Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[CH:10]1[C:18](=[O:19])[CH:17]2[CH:12]([CH:13]3[CH2:21][CH2:20][CH:16]2[CH2:15][CH2:14]3)[C:11]1=[O:22])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:30]1[CH:39]=[N:38][C:37]2[C:32](=[CH:33][CH:34]=[C:35]([Cl:40])[CH:36]=2)[N:31]=1.Cl>CN(C)C=O.ClCCl>[Cl:40][C:35]1[CH:36]=[C:37]2[C:32](=[CH:33][CH:34]=1)[N:31]=[C:30]([O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[C:4]([CH:10]3[C:18](=[O:19])[CH:17]4[CH:12]([CH:13]5[CH2:21][CH2:20][CH:16]4[CH2:15][CH2:14]5)[C:11]3=[O:22])[CH:5]=1)[CH:39]=[N:38]2
Reactant: CCc1ccc(O)cc1C1C(=O)C2C3CCC(CC3)C2C1=O
Reactant: Clc1ccc2nc(Cl)cnc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1C1C(=O)C2C3CCC(CC3)C2C1=O
Temperature: 140 °C

Procedure:
To a mixture of 2-(2-ethyl-5-hydroxyphenyl)hexahydro-4,7-ethanoindene-1,3-dione (83 mg, 0.28 mmol) and anhydrous potassium carbonate (90 mg, 0.56 mmol) is added a solution of 2,6-dichloroquinoxaline (67 mg, 0.34 mmol) in anhydrous dimethylformamide (2.0 ml), and the mixture is heated at 140° C. for 40 minutes under microwave irradiation. The mixture is acidified with 2M aqueous hydrochloric acid and diluted with dichloromethane then filtered. The organic phase is concentrated under reduced pressure and the residue is purified by preparative reverse phase HPLC to afford 2-[5-(6-chloroquinoxalin-2-yloxy)-2-ethylphenyl]hexahydro-4,7-ethanoindene-1,3-dione.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.Cl[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[NH:22][CH:23]=[N:24]2>CN(C=O)C.C([O-])(O)=O.[Na+]>[N:28]1[C:20]([NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:10])[CH2:5][CH2:4]2)=[C:21]2[C:25]([NH:24][CH:23]=[N:22]2)=[N:26][CH:27]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncnc3[nH]cnc23)CC1
Reaction time: 18 h

Procedure:
In DMF (5 mL), benzyl 4-(aminomethyl)-1-piperidinecarboxylate (1.20 g, 4.83 mmol) and 6-chloropurine (448 mg, 2.49 mmol) were combined and treated with TEA in a single portion and aged under N2 at 100° C. for 18 h. The resulting reaction was diluted with sat. NaHCO3 and extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give a brown oil which was purified by silica gel chromatography (20 g, 32–60 μm silica, 99:1:0.1 to 90:10:1 CH2Cl2:CH3OH:NH4OH) to give benzyl 4-[(9H-purin-6-ylamino)methyl]-1-piperidinecarboxylate as a brown oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:33])/[CH:16]=[CH:17]/[C:18]1[CH:22]=[CH:21][N:20]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:19]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:33])/[CH:16]=[CH:17]/[C:18]1[CH:22]=[CH:21][N:20]([S:23]([C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)Nc3ccccc3N)c2)cc1
Reaction time: 93 h
Yield: 54.4 %

Procedure:
0.116 g of (2-{(E)-3-[1-(toluene-4-sulfonyl)-1-H-pyrrol-3-yl]-allanoylamino}-phenyl)-carbamic acid tert-butyl ester (compound A5) are dissolved in 20 ml of dichloromethane at ambient temperature. 2 ml of trifluoroacetic acid (TFA) are added and the solution is stirred for 93 hour. The solvent is evaporated to dryness and to the residue are added 25 ml of water. The water phase is extracted exhaustively with ethyl acetate. Afterwards the combined organic phases are dried over sodium sulfate and filtered. The filtrate is evaporated under vacuo. Then the residue is crystallized from methanol to give 0.050 g of the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11]C)=[O:10])=[C:4]([F:15])[CH:3]=1.[OH-].[K+]>CCO.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:14])[C:9]([OH:11])=[O:10])=[C:4]([F:15])[CH:3]=1
Reactant: COC(=O)C(C)(C)c1ccc(Cl)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: CC(C)(C(=O)O)c1ccc(Cl)cc1F
Temperature: 120 °C
Yield: 84.7 %

