Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[C:15]([NH2:26])=[N:16][CH:17]=[C:18]([C:20]4[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=4)[N:19]=3)=[N:11][N:10]=2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>C(Cl)Cl>[NH2:26][C:15]1[N:16]=[CH:17][C:18]([C:20]2[CH2:21][CH2:22][N:23]([C:36](=[O:39])[CH2:37][CH3:38])[CH2:24][CH:25]=2)=[N:19][C:14]=1[C:12]1[O:13][C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][Br:1])=[CH:8][CH:7]=2)=[N:10][N:11]=1
Reactant: CCC(=O)Cl
Reactant: Nc1ncc(C2=CCNCC2)nc1-c1nnc(-c2ccc(CBr)cc2)o1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)N1CC=C(c2cnc(N)c(-c3nnc(-c4ccc(CBr)cc4)o3)n2)CC1
Reaction time: 0.25 h
Yield: 60.9 %

Procedure:
To a solution of 3-[5-[4-(bromomethyl)phenyl]-1,3,4-oxadiazol-2-yl]-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-amine (34 mg, 0.07 mmol) in anhydrous DCM (500 μL) cooled in an ice water bath under an atmosphere of nitrogen was added DIEA (49 mg, 66 μL, 0.38 mmol) followed by the dropwise addition of a solution of propanoyl chloride (8 mg, 7 μL, 0.08 mmol) in DCM (0.2 mL). The reaction mixture was stirred for 15 minutes. The reaction mixture was diluted with DCM and washed three times with 1M aqueous HCl solution, twice with saturated aqueous NaHCO3 solution and then twice with a solution of brine. The layers were separated and the organic layer was dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to yield 1-[4-[5-amino-6-[5-[4-(bromomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-3,6-dihydro-2H-pyridin-1-yl]propan-1-one (20 mg, 57%). LC/MS m/z 471.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[F:21][C:22]1[CH:23]=[C:24]([CH2:28][CH:29]=O)[CH:25]=[CH:26][CH:27]=1>>[F:21][C:22]1[CH:23]=[C:24]([C:28]2[CH:29]=[N:1][C:2]3[C:3]([C:12]=2[C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)=[CH:4][CH:5]=[CH:6][C:7]=3[C:8]([F:11])([F:10])[F:9])[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Reactant: O=CCc1cccc(F)c1
Product: Oc1cccc(-c2c(-c3cccc(F)c3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and (3-Fluoro-phenyl)-acetaldehyde following the procedure of Example 457: MS (ESI) m/z 384; HRMS: calcd for C22H13F4NO+H+, 384.10060; found (ESI, [M+H]+), 384.0992;
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][O:12][C@H:11]([CH2:15][O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10]1)C1C=CC=CC=1>CO.[C].[Pd]>[ClH:1].[C:17]([O:16][CH2:15][C@H:11]1[O:12][CH2:13][CH2:14][NH:9][CH2:10]1)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(OC[C@@H]1CN(Cc2ccccc2)CCO1)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C(OC[C@@H]1CNCCO1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.2 %

Procedure:
(2S)-4-Benzyl-2-benzoyloxymethylmorpholine hydrochloride (4.0 g) is dissolved in methanol (32 ml) and thereto is added 10 % palladium-carbon (0.8 g), and the mixture is stirred under hydrogen pressure of 5 kg/cm2 at room temperature for 4 hours. Palladium-carbon is filtered off and the solvent is distilled off under reduced pressure. The residue is recrystallized from chloroform-ethanol to give the title compound (1.25 g).
Reaction SMILES: [OH-].[Na+].[C:3]([C:8]1[CH:25]=[CH:24][C:11]([CH2:12][N:13]2[CH:17]=[CH:16][CH:15]=[C:14]2[CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)=[CH:10][CH:9]=1)([O:5]CC)=[O:4]>O.C(O)C>[C:3]([C:8]1[CH:9]=[CH:10][C:11]([CH2:12][N:13]2[CH:17]=[CH:16][CH:15]=[C:14]2[CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)=[CH:24][CH:25]=1)([OH:5])=[O:4]
Reactant: CCOC(=O)c1ccc(Cn2cccc2Cn2ccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(Cn2cccc2Cn2ccnc2)cc1
Yield: 35.5 %

