Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[OH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][C:10]=1[C:25](OCC)=[O:26]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:7][C:5]1[O:4][N:3]=[C:2]([NH:1][C:25]([C:10]2[C:9](=[O:8])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:11]=2)=[O:26])[CH:6]=1
Reactant: CCOC(=O)C1=C(O)c2ccccc2N(c2ccccc2)C1
Reactant: Cc1cc(N)no1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)c2cn(-c3ccccc3)c3ccccc3c2=O)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.6 %

Procedure:
A solution of 6.0 g of 3-amino-5-methylisoxazole and 10 g of 1,2-dihydro-4-hydroxy-1-phenyl-3-quinolinecarboxylic acid, ethyl ester in 150 ml of toluene was refluxed for 16 hours in a soxhlet apparatus containing 10 g of 4 Å molecular sieves. The solution was cooled to room temperature, treated with 30 g of activated manganese dioxide, stirred for three hours at 30° C., and filtered. Evaporation of the volatiles afforded a residue which was purified by means of high pressure liquid chromatography (silica gel: 1% methanol-dichloromethane as the eluent) to yield 5.8 g (49%) of 1,4-dihydro-N-(5-methyl-3-isoxazolyl)-4-oxo-1-phenyl-3-quinolinecarboxamide, m.p. 163°-164° C.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=4[F:38])=[C:23]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=4[F:38])=[C:23]([CH2:25][C:26]([CH3:29])([CH3:27])[CH3:28])[CH:24]=3)[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1ccnc(COc2cnc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2ncc(OCc3cc(C(CC(=O)O)C4CC4)ccn3)cc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(2-(((6-(2-fluoro-5-methoxyphenyl)-5-neopentylpyridin-3-yl)oxy)methyl)pyridin-4-yl)propanoate (182 mg) in THF (2.0 mL) and methanol (1.0 mL) was added 1N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (164 mg) as a white amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[C:41](=[O:48])([O:45][CH2:46][CH3:47])[O:42][CH2:43]Cl>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[Br-].CCOC(C)=O>[C:41](=[O:48])([O:45][CH2:46][CH3:47])[O:42][CH2:43][N:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]2[C:16]([C:17](=[O:18])[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=2[F:33])=[CH:15]1
Reactant: CCOC(=O)OCCl
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(COC(=O)OCC)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To a mixture of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.1 g, 0.2 mmol) and Et3N (114 μL, 0.8 mmol) in DMF (0.6 mL) was added a solution of TBAB (132 mg, 0.4 mmol) in DMF (0.2 mL). The reaction was stirred at 10° C. for 30 min, followed by dropwise addition of a solution of chloromethyl ethyl carbonate (34 mg, 0.25 mmol) in DMF (0.2 mL). The mixture was stirred at 10° C. for another 3 h, then diluted with EtOAc (40 mL) and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=2/1) to afford the title compound as a white solid (85 mg, 73%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[C:5]=2[N:6]=1.N([O-])=O.[Na+].[ClH:17]>[O-]S([O-])(=O)=O.[Cu+2].Cl[Cu]>[Cl:17][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[C:5]=2[N:6]=1
Reactant: Nc1nc2c(F)c(F)ccc2s1
Reactant: Cl
Agent: Cl[Cu]
Agent: [Cu+2]
Agent: O=N[O-]
Product: Fc1ccc2sc(Cl)nc2c1F
Reaction time: 1 h

