Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]([CH:14]([CH2:20][CH:21]2[CH2:23][CH2:22]2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][C:3]=1Br.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.[F-].[Cs+].CCOC(C)=O>COCCOC.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.O>[NH2:1][C:2]1[C:3]([C:30]2[CH:31]=[CH:32][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=2)=[CH:4][C:5]([CH:14]([CH2:20][CH:21]2[CH2:23][CH2:22]2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: CCOC(=O)C(CC1CC1)c1cc(Br)c(N)c(OCC(F)(F)F)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(CC1CC1)c1cc(OCC(F)(F)F)c(N)c(-c2ccc(C(F)(F)F)cc2)c1
Yield: 54.2 %

Procedure:
A mixture of ethyl 2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-3-cyclopropylpropanoate (1.1, 3.3 mmol), 4-trifluoromethylphenylboronic acid (1.26 g, 6.7 mmol), CsF (1.26 g, 8.3 mmol) and Pd (PPh3)4 (0.38 g, 0.33 mmol) in 50 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 50 mL of EtOAc and 50 mL of water were added. The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (0.85 g, 82% yield) as a white solid.
Reaction SMILES: [F:1][C:2](=[C:11]([F:13])[F:12])[CH2:3][CH2:4][S:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[Cl:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:14][C:8]1[S:7][C:6]([S:5][CH2:4][CH2:3][C:2]([F:1])=[C:11]([F:12])[F:13])=[N:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: FC(F)=C(F)CCSc1nccs1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)=C(F)CCSc1ncc(Cl)s1

Procedure:
2-(3,4,4-Trifluoro-3-butenylthio)thiazole (6.75 g, 30 mM) is dissolved in carbon tetrachloride (60 ml). N-chlorosuccinimide (4.8 g) is added to the solution and refluxed for 18 hours by heating. As soon as the reaction has reached room temperature, the mixture is filtered and the solvent is distilled off. The concentrate is purified by column chromatography (eluent: hexane/ethyl acetate=90/10) to obtain 5-chloro-2-(3,4,4-trifluoro-3-butenylthio)thiazole as pale yellow liquid (n20D 1.5326).
Reaction SMILES: [CH:1]([NH:4][C:5](=O)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)([CH3:3])[CH3:2].S(Cl)([Cl:16])=O>>[CH:1]([N:4]=[C:5]([Cl:16])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Product: CC(C)N=C(Cl)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
N-Isopropyl 4-chlorobenzamide (12.7 g, 64.3 mmole) and thionyl chloride (53.81 g, 447 mmole) were heated at reflux with stirring for two hours. Excess thionyl chloride was removed by distillation. The title compound was isolated by distillation (b.p. 65°-70° C. at ~1 mm Hg) to yield 10.7 g (77%) of a light brown yellow liquid.
Reaction SMILES: C(OC([NH:11]/[C:12](=[CH:17]\[C:18]1[C:19]([Cl:25])=[N:20][CH:21]=[CH:22][C:23]=1I)/[C:13]([O:15][CH3:16])=[O:14])=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].N1CCC[C@H]1C(O)=O>O1CCOCC1.[Cu]I>[Cl:25][C:19]1[C:18]2[CH:17]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[NH:11][C:23]=2[CH:22]=[CH:21][N:20]=1
Reactant: COC(=O)/C(=C/c1c(I)ccnc1Cl)NC(=O)OCc1ccccc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1cc2c(Cl)nccc2[nH]1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
Methyl (2Z)-2-{[(benzyloxy)carbonyl]amino}-3-(2-chloro-4-iodopyridin-3-yl)prop-2-enoate (11.46 g, 24.25 mmole), K2CO3 (10.05 g, 72.7 mmole), CuI (0.462 g, 2.425 mmole), and L-proline (0.558 g, 4.85 mmole) were combined in 1,4-dioxane (120 mL). The mixture was degassed (3× pump/N2) then heated to reflux. After stirring at reflux overnight the mixture was cooled to RT, diluted with saturated aqueous NH4Cl, and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered through a pad of Celite, and concentrated. The resulting solid was triturated with Et2O/hexanes to give the title compound (4.6 g, 90%) as an off-white solid. NMR (399 MHz, CDCl3): δ 9.25 (s, 1 H); 8.18 (d, J=5.8 Hz, 1 H); 7.35 (d, J=2.1 Hz, 1 H); 7.29 (d, J=5.9 Hz, 1 H); 3.99 (s, 3 H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30]C(=O)OC(C)(C)C)[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.CC1(C)C(C)(C)OB([C:46]2[CH:47]=[N:48][NH:49][CH:50]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[NH:49]1[CH:50]=[C:46]([C:2]2[N:3]=[C:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[NH:8][C:7]4[N:15]=[CH:16][CH:17]=[CH:18][C:6]=4[N:5]3[C:19]=2[C:20]2[CH:21]=[CH:22][C:23]([C:26]3([NH2:30])[CH2:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)[CH:47]=[N:48]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: NC1(c2ccc(-c3c(-c4cn[nH]c4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 160 °C
Yield: 17.5 %