Procedure:
A solution of sodium hydroxide (0.20 g) in water (20 ml) was added to a solution of 1-(4-carbethoxybenzyl)-2-(imidazol-1-ylmethyl) pyrrole (1.55 g) in ethanol (20 ml) and the mixture was heated under reflux for 8 hours. The solution was evaporated and the residue was taken up in water (25 ml). The solution was acidified with acetic acid and continuously extracted with chloroform to give a solid which was crystallised from isopropanol to give 1-(4-carboxybenzyl)-2-(imidazol-1-ylmethyl)pyrrole (0.50 g), m.p. 190°-191° (d).
Reaction SMILES: [N:1]1[N:2]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=[C:4]2[C:9]=1[CH2:8][CH2:7][NH:6][CH2:5]2.CC1C=CC(S(O)(=O)=O)=CC=1.Cl.[C:28]([O:32][C:33]([NH:35][C@H:36]([C:41](O)=[O:42])[CH2:37][CH:38]([CH3:40])[CH3:39])=[O:34])([CH3:31])([CH3:30])[CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[C:28]([O:32][C:33]([NH:35][C@H:36]([C:41]([N:6]1[CH2:7][CH2:8][C:9]2=[N:1][N:2]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=[C:4]2[CH2:5]1)=[O:42])[CH2:37][CH:38]([CH3:39])[CH3:40])=[O:34])([CH3:30])([CH3:31])[CH3:29]
Reactant: CCOC(=O)Cn1cc2c(n1)CCNC2
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Product: CCOC(=O)Cn1cc2c(n1)CCN(C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C2

Procedure:
In the same manner as in Example I-(1-A) except for using 0.30 g (0.79 mmol) of ethyl 4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-2-acetate.TsOH in place of ethyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-acetate.HCl, 0.18 g (0.79 mmol) of N-t-butoxycarbonyl-L-leucine in place of N-t-butoxycarbonyl-L-4-nirophenylalanine and 0.30 g (0.79 mmol) of TBTU in place of BOP, the reaction was carried out to obtain ethyl 5-(N-t-butoxycarbonyl-L-leucyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-2-acetate as pale brownish solid without purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[N:23]1([CH:29]2[CH2:35][CH2:34][C:33]3[CH:36]=[C:37]([NH2:40])[CH:38]=[CH:39][C:32]=3[CH2:31][CH2:30]2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[N:23]1([CH:29]2[CH2:35][CH2:34][C:33]3[CH:36]=[C:37]([NH:40][C:2]4[N:7]=[C:6]([NH:8][C@@H:9]5[C@@H:14]6[CH2:15][C@@H:11]([CH:12]=[CH:13]6)[C@@H:10]5[C:16]([NH2:18])=[O:17])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=4)[CH:38]=[CH:39][C:32]=3[CH2:31][CH2:30]2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2C(F)(F)F)[C@H]2C=C[C@@H]1C2
Reactant: Nc1ccc2c(c1)CCC(N1CCOCC1)CC2
Product: NC(=O)[C@@H]1[C@H](Nc2nc(Nc3ccc4c(c3)CCC(N3CCOCC3)CC4)ncc2C(F)(F)F)[C@H]2C=C[C@@H]1C2

Procedure:
The title compound was prepared from (1S,2S,3R,4R)-3-(2-Chloro-5-trifluoromethylpyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine in an analogous manner to Example 933 to afford a white solid (41 mg, 60%). Mp: 196-9° C. LCMS (m/e) 543 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.15 (s, 1H), 7.50 (m, 1H), 7.30 (m, 1H), 7.19-7.06 (m, 3H), 6.34 (m, 2H), 5.57 (br s, 1H), 5.51 (br s, 1H), 4.49 (m, 1H), 3.72 (m, 4H), 3.07 (s, 1H), 2.95 (s, 1H), 2.86 (m, 2H), 2.76-2.54 (m, 7H), 2.46 (d, J=8 Hz, 1H), 2.21 (d, J=9 Hz, 1H), 2.01 (m, 2H), 1.63 (d, J=9 Hz, 1H), 1.48 (m, 2H).
Reaction SMILES: C(OC(N[C@@H](CC1C=CC=CC=1)C(O)=O)=O)(C)(C)C.C(O[C:25]([NH:27][C@H:28]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][C@H]2COC(C)(C)O2)=[CH:34][CH:33]=1)[C:29]([OH:31])=O)=[O:26])(C)(C)C.FC(F)(F)C(O)=O.[NH2:54][C@@H:55]([CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[C:56]([NH:58][C:59]1[CH:64]=[CH:63][C:62]([I:65])=[CH:61][CH:60]=1)=[O:57].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>>[I:65][C:62]1[CH:63]=[CH:64][C:59]([NH:58][C:56](=[O:57])[C@@H:55]([N:54]2[C:29](=[O:31])[C@@H:28]([C:32]3[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=3)[NH:27][C:25]2=[O:26])[CH2:66][C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)=[CH:60][CH:61]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)Nc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OC[C@H]2COC(C)(C)O2)cc1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc([C@H]2NC(=O)N([C@@H](Cc3ccccc3)C(=O)Nc3ccc(I)cc3)C2=O)cc1