Procedure:
Methyl 2-(4-chloro-2-fluorophenyl)-2-methylpropanoate (8.11 g, 35.2 mmol) was dissolved in EtOH (70.3 mL) in a vial. KOH (3.95 g, 70.3 mmol) was added, and the sealed vial was heated at 120° C. for 2 hours. The reaction mixture was then diluted with 75 mL of diethyl ether, added to a separatory funnel, partitioned with water, washed with 75 mL of water, and separated. The aqueous layer was acidified to pH=3 with 3N HCl and extracted 2 times with 100 mL of diethyl ether. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (6.46 g) as a light yellow solid. MS (m/z)=217 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1(=[N:14][OH:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Cl[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.O>CN(C=O)C>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([O:15][N:14]=[C:7]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: ON=C1CCCCCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(ON=C2CCCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 80.6 %

Procedure:
Potassium t-butoxide (19 g, 1600 mmol) was added in portions to a cooled (2° C.) solution of cycloheptanone oxime (19 g, 150 mmol) in DMF (150 mL). The cooled reaction mixture was stirred for 40 minutes and then 1-chloro-4-nitrobenzene (25 g, 160 mmol) in DMF (50 mL) was added over 5 minutes. The reaction mixture was stirred at ˜10° C. for 30 minutes and then allowed to warm to room temperature and stirred for an additional 2 hours, and then stood at ambient temperature for 16 hours. The reaction mixture poured into water (1600 mL) with stirring. The mixture was stirred for an additional 20 minutes and then allowed to stand at room temperature for 5 hours. The precipitate was collected by filtration and washed with water. Recrystallization of the crude material from hexane provided cycloheptanone O-(4-nitro-phenyl)-oxime (30 g). Cycloheptanone O-(4-nitro-phenyl)-oxime (12 g, 50 mmol) was dissolved in warm isopropanol (120 mL) and 12 N hydrochloric acid (17 mL) was added. The reaction mixture was heated to reflux for 4 hours and then cooled in an ice bath. The solid was collected by filtration, washed with water and cold isopropanol, and dried in an oven to give 2-nitro-7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan (7.8 g, 34 mmol). A mixture of 2-nitro-7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan (5.8 g, 25 mmol) and Raney nickel (-5.6 g wet weight) in ethanol (270 mL) was hydrogenated at 50 PSI on a Parr shaker overnight. The mixture was filtered through Celite® and the filtrate was concentrated. The crude solid was purified by flash column chromatography (gradient elution with 15-25% ethyl acetate-hexanes) to give 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (4.6 g). Mp 98-99° C.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.Br[C:10]1[C:18]2[C:17]([O:19][CH3:20])=[N:16][C:15]([NH:21]C=O)=[N:14][C:13]=2[N:12]([C@@H:24]2[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[C@@H:26]([O:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH2:25]2)[CH:11]=1>C(#N)C.CN(C=O)C>[Cl:1][C:10]1[C:18]2[C:17]([O:19][CH3:20])=[N:16][C:15]([NH2:21])=[N:14][C:13]=2[N:12]([C@@H:24]2[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[C@@H:26]([O:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH2:25]2)[CH:11]=1
Reactant: COc1nc(NC=O)nc2c1c(Br)cn2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1nc(N)nc2c1c(Cl)cn2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Reaction time: 8 h

Procedure:
Using N-chlorosuccinimide, the substance was prepared and worked up in analogy with compound (19). The halogenation reaction time was 8 hours. Acetonitrile/DMF (4:1) was used as the solvent. Colorless solid (70%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1>C(Cl)Cl.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][O:5][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1
Reactant: OCCCBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: BrCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
To a solution of 3-bromopropan-1-ol (8 g, 57.9 mmol) in DCM (100 mL) was added PPTS (891 mg, 3.6 mmol), then dihydropyran (7.3 g, 86.9 mmol) was added dropwise at 0° C. The mixture was stirred at room temperature overnight. It was partitioned between DCM and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography eluting with petroleum ether/ethyl acetate (50:1) to give 2-(3-bromopropoxy)tetrahydro-2H-pyran (8.9 g, 69.0% yield) as a light yellow oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([CH:20]([C:22]2[C:30]3[C:25](=[N:26][CH:27]=[C:28]([Cl:31])[CH:29]=3)[NH:24][CH:23]=2)O)=[C:14]([Cl:32])[CH:13]=1.C(#N)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[Cl:32][C:14]1[C:15]([CH2:20][C:22]2[C:30]3[C:25](=[N:26][CH:27]=[C:28]([Cl:31])[CH:29]=3)[NH:24][CH:23]=2)=[CH:16][C:17]([O:18][CH3:19])=[C:12]([CH:13]=1)[O:11][CH2:10][C:2]1[NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=1
Reactant: COc1cc(C(O)c2c[nH]c3ncc(Cl)cc23)c(Cl)cc1OCc1nc2ccccc2[nH]1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Cc2c[nH]c3ncc(Cl)cc23)c(Cl)cc1OCc1nc2ccccc2[nH]1
Temperature: 70 °C