Procedure:
To a mixture of 2-amino-4,5-difluoro-1,3-benzothiazole (130 mg, 0.70 mmol) and CuSO4 (20 mg) in conc. HCl (20 mL) was added NaNO2 (96 mg, 1.4 mmol, 2 eq, dissolved in 5 mL of water) dropwise at −10° C. over about 15 min. The reaction mixture was stirred for 1 h, poured into a solution of CuCl (67 mg, 0.7 mmol, 1 eq.) in conc. HCl (20 mL), and stirring was continued at ambient temp. for 30 min. The reaction mixture was extracted with diethyl ether (3×30 mL). The combined organic layers were washed with water (10 mL), dilute ammonium hydroxide (10 mL), brine (20 ml), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluted by 2% methanol in methylene chloride) to afford the title compound. 1H-NMR (CDCl3, 300 MHz): δ=7.20-7.15 (m, 1H), 7.13-7.04 (m, 1H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[C:15]2=[O:21])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[F:23][C:24]([F:34])([F:35])[C:25]1[CH:26]=[C:27]([NH:31][C:32]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][C:10]([N:8]3[CH2:7][CH2:6][C:3]4([CH2:5][CH2:4]4)[C@H:2]([OH:1])[CH2:9]3)=[O:22])[C:15](=[O:21])[C@@H:16]2[CH3:20])=[O:33])[CH:28]=[CH:29][CH:30]=1
Reactant: C[C@@H]1NCCN(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C1=O
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Product: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1cccc(C(F)(F)F)c1
Yield: 24 %

Procedure:
In analogy to the procedure described in Example 25, (S)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (intermediate 13) and 3-(trifluoromethyl)phenyl isocyanate gave the titled compound in 24% yield as white foam. MS: 497.2 (MH+).
Reaction SMILES: FC1C=CC(CC(N)=O)=CC=1.C(Cl)(=O)C(Cl)=O.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:28][C:29](=O)[O:30]C)=[O:27])=[CH:21][CH:20]=1>ClC(Cl)C>[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][C:26]([N:28]=[C:29]=[O:30])=[O:27])=[CH:23][CH:24]=1
Reactant: COC(=O)NC(=O)Cc1ccc(F)cc1
Agent: NC(=O)Cc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(Cl)Cl
Product: O=C=NC(=O)Cc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a solution/suspension of 4-fluorophenylacetamide (77 mg, 0.50 mmol, see generally, J. Med. Chem. 2003, 46, 4333–4341, the disclosure of which is herein incorporated by referene) in dichloroethane (2 mL) was added oxalyl chloride (0.175 mL, 2.00 mmol). The reaction was heated at 80° C. for 24 h and then 70° C. for two days. By this time, most of the solids had dissolved and the reaction was yellow. LC/MS analysis found a peak with a molecular weight of 211 corresponding to methyl 2-(4-fluorophenyl)acetylcarbamate, resulting from quenching of the isocyanate with methanol. The reaction was concentrated in vacuo to give a yellow slurry. The slurry was redissolved in dichloroethane (2 mL) and again concentrated in vacuo. The resulting residue was redissolved again in dichloroethane (2 mL) to give a 0.25 M solution of 2-(4-fluorophenyl)acetyl isocyanate in dichloroethane, which was used directly in subsequent reactions.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[C:10]1([S:16][C:2]2[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Sc1ccccc1
Reactant: Cc1cc(C)cc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: Cc1cc(C)cc(Sc2ccccc2)c1
Yield: 91.4 %

Procedure:
The general procedure in example 39 was followed. 5-Iodo-m-xylene (144 μL, 1.0 mmol), thiophenol (103 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the 3,5-dimethylphenyl phenyl sulfide (196 mg, 92% yield) as colorless liquid. Column chromatography solvent (hexane). Rf=0.5 (hexane). 1H NMR (CDCl3, 300 MHz) δ 7.19-7.29 (m, 5 H), 6.97 (s, 2 H), 6.87 (s, 1 H). MS (EI) m/z (relative intensity) 214 (100), 137 (30).
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:9]=[C:8]([C@@H:10]([NH:13][C:14]([C:16]2[C:17]3[CH:24]=[N:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[C:18]=3[CH:19]=[N:20][CH:21]=2)=[O:15])[CH2:11][CH3:12])[CH:7]=[CH:6][N:5]=1)[CH3:3]>CC(C)=O.O=[Mn]=O>[C:2]([C:4]1[CH:9]=[C:8]([C@@H:10]([NH:13][C:14]([C:16]2[C:17]3[CH:24]=[N:23][N:22]([C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)[C:18]=3[CH:19]=[N:20][CH:21]=2)=[O:15])[CH2:11][CH3:12])[CH:7]=[CH:6][N:5]=1)(=[O:1])[CH3:3]
Reactant: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(C(C)O)c1
Agent: O=[Mn]=O
Solvent: CC(C)=O
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(C(C)=O)c1
Reaction time: 18 h