Procedure:
Prepared by the same method as described in example 1 except that (i) (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid was used in place of (2S,3S)-2-tert-butoxycarbonylamino-3-phenyl-butyric acid in step 1, (ii) 4-iodoaniline was used in place of 4-bromoaniline in step 2, and (iii) the trifluoroacetic acid salt of (S)-2-amino-N-(4-iodo-phenyl)-3-phenyl-propionamide was isolated in step 3 and used directly in step 4 with 1.0 equivalent of triethylamine and (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride as the coupling reagent in place of O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexaflurorophosphate.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].C(OC([NH:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1)=O)(C)(C)C.N12CCCN=C1CCCCC2>C(#N)C>[NH2:27][CH:28]1[CH2:32][CH2:31][N:30]([C:8]2[N:9]([CH:12]3[CH2:14][CH2:13]3)[C:10]3[C:5]([C:6](=[O:18])[C:7]=2[C:15]([OH:17])=[O:16])=[CH:4][C:3]([F:19])=[CH:2][N:11]=3)[CH2:29]1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: NC1CCN(c2c(C(=O)O)c(=O)c3cc(F)cnc3n2C2CC2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A suspension of 5.65 g (20 mmole) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8 -naphthyridine-3-carboxylic acid, 4.65 g (25 mmole) of 3-t-butoxycarbonylaminopyrrolidine, 7.9 g (50 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 150 mL of acetonitrile was stirred at 60° C. for one hour. The solvent was removed in vacuo and the residue was dissolved in 100 mL of trifluoroacetic acid. After stirring at room temperature for one hour, the solvent was removed in vacuo and the residue was suspended in water and the pH adjusted to 11.5 with 50% sodium hydroxide. After filtering through a fiberglass pad to clarify, the filtrate was acidified to 6.6 with 6M hydrochloric acid. The resulting precipitate was removed by filtration, washed with water, 2-propanol, ether, and dried in vacuo to give 6.5 g (98%) of the title compound, mp 284°-286° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.S([O-])([O-])(=O)=O.[K+].C([NH:48][CH2:49][CH2:50][CH2:51][N:52]([CH2:57][CH2:58][CH2:59][NH:60]C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[CH2:53][C:54]([OH:56])=[O:55])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.[K+].CN1CCOCC1>CN1C(=O)CCC1>[NH2:48][CH2:49][CH2:50][CH2:51][N:52]([CH2:57][CH2:58][CH2:59][NH2:60])[CH2:53][C:54]([OH:56])=[O:55]
Reactant: O=C(O)CN(CCCNC(=O)OCC1c2ccccc2-c2ccccc21)CCCNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)([O-])[O-]
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: NCCCN(CCCN)CC(=O)O
Reaction time: 2.5 h
Yield: 457.9 %