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.09 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (35 mg, 0.18 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (6.3 mg, 0.01 mmol) and K3PO4 (72 mg, 0.27 mmol) in DMF/water (0.9 mL, 6:1, v/v) was heated at 160° C. under microwave irradiation for 2 hour in total. After cooling to room temperature, the mixture was diluted with EtOAc and washed with water (×3). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by HPLC. To the fraction, conc. HCl (3 mL) and methanol (3 mL) were added and the residue was evaporated after 24 h. The residue was purified by HPLC to give the titled compound as a white solid (7 mg, 15%). 1HNMR (CD3OD) 400 MHz δ: 8.23 (s, 1H), 8.07 (dd, J=4.9, 1.4 Hz, 1H), 7.95 (dd, J=7.7, 1.4 Hz, 1H), 7.65 (s, 2H), 7.56 (d, J=8.6 Hz, 2H), 7.41 (d, J=8.0 Hz, 2H), 7.39 (t, J=7.4 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.16 (t, J=7.4 Hz, 1H), 7.01 (dd, J=8.0, 1.7 Hz, 1H), 6.70 (dd, J=8.0, 5.2 Hz, 1H), 2.84-2.76 (m, 2H), 2.65-2.57 (m, 2H), 2.31-2.22 (m, 1H), 2.05-1.95 (m, 1H); LCMS: 446 [M+H].
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH:20]3[CH2:21][CH2:22][CH2:23][CH:16]2[CH2:17][CH2:18][CH2:19]3)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.CCOC(C)=O.[Pd]>[CH:16]12[CH:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[CH:20]([CH2:19][CH2:18][CH2:17]1)[CH2:21][CH2:22][CH2:23]2
Reactant: c1ccc(COc2ccc(C3C4CCCC3CCC4)cc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Oc1ccc(C2C3CCCC2CCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 9-(4-benzyloxy-phenyl)-bicyclo[3.3.1]nonane (4.4 g, 14.6 mmol) in MeOH (100 mL) and EtOAc (100 mL) (warmed to 40° C. to facilitate dissolution, then cooled to room temperature) was added 10% Pd/C (0.5 g) under N2. This mixture was stirred under H2 (1 atm) overnight. The reaction mixture was then filtered through celite. The filtrate was concentrated to give the title compound as a solid.(3.1 g).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][N:14]([C:16]2[S:17][C:18]3[CH:24]=[C:23]([NH:25][C:26]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=5)=[CH:30][CH:29]=4)=[O:27])[CH:22]=[CH:21][C:19]=3[N:20]=2)[CH3:15])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:15][N:14]([CH2:13][CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[C:16]1[S:17][C:18]2[CH:24]=[C:23]([NH:25][C:26]([C:28]3[CH:29]=[CH:30][C:31]([C:34]4[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=4)=[CH:32][CH:33]=3)=[O:27])[CH:22]=[CH:21][C:19]=2[N:20]=1
Reactant: CN(CC1CCN(C(=O)OC(C)(C)C)C1)c1nc2ccc(NC(=O)c3ccc(-c4ccc(F)cc4)cc3)cc2s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CC1CCNC1)c1nc2ccc(NC(=O)c3ccc(-c4ccc(F)cc4)cc3)cc2s1
Reaction time: 0.25 h
Yield: 95 %