Procedure:
[4-(1H-Benzoimidazol-2-ylmethoxy)-2-chloro-5-methoxy-phenyl]-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (138, 1.25 g, 0.00266 mol) was dissolved in acetonitrile (100 mL, 2 mol) and trifluoroacetic acid (5.65 mL, 0.0734 mol) and triethylsilane (11.3 mL, 0.0708 mol) were added. The reaction was heated at 70° C. for 2.5 hours. The reaction was concentrated and ethyl acetate and 1M aqueous potassium carbonate were added. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was adsorbed onto silica and purified with silica gel column chromatography, eluting with 0-8% methanol:dichloromethane to provide the desired compound as a solid, which was washed with a minimum of ethyl acetate and hexanes and filtered. The collected solid was dried to provide P-2104 (232 mg, 19%). MS (ESI) [M+H+]+=453.1, 455.1.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][C:16]3[C:17]([CH3:22])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:7]([C:12]([NH2:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].C([O-])([O-])=O.[K+].[K+].Cl[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36]>CS(C)=O>[NH2:14][C:12]([C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[NH:15][C:16]1[C:17]([CH3:22])=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH:4][C:3]([O:23][CH3:24])=[C:2]([O:1][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH:11]=2)=[O:13]
Reactant: COc1cc2c(Nc3ccccc3C)c(C(N)=O)cnc2cc1O
Reactant: COC(=O)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)CCCOc1cc2ncc(C(N)=O)c(Nc3ccccc3C)c2cc1OC

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-(2-toluidino)-3-quinolinecarboxamide (0.026 g, 0.080 mmol), DMSO (2.5 ml), K2CO3 (0.017 g, 0.12 mmol), and methyl 4-chlorobutanoate (0.011 g, 0.080 mmol) was refluxed for 2 h. The reactionmixture was filtered, evaporated and chromatographed on silica furnishing the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([OH:21])=O)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[N:51]1([C:56]2[CH:61]=[CH:60][C:59]([NH2:62])=[CH:58][CH:57]=2)[CH:55]=[N:54][N:53]=[N:52]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19](=[O:21])[NH:62][C:59]3[CH:60]=[CH:61][C:56]([N:51]4[CH:55]=[N:54][N:53]=[N:52]4)=[CH:57][CH:58]=3)[N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Reactant: Nc1ccc(-n2cnnn2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)Nc3ccc(-n4cnnn4)cc3)cs2)CC1
Reaction time: 8 h

Procedure:
4-(4-Carboxy-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.28 mmol) was dissolved in anhydrous DMF (20 mL). To the solution was added triethylamine (4 eq.) and O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (1.5 eq.). The reaction was allowed to stir at room temperature for 5 minutes before 4-tetrazol-1-yl-phenylamine (1.2 eq.) was added. The reaction was stirred overnight, quenched with water, extracted with ethylacetate, washed with brine, dried over sodium sulfate and filtered. The organic filtrate was concentrated in vacuo and the residual oil was purified by column chromatography (EtOAC/Hex) furnishing the expected product. 1H NMR (CDCl3): δ 9.37 (1H, s), 9.02 (1H, s), 8.14 (1H, s), 7.96 (2H, d), 7.72 (2H, d), 4.23 (2H, m), 3.20 (1H, m), 2.91 (2H, m), 2.14 (2H, m), 1.79 (2H, m), 1.45 (9H, s).
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[CH2:9][C:10](=[O:12])[CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[N:17](OCCCC)=O.[ClH:24]>CCOCC>[ClH:24].[NH2:17][CH:9]1[C:8]2[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=2[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:11][CH:10]1[OH:12]
Reactant: O=C1Cc2ccccc2-c2ccccc2C1
Reactant: CCCCON=O
Agent: Cl
Solvent: CCOCC
Product: NC1c2ccccc2-c2ccccc2CC1O
Temperature: 0 °C