Procedure:
To a solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid {(S)-1-[2-(1-hydroxy-ethyl)-pyridin-4-yl]-propyl}-amide (71 mg, 0.17 mmol) in acetone (4 mL) was added MnO2 (147 mg, 1.69 mmol). After 18 hours, the reaction was monitored by HPLC-MS indicating a 1:3 mixture of product to starting material. The mixture was filtered through diatomaceous earth rinsing with acetone (200 mL) and the filtrate was concentrated in vacuo. The residue was diluted with acetone (4 mL) and MnO2 (147 mg, 1.69 mmol) was added. After 5 hours, the reaction was filtered through diatomaceous earth, rinsed with acetone and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluting with using a gradient of 10-100% EtOAc in heptane to afford 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-1-(2-acetyl-pyridin-4-yl)-propyl]-amide as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[OH:10]O>C(O)(=O)C>[CH:1]1([C:4]2[CH:5]=[N+:6]([O-:10])[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: OO
Reactant: c1cncc(C2CC2)c1
Solvent: CC(=O)O
Product: [O-][n+]1cccc(C2CC2)c1
Yield: 67.1 %

Procedure:
1.93 g of 3-cyclopropylpyridine (synthesized according to a method disclosed in Tetrahedron Lett. 2002, 39, 6987-6990) was dissolved in 15 mL of acetic acid, then 2.4 g of hydrogen peroxide solution (31%) was added thereto, and heated overnight under reflux. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in chloroform, and washed with a saturated aqueous solution of sodium hydrogen carbonate and water in the subsequent order. The organic layer was dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and 1.47 g of 3-cyclopropylpyridine 1-oxide [121-1] was obtained as a brown oily product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C@@:8]2([CH3:25])[N:14](CC3C=CC(OC)=CC=3)[C:13](=[O:24])[CH2:12][CH2:11][O:10][CH2:9]2)[CH:7]=1.C1(OC)C=CC=CC=1.FC(F)(F)S(O)(=O)=O.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C@@:8]2([CH3:25])[NH:14][C:13](=[O:24])[CH2:12][CH2:11][O:10][CH2:9]2)[CH:7]=1
Reactant: COc1ccc(CN2C(=O)CCOC[C@@]2(C)c2cc(Br)ccc2F)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C[C@@]1(c2cc(Br)ccc2F)COCCC(=O)N1
Temperature: 73 °C
Yield: 3.4 %