Procedure:
Place 3-[({6-{(4′-fluoro-biphenyl-4-carbonyl)-amino]-benzothiazol-2-yl}-methyl-amino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester in DCM (50 mL). Add trifluoroacetic acid (100 mL) and stir at rt for 6 h. Concentrate in vacuo and then add DCM:Hexane and concentrate in vacuo. Dissolve the residue in 1:1 MeOH:DCM and add polyvinyl pyridine (3 g) and stir for 15 min. Filter the solution and wash the resin with DCM. Collect the filtrate and concentrate in vacuo to yield 1.50 g (95%) of the title compound. mass spectrum (ion-spray): (m/z)=461.0 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[C:16]([CH3:17])=[C:15]([O:18][CH3:19])[C:14]([CH3:20])=[CH:13][N:12]=1)=O>C1COCC1>[OH:8][CH2:9][C:11]1[C:16]([CH3:17])=[C:15]([O:18][CH3:19])[C:14]([CH3:20])=[CH:13][N:12]=1
Reactant: COC(=O)c1ncc(C)c(OC)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1c(C)cnc(CO)c1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
Lithium aluminum hydride (0.94 g, 25.4 mmol) was dissolved in 100 ml of absolute THF and added in a dropwise manner to a stirred solution of compound 8 (2.5 g, 12.82 mmol) in 20 ml of THF at 0° C. The mixture was stirred at 0° C. for 2 hr. Excess LiAlH4 was then destroyed with ethyl acetate. The combined organic phases were dried, filtered, and evaporated in vacuo to give compound 9 (1.1 g, 50% yield). It gave same analytic data as those of an authentic sample.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH2:25][C:24]([CH3:26])=[N:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[O:9])=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].CC(O)(C)C.[H][H]>CC([C@@H](N)C(N)(C1C=CC(OC)=CC=1)C1C=CC(OC)=CC=1)C.COC1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C(C2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC(OC)=NC=2OC)=C(OC)N=1.Cl[Ru]Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[OH:9])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CC1=NN=C(Nc2nc(C(=O)c3ccc(F)cc3)nc3ccccc23)C1
Agent: Cl[Ru]Cl
Agent: CC(C)(C)[O-]
Agent: COc1cc(P(c2ccccc2)c2ccccc2)c(-c2c(P(c3ccccc3)c3ccccc3)cc(OC)nc2OC)c(OC)n1
Solvent: CC(C)(C)O
Product: Cc1cc(Nc2nc([C@@H](O)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Temperature: 40 °C
Reaction time: 18 h
Yield: 82.3 %

Procedure:
A stirred mixture of (4-fluorophenyl)(4-(5-methyl-4H-pyrazol-3-ylamino)quinazolin-2-yl)methanone (16.66 g, 48 mmol) and [(R)-P-Phos RuCl2 (R)-DAIPEN] (217 mg, 0.192 mmol) at room temperature was subjected to five cycles of pressurizing with nitrogen to 40 psi followed by depressurization. Then 1M KOtBu/tBuOH (576 μL, 0.0.576 mmol) in 9:11-PrOH/H2O (4 mL) was added and the mixture was subjected to five cycles of pressurizing with nitrogen to 40 psi followed by depressurization. The stirred mixture was then subjected to ten cycles of pressurizing with hydrogen to 435 psi followed by depressurization. The mixture was then stirred at 900 rpm under hydrogen (435 psi) at 40° C. for 18 hrs. The mixture was allowed to cool to room temperature and then carefully vented. The resulting precipitate was collected by filtration and washed with cold MeOH (100 mL) to afford (S)-(4-fluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)methanol as a white solid (13.8 g). Chiral HPLC indicated a >99% enantiomeric excess of the earlier eluting enantiomer.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([OH:15])[C@@H:13]([CH2:16][OH:17])[CH2:12][NH:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:19][CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:8][C@H:9]1[C@H:14]([OH:15])[C@@H:13]([CH2:16][OH:17])[CH2:12][N:11]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@H]1CNC[C@@H](OCc2ccccc2)[C@@H]1O
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCN1C[C@H](CO)[C@@H](O)[C@H](OCc2ccccc2)C1
Yield: 66.3 %

Procedure:
(3R,4R,5R)-3-Benzyloxy-5-hydroxymethyl-4-piperidinol (87 mg, 0.37 mmol), 1-iodobutane (81 mg, 0.44 mmol, 50 μl), potassium carbonate (154 mg, 1.1 mmol) and dry acetone (8 ml) were stirred for 24h at 40° C. under a nitrogen atmosphere. The solvent was evaporated in vacuo, and the residue purified on a silica gel column (Eluent: ethyl acetate/methanol/25% ammonium hydroxide (6/1/1%)). This afforded the free base of (3R,4R,5R)-3-benzyloxy-1-butyl-5-hydroxymethyl-4-piperidinol (Yield: 72 mg, 67%).
Reaction SMILES: [H-].[Na+].C(O[C:6](=O)[CH2:7][C@@H:8]([N:10]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:11][C:12]([O:14]CC)=O)C)C.[CH2:25](O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C.Cl>[CH2:17]([N:10]1[CH2:8][C@@H:7]([CH3:6])[CH2:25][C:12](=[O:14])[CH2:11]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCO
Reactant: CCOC(=O)C[C@H](C)N(CC(=O)OCC)Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@H]1CC(=O)CN(Cc2ccccc2)C1
Temperature: 120 °C
Yield: 43 %

