C@H]1Cc1ccccc1
Yield: 63.4 %

Procedure:
Analogously to Example 1B), by reacting 7.2 g of p-toluene-sulphonic acid (4S,5S)-4-benzyl-2-oxo-oxazolidin-5-ylmethyl ester (Example 11) with 4.8 g of N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide there are obtained 5.4 g (45%) of (3S,4aS,8aS)-2-[(4S,5R)-4-benzyl-2-oxo-oxazolidin-5-ylmethyl]-N-tert.-butyl-decahydro-isoquinoline-3-carboxamide p-tolylsuphonate, m.p. 202°-204° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]1[C:14]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:15][CH:16]=[C:9]1[C:8](=[O:24])[NH:7]2)(=O)[CH3:2].C(O)(=O)C>[OH-].[OH-].[Pd+2].[H][H]>[CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]1[C:14]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:15][CH:16]=[C:9]1[C:8](=[O:24])[NH:7]2)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CCc1ncc2c(=O)[nH]c3cc(C(C)=O)ccc3n12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOC(=O)CCc1ncc2c(=O)[nH]c3cc(CC)ccc3n12

Procedure:
A mixture of ethyl 3-(7-acetyl-4-oxo-4,5-dihydroimidazo[1,5-a]-quinoxalin-1-yl)propanoate as synthesized in above Example 183, 131 mg, Pearlman's catalyst 100 mg and acetic acid 5 mL was stirred in hydrogen atmosphere at room temperature for 43 hours. Then 75 mg of Pearlman's catalyst was added and the reaction liquid was mildly heated. Twenty-two hours later, the reaction liquid was filtered through Celite, and 30 mL of water was added to the filtrate. The precipitate was recovered by filtration, washed with water and dried in flowing air under heating to provide 65 mg of the title compound.