Procedure:
A solution of (R)-3-(5-bromo-2-fluoro-phenyl)-4-(4-methoxy-benzyl)-3-methyl-[1,4]oxazepan-5-one (2.278 g, 5.39 mmol) and anisole (10.7 g, 98.7 mmol) in trifluoroacetic acid (28 ml) was treated dropwise within 6 minutes at room temperature with trifluoromethanesulfonic acid (9.47, 61.9 mmol). After complete addition, the reaction mixture was heated at 73° C. for 24 hours. Following TLC no starting material in a complex mixture of products. For the workup, the cold mixture was poured carefully under stirring into a mixture of saturated sodium hydrogen carbonate solution (200 ml) and ice. The extraction with ethyl acetate (500 ml) and re-extraction of the separated aqueous layer with ethyl acetate (250 ml) was followed by washing the combined organic layers with saturated sodium hydrogen carbonate solution (200 ml) and brine (200 ml). The organic phase was dried over sodium sulfate, then evaporated at reduced pressure. Chromatography on silica gel using a gradient of heptane and ethyl acetate=100/0 to 20/10 as the eluent yielded a product containing fraction of 628 mg which was engaged in the next step without further purification and characterisation. For characterisation of the title compound another fraction of 104 mg was again purified by chromatography on Silicycle-Si-amine column using a gradient of heptane and ethyl acetate=100/0 to 20/10 as the eluent yielding the pure (R)-3-(5-bromo-2-fluoro-phenyl)-3-methyl-[1,4]oxazepan-5-one (intermediate C11A) as a beige foam (56 mg). MS (ISP): m/z=302.2, 304.1 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C@H:3]([CH2:5][C@@H:6]([CH:9]([CH3:11])[CH3:10])[CH:7]=[CH2:8])[OH:4].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:55]([CH2:58][C@H:59]([O:63][C:64](=[O:80])[CH:65]([CH2:73][C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1)[CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[C:60](O)=[O:61])(=[O:57])[NH2:56]>C(#N)C>[CH2:73]([CH:65]([CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[C:64]([O:63][C@H:59]([C:60](=[O:61])[NH:1][C@@H:2]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)[C@@H:3]([OH:4])[CH2:5][C@@H:6]([CH:9]([CH3:11])[CH3:10])[CH:7]=[CH2:8])[CH2:58][C:55](=[O:57])[NH2:56])=[O:80])[C:74]1[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=1
Reactant: C=C[C@@H](C[C@H](O)[C@@H](N)CC1CCCCC1)C(C)C
Reactant: NC(=O)C[C@H](OC(=O)C(Cc1ccccc1)Cc1ccccc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](CC(N)=O)OC(=O)C(Cc1ccccc1)Cc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 61 %

Procedure:
100 mg of (αS,βS)-β-amino-α-[(S)-2-isopropyl-3-butenyl]cyclohexanepropanol in 20 ml of acetonitrile were treated with 0.080 ml of Hunig base, 174 mg of BOP and 140 mg of (S)-3-carbamoyl-2-(dibenzylacetoxy)propionic acid and stirred at room temperature for 12 hours. Thereafter, the reaction solution was poured onto 1N hydrochloric acid/ice, extracted with ethyl acetate, the extracts were washed with sodium carbonate solution and, finally, dried over sodium sulfate. The solvent was then removed under reduced pressure and the residue was chromatographed on silica gel with a 20:1 mixture of methylene chloride and methanol, to obtain 142 mg (60%) of (S)-2-carbamoyl-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2 -hydroxy-4-isopropyl-5-hexenyl]- carbamoyl]ethyl dibenzylacetate in the form of a resin. MS: 591 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1COc1cccc(Cl)c1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COc2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-[(3-chlorophenoxy)methyl]benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: C(OC([N:8]([C:10]1([C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[CH2:12][CH2:11]1)[CH3:9])=O)(C)(C)C.C(N(CC)CC)C.F[C:26]1[CH:27]=[CH:28][C:29]2[C:39](=[O:40])[C:38]([C:41]([OH:43])=[O:42])=[CH:37][N:31]3[C@@H:32]([CH3:36])[CH2:33][O:34][C:35]=1[C:30]=23>CS(C)=O>[CH3:36][C@@H:32]1[N:31]2[CH:37]=[C:38]([C:41]([OH:43])=[O:42])[C:39](=[O:40])[C:29]3[CH:28]=[CH:27][C:26]([N:15]4[CH2:16][CH2:17][C@@H:13]([C:10]5([NH:8][CH3:9])[CH2:11][CH2:12]5)[CH2:14]4)=[C:35]([C:30]=32)[O:34][CH2:33]1
Reactant: C[C@H]1COc2c(F)ccc3c(=O)c(C(=O)O)cn1c23
Reactant: CN(C(=O)OC(C)(C)C)C1([C@@H]2CCNC2)CC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CNC1([C@@H]2CCN(c3ccc4c(=O)c(C(=O)O)cn5c4c3OC[C@@H]5C)C2)CC1
Temperature: 100 °C
Yield: 70.4 %

