Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@@H:12]([C:14]3[O:18][NH:17][C:16](=[O:19])[CH:15]=3)[CH2:11][CH2:10][N:9]2C(OC)=O)=[C:4]([F:24])[CH:3]=1.Br>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@@H:12]([C:14]3[O:18][NH:17][C:16](=[O:19])[CH:15]=3)[CH2:11][CH2:10][NH:9]2)=[C:4]([F:24])[CH:3]=1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(Cl)cc1F
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](c3ccc(Cl)cc3F)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
(2R,4S)-Methyl 2-(4-chloro-2-fluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.504 g, 1.42 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 11.20 mL, 63.93 mmol) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(4-chloro-2-fluorophenyl)piperidin-4-yl)isoxazol-3(2H)-one (313 mg, 74%). 1H NMR (600 MHz, dmso) δ 1.35 (q, 1H), 1.46 (dq, 1H), 1.86 (d, 1H), 1.94 (d, 1H), 2.73 (dt, 1H), 2.90 (tt, 1H), 3.10 (td, 1H), 3.91 (d, 1H), 5.73 (s, 1H), 7.25 (dd, 1H), 7.34 (dd, 1H), 7.55 (t, 1H). HRMS Calcd for [C14H14ClFN2O2+H]+: 297.0806. Found: 297.0786.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12]C(OCC2C=CC=CC=2)=O)[CH2:10][CH2:9][N:8]([CH2:23][CH2:24][O:25][C:26]2[CH:35]=[N:34][C:33]3[C:28](=[CH:29][C:30]([O:36][CH3:37])=[CH:31][CH:32]=3)[N:27]=2)[CH2:7]1)=[O:5])[CH3:2]>[Pd].CO>[CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH2:12])[CH2:10][CH2:9][N:8]([CH2:23][CH2:24][O:25][C:26]2[CH:35]=[N:34][C:33]3[C:28](=[CH:29][C:30]([O:36][CH3:37])=[CH:31][CH:32]=3)[N:27]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CN(CCOc2cnc3ccc(OC)cc3n2)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)[C@@H]1CN(CCOc2cnc3ccc(OC)cc3n2)CC[C@@H]1N
Reaction time: 4 h
Yield: 90.8 %

Procedure:
10% Palladium on activated carbon (188 mg, 0.18 mmol, 0.5 eq) is added at room temperature to a stirred solution of (3R,4S)-4-benzyloxycarbonylamino-1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidine-3-carboxylic acid ethyl ester (200 mg, 0.35 mmol, 1.0 eq) in methanol (20 mL). The mixture is hydrogenated for 4 hours, then filtered through decalite. Solvent is removed to afford (3R,4S)-4-amino-1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidine-3-carboxylic acid ethyl ester as a yellow oil (119 mg, 81% yield).
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[C:19]1([CH:25]([CH3:30])[C:26]([O:28][CH3:29])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN(P(N(C)C)(N(C)C)=O)C.CI.[Cl-].[NH4+]>C1COCC1.O>[CH3:30][C:25]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:1])[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)C(C)c1ccccc1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: COC(=O)C(C)(C)c1ccccc1
Temperature: -30 °C
Reaction time: 0.33 h
Yield: 67 %

