Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[C:7]([CH3:12])[N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:15]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:11][N:8]1[C:7]([CH3:12])=[C:6]2[C:10]([C:2]([C:15]3[C:16]([CH3:21])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=3[CH3:13])=[CH:3][CH:4]=[CH:5]2)=[N:9]1
Reactant: Cc1c2cccc(Br)c2nn1C
Reactant: Cc1cc(C)c(B(O)O)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: Cc1cc(C)c(-c2cccc3c(C)n(C)nc23)c(C)c1
Temperature: 100 °C
Reaction time: 22 h

Procedure:
A flask containing 7-bromo-2,3-dimethyl-2H-indazole (3.23 g, 14.4 mmol), 2,4,6-trimethylphenyl boronic acid (3.51 g, 21.4 mmol), freshly ground potassium phosphate (6.04 g, 28.5 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.225 g, 0.572 mmol), and palladium(II) acetate (0.032 g, 0.14 mmol) was evacuated and back-filled with nitrogen. Toluene (50 mL) was added, and the yellow-orange mixture was stirred at 100° C. for 22 h then allowed to cool. Ether (200 mL) was added, and the yellow solution was decanted from a dark granular solid. The organic layer was sequentially washed with 200 mL of a 10% aqueous NaOH solution and 200 mL of a saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated to a pale yellow solid. Column chromatography (0→33% EtOAc/hexanes) afforded 2,3-dimethyl-7-(2,4,6-trimethyl-phenyl)-2H-indazole as an off-white solid (7: R=R′=Me, Ar=2,4,6-trimethylphenyl; 3.03 g, 79%; m.p. 162-164).
Reaction SMILES: C(OC([N:8]1[C:13]2([C:16]([OH:18])=[O:17])[CH2:14][CH2:15][CH:9]1[CH2:10][O:11][CH2:12]2)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:9]12[NH:8][C:13]([C:16]([OH:18])=[O:17])([CH2:14][CH2:15]1)[CH2:12][O:11][CH2:10]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1(C(=O)O)COC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C12CCC(COC1)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.8 %

Procedure:
To a solution of 8-tert-butoxycarbonyl-3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylic acid (40 mg, 0.15 mmol) in DCM (3 mL) was added TFA (1 mL), The mixture was stirred at room temperature for 4 h. The mixture was concentrated in vacuo to afford 3-oxa-8-azabicyclo[3.2.1]octane-5-carboxylic acid 81a (20 mg, 85%) which was used for next step without further purification. MS: calc'd (MH+) 158, measured (MH+) 158.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH:42]([NH:45][C@@H:46]([CH2:53][CH2:54][CH3:55])[CH2:47][N:48]1[CH2:51][CH:50]([OH:52])[CH2:49]1)([CH3:44])[CH3:43]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:45]([C@@H:46]([CH2:53][CH2:54][CH3:55])[CH2:47][N:48]2[CH2:51][CH:50]([OH:52])[CH2:49]2)[CH:42]([CH3:44])[CH3:43])=[O:8])=[CH:9][CH:10]=1
Reactant: CCC[C@@H](CN1CC(O)C1)NC(C)C
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC[C@@H](CN1CC(O)C1)N(C(=O)c1ccc(Cl)cc1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
To a mixture of 4-chlorobenzoic acid (0.067 g, 0.43 mmol) and TBTU (0.137 g, 0.43 mmol) in DCM (2 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.222 mL, 1.28 mmol). The suspension was stirred at rt for 30 min. A solution of (S)-1-(2-(isopropylamino)pentyl)azetidin-3-ol (Compound O2.1) (0.142 g, 0.43 mmol) in DCM (1 mL) was added and the reaction mixture was stirred at rt overnight. The reaction was washed with saturated NaHCO3 solution (2 ml). The organic phase was concentrated using a vacuum centrifuge. The residue was dissolved in MeOH (2 ml) and 1M NaOH (aq., 0.5 ml) was added. The mixture was stirred at rt for 1.5 h. Acetic acid (110 mg) was added and the mixture was concentrated. The residue was dissolved in DCM (3.5 ml) and washed with saturated NaHCO3 solution (2 ml). The organic phase was concentrated using a vacuum centrifuge and the residue purified by preparative HPLC affording the title compound (20 mg, 14%). Mixture of rotamers: 1H NMR (600 MHz, DMSO-d6) δ 0.62-0.78, 0.76-0.93, 0.93-1.14, 1.14-1.54, 1.67-1.93, 2.24-2.40, 2.41-2.77, 2.76-2.97, 2.96-3.15, 3.16-3.45, 3.45-3.75, 3.96-4.20, 5.12-5.31, 7.17-7.35, 7.38-7.52. Number of protons: 27. HRMS (M+H)+: calculated 339.1839. found 339.1866
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[OH:13].[N+:14]([O-])([OH:16])=[O:15]>>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([N+:14]([O-:16])=[O:15])=[C:6]2[OH:13]
Reactant: COc1ccc2nccc(O)c2n1
Reactant: O=[N+]([O-])O
Product: COc1ccc2ncc([N+](=O)[O-])c(O)c2n1
Temperature: 67 °C
Yield: 70 %