Procedure:
After adding 3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cyclopropyl]pyrrolidine (125 mg, 521 μmol) and triethylamine (0.50 ml) to dried dimethyl sulfoxide (1 ml), 10-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (132 mg, 500 μmol) was added thereto and stirred while heating in an oil bath of 100° C. for 20 hours under a nitrogen atmosphere. After concentrating the reaction solution under a reduced pressure, the residue was dissolved in chloroform (100 ml). After washing the organic layer with a 10% aqueous citric acid solution (50 ml) and saturated saline solution (50 ml), the organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, and after adding concentrated hydrochloric acid (3 ml) to the residue while cooling with ice, it was stirred at room temperature for 30 minutes. After adding water (3 ml) to the reaction solution and washing the yellow acidic aqueous solution with chloroform (50 ml×3), the pH was adjusted to 12.0 with an aqueous sodium hydroxide solution. After adjusting the pH of the basic aqueous solution to 7.4 with 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×3) was performed. After drying over anhydrous sodium sulfate, the solvent was evapolated under a reduced pressure. The residue thus obtained was then purified by recrystallization from ethanol-ammonia water and then dried under a reduced pressure. 135 mg (70%) of the title compound was thereby obtained in the form of yellow crystals.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:17][CH:18]([NH:21]C(=O)OCC3C=CC=CC=3)[CH2:19][OH:20])[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]2[C:5](=[O:32])[N:4]([CH3:33])[C:3]1=[O:34].CN1C2=CN(CC3COC(=O)N3)C(C3C=CC=CC=3)=C2C(=O)N(C)C1=O>[Pd].C(O)C>[NH2:21][CH:18]([CH2:19][OH:20])[CH2:17][N:9]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:6]2[C:7]([N:2]([CH3:1])[C:3](=[O:34])[N:4]([CH3:33])[C:5]2=[O:32])=[CH:8]1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CC(CO)NC(=O)OCc3ccccc3)cc2n(C)c1=O
Agent: [Pd]
Agent: Cn1c(=O)c2c(-c3ccccc3)n(CC3COC(=O)N3)cc2n(C)c1=O
Solvent: CCO
Product: Cn1c(=O)c2c(-c3ccccc3)n(CC(N)CO)cc2n(C)c1=O
Reaction time: 18 h

Procedure:
A mixture of benzyl (1-(1,3-dimethyl-2,4-dioxo-5-phenyl-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)-3-hydroxypropan-2-yl)carbamate and 1,3-dimethyl-6-((2-oxooxazolidin-4-yl)methyl)-5-phenyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (1.67 g) and 10% palladium on carbon (200 mg, 3.61 mmol) were suspended in ethanol (50 ml) and stirred under an atmosphere of hydrogen for 18 hours. The mixture was passed through pre-packed Celite® cartridge (10 g, filter material) and the residue washed with ethanol (20 ml). The combined filtrates were evaporated under vacuum. The residue was suspended in THF (18 ml) and water (5 ml). Lithium hydroxide (20 mg) was added and the mixture stirred at room temperature for 4 hours, then quenched with 2M HCl (aq). NaHCO3(aq) solution (20 ml) was added to achieve pH 6 and the mixture extracted with DCM (3×30 ml), passed through a hydrophobic frit and evaporated under vacuum to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:18]([CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[N:17][C:9]2[C@H:10]3[N:14]([C:15](=[O:16])[C:8]=2[C:7]=1[C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][CH:26]=1)[CH2:13][CH2:12][CH2:11]3)=[O:5])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:55][C@H:56]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH2:58][CH2:57]1>ClCCl>[C@H:56]1([NH:55][C:29]([C:28]2[CH:32]=[CH:33][C:25]([C:7]3[C:8]4[C:15](=[O:16])[N:14]5[C@H:10]([C:9]=4[N:17]=[C:18]([CH2:19][CH2:20][C:21]([F:23])([F:22])[F:24])[C:6]=3[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:12][CH2:13]5)=[CH:26][CH:27]=2)=[O:31])[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH2:58][CH2:57]1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: CCOC(=O)c1c(CCC(F)(F)F)nc2c(c1-c1ccc(C(=O)O)cc1)C(=O)N1CCC[C@@H]21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)c1c(CCC(F)(F)F)nc2c(c1-c1ccc(C(=O)N[C@@H]3CCc4ccccc43)cc1)C(=O)N1CCC[C@@H]21
Reaction time: 3 h
Yield: 49.2 %