Procedure:
To a suspension of sodium hydride (55% dispersion in mineral oil, 6.4 g, 14 mmol) in toluene (90 ml) was added (S)-3-(benzyl-ethoxycarbonylmethyl-amino)-butyric acid ethyl ester (20.3 g, 0.06 mol) in toluene (10 ml), followed by ethanol (1 ml). A vigorous reaction ensued, after 15 minutes the reaction was diluted with ethyl acetate, washed with 10% aq. citric acid solution, dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (ethyl acetate/heptane 1:9) affording a complex mixture of diastereomers (7.2 g, 42%). A portion of this material (3.5 g, 13 mmol) was dissolved in 25% aq. hydrochloric acid solution (20 ml) and heated in a loosely closed tube at 120° C. for 36 h. The solvent was evaporated, the residue redissolved in dichloromethane, washed with sat. aq. sodium hydrogencarbonate solution, dried (Na2SO4) and concentrated. Purification by flash column chromatography (ethyl acetate/heptane 1:4) afforded the titled product as a crystalline solid (1.1 g, 43%). MS (ISP)=204.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=N[CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])=[N:6][CH:7]=1.BrC1C=CC=[C:28]([F:32])C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:28]([F:32])[CH:19]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])=[N:6][CH:7]=1
Reactant: Fc1cccc(Br)c1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccc(F)cn2)n1
Product: Cc1ccc(Nc2cccc(F)c2)c(C(=O)Nc2ccc(F)cn2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (5-fluoro-pyridin-2-yl)-amide (example 8) in accordance with the general method of example 20 using 1-Bromo-3-fluorobenzene instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow crystalline solid, MS (ISP): m/e=341.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5].[C:12](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.O>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[CH:4]=[O:5]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1c(O)cc(Cl)cc1Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(Cl)cc(Cl)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
To a stirred solution of 2,4-dichloro-6-hydroxybenzaldehyde (1.85 g, 9.69 mmol) in N,N-dimethylformamide (20 mL) at ambient temperature was added solid potassium carbonate (1.47 g, 10.7 mmol), and the resulting yellow mixture was stirred at ambient temperature for 30 minutes. Iodomethane (2.42 mL, 38.7 mmol) was added, and the resulting mixture was stirred in an oil bath set to 50° C. for 30 minutes. The mixture was cooled to ambient temperature and diluted with water (200 mL). After stirring for 10 minutes, the precipitate that formed was collected by filtration, washed with water, and dried under vacuum to afford 2,4-dichloro-6-methoxybenzaldehyde as an off-white powder (1.93 g, 97% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH2:17][N:16]([C:21](OC(C)(C)C)=[O:22])[CH2:15]3)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.C(OCC)(=O)C.[CH2:35]([O:37][C:38]([C@@H:40]1[CH2:42][C@H:41]1C(O)=O)=[O:39])[CH3:36].CCN=C=NCCCN(C)C>ClCCl.CO.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH2:17][N:16]([C:21]([C@@H:41]2[CH2:42][C@H:40]2[C:38]([O:37][CH2:35][CH3:36])=[O:39])=[O:22])[CH2:15]3)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)[C@@H]1C[C@H]1C(=O)O
Reactant: CCc1[nH]c(C(=O)Nc2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1C(=O)N1Cc2ccc(NC(=O)c3nc(Cl)c(CC)[nH]3)cc2C1
Reaction time: 0.33 h
Yield: 64.7 %

Procedure:
tert-Butyl 5-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-1,3-dihydro-2H-isoindole-2-carboxylate (described in Example (92a), 0.17 g, 0.42 mmol) was dissolved in dichloromethane (3 mL) and methanol (1 mL). A 4 N hydrochloric acid/ethyl acetate solution (15 ml, 60 mmol) was added, followed by stirring for 20 minutes. The solvent was evaporated under reduced pressure. The resulting residue was dissolved in dichloromethane (5 mL) and DMA (5 mL). trans-2-(Ethoxycarbonyl)cyclopropanecarboxylic acid (described in Wessjohann, Ludger A.; Fulhorst, Michael; Zakharova, Svetlana, Pol. J. Chem., 80, 4, 2006, 673-678, 87 mg, 0.55 mmol), WSC (191 mg, 1 mmol) and DMAP (10 mg) were added, and the mixture was stirred at room temperature for one hour. The reaction solution was concentrated, diluted with ethyl acetate, washed with water and brine, and dried over anhydrous magnesium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: chloroform/methanol=95/5, 90/10) to obtain 117 mg of the title compound as a light brown solid (65%).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:40][C:17]3=[N:18][CH:19]=[C:20]([C:22]4[CH:23]=[C:24]([CH:37]=[CH:38][CH:39]=4)[C:25]([NH:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([CH3:30])[CH3:29])=[O:26])[CH:21]=[C:16]3[C:15]=2[CH:41]=[O:42])=[CH:10][CH:9]=1>CN(C=O)C.CCOC(C)=O>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:40][C:17]3=[N:18][CH:19]=[C:20]([C:22]4[CH:39]=[CH:38][CH:37]=[C:24]([C:25](=[O:26])[NH:27][C:28]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)([CH3:30])[CH3:29])[CH:23]=4)[CH:21]=[C:16]3[C:15]=2[C:41]([OH:1])=[O:42])=[CH:10][CH:9]=1
Reactant: O=S([O-])OO
Reactant: CC(C)(NC(=O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(C=O)c3c2)c1)c1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(NC(=O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(C(=O)O)c3c2)c1)c1ccccc1
Reaction time: 72 h
Yield: 33.3 %