Procedure:
A round bottom flask was charged with 5,7-dihydro-6H-dibenzo[a,c]cyclohepten-6-one (1.0 g, 4.81 mmol) (CAS# 1139-82-8, prepared as described in Tetrahedron Letters, Vol. 28, No. 23, (1987), pp 2633–2636) and butyl nitrite (0.673 ml, 5.77 mmol) (Aldrich) in Et2O. The solution was cooled to 0° C. and treated drop-wise with a saturated solution of HCl(g)/Et2O. After 5 h at 0° C. the resulting precipitate was filtered, rinsed with cold Et2O and vacuum dried to give the title compound as a colorless solid.
Reaction SMILES: C(O[C:4]([C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:23]=[CH:22][C:21](=[O:24])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[CH2:7]1)=[O:5])C.C(N(CC)CC)C.Cl.[F:33][CH2:34][CH2:35][NH2:36]>CO>[F:33][CH2:34][CH2:35][NH:36][C:4]([C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:23]=[CH:22][C:21](=[O:24])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[CH2:7]1)=[O:5]
Reactant: NCCF
Reactant: CCOC(=O)[C@H]1CN(c2ccc(N3C=CC(=O)CC3)cc2)C(=O)O1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C1C=CN(c2ccc(N3C[C@H](C(=O)NCCF)OC3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (5R)-3-[4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)phenyl]-2-oxo-5-oxazolidinecarboxylic acid ethyl ester (EXAMPLE 72, Step 5, 226 mg, 0.68 mmol) in MeOH (2 mL) is added triethylamine (0.48 mL, 5.0 equiv.). Then 2-fluoroethylamine hydrochloride (136 mg, 2.0 equiv.) is added to the solution. The reaction mixture is heated at 50–60° C. for 5 h, followed by stirring overnight at room temperature. Solvent is removed and the residue is dissolved in 20% MeOH/CH2Cl2 and purified by column chromatography (10% MeOH/CH2Cl2). The title compound is obtained as a yellow solid (100 mg, 42,%), 1H NMR (300 MHz, DMSO) δ 8.69 (t, 1H), 7.75–7.27 (m, 5H), 5.09 (dd, 1H), 4.98 (d, 1H), 4.55 (t, 1H), 4.39 (t, 1H), 4.29 (t, 1H), 4.02–3.93 (m, 3H), 3.51–3.37 (m, 2H), 2.50–2.45 (m, 2H); MS for C17H18FN3O4 m/z 348.5 (M+H)+.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C([O-])([O-])=O.[K+].[K+].[C:20]1([CH3:32])[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CN(C=O)C>[N+:11]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[N:29]1[CH2:30][CH2:31][N:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:32])[CH2:27][CH2:28]1)[C:6]([OH:8])=[O:7])([O-:13])=[O:12]
Reactant: Cc1ccccc1N1CCNCC1
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccccc1N1CCN(c2ccc(C(=O)O)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-fluoro-3-nitro-benzoic acid (6.0 g, 32.4 mmol) in DMF (20 mL), K2CO3 (8.94 g, 64.8 mmol) was added, followed by 1-o-tolyl-piperazine (6.85 g, 38.9 mmol), and the reaction mixture was stirred at room temperature for 16 h. DMF (5.0 mL) was added and filtered. The solid was washed with MeOH (300 mL) and methanol layer was evaporated to give the acid 3-nitro-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid in the first crop (4.0 g, 36%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:46])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:43]=[CH:42][C:34]([C:35]([O:37][CH2:38][C:39]([OH:41])=O)=[O:36])=[CH:33][C:32]=2[O:44][CH3:45])=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:80][CH2:81][CH2:82][O:83][CH2:84][CH2:85][OH:86]>O1CCCC1>[OH:86][CH2:85][CH2:84][O:83][CH2:82][CH2:81][NH:80][C:39]([CH2:38][O:37][C:35](=[O:36])[C:34]1[CH:42]=[CH:43][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:46])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:29])=[C:32]([O:44][CH3:45])[CH:33]=1)=[O:41]
Reactant: COc1cc(C(=O)OCC(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: NCCOCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(C(=O)OCC(=O)NCCOCCO)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reaction time: 0.5 h
Yield: 14.2 %