Procedure:
To a stirred solution of 4-[(9aS)-3-(ethoxycarbonyl)-5-oxo-2-(3,3,3-trifluoropropyl)-7,8,9,9a-tetrahydro-5H-pyrido[2,3-α]pyrrolizin-4-yl]benzoic acid (0.075 g, 0.162 mmol) in 1 mL of dichloromethane, EDCI (0.037 g, 0.194 mmol), HOBT (0.026 g, 0.194 mmol) and (R)-(−)-1-aminoindane (0.051 g, 0.324 mmol) were added. The reaction mixture was allowed to stir for ˜3 h. The mixture was then concentrated and redissolved in 1 mL of ethyl acetate. The organics were then washed with saturated aqueous NaHCO3 and brine. Filtration followed by concentration provided a brown oil which was purified by radial chromatography (ethyl acetate/hexanes (4:1)) to yield 0.046 g (49%) of the desired product as a white solid: 1H NMR (CDCl3, 400 MHz) δ 7.86–7.77 (d, 2H, J=8.27), 7.45–7.37 (d, 2H, J=8.28), 7.36–7.29 (d, 1H, J=6.38), 7.28–7.16 (m, 3H), 6.48–6.37 (m, 1H), 5.72–5.64 (q, 1H, J=7.59), 4.71–4.63 (dd, 1H, J=10.34, J=6.21), 4.13–3.96 (m, 2H), 3.72–3.58 (m, 1H), 3.38–3.26 (m, 1H), 3.22–3.08 (m, 2H), 3.07–2.96 (m, 1H), 2.96–2.83 (m, 1H), 2.79–2.56 (m, 3H), 2.55–2.38 (m, 1H), 2.38–2.22 (m, 2H), 1.98–1.84 (m, 1H), 1.45–1.27 (m, 1H), 1.04–0.95 (t, 3H, J=7.07); TLC (EtOAc/Hex(4:1)): Rf=0.3; RP-HPLC (BDS Hypersil C-18 25 cm×4.6 mm; 10–100% CH3CN in H2O with 0.1% TFA buffer, 30 minutes; 1 mL/min) tr=11.8 min, 94.1% purity.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:23])=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]3[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:7][C:6]=2[CH:22]=1.[H-].[Na+].[CH3:26][Si:27]([CH3:34])([CH3:33])[CH2:28][CH2:29][O:30][CH2:31]Cl.O>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[C:3]([F:23])=[CH:4][C:5]2[N:9]([CH2:31][O:30][CH2:29][CH2:28][Si:27]([CH3:34])([CH3:33])[CH3:26])[C:8]([C@@H:10]3[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[N:7][C:6]=2[CH:22]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(F)c(Br)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(Br)c(F)cc2n1COCC[Si](C)(C)C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
To a solution of (S)-tert-butyl 2-(6-bromo-5-fluoro-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (2.5 g, 6.4 mol) in THF (32 mL) was added sodium hydride (0.27 g, 6.8 mmol) and stirring was continued for 30 minutes. 2-(Trimethylsilyl)-ethoxymethyl chloride (1.2 mL, 6.8 mmol) was added and stirring was continued for 30 minutes. Water was added to quench the reaction. The mixture was diluted with EtOAc, washed with 1N HCl, H2O, and brine, dried (Na2SO4), filtered and concentrated to an oil. The oil was purified by flash chromatography (0-30% EtOAc/hexane) to give the title compound (2.9 g, 5.7 mmol, 89%).