Procedure:
Fuming HNO3 (500 mL) was cooled to 10-15° C. and the compound of Example 1 (80 g, 1 eq.) was added in portions over a period of 20 min. The reaction mixture was heated to 67° C. for 4 h. The mixture was cooled to 20° C. and added to ice (2 kg) with stirring. The yellow suspension was filtered and the product was washed with water (1500 mL). After drying, a yellow solid (70 g; 70% yield) was obtained.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].N1C=CC=CC=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[C:2]([F:10])([F:11])[F:1])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: Nc1ccccc1C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccccc1C(F)(F)F)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.4 %

Procedure:
A solution of 2-(trifluoromethyl) aniline (693 mg, 4.30 mmol) and pyridine (438 μL, 5.87 mmol) in DCM (40 mL) was treated with 4-bromobenzene sulfonyl chloride (1.0 g, 3.91 mmol) and stirred at room temperature for 18 hours. The mixture was diluted with DCM, washed with 1N HCl, sat. NaHCO3, water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-20% EtOAc in cyclohexane) and triturating with pentane gave 4-bromo-N-(2-trifluoromethyl-phenyl)-benzenesulfonamide (719 mg, 48% yield) as a colourless crystalline solid. 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=8.2 Hz, 1H), 7.65-7.47 (m, 6H), 7.29-7.20 (m, 1H), 6.85 (br s, 1H), LCMS (m/z, Method A) ES+ 380.0 [M+1]+.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8](CC(O)=O)=[CH:9][CH:10]=[CH:11][CH:12]=1>CN(C)C=O.C(Cl)Cl>[C:7]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12]([CH2:1][C:2]([Cl:4])=[O:3])=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1ccccc1-c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.3 %

Procedure:
Oxalyl chloride (246 μl, 2.86 mmol) and one drop of dimethylformamide were added dropwise to a suspension of biphenylacetic acid (30 mg, 1.41 mmol) in methylene chloride (10 ml). The mixture was stirred at room temperature for 20 minutes. The solvent was evaporated and the residue was coevaporated with toluene twice to give 310 mg of the title product as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([NH:14][C:15](=[O:33])[CH2:16][C:17]1[N:21]([CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[CH:20]=[N:19][CH:18]=1)[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34]1([CH2:44][NH2:45])[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[CH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[CH2:22][N:21]1[C:17]([CH2:16][C:15]([NH:14][CH:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:11]([NH:45][CH2:44][C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][CH:35]=2)=[O:13])=[O:33])=[CH:18][N:19]=[CH:20]1
Reactant: CC(C)(C)OC(=O)NCC(NC(=O)Cc1cncn1Cc1ccc2ccccc2c1)C(=O)O
Reactant: NCc1cccc2ccccc12
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(NC(=O)Cc1cncn1Cc1ccc2ccccc2c1)C(=O)NCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the acid prepared in step F (125 mg, 0.276 mmol), 1-naphthylmethylamine (39 μl, 0.28 mmol), HOBT (38.1 mg, 0.28 mmol), and triethylamine (40.0 μl, 0.29 mmol) in DMF (3.0 ml) at 0° C., was added EDC (53.0 mg, 0.28 mmol). The reaction was stirred at room temperature for 4 hrs, diluted with EtOAc and the organic layer washed with sat. aq NaHCO3, brine and dried (Na2SO4). The solvent was evaporated in vacuo to afford the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10]C)=[O:9])=[CH:4][N:3]=1.[CH:12]1([OH:17])[CH2:16][CH2:15][CH2:14][CH2:13]1.[OH-].[Li+]>>[CH:12]1([O:17][C:2]2[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][N:7]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COC(=O)c1cnc(Cl)nc1
Reactant: OC1CCCC1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1cnc(OC2CCCC2)nc1
Temperature: 25 °C
Yield: 32 %