Procedure:
HATU (66.5 mg, 0.175 mmol, 0.7 mole eq.) in NMP (0.5 mL) were added to a solution of N,N-bis[3-(Fmoc-amino)propyl]glycine potassium sulphate (115.5 mg, 0.15 mmol, 0.6 mole eq.) and NMM (33.05 μL, 0.3 mmol, 1.2 mole eq.) in NMP (1 mL). This solution was dropwise added in 5 min to a suspension of r-BHD (Compound 1) (100 mg, 0.25 mmol) in NMP (5 mL) containing NMM (27.5 μL, 0.25 mmol, 1 mole eq.). The reaction mixture was stirred at room temp. monitoring the reaction by RP-HPLC (eluent: from 30% to 100% of B in 20 mim; tR=13.4 min). After 2.5 h, Compound 1 (57.7 mg, 0.08 mmol, 0.3 mole eq.) was added again to the reaction mixture. After 2.5 h the reaction was stopped and the solvent evaporated under reduced pressure. The yellow-orange oil was suspended in water at 0° C. under stirring obtaining a white precipitate that was purified by RP-CC (LiChroprep RP-8, 40-63 μm; 170×20 mm; eluent: CH3CN/H2O/HCl=50:50:0.1, 1 mL/min) giving Compound 2 (130 mg; 55% yield). The Fmoc-protected bis-amino derivative (Compound 2) appeared to be pure by T.L.C. inspection (CH3CN/H2O/HCl=50:50:0.1). 1HNMR (200 MHz, DMSO): δ 9.63 (br s, 1H), 8.64 (br s, 3H), 7.87 (d, 4H), 7.65 (d, 4H), 7.43-7.27 (m, 8H), 6.41 (d, 2H), 4.31-4.14 (m, 8H), 3.85 (s, 2H), 3.14-3.03 (m, 11H), 2.82-2.76 (m, 4H), 2.6 (d, 2H), 1.76-1.25 (m, 20H) ESI-MS (m/e): calculated [M+H]+ 944.5, found 944.5.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=[O:13].Cl>O1CCCC1>[Cl:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:13]
Reactant: C1CCNCC1
Reactant: O=C(Cl)c1cccc(CCl)c1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(c1cccc(CCl)c1)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86436.8 %

Procedure:
To an ice-cooled solution of piperidine (67.6 g, 0.793 mole) in tetrahydrofuran (1 L) was added dropwise a solution of 3-chloromethylbenzoyl chloride (100.0 g, 0.529 mmol). When the addition was complete, the reaction mixture was allowed to warm to ambient temperature and was left to stir overnight. The reaction mixture was poured into a solution of 1N hydrochloric acid. This solution was extracted with diethyl ether. The ether extracts were combined, washed with water, dried (MgSO4), and concentrated to afford 108.7 g (86%) of N-(3-(chloromethyl)benzoyl)piperidine (10) as a pale yellow oil whose 1H NMR in CDCl3 supported the structure.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@@H:13]2[C@@H:9]([O:10][C:11]([CH3:15])([CH3:14])[O:12]2)[C@H:8]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3Cl)[CH2:7]1)(=[O:3])[CH3:2].[Br-].[CH2:27]([Zn+])[CH:28]([CH3:30])[CH3:29]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:4][CH2:5][C@@H:6]1[C@@H:13]2[C@@H:9]([O:10][C:11]([CH3:15])([CH3:14])[O:12]2)[C@H:8]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(C)C[Zn+]
Reactant: CC(=O)OC[C@H]1C[C@@H](n2cnc3c(Cl)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1C[C@@H](n2cnc3c(CC(C)C)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Temperature: 60 °C
Yield: 45 %

Procedure:
To a solution of [(3aR,4R,6R,6aS)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methyl acetate (250.0 mg, 0.68 mmol) in degassed THF (6 mL) under nitrogen was added Pd(PPh3)4 (44 mg, 0.038 mmol) followed by 0.5 M of isobutylzinc bromide in tetrahydrofuran (2.04 mL) dropwise over 15 min. The reaction was heated at 60° C. for 1 hour. The reaction was cooled then quenched with saturated aq NH4Cl, extracted with EtOAc and the organic phase was washed with saturated aq EDTA.Na2 solution then water. The organic phase was concentrated and the residue purified by flash chromatography (0 to 100% EtOAc/DCM) to provide the title compound (120 mg, 45%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:20])[C@H:4]([CH2:16][CH:17]([CH3:19])[CH3:18])[NH:5]C(OCC1C=CC=CC=1)=O.[H][H]>[Pd].CO>[CH3:1][NH:2][C:3](=[O:20])[C@H:4]([CH2:16][CH:17]([CH3:19])[CH3:18])[NH2:5]
Reactant: [H][H]
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CNC(=O)[C@@H](N)CC(C)C

