Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:6]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:29](=[O:30])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22]3)=[CH:16][CH:15]=2)[C:7]([O:9]C(C)(C)C)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH:6]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:29](=[O:30])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22]3)=[CH:16][CH:15]=2)[C:7]([OH:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(Cn2[nH]c3ccccc3c2=O)cc1)C1CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C(c1ccc(Cn2[nH]c3ccccc3c2=O)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
71.0 mg (0.17 mmol) of tert-butyl(+/−)-cyclopentyl{4-[(3-oxo-1,3-dihydro-2H-indazol-2-yl)-methyl]phenyl}acetate were initially charged in 400 μl of dichloromethane, and 134 μl of trifluoroacetic acid were added. The mixture was stirred at RT for 2 h. The reaction mixture was then concentrated on a rotary evaporator, and the residue was dried under high vacuum. This gave 82 mg of crude product, which was used without further purification.
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH:33]C(=O)C)[N:28]=3)=[C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][S:17]([C:20]4[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=4)(=[O:19])=[O:18])[N:11]3[C:7]=2[N:6]=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+]>Br>[OH:2][C:3]1[C:8]2[C:9]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH2:33])[N:28]=3)=[C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][S:17]([C:20]4[CH:21]=[CH:22][C:23]([CH3:24])=[CH:25][CH:26]=4)(=[O:18])=[O:19])[N:11]3[C:7]=2[N:6]=[CH:5][CH:4]=1
Reactant: COc1ccnc2c1c(-c1ccnc(NC(C)=O)n1)c1ccnc(NS(=O)(=O)c3ccc(C)cc3)n12
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)Nc2nccc3c(-c4ccnc(N)n4)c4c(O)ccnc4n23)cc1
Yield: 78.2 %

Procedure:
A solution of 25 (10 mg, 0.02 mmol) in HBr (48%) was refluxed for 10 min. The solution was basified with NaHCO3 and extracted with CH2Cl2. The organic solution was dried, filtrated and evaporated to obtain 26 (7 mg, 78%) as a yellow solid.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:35])[CH:17]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)=[CH:11][CH:10]=1)=[O:7])C>C(O)C>[C:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:35])[CH:17]([NH:24][S:25]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)=[CH:11][CH:10]=1)([OH:7])=[O:5]
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(Cn2ccnc2)NS(=O)(=O)c2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1ccc(NC(=O)C(Cn2ccnc2)NS(=O)(=O)c2ccc(F)cc2)cc1
Reaction time: 5 h
Yield: 35.4 %

Procedure:
2N NaOH (1.085 ml) was added to a solution of (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonyl-amino)-3-(1H-imidazol-1-yl)propanamide (103 mg) in ethanol (5 ml) and the whole was stirred for 5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, washed with ethyl acetate 3 times, neutralized by 2N HCl (1.085 ml), and then extracted with ethyl acetate. The combined ethyl acetate layers were washed with a saturated saline solution and dried over Na2SO4. The solvent was evaporated under reduced pressure to obtain (RS)-N-(4-(carboxymethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide (34.3 mg).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([F:12])[C:3]=1[C:4](Cl)=O.[Cl:13][C:14]1[N:15]=[N:16][C:17]([NH:24][NH2:25])=[CH:18][C:19]=1[C:20]([CH3:23])([CH3:22])[CH3:21]>CN1CCCC1=O.C(OCC)(=O)C>[Cl:13][C:14]1[C:19]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:18][C:17]2[N:16]([C:4]([C:3]3[C:7]([F:12])=[CH:8][CH:9]=[C:10]([F:11])[C:2]=3[F:1])=[N:25][N:24]=2)[N:15]=1
Reactant: CC(C)(C)c1cc(NN)nnc1Cl
Reactant: O=C(Cl)c1c(F)ccc(F)c1F
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc2nnc(-c3c(F)ccc(F)c3F)n2nc1Cl
Temperature: 160 °C
Yield: 78 %

Procedure:
2,3,6-Trifluorobenzoyl chloride (4.0 g) was added dropwise to a cooled (15° C.) solution of 3-chloro-4-(1,1-dimethylethyl)-6-hydrazinylpyridazine (4 g) in dry 1-methyl-2-pyrrolidinone (50 ml). After the addition the reaction mixture was heated at 160° C. for 24 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 ml), and washed twice with water (200 ml). The organic phase was separated, dried (sodium sulfate), and evaporated at reduced pressure. The residue was crystallised from dichloromethane on dilution with diethyl ether to afford the title compound (5.3 g) as a colourless solid: 1H NMR (400 MHz, DMSO-d6) δ1.52 (9H, s), 7.50 (1H, m), 7.92 (1H, m), 8.45 (1H, s); MS (ES30) m/z 341/343 [MH]+.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C(N(CC)CC)C.[I:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>ClCCl>[I:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([N:3]([CH3:4])[CH3:2])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(I)cc1