Procedure:
The title compound was synthesized as described for Intermediate example I-81 in 32% yield starting from methyl 2-chloropyrimidine-5-carboxylate and cyclopentanol. The reduction was performed using 3 equiv of lithium hydroxide, the reaction mixture was stirred at ambient temperature over night; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.99 (s, 2 H), 5.38-5.48 (m, 1 H), 1.89-2.04 (m, 2 H), 1.67-1.83 (m, 4 H), 1.55-1.67 (m, 2 H); MS (ESI) m/z 207[M−H+].
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(B(CC)[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)C.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O1CCCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:2]2[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH:12]=2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:18]=1
Reactant: CCB(CC)c1cccnc1
Reactant: CCOC(=O)c1cc(Cl)ccc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2cccnc2)ccc1C
Temperature: 25 °C
Yield: 97.1 %

Procedure:
Ethyl 5-chloro-2-methylbenzoate (16.60 g, 83.56 mmol) and diethyl-(3-pyridyl)borane (13.52 g, 91.92 mmol) were dissolved in 100 mL tetrahydrofuran in a 500 mL round bottom flask equipped with a magnetic stirrer. Sodium carbonate (26.57 g, 250.69 mmol) and 50 mL water were added followed by palladium acetate (0.38 g, 1.67 mmol) and (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (AmPhos, 0.92 g, 2.51 mmol) and 25 mL ethanol. The mixture was heated at reflux for 6 h then cooled to ambient temperature. The mixture was diluted with 600 mL water and extracted with diethyl ether (2×300 mL). The organic phases were combined and extracted with 1N HCl (3×200 mL). The acidic extractions were combined and made basic with 5N aqueous sodium hydroxide. This basic layer was extracted with diethyl ether (3×500 mL) and the extracts were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 19.57 g (97%) of ethyl 5-(3-pyridyl)-2-methylbenzoate as a brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C@@H:6]([N:10](CC1C=CC=CC=1)[C@H](C1C=CC=CC=1)C)[CH2:7][CH2:8][CH3:9])[CH3:2]>CCO.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C@@H:6]([NH2:10])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCC[C@@H](CC(=O)OCC)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCC[C@H](N)CC(=O)OCC
Reaction time: 16 h
Yield: 87.3 %