Procedure:
Oxone (28 mg, 0.046 mmol) was added to a stirring solution of 3-(2-(4-fluorophenyl)-3-formylfuro[2,3-b]pyridin-5-yl)-N-(2-phenylpropan-2-yl)benzamide (20 mg, 0.042 mmol) in DMF (0.5 mL) at room temperature. It was allowed to stir for 3 days. An additional amount of Oxone (28 mg, 0.046 mmol) was added and the reaction was allowed to stir overnight. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the expected product 2-(4-fluorophenyl)-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)furo[2,3-b]pyridine-3-carboxylic acid (7 mg, 0.014 mmol, 34% yield) consistent by LCMS and NMR. 1H NMR (500 MHz, MeOD) δ ppm 7.42 (1H, d, J=2.14 Hz), 7.31-7.39 (2H, m), 6.93-7.02 (2H, m), 6.87 (1H, s), 6.59 (2H, t, J=8.70 Hz), 6.34 (1H, t, J=7.63 Hz), 6.20 (2H, d, J=7.63 Hz), 5.97-6.07 (4H, m), 5.92 (1H, t, J=7.32 Hz), 0.52 (6H, s). LC-MS retention time: 1.15 min; m/z (MH+): 495. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 mM, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:11]([O:15][CH2:16][C@@H:17]([OH:19])[CH3:18])([CH3:14])([CH3:13])[CH3:12].O.[Br:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28](F)[CH:29]=1)[C:25]#[N:26]>CN(C=O)C>[Br:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([O:19][C@@H:17]([CH3:18])[CH2:16][O:15][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:29]=1)[C:25]#[N:26]
Reactant: N#Cc1cc(F)cc(Br)c1
Reactant: C[C@H](O)COC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](COC(C)(C)C)Oc1cc(Br)cc(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 112.6 %

Procedure:
To a stirred suspension of sodium bis(trimethylsilyl)amide (74.25 mmol; 14.33 g) in DMF (150 mL) at 23° C. was added (S)-tert-butoxy-2-propanol (74.25 mmoles, 9.82 g) over 15 minutes. A slight exotherm was observed (cold water cooling bath applied). A solution of 3-bromo-5-fluorobenzonitrile (49.50 mmol, 10.0 g) in DMF (40 mL) was added over 15 minutes with cold water bath still present. An exotherm (3° C.) was observed and the mixture turned from yellow to brown. DMF (10 mL) was added and the mixture stirred at ambient temperature for 1 hour. The reaction was quenched by addition of aqueous HCl (2M, 100 mL), maintaining temperature below 25° C. The mixture was diluted with water (200 mL) and extracted with 2:1 EtOAc/MTBE (3×200 mL). The organic layers were combined, washed with water (3×200 mL) and dried over MgSO4, and the solvent removed in vacuo affording the title compound as an orange oil (17.4 g). Further drying in vacuo at 23° C. gave the title product (15.5 g, ˜100%).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]CC)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:28]=[CH:29][C:30]([N:32]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:33]([CH3:35])=[O:34])=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:28]=[CH:29][C:30]([N:32]([NH:36][C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[C:33]([CH3:35])=[O:34])=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(N(NC(=O)OC(C)(C)C)C(C)=O)ccc2n1Cc1ccc(-c2ccccc2C(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCc1nc2cc(N(NC(=O)OC(C)(C)C)C(C)=O)ccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 72 from ethyl 4'-[(2-n-butyl-5-(tert.butoxycarbonylaminoacetamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and 2N sodium hydroxide.