Procedure:
A solution of n-butyl lithium in hexane (1.44N, 60.0 ml, 86.4 mmol) was added to a solution of diisopropylamine (9.07 g, 89.6 mmol) in anhydrous THF (200 ml) cooled at -30° C. under argon atmosphere, and the mixture was stirred for 20 minutes. To this reaction mixture were added a solution of methyl 2-phenylpropionate (10.5 g, 64.0 mmol) in 10 ml of anhydrous THF and HMPA (16.5 g, 92.0 mmol), and the mixture was stirred at -30° C. for 10 minutes and then at 0° C. for 45 minutes. To this reaction solution was added a solution of methyl iodide (13.6 g, 96.0 mmol) in anhydrous THF (30 ml) at -30° C., and the mixture was stirred at -30° C. for 1 hour. This reaction mixture was added to an aqueous saturated solution of ammonium chloride (400 ml) and water (50 ml) was added. The mixture was extracted with ether (400 ml). The aqueous layer further extracted with ethyl acetate. The combined organic layers were washed with water (300 ml) and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was distilled (b.p. 99°-100° C./6 mmHg) to give an oil of methyl 2-methyl-2-phenylpropionate (7.63 g, 42.9 mmol, 67.0%). This compound was assigned the structure by the following data:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]([OH:7])=O.CS(Cl)(=O)=O.[NH2:13][C:14]1[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][C:15]=1[C:16]([NH:18][CH3:19])=[O:17]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:24][C:22]1[CH:21]=[CH:20][C:15]([C:16]([NH:18][CH3:19])=[O:17])=[C:14]([NH:13][C:5](=[O:7])[CH2:4][CH2:3][O:2][CH3:1])[CH:23]=1
Reactant: COCCC(=O)O
Reactant: CNC(=O)c1ccc(Br)cc1N
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CNC(=O)c1ccc(Br)cc1NC(=O)CCOC
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a mixture of 3-methoxypropanoic acid (0.25 mL, 2.62 mmol), DMAP (0.64 g, 5.24 mmol) and dry DCM (5 mL) was added methanesulfonyl chloride (0.22 mL, 2.88 mmol) dropwise at 0° C. under nitrogen atmosphere. 2-Amino-4-bromo-N-methylbenzamide (0.3 g, 1.31 mmol) was added after stirring for 1 h, and the temperature was allowed to rise to room temperature slowly. The reaction mixture was quenched with sat. NH4Cl solution after 3 h and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with NaHCO3, dried over Na2SO4, filtered, and evaporated to give 0.39 g of the target compound. MS (ESI): 315, 317 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:12](=[C:14]([C:18](O)=[O:19])[CH:15]=[CH:16][CH:17]=3)[N:13]=2)=[CH:5][CH:4]=1.Cl.Cl.[NH2:24][CH:25]1[CH2:32][CH:31]2[N:33]([CH3:34])[CH:27]([CH2:28][CH2:29][CH2:30]2)[CH2:26]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:34][N:33]1[CH:27]2[CH2:28][CH2:29][CH2:30][CH:31]1[CH2:32][CH:25]([NH:24][C:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:11]3[O:10][C:9]([C:6]4[CH:5]=[CH:4][C:3]([N:2]([CH3:21])[CH3:1])=[CH:8][CH:7]=4)=[N:13][C:12]=13)=[O:19])[CH2:26]2
Reactant: CN(C)c1ccc(-c2nc3c(C(=O)O)cccc3o2)cc1
Reactant: CN1C2CCCC1CC(N)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(C)c1ccc(-c2nc3c(C(=O)NC4CC5CCCC(C4)N5C)cccc3o2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38.1 %

Procedure:
A mixture of 2-(4-dimethylaminophenyl)benzoxazole-4-carboxylic acid (78 mg, 0.32 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (86 mg, 0.38 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (86 mg, 0.45 mmol) and 1-hydroxybenzotriazole (122 mg, 0.90 mmol) in DMF (5 mL) was stirred for 10 min at room temperature, then DIPEA (0.26 mL, 1.6 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (20 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) and recrystallized from acetonitrile to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-dimethylaminophenyl)benzoxazole-4-carboxamide (51 mg, 41%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.21 (d, J=7.0 Hz, 1H), 8.15-8.09 (m, 3H), 7.61 (d, J=8.0 Hz, 1H), 7.35 (t, J=8.0 Hz, 1H), 6.80 (d, J=9.0 Hz, 2H), 4.61-4.54 (m, 1H), 3.10-3.15 (m, 8H), 2.68-2.62 (m, 2H), 2.55 (s, 3H), 2.05-1.96 (m, 2H), 1.59-1.49 (m, 4H), 1.22-1.19 (m, 1H); MS (ESI+) m/z 419 (M+H); HPLC 93.1% (AUC), tR=16.55 mm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19]C)=[CH:16][CH:17]=2)[CH:12]=[C:11]([CH3:21])[C:10]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4](/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[CH:12]=[C:11]([CH3:21])[C:10]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3F)c(-c3ccccc3)c(C)cc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2cc(O)ccc2c(Oc2ccc(/C=C/C(=O)O)cc2F)c1-c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 101.5 %

