Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([C:14]([OH:16])=O)=[N:6]2)[CH2:4][CH2:3][CH2:2]1.[NH2:17][C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:21]([CH2:31][C:32]2([OH:38])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:20][CH2:19]1.C(P(=O)(OCC)OCC)#N.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([C:14]([NH:17][C@H:18]3[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[C@@H:21]([CH2:31][C:32]4([OH:38])[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)[CH2:20][CH2:19]3)=[O:16])=[N:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(O)c1nn(C2CCC2)c2ccccc12
Reactant: CC(C)(C)OC(=O)N1C[C@H](N)CC[C@@H]1CC1(O)CCOCC1
Agent: CCOP(=O)(C#N)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2nn(C3CCC3)c3ccccc23)CC[C@@H]1CC1(O)CCOCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.7 %

Procedure:
The mixture of 1-cyclobutyl-1H-indazole-3-carboxylic acid (135 mg, 0.63 mmol, step 2 of Example 4), tert-butyl cis-5-amino-2-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidine-1-carboxylate (197 mg, 6.27 mmol, step 5 of Example 2), diethyl cyanophosphonate (0.13 mL, 0.75 mmol), and N,N-diisopropylethylamine (0.16 mL, 0.94 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 12 h. Then the mixture was poured onto aqueous saturated sodium hydrogencarbonate (100 mL), and the aqueous layer was extracted with ethyl acetate/toluene (3:1, 100 mL×3). The combined organic layer was concentrated under reduced pressure. The residue was chromatographed on a column of silica gel eluting with ethyl acetate/n-hexane (1:2) to give 112 mg (35%) of the title compound as a pale yellow amorphous.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[C:13]([F:16])([F:15])[F:14].[N:17]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl.O>[NH:1]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[C:13]([F:16])([F:14])[F:15])[NH2:17]
Reactant: Nc1ccc2[nH]c(=O)cc(C(F)(F)F)c2c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc2[nH]c(=O)cc(C(F)(F)F)c2c1
Temperature: -1 °C
Reaction time: 1 h

Procedure:
In a 250 mL rb flask a suspension of Compound 200 (structure 3 of Scheme XXXIII) (2.28 g, 10 mmol) in 10 mL conc. HCl was cooled to −1° C. and a solution of NaNO2 (0.40 g, 12 mmol) in water (5 mL) was added dropwise in 20 min. The dark yellow suspension was stirred at −1° C. for 1 h and then a solution of SnCl2.2H2O (5.2 g, 15 mmol) in conc HCl (10 mL) was added dropwise in 10 min. The light yellow suspension of Compound 793 was stirred at −1° C. for 2 h and then used directly or kept in a refrigerator at −1° C. until it was used (the crude compound can be stored for at least one month without decomposition).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][NH:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.Cl[C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>>[F:29][C:28]1[C:23]([N:17]2[CH2:18][CH2:19][C:11]3[C:10]([NH:9][C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:20])[F:21])=[CH:8][CH:7]=4)=[N:15][CH:14]=[N:13][C:12]=3[CH2:16]2)=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: Fc1cccnc1Cl
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CCNC3)cc1
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cccnc1N1CCc2c(ncnc2Nc2ccc(C(F)(F)F)cc2)C1
Temperature: 170 °C

Procedure:
The title compound was prepared according to the procedure given for Example 9 using N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (0.15 g, 0.51 mmol), 2-chloro-3-fluoropyridine (0.134 g, 0.10 mmol), N,N-diisopropylethylamine (0.133 mL, 0.76 mmol) and heating the reaction mixture 9 h at 170° C. to obtain 0.062 g of a white solid.
Reaction SMILES: CO.[NH2:3][OH:4].[CH2:5]([O:7][CH:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=O)[C:19]([NH:21][CH3:22])=[O:20])[CH3:9])[CH3:6]>O>[CH2:5]([O:7][CH:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=[N:3][OH:4])[C:19]([NH:21][CH3:22])=[O:20])[CH3:9])[CH3:6]
Reactant: NO
Reactant: CCOC(C)OCc1ccccc1C(=O)C(=O)NC
Solvent: CO
Solvent: O
Product: CCOC(C)OCc1ccccc1C(=NO)C(=O)NC
Yield: 37.5 %