Procedure:
To a solution of (S)-3-[Benzyl-((S)-1-phenyl-ethyl)-amino]-hexanoic acid ethyl ester (20.8 g, 59 mmol) in EtOH (50 mL) is added Pd(OH)2 (20% in carbon) (2 g). The mixture is stirred under hydrogen atmosphere with 40 psi for 16 hours. The mixture is filtered and the filtrate is concentrated to give the title compound (8.2 g, 87%).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH:7]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4].[C:14](#N)[CH3:15]>>[CH:7]1([CH2:6][CH:2]([N:1]2[CH2:15][C:14]3[C:2](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:3]2=[O:4])[C:3]([OH:5])=[O:4])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: NC(CC1CCCCCC1)C(=O)O
Reactant: CC#N
Product: O=C(O)C(CC1CCCCCC1)N1Cc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
A solution of phthalic dicarboxaldehyde (248 mg; 1.80 mmol) and 2-Amino-3-cycloheptyl-propionic acid (318 mg; 1.72 mmol) in acetonitrile was heated to reflux for 18 h. The mixture was then allowed to cool to room temperature and the mixture stored in the refrigerator for 3 h. The solid was filtered off, rinsed with cold acetonitrile and air dried to give 424 mg (82%) of 3-Cycloheptyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid as a beige solid: EI-HRMS m/e calcd for C18H23NO3 (M+) 301.1678, found 301.1668.
Reaction SMILES: N[C:2]1[C:3]([Cl:13])=[CH:4][C:5]([Br:12])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.S(=O)(=O)(O)O.N([O-])=O.[Na+].N1C2C(=CC=CC=2)C=CC=1.O[PH2]=O.[OH-].[Na+]>O>[Br:12][C:5]1[CH:4]=[C:3]([Cl:13])[CH:2]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: Nc1c(Cl)cc(Br)c2cccnc12
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: O=[PH2]O
Solvent: O
Solvent: c1ccc2ncccc2c1
Product: Clc1cc(Br)c2cccnc2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 8-amino-5-bromo-7-chloroquinoline (700 mg, 2.72 mmol) in water (27 mL) at 0° C. was added concentrated sulfuric acid until the solid was mostly dissolved and the solution was a bright yellow. A solution of NaNO2 (375 mg, 5.44 mmol) in water (7 mL) was added dropwise to the stirring quinoline solution. After stirring at 0° C. for an additional 15 minutes, the cold solution was slowly added to stirring H3PO2 (6.5 mL, 54 mmol) at 65° C. Following complete addition of the cold solution, the mixture continued to be stirred at 65° C., and additional H3PO2 was added until the solution became colorless and no additional product formation was observed by LC/MS. Upon completion, the mixture was allowed to cool to room temperature, neutralized with 1M NaOH (aq), then extracted twice with EtOAc. The combined organics were washed with water (2×50 mL) then saturated NaCl (aq) (50 mL). The organics were dried over Na2SO4, filtered, then concentrated. The residue was purified by silica gel chromatography eluting with 0-5% EtOAc/hexanes to afford the title compound as a white solid: 1H NMR (500 MHz, CDCl3): δ 8.95 (dd, J=1.4, 4.1 Hz, 1H), 8.50 (d, J=8.5 Hz, 1H), 8.10 (d, =0.9 Hz, 1H), 7.83 (d, J=1.8 Hz, 1H), 7.52 (dd, J=4.1, 8.5 Hz, 1H); LC6: 3.90 min. (M+H) 244.
Reaction SMILES: [F:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[CH2:4][C:5]1[C:6]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:7]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)[C:8]2[C:15](=[O:16])[N:14]3[C@@H:10]([CH2:11][CH2:12][CH2:13]3)[C:9]=2[N:17]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[N:58]1([NH2:67])[C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[CH2:60][CH2:59]1>ClCCl>[F:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[CH2:4][C:5]1[C:6]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:7]([C:18]2[CH:19]=[CH:20][C:21]([C:22]([NH:67][N:58]3[C:66]4[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=4)[CH2:60][CH2:59]3)=[O:23])=[CH:25][CH:26]=2)[C:8]2[C:15](=[O:16])[N:14]3[C@@H:10]([CH2:11][CH2:12][CH2:13]3)[C:9]=2[N:17]=1
Reactant: NN1CCc2ccccc21
Reactant: CCOC(=O)c1c(Cc2ccc(F)cc2F)nc2c(c1-c1ccc(C(=O)O)cc1)C(=O)N1CCC[C@@H]21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)c1c(Cc2ccc(F)cc2F)nc2c(c1-c1ccc(C(=O)NN3CCc4ccccc43)cc1)C(=O)N1CCC[C@@H]21
Reaction time: 3 h
Yield: 38.2 %