Procedure:
Compound 26 (122 mg, 0.29 mmol, 1 equiv) was dissolved in CH2Cl2 (25 mL) and cooled to 0° C. under N2. BBr3 (135 μL, 1.42 mmol, 5 equiv) was added dropwise and the resulting solution was allowed to stir at 0° C. for 3 h. The reaction mixture was then poured into ice and the product extracted into EtOAc (250 mL). The organics were washed with saturated aqueous NaCl (100 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel flash column chromatography (50% EtOAc in hexanes) to provide the title compound (27) (122 mg, 66%) as a yellow solid. 1HNMR (400 MHz, DMSO-d6): δ 9.89 (s, 1H), 7.61-7.51 (m, 3H), 7.39 (m, 1H), 7.31-7.15 (m, 7H), 7.01 (m, 1H), 6.38 (m, 2H), 2.15 (s, 3H). MS m/z 413.4 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([NH:13][CH2:14][C:15]([CH2:21][NH:22][C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)([OH:20])[C:16]([F:19])([F:18])[F:17])[CH3:12]>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:13]([CH2:11][CH3:12])[CH2:14][C:15]([CH2:21][NH:22][C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:33]1[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=1)([OH:20])[C:16]([F:17])([F:19])[F:18])=[O:6]
Reactant: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Reactant: O=C(O)c1ccccc1Cl
Product: CCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccccc1Cl

Procedure:
Prepared similarly to Example 1 from 2-chlorobenzoic acid and 3-(ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-6-methyl-1H-indazol-4-yl]amino}methyl)-2-propanol.
Reaction SMILES: Cl[C:2]1[N:3]([CH3:13])[C:4](=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].[F:14][C:15]1[CH:20]=[C:19]([S:21][CH3:22])[CH:18]=[CH:17][C:16]=1[NH2:23]>>[F:14][C:15]1[CH:20]=[C:19]([S:21][CH3:22])[CH:18]=[CH:17][C:16]=1[NH:23][C:2]1[N:3]([CH3:13])[C:4](=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(=O)n(C)c1Cl
Reactant: CSc1ccc(N)c(F)c1
Product: COC(=O)c1ccc(=O)n(C)c1Nc1ccc(SC)cc1F

Procedure:
Methyl 2-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate was prepared from methyl 2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate and 2-fluoro-4-(methylthio)benzenamine as described in Step C of Example 153.
Reaction SMILES: Cl[C:2]1[S:6][C:5](=[N:7][C:8](=[O:10])[CH3:9])[N:4]([CH2:11][CH2:12][O:13][CH3:14])[CH:3]=1.[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C(O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C:2]1[S:6][C:5](=[N:7][C:8](=[O:10])[CH3:9])[N:4]([CH2:11][CH2:12][O:13][CH3:14])[CH:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: COCCn1cc(Cl)sc1=NC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COCCn1cc(-c2ccc(F)cc2F)sc1=NC(C)=O
Temperature: 85 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
A flask was charged with the product from Example 120A (10.2 g, 42.6 mmol), 2,4-difluorophenylboronic acid (8.08 g, 51.1 mmol), Na2CO3 (64.0 mL of a 2 M aqueous solution, 128 mmol) and PdCl2(PPh3)2 (1.5 g, 2.13 mmol) in 100 mL of DME/H2O/ethanol (7:3:2). The mixture was warmed to 85° C. and stirred overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with water. The organic extract was dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography on SiO2 using a gradient of 0% to 100% ethyl acetate:hexane to provide 11.5 g (86%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 2.17 (s, 3 H) 3.27 (s, 3 H) 3.71 (t, J=5.3 Hz, 2 H) 4.37 (t, J=5.4 Hz, 2 H) 7.17-7.24 (m, 1 H) 7.38-7.48 (m, 1 H) 7.64-7.74 (m, 1 H) 7.88 (s, 1 H); MS (ESI+) m/z 313 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:18]([C:19]([NH:21][CH3:22])=[O:20])=[C:11]3[CH:12]=[C:13]([O:16]C)[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[B-](Br)(Br)(Br)[S+](C)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:18]([C:19]([NH:21][CH3:22])=[O:20])=[C:11]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(OC)cc12
Agent: C[S+](C)[B-](Br)(Br)Br
Solvent: Cc1ccccc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(O)cc12
Temperature: 105 °C
Reaction time: 40 h