Procedure:
Methanol (4 ml) and 50% aqueous hydroxylamine solution (0.4 g, 0.006 mol) were added to 2-[2-{(1-ethoxyethyl)oxymethyl}phenyl]-N-methyl-2-oxoacetamide (0.53 g, 0.002 mol). The mixture was stirred under reflux for 5 hours. After completion of the reaction, water (100 ml) was added, and the mixture was extracted with dichloromethane (50 ml) twice. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain 2-[2-{(1-ethoxyethyl)oxymethyl}phenyl]-2-hydroxyimino-N-methylacetamide (Isomer A: 0.21 g (Yield: 37.5%), colorless oil; Isomer B: 0.14 g (Yield: 25.0%), colorless crystals).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>C(OCCOCC)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1csc(Br)n1
Reactant: OB(O)c1ccccc1Cl
Agent: [Pd]
Agent: CCOCCOCC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1csc(-c2ccccc2Cl)n1
Temperature: 80 °C
Yield: 63.3 %

Procedure:
To a solution of ethyl 2-bromo-4-thiazolecarboxylate (2.0 g, 8.5 mmol), prepared as described above, in ethylene glycol diethyl ether (15 mL) is added 2-chlorophenylboronic acid (1.73 g, 11.1 mmol), 2N sodium carbonate (17 mL) and tetrakis(triphenylphosphine) palladium (0) (492 mg, 0.43 mmol). The reaction is subsequently sealed and heated to 80° C. for 3 hours under an argon atmosphere. Once complete, the reaction mixture is poured into CH2Cl2 and of water is added. The organic layer is separated, dried over sodium sulfate and concentrated to provide a yellow oil. The crude product is purified by column chromatography (10% ethyl acetate in hexanes) to afford 1.44 g of ethyl 2-(2-chlorophenyl)-4-thiazolecarboxylate.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([F:15])=[CH:10][CH:9]=2)=O.[NH2:16][NH2:17]>C(O)C>[F:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[N:6][C:5]([C:3]([NH:16][NH2:17])=[O:2])=[CH:14]2
Reactant: NN
Reactant: COC(=O)c1cc2cc(F)ccc2cn1
Solvent: CCO
Product: NNC(=O)c1cc2cc(F)ccc2cn1
Yield: 84.4 %

Procedure:
A solution of 6-fluoro-isoquinoline-3-carboxylic acid methyl ester (27 g) and hydrazine (42 g, 10 equiv.) in ethanol (500 mL) was refluxed for 2 h. The reaction mixture was concentrated under high vacuum to remove hydrazine, and the resulting residue was triturated with ethanol (100 mL) to give 6-fluoro-isoquinoline-3-carboxylic acid hydrazide as a light yellow solid (22.8 g, 84%). LRMS (M+H+) m/z 206.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([NH2:9])=[O:8].[H][H].C(O)C.[C:15]([OH:18])(=[O:17])[CH3:16]>[Pt]=O>[C:15]([OH:18])(=[O:17])[CH3:16].[C:15]([OH:18])(=[O:17])[CH3:16].[NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH:2]1[C:7]([NH2:9])=[O:8]
Reactant: [H][H]
Reactant: NC(=O)c1cnccn1
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CCO
Product: NC(=O)C1CNCCN1

Procedure:
One hundred twenty-five grams of pyrazinamide were hydrogenated in the presence of 2.5 L of 6:1 ethanol/acetic acid and 62.6 g of platinum oxide at 60 psi and 60° C. After hydrogen uptake ceased, the reaction mixture was filtered through a Celite® pad and concentrated in vacuo. Trituration with ethyl acetate afforded 219.57 g of the desired subtitle intermediate, m.p. 90-92° C.
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([N:11]2[CH2:39][C:15]3([CH2:18][N:17]([CH2:19][CH2:20][C:21]4[CH:22]=[C:23]([CH:36]=[CH:37][CH:38]=4)[CH2:24][CH2:25][O:26][CH2:27][CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[CH2:16]3)[O:14][CH2:13][CH2:12]2)=[O:10])[N:8]=1)([CH3:3])[CH3:2].[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41].C1(C)C=CC=CC=1>C(Cl)Cl>[F:43][C:42]([F:45])([F:44])[C:40]([OH:46])=[O:41].[CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([N:11]2[CH2:39][C:15]3([CH2:16][N:17]([CH2:19][CH2:20][C:21]4[CH:22]=[C:23]([CH:36]=[CH:37][CH:38]=4)[CH2:24][CH2:25][O:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:18]3)[O:14][CH2:13][CH2:12]2)=[O:10])[N:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CN(CCc4cccc(CCOCCC(=O)OC(C)(C)C)c4)C3)C2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)c1nc(C(=O)N2CCOC3(CN(CCc4cccc(CCOCCC(=O)O)c4)C3)C2)cs1
Reaction time: 1 h