Procedure:
A mixture of intermediate 20A (1.20 g, 4.31 mmol) and 10% palladium on carbon (300 mg) in MeOH (30 mL) was hydrogenated with a Parr shaker under 55 psi of hydrogen gas for 3 h. After filtration through celite, the filtrate was evaporated and azeotroped with EtOAc to give the desired intermediate 20B as white solid (quant. yield).LCMS (+ESI) m/z 145.1 [M+H]+.
Reaction SMILES: [C:1]([O:6][CH2:7][C:8](F)(F)C(F)(F)C(F)(F)F)(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:18]([O:23][CH2:24][CH2:25][N:26]=[C:27]=[O:28])(=[O:22])[C:19]([CH3:21])=[CH2:20]>CC(N(C)C)=O>[CH3:4][C:2]([C:1]([O:6][CH2:7][CH2:8][OH:22])=[O:5])=[CH2:3].[CH3:21][C:19]([C:18]([O:23][CH2:24][CH2:25][OH:5])=[O:22])=[CH2:20].[C:18]([O:23][CH2:24][CH2:25][N:26]=[C:27]=[O:28])(=[O:22])[C:19]([CH3:21])=[CH2:20]
Reactant: C=C(C)C(=O)OCC(F)(F)C(F)(F)C(F)(F)F
Agent: C=C(C)C(=O)OCCN=C=O
Solvent: CC(=O)N(C)C
Product: C=C(C)C(=O)OCCO

Procedure:
The process of Example 6 is repeated, but using heptafluoropropylmethyl methacrylate (F7MA) as fluorinated comonomer and using an amount of 2-isocyanatoethyl methacrylate (IEM) to give a prepolymer with a composition in mol % of: DMA/F7MA/HEMA/HEMA+IEM=80/12.5/5.65/1.85.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][C:6]([CH2:7][C@H:8]2[CH2:12][CH2:11][C:10](=[O:13])[N:9]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:5][CH:4]=1.CC(C)=[O:27]>[OH-].[Na+]>[C:17]([O:16][C:14]([NH:9][C@@H:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:24])([F:23])[F:1])=[CH:22][CH:21]=1)[CH2:12][CH2:11][C:10]([OH:13])=[O:27])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@@H]1Cc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N[C@H](CCC(=O)O)Cc1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 93 %

Procedure:
(R)-tert-Butyl 2-(4-(trifluoromethyl)benzyl)-5-oxopyrrolidine-1-carboxylate (4.0 g, 12 mmol) was dissolved in 25 mL acetone and 40 mL of 1.0 M aqueous sodium hydroxide. The resulting mixture was stirred for 30 minutes. The acetone was removed and the mixture was acidified with 5.0 M HCl. The resulting solid was filtered and washed with water twice. The crude product was recrystallized from hexane/EtOAc solvent (10:1 ratio, total volume hexane: 100 mL). After the solution was cooled, the crystals slowly appeared and the solution was put in the freezer for 2 hours. Filtration of the solid afforded the desired compound as a white crystalline solid (3.9 g, 93%). MS (API-ES) m/z (%): 384.1 (100%, M++Na).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:21]([NH2:23])=[O:22])[C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[C:9]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[CH:8]=3.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=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].C(Cl)Cl.COCCOC>[O:18]1[CH2:19][CH2:20][N:15]([C:9]2[CH:8]=[C:7]3[C:12]([C:13]4[CH:14]=[C:2]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH:3]=[C:4]([C:21]([NH2:23])=[O:22])[C:5]=4[NH:6]3)=[CH:11][CH:10]=2)[CH2:16][CH2:17]1
Reactant: NC(=O)c1cc(Br)cc2c1[nH]c1cc(N3CCOCC3)ccc12
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: NC(=O)c1cc(-c2ccccc2)cc2c1[nH]c1cc(N3CCOCC3)ccc12
Temperature: 105 °C