Procedure:
To a suspension containing 2-(4-fluorophenyl)-5-methoxy-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide (0.30 g, 1.0 mmol) and toluene (10 mL), was added boron tribromide-methylsulfide complex (1.3 g, 4.0 mmol) in one portion. The mixture was stirred in a closed vessel at 105° C. for 40 h under a nitrogen atmosphere, cooled to room temperature and extracted with aqueous sodium hydroxide (3×20 mL, 2.0 M). The combined aqueous extracts were neutralized with aqueous HCl (2.0 M, approx. 60 mL) and extracted with ethyl acetate (3×50 mL). The combined organic portions were dried over MgSO4, filtered and concentrated to afford 2-(4-fluorophenyl)-5-hydroxy-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide as a tan solid which was used without further purification. 1H NMR (500 MHz, DMSO-D6) δ ppm 10.69 (s, 1 H), 8.55 (d, J=7.32 Hz, 1H), 7.75-7.82 (m, 2H), 7.50 (d, J=4.58 Hz, 1H), 7.28 (t, J=9.00 Hz, 2H), 7.05 (d, J=2.44 Hz, 1H), 6.65 (dd, J=7.48, 2.59 Hz, 1H), 2.72 (d, J=4.58 Hz, 3H). LCMS: retention time: 1.102 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10u, C18, 3.0×50 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 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 285 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10].[F:11][C:12]([F:16])([F:15])[CH2:13][OH:14].CC(C)([O-])C.[K+]>>[CH3:10][O:9][C:3]1[C:4]([CH3:8])=[N:5][CH:6]=[CH:7][C:2]=1[O:14][CH2:13][C:12]([F:16])([F:15])[F:11]
Reactant: COc1c(Cl)ccnc1C
Reactant: OCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COc1c(OCC(F)(F)F)ccnc1C
Temperature: 110 °C
Yield: 46.8 %

Procedure:
A mixture of 4-chloro-3-methoxy-2-methylpyridine (7.8 g), 2,2,2-trifluoroethanol (24.7 g) and potassium t-butoxide (27.76 g) was heated at 110° C. for 18 hours, then concentrated, diluted with water, and extracted twice with chloroform. The extract was dried, from which chloroform was evaporated, and the residue was purified by column chromatography on silica gel (chloroform-methanol (400:9)), to give 3-methoxy-2-methyl-4-(2,2,2-trifluoroethoxy)pyridine (5.12 g) as a white or pale yellow solid.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[C@@H:13]12[C:22](=O)[O:21][C:19](=[O:20])[C@@H:14]1[CH2:15][CH2:16][CH2:17][CH2:18]2>C(O)(=O)C>[C:22]1(=[O:21])[N:1]([CH:2]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:3][C:4]([OH:6])=[O:5])[C:19](=[O:20])[C@H:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C@@H:13]12
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: NC(CC(=O)O)c1ccccc1
Solvent: CC(=O)O
Product: O=C(O)CC(c1ccccc1)N1C(=O)[C@H]2CCCC[C@H]2C1=O
Temperature: 25 °C
Yield: 58 %