Procedure:
A solution of tert-butyl 3-(3-(2-(8-(2-isopropylthiazole-4-carbonyl)-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)ethyl)phenethoxy)propanoate (460 mg) (example 176 step g) in DCM (6 mL) was treated with TFA (2 mL) and the solution allowed to stand at RT for 1 hour. Toluene (10 mL) was added and the solvents were evaporated under reduced pressure and the residue dissolved in acetonitrile and the solution evaporated under reduced pressure to afford the subtitled compound. Yield 500 mg.
Reaction SMILES: [CH3:1][C:2](OC(C)=O)=[O:3].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[NH:15]1[CH2:18][CH:17]([NH:19][C:20]2[C:21]([CH3:40])=[N:22][C:23]3[C:28]([N:29]=2)=[C:27]([C:30]2[NH:38][C:37]4[CH2:36][CH2:35][NH:34][C:33](=[O:39])[C:32]=4[CH:31]=2)[CH:26]=[CH:25][CH:24]=3)[CH2:16]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:2]([N:15]1[CH2:16][CH:17]([NH:19][C:20]2[C:21]([CH3:40])=[N:22][C:23]3[C:28]([N:29]=2)=[C:27]([C:30]2[NH:38][C:37]4[CH2:36][CH2:35][NH:34][C:33](=[O:39])[C:32]=4[CH:31]=2)[CH:26]=[CH:25][CH:24]=3)[CH2:18]1)(=[O:3])[CH3:1]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1CNC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CC(Nc2nc3c(-c4cc5c([nH]4)CCNC5=O)cccc3nc2C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.4 %