Procedure:
In a 20 mL round-bottomed flask, 2-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)acetic acid (Example 69, 150 mg, 152 μL, 222 μmol), HATU (84.6 mg, 222 μmol) and Hunig's base (86.2 mg, 117 μL, 667 μmol) were combined with dry tetrahydrofuran (2 mL) to give an off-white suspension at room temperature. It was stirred for 30 min and the solution became clear. 2-(2-Aminoethoxy)ethanol (23.4 mg, 16.0 μL, 222 μmol) was added. After stirring at room temperature overnight, the reaction mixture was concentrated. The residue was reconstituted with ethyl acetate. It was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was absorbed on small amount of silica gel and loaded on a 24 g pre-packed silica gel column. Eluting the column with ethyl acetate gave 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid [2-(2-hydroxy-ethoxy)-ethylcarbamoyl]-methyl ester as an off-white solid (24 mg, 15% yield). LCMS (ES+) m/z calcd. for C37H41Cl2F2N4O7 [(M+H)+]: 761. found: 761.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[CH:5]=[CH:4][N:3]=1.[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[N:10][O:11][C:12]=2[CH2:13][Br:20])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1ccnc(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1onc(-c2ccccc2)c1-c1ccnc(Br)c1
Reaction time: 18 h
Yield: 56.9 %

Procedure:
A stirred solution of the above Compound 17a (404 mg, 1.28 mmol), N-bromosuccinimide (239 mg, 1.35 mmol) and AIBN (11 mg, 0.064 mmol) in CCl4 (3 mL) was heated to reflux and placed under a 300 W lamp for 18 h. The solution was diluted with CH2Cl2 (15 mL), extracted with H2O (3×10 mL), brine (40 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (SiO2, 15-20% EtOAc-hexanes) provided the title compound (287 mg, 0.728 mmol, 57%).
Reaction SMILES: ClC(OC(Cl)C)=O.[N:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH:22]1[CH2:27][CH2:26][N:25](CC2C=CC=CC=2)[CH2:24][CH2:23]1)[C:15]([C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)=[O:16]>ClCCCl>[N:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:15]([C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)=[O:16]
Reactant: O=C(c1ccco1)N(c1cnccn1)C1CCN(Cc2ccccc2)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: O=C(c1ccco1)N(c1cnccn1)C1CCNCC1
Temperature: 0 °C
Yield: 72.6 %

Procedure:
A solution of 1-chloroethyl chloroformate (9.7 ml, 90 mmol) in 1,2-dichloroethane (25 ml) was added to an ice-chilled solution of N-(2-pyrazinyl)-N-(1-phenylmethyl-4-piperidinyl)-2-furanamide (45 mmol) and 1,2-dichloroethane (125 ml). The reaction mixture was stirred under reflux for 5 hours, then cooled and concentrated under vacuum. The crude carbamate residue was dissolved in methanol (150 ml) and the reaction solution was heated under reflux for 2 hours. The reaction solution was cooled, decolorizing carbon (10 g, Darco G-60) was added to the mixture, then the suspension was heated and stirred under reflux for 15 minutes. The suspension was filtered through Celite and the filtrate was concentrated under vacuum. The residue was suspended in hot isopropanol (100 ml), then cooled and filtered. The pale maize colored powder was dried under vacuum (85° C., 0.01 mm Hg, 2 hours) to yield N-(2-pyrazinyl)-N-(4-piperidinyl)-2-furanamide (8.9 g, 72%) as the hydrochloride salt.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH3:17])[N:14]=[C:15]([CH3:16])[C:3]=12.[CH3:18][NH2:19]>O1CCCC1.C(OCC)(=O)C>[CH3:17][N:13]1[C:4]2=[N:5][CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]([NH:19][CH3:18])=[C:3]2[C:15]([CH3:16])=[N:14]1
Reactant: CCOC(=O)c1cnc2c(c(C)nn2C)c1Cl
Reactant: CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc2c(c(C)nn2C)c1NC
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
A mixture of 1.268 g (5 mmol) of ethyl 4-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate and 7.5 ml (15 mmol) of methylamine in tetrahydrofuran (2.0 molar solution) was stirred at room temperature overnight and refluxed for 2 hours. The solvent was removed to give a white solid. The solid was dissolved in ethyl acetate and the solution washed with H2O, 1M NaHCO3, brine and dried (Na2SO4). The solvent was removed to give a white solid. Crystallization from ethyl acetate gave 0.715 g of white solid; Mass spectrum (ES) 249.2 (M+H).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[O:14]([CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(OC[C@@H]2CCCN2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.8 %

Procedure:
To a solution of (S)-(+)-N-Boc-2-phenoxymethylpyrrolidine (0.81 g. 2.9 mmol) in 5 mL of CH2Cl2 in 0° C. was added 5 mL of TFA dropwise over 1 hour. The solution was warmed to room temperature and stirred for 1.5 hours. The reaction mixture was slowly poured into 30 mL of 10% NaOH and extracted thrice with 20 mL CH2Cl2. The organic layer was then dried over Na2SO4, filtered and concentrated under reduced pressure to give a light yellow oil (0.41 g, 79%). ES (+) MS m/e=178 (M+H).