Procedure:
A stirred mixture 3-amino-3-phenylpropionic acid and cis-1,2-cyclohexanedicarboxylic anhydride in 10 mL of acetic acid under nitrogen was heated to reflux for 4 h and then allowed to cool to room temperature. The resulting mixture was concentrated to an orange yellow oil. This oil was crystallized from a 1/1 mixture of ethyl acetate/hexane to afford 1.77 g (58%) of 3-(cis-hexahydrophthalimido)-3-phenylpropionic acid as white crystals: 1H NMR (DMSO-d6) δ 12.45 (br s, 1 H, COOH), 7.33 (m, 5 H, Ph), 5.48 (dd, 1 H, J=6.3, 9.6, CH), 3.41 (dd, 1 H, J=16.5, 9.6 Hz), 3.14 (dd, 1H, J=16.5, 6.3 Hz), 2.50 (m, 2 H), 1.8-1.1 (m, 8 H); 13C NMR (DMSO-d6) δ 179.3, 179.2, 171.7, 138.7, 128.4, 127.5, 126.8, 50.1, 38.7, 38.6, 35.2, 23.0, 22.9, 21.1. Anal. Calcd for C17H19NO4. Theory: C, 67.76; H, 6.36; N, 4.65. Found: C, 67.52; H, 6.20; N, 4.60.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH2:29])=[O:28].CO[C:35](OC)([N:37](C)C)[CH3:36].Cl.NO.[OH-].[Na+]>O1CCOCC1.O.C(O)(=O)C>[CH3:36][C:35]1[N:29]=[C:27]([C:26]2[CH:25]=[C:24]([CH:32]=[CH:31][CH:30]=2)[CH2:23][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]3([C:22]4[C:13](=[CH:14][C:15]5[O:20][CH2:19][CH2:18][O:17][C:16]=5[CH:21]=4)[O:12][CH2:11]3)[C:2]2=[O:1])[O:28][N:37]=1
Reactant: COC(C)(OC)N(C)C
Reactant: NC(=O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)c1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1noc(-c2cccc(CN3C(=O)C4(COc5cc6c(cc54)OCCO6)c4ccccc43)c2)n1
Temperature: 25 °C
Yield: 6.9 %

Procedure:
A solution of 3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzamide (0.50 g, 1.17 mmol) and N,N-dimethylacetamide dimethyl acetal (0.60 mL, 4.1 mmol) in 1,4-dioxane (10 mL) was stirred at 110° C. for 3 h, allowed to cool to ambient temperature and concentrated in vacuo. Hydroxylamine hydrochloride (0.11 g, 1.6 mmol), 1,4-dioxane (10 mL), glacial acetic acid (10 mL) and 2 M aqueous sodium hydroxide (0.85 mL, 1.70 mmol) were then added and the mixture was heated at 90° C. for 2 h. The mixture was allowed to cool to ambient temperature and water was added, causing a precipitate to be deposited. The solid was collected by filtration, washed with water and hexanes and recrystallized from dichloromethane/hexanes to afford 1′-[3-(3-methyl-1,2,4-oxadiazol-5-yl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.038 g, 6%) as a colorless solid: mp 80-89° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.09-8.12 (m, 2H), 7.54-7.57 (m, 2H), 7.15-7.18 (m, 2H), 7.00-7.03 (m, 1H), 6.74-6.77 (m, 1H), 6.50 (s, 1H), 6.29 (s, 1H), 5.14-5.17 (m, 1H), 4.89-4.92 (m, 2H), 4.65-4.67 (m, 1H), 4.13-4.17 (m, 4H), 2.43 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.6, 174.9, 167.9, 155.3, 144.7, 141.7, 138.4, 137.0, 132.3, 131.4, 129.9, 128.9, 127.4, 126.8, 124.8, 124.1, 123.7, 120.8, 111.6, 109.1, 99.5, 80.2, 64.5, 63.9, 58.1, 43.7, 11.7; MS (ES+) m/z 467.8 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=2)[C:10]2[C:5](=[CH:6][C:7]([C:24]3[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:8][N:9]=2)[N:4]=1>Br.C(O)(=O)C>[F:33][C:30]([F:31])([F:32])[C:29]1[C:24]([C:7]2[CH:6]=[C:5]3[C:10]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][N:15]=4)=[CH:12][C:3]([OH:2])=[N:4]3)=[N:9][CH:8]=2)=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1cc(Nc2ccc(C(F)(F)F)cn2)c2ncc(-c3ncccc3C(F)(F)F)cc2n1
Agent: Br
Solvent: CC(=O)O
Product: Oc1cc(Nc2ccc(C(F)(F)F)cn2)c2ncc(-c3ncccc3C(F)(F)F)cc2n1