Procedure:
Ac2O (4.49 μl, 0.048 mmol) was added to a mixture of 2-(3-(azetidin-3-ylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one 2,2,2-trifluoroacetate (20.0 mg, 0.043 mmol) and DIPEA (0.023 mL, 0.130 mmol) in DCM (1.0 mL), and the resulting yellow suspension was stirred at 25° C. for 10 min. The mixture was concentrated in vacuo, and the residue was taken up in in DMSO (2.0 mL) and purified by reversed-phase HPLC (Phenomenex Gemini C18 column (150×30 mm, 10 μm), 35 mL/min, 5-100% ACN/H2O+0.1% TFA) to provide 2-(3-((1-acetylazetidin-3-yl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one 2,2,2-trifluoroacetate (19.0 mg, 0.038 mmol, 87% yield) as a red solid: 1H NMR (400 MHz, MeOH-d4) δ ppm 7.86 (1H, d, J=7.4 Hz), 7.66 (1H, d, J=7.4 Hz), 7.44 (1H, t, J=7.8 Hz), 7.18 (1H, s), 4.89-4.97 (1H, m), 4.69 (1H, t, J=8.3 Hz), 4.46 (1H, dd, J=9.9, 8.1 Hz), 4.23 (1H, dd, J=9.2, 5.1 Hz), 4.05 (1H, dd, J=10.4, 5.1 Hz), 3.64 (2H, t, J=7.1 Hz), 3.04 (2H, t, J=7.0 Hz), 2.66 (3H, s), 1.91 (3H, s). 19F NMR (376 MHz, MeOH-d4) δ ppm −77.73 (3F, s). m/z (ESI, +ve) 391.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1([CH:14]=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.[BH4-].[Na+].C(OCC)(=O)C>CO.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=CC1(c2cc(Cl)ccc2Cl)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: OCC1(c2cc(Cl)ccc2Cl)CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
A solution of 1-(2,5-dichlorophenyl)-cyclopentanecarbaldehyde (199) (25 g, 103.305 mmol) in methanol (300 mL), was cooled in ice bath, NaBH4 (7.816 g, 206.612 mmol) was added portion-wise and the mixture was stirred for 3 h at room temperature. Silica thin layer chromatography was performed (10% ethyl acetate in hexane, Rf=0.5). After completion of the reaction, it was quenched with saturated NH4Cl solution (100 mL), methanol was removed from the reaction mixture under reduced pressure, the residue was diluted with water and the mixture was extracted with dichloromethane, the combined organic layer was washed with brine, dried, and concentrated. The concentrate was purified using normal silica gel (100-200 mesh) column chromatography using a gradient eluent of 2 to 10% ethyl acetate in hexane to get [1-(2,5-dichlorophenyl)-cyclopentyl]-methanol (200) (23 g, 90.82%) as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=S)=[CH:7][CH:6]=1)=[O:4].[C:14]([O:18][C:19](=[O:45])[NH:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]1[CH:30]=[C:29]([C:31]([N:33]([CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])[CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])[CH:28]=[CH:27][C:26]=1[NH2:44])([CH3:17])([CH3:16])[CH3:15]>O1CCCC1>[CH3:42][CH:41]([CH3:43])[CH2:40][CH2:39][N:33]([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C:31]([C:29]1[CH:28]=[CH:27][C:26]2[N:44]=[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)[N:24]([CH2:23][CH2:22][CH2:21][NH:20][C:19]([O:18][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:45])[C:25]=2[CH:30]=1)=[O:32]
Reactant: COC(=O)c1ccc(N=C=S)cc1
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccc(N)c(NCCCNC(=O)OC(C)(C)C)c1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Nc2nc3ccc(C(=O)N(CCC(C)C)CCC(C)C)cc3n2CCCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
4-methoxycarbonylphenyl isothiocyanate (327 mg, 1.5 eq) and N-methylcyclohexylcarbodiimide-N-methyl-polystyrene resin (acquired from Novabiochem; charge 1.9 mmol/g; 1.75 g, 3 eq) are added successively to a solution of tert-butyl-3-[(2-amino-5-{[bis(3-methylbutyl)amino]carbonyl}phenyl)amino]propylcarbamate (500 mg, 1 eq) in tetrahydrofuran (30 ml). The mixture is heated under reflux for 17 hours then cooled down to ambient temperature and aminomethylpolystyrene resin (acquired from Novabiochem, 2 eq) is added. After stirring for 4 hours at ambient temperature, the mixture is filtered on frit and the filtrate is concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: heptane/ethyl acetate 1:1) produces the expected compound in the form of a white solid (409 mg; 60% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH2:13][C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[N:19][NH:20]2)=[CH:16][CH:15]=1>>[NH:20]1[C:21]2[C:17](=[CH:16][CH:15]=[C:14]([N:13]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[CH:22]=2)[CH:18]=[N:19]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: O=C1Nc2ccc(F)cc2C1=O
Product: O=C1Nc2ccc(F)cc2C1=Nc1ccc2cn[nH]c2c1
Yield: 54.2 %

Procedure:
The title compound (76 mg, 54%) was synthesized as a dark red solid according to the method described for Example A74 using 5-fluoroisatin (82.5 mg, 0.5 mmol) and 6-aminoindazole (66.5 mg, 0.5 mmol). NMR analysis indicated a 79:21 mixture of E/Z isomers. 1H NMR (400 MHz, DMSO-d6) δ 13.08 (s, 1H, NH), 11.03 (s, 1H, NH), 8.11 (s, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.22 (dt, J=9.2 Hz, 2.8 Hz, 1H), 6.90 (dd, J=8.4 Hz, 4.4 Hz, 1H), 6.82-6.77 (m, 1H), 5.98 (dd, J=8.0 Hz, 2.0 Hz, 1H); MS ESI 281.0 [M+H]+, calcd for [C15H9FN4O+H]+ 281.1.
Reaction SMILES: C(OC[CH:10]([C:19]1[NH:20][C:21]([C:29]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:30]=2[N:31]=[C:32]([NH:40][C:41]2(C)[CH2:43][CH2:42]2)[C:33]([CH3:39])=[N:34]3)=[CH:22][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C1C=CC=CC=1.C(OC(NCC(=O)CC([O-])=O)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+].BrCC(C1C(F)=CC=C2C=1N=C(NC1CC1)C(C)=N2)=O.C(OC(NCC(=O)C(CC(C1C=CC=C2C=1N=C(NC1CC1)C(C)=N2)=O)C(OCC)=O)=O)(C)(C)C>CN(C=O)C.CCO.CC(O)=O>[C:15]([O:14][C:12]([NH:11][CH2:10][C:19]1[NH:20][C:21]([C:29]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:30]=2[N:31]=[C:32]([NH:40][CH:41]2[CH2:42][CH2:43]2)[C:33]([CH3:39])=[N:34]3)=[CH:22][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:13])([CH3:16])([CH3:17])[CH3:18]
Reactant: CCOC(=O)c1cc(-c2cccc3nc(C)c(NC4(C)CC4)nc23)[nH]c1C(COCc1ccccc1)NC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)NCC(=O)CC(=O)[O-]
Agent: CCOC(=O)C(CC(=O)c1cccc2nc(C)c(NC3CC3)nc12)C(=O)CNC(=O)OC(C)(C)C
Agent: Cc1nc2ccc(F)c(C(=O)CBr)c2nc1NC1CC1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cccc3nc(C)c(NC4CC4)nc23)[nH]c1CNC(=O)OC(C)(C)C
Yield: 35 %