Procedure:
To a stirred solution of 4-[(9aS)-2-(2,4-difluorobenzyl)-3-(ethoxycarbonyl)-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-α]pyrrolizin-4-yl]benzoic acid (0.150 g, 0.305 mmol) in 2 mL of dichloromethane, EDCI (0.070 g, 0.365 mmol), HOBT (0.049 g, 0.365 mmol) and 1-indolinamine (ref. Wijngaarden, I. et. al., J Med Chem, 1993, 36, 3693–99) (0.082 g, 0.609 mmol) were added. The reaction mixture was allowed to stir for ˜3 h. The reaction mixture was concentrated and redissolved in 1 mL of ethyl acetate. The organics were then washed with saturated aqueous NaHCO3 and brine. Filtration and concentration provided a brown oil which was purified by radial chromatography (dichloromethane/methanol (10:1)) to yield 0.071 g (38%) of the desired product as a tan solid: 1H NMR (CDCl3, 400 MHz) δ 7.90–7.85 (d, 2H, J=8.27), 7.53–7.45 (m, 2H), 7.23–7.11 (m, 3H), 6.83–6.73 (m, 2H), 4.74–4.67 (dd, 1H, J=10.5, J=6.38), 4.42–4.23 (q, 2H, J=15.34), 3.99–3.90 (m, 2H), 3.74–3.65 (m, 3H), 3.40–3.32 (m, 1H), 3.14–3.06 (m, 2H), 2.50–2.42 (m, 1H ), 2.37–2.26 (m, 2H), 1.70–1.50 (m, 3H), 1.46–1.31 (m, 1H), 0.95–0.84 (t, 3H, J=7.24); low resolution MS (ES+) m/e 609 (MH+); RP-HPLC (BDS Hypersil C-18 25 cm×4.6 mm; 10–100% CH3CN in H2O with 0.1% TFA buffer; 30 minutes; 1 mL/min) tr=8.12 min, 93.3% purity.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH:12][C:13]3[O:14][C@:15]4([CH2:23][N:24]=3)[CH:20]3[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]3)[CH2:16]4)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1>C1COCC1>[C:1]1([C:7]2[S:11][C:10]([NH:12][C:13]3[O:14][C@:15]4([CH2:23][N:24]=3)[CH:20]3[CH2:19][CH2:18][N+:17]([O-:33])([CH2:22][CH2:21]3)[CH2:16]4)=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cnc(NC3=NC[C@@]4(CN5CCC4CC5)O3)s2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: [O-][N+]12CCC(CC1)[C@]1(CN=C(Nc3ncc(-c4ccccc4)s3)O1)C2
Yield: 27.6 %

Procedure:
(R)—N-(5-Phenylthiazol-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.101 g, 0.297 mmol) was dissolved in THF (15 mL) and treated with m-CPBA (0.061 g, 0.356 mmol) for 30 min. at room temperature. The reaction was concentrated in vacuo to afford the crude product. The crude product was purified by reverse phase HPLC to yield pure fractions. The fractions were concentrated via vacuo and dried in a vac. oven for 18 hours to yield (S)-2-(5-phenylthiazol-2-ylamino)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]1′-oxide (0.03 g, 0.082 mmol, 27.8% yield) as a white powder. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.86-8.12 (m, 1H), 7.64 (br. s., 2H), 7.44 (s, 3H), 4.13-4.31 (m, 3H), 3.97-4.07 (m, 1H), 3.90 (d, J=10.7 Hz, 4H), 3.54-3.74 (m, 1H), 2.28-2.42 (m, 1H), 1.95-2.24 (m, 3H). LC/MS: retention time 1.04 (M+1=357.1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:11][CH2:12][C:13]([NH2:15])=[O:14]>>[N:1]1([CH2:11][CH2:12][C:13]([NH2:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: NC(=O)CCBr
Reactant: c1ccc2[nH]ccc2c1
Product: NC(=O)CCn1ccc2ccccc21

Procedure:
The title compound was prepared from 1H-indole (0.500 g, 4.27 mmol) and 3-bromopropanamide (0.650 g, 4.27 mmol) following a procedure similar to General Procedure A. The title compound was purified by preparatory HPLC method 1 and isolated as a white solid (0.339 g, 42%). 1H NMR (400 MHz, MeOD): δ 7.53 (d, J=7.9 Hz, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.19 (d, J=2.9 Hz, 1H), 7.16 (t, J=7.5 Hz, 1H), 7.03 (t, J=7.4 Hz, 1H), 6.42 (d, J=2.8 Hz, 1H), 4.47 (t, J=6.8 Hz, 2H), 2.70 (t, J=6.8 Hz, 2H). 13C NMR (100 MHz, DMSO-d6): δ 172.4, 135.9, 129.0, 128.6, 121.4, 120.8, 119.4, 110.2, 101.0, 42.3, 36.2. ESI-LRMS: [M+H]+=189.1 m/z. ESI-HRMS: calc. for C11H12N2O1: [M+H]+=189.1022 m/z, found: [M+H]+=189.1030 m/z.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:17](=[O:19])[CH3:18])[C:10]([OH:16])=[CH:11][CH:12]=2)[CH:7]=1.[Br:21][CH2:22][CH2:23][CH2:24]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:17](=[O:19])[CH3:18])[C:10]([O:16][CH2:24][CH2:23][CH2:22][Br:21])=[CH:11][CH:12]=2)[CH:7]=1
Reactant: BrCCCBr
Reactant: COC(=O)COc1ccc2ccc(O)c(C(C)=O)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc2ccc(OCCCBr)c(C(C)=O)c2c1
Yield: 95 %