Procedure:
3-Bromo-7-morpholino-9H-carbazole-1-carboxamide (34 mg, 0.091 mmol), phenylboronic acid (22.16 mg, 0.182 mmol), PdCl2(dppf)-CH2Cl2 adduct (7.42 mg, 9.09 μmol), and Na2CO3 (2M) (0.182 mL, 0.363 mmol) were mixed with DME (1 mL) in a sealed microwave vial. The mixture was flushed with N2 and heated at 105° C. in an oil bath for 1.5 hrs. The mixture was purified using preparative HPLC to give titled product. MS (ESI) m/z 372.13 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.12 (s, 1H), 8.47 (s, 1H), 8.30 (s, 1H), 8.16 (s, 1H), 8.05 (d, 1H, J=8.5), 7.87 (d, 2H, J=8.3), 7.50(m, 3H), 7.34 (t, 1H, J=7.4), 7.24 (s, 1H), 6.93 (dd, 1H, J=8.5, 1.9), 3.8 (m, 4H), 3.19 (m, 4H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([C:13]#[N:14])[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:36]5[NH:37][C:38]([CH:41]6[CH2:47][C:44]7([CH2:46][CH2:45]7)[CH2:43][N:42]6[C:48](=[O:58])[CH:49]([NH:53][C:54]([O:56][CH3:57])=[O:55])[CH:50]([CH3:52])[CH3:51])=[N:39][CH:40]=5)[CH:32]=4)[CH:27]=3)=[CH:22][CH:21]=2)=[CH:18][N:19]=1)=O)(C)(C)C.[ClH:59]>C(Cl)Cl>[ClH:59].[ClH:59].[ClH:59].[CH3:57][O:56][C:54](=[O:55])[NH:53][CH:49]([C:48]([N:42]1[CH:41]([C:38]2[NH:37][C:36]([C:31]3[CH:30]=[CH:29][C:28]4[C:33](=[CH:34][CH:35]=[C:26]([C:23]5[CH:24]=[CH:25][C:20]([C:17]6[NH:16][C:15]([CH:9]7[CH2:10][CH:11]([C:13]#[N:14])[CH2:12][NH:8]7)=[N:19][CH:18]=6)=[CH:21][CH:22]=5)[CH:27]=4)[CH:32]=3)=[CH:40][N:39]=2)[CH2:47][C:44]2([CH2:45][CH2:46]2)[CH2:43]1)=[O:58])[CH:50]([CH3:52])[CH3:51]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC(C#N)CN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC(C#N)CN6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reaction time: 2.5 h
Yield: 99 %

Procedure:
A solution of 4-Cyano-2-{5-[4-(6-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (1.000 g, 1.28 mmol) in DCM (16 mL) was treated with HCl (4.0 M in dioxane, 3.2 mL, 12.8 mmol). After 2.5 h, the solid was filtered off and rinsed with EtOAc to provide the title compound (1.004 g, 99%).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=12.[F:13][C:14]1[CH:15]=[C:16]([CH:25]=[CH:26][CH:27]=1)[O:17][C:18]1[S:22][C:21]([CH2:23][NH2:24])=[CH:20][CH:19]=1.F[P-](F)(F)(F)(F)F.N1([P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.O>[F:13][C:14]1[CH:15]=[C:16]([CH:25]=[CH:26][CH:27]=1)[O:17][C:18]1[S:22][C:21]([CH2:23][NH:24][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[N:4]([CH:3]=[CH:2][N:1]=3)[CH:9]=2)=[O:12])=[CH:20][CH:19]=1
Reactant: NCc1ccc(Oc2cccc(F)c2)s1
Reactant: O=C(O)c1ccc2nccn2c1
Agent: CN(C)[P+](N(C)C)(N(C)C)n1nnc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Oc2cccc(F)c2)s1)c1ccc2nccn2c1
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 46.3 %

Procedure:
To a solution of imidazo[1,2-a]pyridine-6-carboxylic acid (87 mg, 0.54 mmol) and C-(5-(3-fluorophenoxy)thiophen-2-yl)methylamine (120 mg, 0.54 mmol) in N,N-dimethylformamide (5 mL) were added benzotriazol-1-yl-tris(dimethylamino)phosphonium hexafluorophosphate (240 mg, 0.54 mmol) and triethylamine(0.15 mL, 1.08 mmol), and the solution was stirred for 40 minutes at 80° C. Water and ethyl acetate were added to the reaction mixture for extraction, and the organic layer was washed twice with water. Silica gel was added to the organic layer, solvent was evaporated in vacuo for adsorption, purification was carried out by silica gel column chromatography (hexane:ethyl acetate=1:1, then ethyl acetate), and the title compound (90 mg, 0.25 mmol, 45.4%) was obtained as a light brown oil.