Procedure:
This compound (0.25 g, 35% yield) as a yellow solid was prepared according to the procedures described for Intermediate 355b, using 4-((tert-butoxycarbonyl)amino)-3-oxobutanoate (601) (0.45 g, 1.84 mmol), K2CO3 (0.53 g, 3.83 mmol), 2-bromo-1-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)ethanone (613) (0.49 g, 1.53 mmol) in DMF (4 mL) as starting material, followed by subsequent treatment of ethyl 4-((tert-butoxycarbonyl)amino)-2-(2-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxobutanoate (363a: m/z (ESI, +ve) 485.1 (M+H)+) with NH4OAc (0.36 g, 4.6 mmol) in EtOH (6 mL) and AcOH (1.5 mL). 1H NMR (400 MHz, DMSO-d6) δ 12.56 (br. s., 1H), 7.60 (dd, J=0.98, 8.02 Hz, 1H), 7.54 (d, J=1.96 Hz, 1H), 7.31-7.39 (m, 2H), 7.06 (br. s., 1H), 4.50 (d, J=5.48 Hz, 2H), 4.22 (q, J=7.04 Hz, 2H), 3.03 (br. s., 1H), 2.49 (s, 3H), 1.38 (s, 9H), 1.30 (t, J=7.04 Hz, 3H), 0.96-1.02 (m, 2H), 0.62-0.69 (m, 2H). m/z (ESI, +ve) 466.2 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)C.[OH-].[Na+]>O>[F:14][C:10]1[CH:9]=[C:8]([CH2:7][CH2:6][CH2:5][C:4]([OH:15])=[O:3])[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)CCCc1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCCc1cccc(F)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Crude 4-(3-fluorophenyl)butyric acid ethyl ester (10.5-kg), water (15.8 L) and 50% NaOH (12.0 kg) were charged to a reactor and stirred at 50° C. for 2 hours. The hydrolysis generated a mild exotherm to 55° C. The biphasic mixture became monophasic. Completion of the hydrolysis was confirmed by LC. The reaction mixture was cooled to 20° C. and washed with hexanes 15 kg (containing antistatic agent “ASA 3”) to remove 3′3-difluorobiphenyl impurity generated in the previous step. After phase separation the aqueous layer was acidified with 37% concentrated HCl (16.7 kg), keeping the exotherm below 40° C. Upon cooling the aqueous layer was extracted with MTBE (15 kg in three 5 kg extractions). The solvent was removed by vacuum distillation and excess MTBE removed with a hexane strip. The resulting 4-(3-fluoro-phenyl)-butyric acid (8.83 kg) was removed from the reactor as an oil and used without further purification: MS (M+1)=182; H1 NMR (300 MHz): δ ppm (CDCl3): 1.965 (2H, p, J=4.9, 2.47 hz), 2.37 (2H, t, J=2.47 Hz), 2.66 (2H, t, J=2.45), 6.87 (2H, m), 6.95 (1H, d, J=2.63), 7.22 (1H, m) 11.2 (0.2H, bs).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9]3(OCC[O:13]3)[CH2:10]2)=[CH:5][CH:4]=1)#[CH:2]>C1COCC1.Cl.C(OCC)C>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[CH2:10]2)=[CH:5][CH:4]=1)#[CH:2]
Reactant: C#Cc1ccc2c(c1)CC1(CC2)OCCO1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#Cc1ccc2c(c1)CC(=O)CC2
Reaction time: 2 h
Yield: 46.7 %