Procedure:
A mixture of 4.989 g of [(8-acetyl-7-hydroxy-2-naphthalenyl)oxy]acetic acid methyl ester, 18 ml of 1,3-dibromopropane and 3.7 g of anhydrous potassium carbonate in 150 ml of anhydrous acetone was stirred at reflux for 16.5 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was chromatographed on 250 g of silica gel. Elution with 10% ethyl acetate-toluene gave 6.730 g (95% yield) of [[8-acetyl-7-(3-bromopropoxy)-2-naphthalenyl]oxy]acetic acid methyl ester as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:15]3[O:16][C:17]4[C:22]([C:23](=[O:32])[C:24]=3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:13][CH3:14])[N:9]=[C:10](I)[C:3]=12.C([N:40]1[C:48]2[C:43](=[CH:44][CH:45]=[C:46](B3OC(C)(C)C(C)(C)O3)[CH:47]=2)[C:42]([CH3:58])=[N:41]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:15]3[O:16][C:17]4[C:22]([C:23](=[O:32])[C:24]=3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:13][CH3:14])[N:9]=[C:10]([C:46]3[CH:47]=[C:48]4[C:43]([C:42]([CH3:58])=[N:41][NH:40]4)=[CH:44][CH:45]=3)[C:3]=12
Reactant: CCC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(I)c2c(N)ncnc21
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CN(C)C=O
Product: CCC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2ccc3c(C)n[nH]c3c2)c2c(N)ncnc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 5.7 %

Procedure:
To a solution of Example 57g (0.400 g, 0.738 mmoles) in DMF (4 ml), ethanol (2 ml) and water (2 ml), N-Boc-3-methyl-6-indazoleboronic acid pinacol ester 98 (0.397 g, 1.108 mmoles) and sodium carbonate (0.157 g, 1.47 mmoles) were added and the system is degassed for 30 min Tetrakistriphenylphosphine Palladium (0.043 g, 0.037 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as off-white solid (0.023 g, 6% yield). MP: 268-270° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 12.75(s,1H), 8.07(s,1H), 8.04(dd, J=7.9,1.5 Hz, 1H),7.86(m, 2H),7.69(d, J=8.2 Hz, 1H),7.64(s,1H), 7.53(t, J=7.9 Hz, 1H),7.35(dd, J=8.2,1.4 Hz, 1H),7.33(br s,1H), 7.09(dt, J=8.9,2.2 Hz, 1H), 6.90(br s,2H), 5.85(t, J=6.1 Hz, 1H),2.51(s,3H),2.50(m,2H), 0.82(t, J=7.3 Hz, 3H). Mass: 545.96 (M+).
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1(C)C=CC(S(O)(=O)=O)=CC=1.[C:17]1([C:23]2([C:29]([OH:31])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>CO>[C:17]1([C:23]2([C:29]([O:31][CH3:6])=[O:30])[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1(c2ccccc2)CCNCC1
Temperature: 0 °C

Procedure:
270 ml of methanol are taken. 10.6 ml sulphuric acid and 25 g 4-phenyl-4-piperidine-carboxylic acid p-toluenesulphonic acid are added with stirring. The reaction mixture is refluxed for 9 h, cooled and carefully poured onto a mixture of ice water and 10 M NaOH. The precipitated solid is suction filtered, washed with water and dried. 11.2 g (V-15) are obtained as a solid.