Procedure:
Heat a solution of 2-methoxy-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[5-(trifluoromethyl)pyridin-2-yl]-[1,5]naphthyridin-4-amine (300 mg) in 33% hydrogen bromide in acetic acid (10 mL) at 100° C. for 18 hours. Evaporate to dryness, add saturated aqueous sodium bicarbonate (10 mL) and extract with EtOAc. Dry over Na2SO4, and concentrate under vacuum.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29]>C[O-].[Na+].CO>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCCC(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 23.7 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (88 mg, 0.27 mmol) and beta-alanine (122 mg, 1.38 mmol) in 2.2 ml of 0.5 M NaOMe/MeOH solution was microwaved at 120° C. for 10 min. Reaction mixture was concentrated. The residue was dissolved in water (80 ml) and extracted with EtOAc, which was discarded. The aqueous layer was acidified by 1 N HCl to pH=3-4 and extracted with EtOAc. Organic layer was dried over MgSO4, filtered and concentrated. The crude product was triturated with hot MeOH and then CH2Cl2. Solid was collected and dried to provide the title compound 24 mg (0.064 mmol) in 24% yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:17]([O:18][C:19](=[O:22])[CH2:20][CH3:21])[C@H:12]3[O:13][C:14](=[O:16])[CH3:15])[C:4]=2[N:5]=[CH:6][N:7]=1.[N+:30]([O-])([OH:32])=[O:31].S(=O)(=O)(O)O>ClCCl.O>[NH2:1][C:2]1[C:3]2[C:10]([N+:30]([O-:32])=[O:31])=[CH:9][N:8]([C@@H:11]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:17]([O:18][C:19](=[O:22])[CH2:20][CH3:21])[C@H:12]3[O:13][C:14](=[O:16])[CH3:15])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCC(=O)O[C@H]1[C@@H](OC(C)=O)[C@H](n2ccc3c(N)ncnc32)O[C@@H]1COC(C)=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: CCC(=O)O[C@H]1[C@@H](OC(C)=O)[C@H](n2cc([N+](=O)[O-])c3c(N)ncnc32)O[C@@H]1COC(C)=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of the product from Step 4 (1.5 g, 3.69 mmol) in dichloromethane (25 mL) was cooled to 0° C. and a 1:1 mixture of fuming nitric acid and sulfuric acid (4 mL) was added dropwise and the reaction was vigorously stirred at 0° C. for 20 min. The reaction was quenched with ice cold saturated sodium bicarbonate solution. The quenched reaction was diluted with water and extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by plating on silica gel with dichloromethane and eluded by ramping to 5% methanol in dichloromethane to give 600 mg (36%);
Reaction SMILES: [CH2:1]([C:4]1[C:13]2[O:12][C:11]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][C:5]=1[OH:28])[CH2:2][CH3:3].[C:29](O)(=[O:31])[CH3:30]>[Cl-].[Zn+2].[Cl-]>[C:29]([C:6]1[C:5]([OH:28])=[C:4]([CH2:1][CH2:2][CH3:3])[C:13]2[O:12][C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:10][CH2:9][C:8]=2[CH:7]=1)(=[O:31])[CH3:30]
Reactant: CCCc1c(O)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2
Reactant: CC(=O)O
Agent: [Cl-]
Agent: [Zn+2]
Product: CCCc1c(O)c(C(C)=O)cc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2
Reaction time: 6 h

Procedure:
To a solution of 790 mg (2.01 mmol) of the title product of Example 44 in 4 ml of acetic acid was added 547 mg (4.02 mmol) of anhydrous zinc chloride. The mixture was stirred for six hours at reflux, and then permitted to cool. The mixture was partitioned between ethyl acetate and dilute hydrochloric acid. The aqueous layer was further extracted with two portions of ethyl acetate. The combined organic extracts were washed successively with five portions of aqueous sodium bicarbonate, water, and then brine. The extracts were dried over sodium sulfate, filtered, and the solvent removed under reduced pressure. Chromatography of the residue over silica gel using 25% ethyl acetate/hexane as eluent gave the title compound, 230 mg.