Procedure:
A solution of 7′-ethynyl-3′,4′-dihydrospiro[1,3-dioxolane-2,2′(1′H)-naphthalene] (0.85 g, 3.9 mmol ) in THF (15 ml ) and 1N HCl (5 ml) was stirred overnight at room temperature. Concentrated HCl (2×0.5 ml) was then added in two aliquots 2 hours apart. After stirring a further 2 hours the solution was diluted with diethyl ether, the aqueous phase was separated, and the solution dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel (15 g) eluting with diethyl ether:hexane (1:9→1:4) to give 7-ethynyl-2-tetralone as a solid (0.31 g). 1H NMR (CDCl3, 200 MHz) δ: 2.54 (t, J=7 Hz, 2H, CH2), 3.05 (s, 1H, ethynyl H), 3.06 (t, J=7 Hz, 2H, CH2), 3.56 (s, 2H, CH2), 7.18 (d, J=8 Hz, 1H, Ar), 7.26 (s, 1H, Ar), 7.34 (d, J=8 Hz, 1H, Ar).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[NH:10][C:9]2=[O:18])=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][C:21]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.O.Cl[Pd]Cl.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.[Fe+2]>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:18])[C:8]2=[CH:7][C:5]1[O:6][C:2]([C:21]2[CH:22]=[C:23]([CH:24]=[CH:25][C:20]=2[F:19])[C:26]([O:28][CH3:29])=[O:27])=[CH:3][CH:4]=1
Reactant: COC(=O)c1ccc(F)c(B(O)O)c1
Reactant: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(Br)o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(F)c(-c2ccc(C=C3C(=O)Nc4ccc(Cl)cc43)o2)c1
Temperature: 110 °C

Procedure:
To 3-((5-bromofuran-2-yl)methylene)-5-chloroindolin-2-one (150 mg, 0.466 mmol) in dioxane/water (2850/150 μL) was added 2-fluoro-5-(methoxycarbonyl)phenylboronic acid (111 mg, 0.559 mmol) and Cs2CO3 (456 mg, 1.398 mmol). The mixture was degassed with nitrogen for 5 minutes, then PdCl2 dppf (17 mg, 0.023 mmol) was added. The mixture was heated in microwave for 40 minutes at 110° C. Water was added and the solid formed was isolated by filtration to yield methyl 3-(5-((5-chloro-2-oxoindolin-3-ylidene)methyl)furan-2-yl)-4-fluorobenzoate. LCMS (M+1=398).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([OH:21])[CH:15]=[CH:14]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:38][C:39]([CH3:44])([CH3:43])[C:40](Cl)=[O:41].CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([O:21][C:40](=[O:41])[C:39]([CH3:44])([CH3:43])[CH3:38])[CH:15]=[CH:14]3)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.8 %

Procedure:
Dissolve the product of Example 3 (220 mg, 0.43 mmol) in pyridine (5 mL) and treat sequentially with trimethylacetyl chloride (0.144 mL, 1.17 mmol) and dimethylaminopyridine (DMAP, catalytic amount). Stir at ambient temperature for 18 hours and evaporate pyridine. Re-constitute the residue in ethyl acetate and wash with saturated aqueous NH4Cl, saturated aqueous NaHCO3, and brine. Dry the organic layer (Na2SO4), filter, and evaporate to obtain 277 mg of crude material. Pre-adsorb onto silica gel and chromatograph on a SiO2 column eluting the material with methanol in dichloromethane (0 to 6%) to give 235 mg of 2,2-dimethyl-propionic acid 6-(4-methanesulfonyl-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-yl ester. Dissolve the free base in a mixture of ethyl acetate and diethyl ether (20 mL; 1:1). Cool in an ice bath and treat with 2M HCl in diethyl ether (0.3 mL, 0.6 mmol). Collect the precipitate on filter paper and rinse with diethyl ether to obtain 220 mg of the title compound (80%): mass spectrum (ion spray): m/z=602.4 (M+H—HCl).