Procedure:
A suspension of dimethylamine hydrochloride (2.45 g, 30 mmol) in dichloromethane (150 ml) was cooled in an ice/methanol bath and then treated with triethylamine (6.0 g, 59 mmol) followed by 4-iodobenzoyl chloride (8.0 g, 30 mmol) portionwise with stirring under an atmosphere of argon. The reaction mixture was allowed to stir at room temperature for 30 minutes before the solution was washed with water (2×100 ml). The organic layer was separated, dried over sodium sulphate, and evaporated under reduced pressure to give the title compound as a light beige coloured solid (7.73 g, 94%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([O:13]C2C=CC=CC=2)=O)[N:7]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[N:34]=[CH:33][N:32]=[C:31]2[O:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44].C(N(CC)C(C)C)(C)C>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:44][C:43]2[CH:45]=[CH:46][CH:47]=[C:41]([O:40][C:31]3[C:30]4[C:35](=[CH:36][C:37]([O:38][CH3:39])=[C:28]([O:27][CH3:26])[CH:29]=4)[N:34]=[CH:33][N:32]=3)[CH:42]=2)=[O:13])[N:7]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CCOC(=O)Cn1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cn1nc(C(C)(C)C)cc1NC(=O)Nc1cccc(Oc2ncnc3cc(OC)c(OC)cc23)c1
Yield: 66 %

Procedure:
In the manner described in Example 159B, ethyl 2-[3-tert-butyl-5-(phenoxycarbonylamino)-1H-pyrazol-1-yl]acetate from the previous step (0.138 g, 0.4 mmol) was reacted with 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (0.119 g, 0.4 mmol), and N,N-diisopropylethylamine (0.5 mL) in THF (6 mL) at 50° C. for 7 hours, to afford ethyl 2-(3-tert-butyl-5-{3-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]ureido}-1H-pyrazol-1-yl)acetate as solid (0.145 g, 66%). 1H NMR (300 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.59 (s, 1H), 8.56 (s, 1H), 7.59 (m, 1H), 7.56 (s, 1H), 7.39 (m, 2H), 7.22 (d, 1H), 6.94 (d, 1H), 6.11 (s, 1H), 4.85 (s, 2H), 4.16 (q, 2H), 3.99 (s, 6H), 1.19 (t and s, 12H); LC-MS (ESI) m/z 549 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[N+:15]([O-])=O.[H][H]>O1CCCC1.[Pd]>[F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[NH2:15]
Reactant: [H][H]
Reactant: CS(=O)(=O)c1ccc(Oc2ccc(F)cc2F)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2ccc(F)cc2F)c(N)c1
Yield: 94.5 %

Procedure:
A solution of Example 252a (10.0 g, 30.4 mmol) in tetrahydrofuran (150 mL) was added to 10% Pd/C (1.616 g, 15.18 mmol) in a 250 mL bottle and the mixture was stirred for 24 hour under a 30 psi hydrogen atmosphere at 40° C. The mixture was filtered through a nylon membrane and concentrated. The residue was purified flash chromatography (silica gel, 70:30 ethyl acetate/hexanes) to provide the title compound (8.6 g, 55% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[C:16]1([CH:22]([CH3:25])[CH2:23][NH2:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:24][CH2:23][CH:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:25])=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: CC(CN)c1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1CNCC(C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 21, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 2-phenyl-propylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8]([CH2:15][CH:16]([C:21]([CH2:23][Si](C)(C)C)=[CH2:22])[CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:7][CH2:6]2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:17]([CH:16]1[CH2:15][N:8]2[CH2:7][CH2:6][C:5]3[C:10]([CH:9]2[CH2:22][C:21]1=[CH2:23])=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:18]([CH3:20])[CH3:19]
Reactant: C=C(C[Si](C)(C)C)C(CC(C)C)CN1CCc2cc(OC)c(OC)cc2C1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=C1CC2c3cc(OC)c(OC)cc3CCN2CC1CC(C)C
Yield: 37.6 %

Procedure:
6,7-dimethoxy-2-(4-methyl-2(3-(trimethylsilyl)prop-1-ene-2-yl)pentyl)-1,2,3,4-tetrahydroisoquinoline (Formula 5; 18.4 mg, 0.0693 mmol) and a 4 Å molecular sieve (100 mg) were put into anhydrous CH2Cl2 (0.5 mL) and stirred. A solution obtained by dissolving 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ; 19.3 mg, 0.104 mmol) and LiClO4 (2.19 mg, 0.0208 mmol) in anhydrous CH2Cl2 (0.5 mL) in a separate container was slowly added to the reaction solution and stirred for 20 min. A saturated NaHCO3 aqueous solution (1 mL) was added thereto to complete the reaction. An organic layer was extracted, and then the organic layer collected was washed with distilled water and a brine solution. Anhydrous magnesium sulfate was used to dry the organic layer, filtration under reduced pressure and evaporation under reduced pressure were performed, and then column chromatography was used to obtain 8.22 mg (yield 55%) of the title compound.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[C:7]#[N:8])[CH:2]=[CH2:3].C(N(CC)CC)C.[Cl:20][C:21]([Cl:26])([Cl:25])[C:22](Cl)=[O:23]>ClCCl>[Cl:20][C:21]([Cl:26])([Cl:25])[C:22]([O:12][C:11]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[CH2:1][CH:2]=[CH2:3])=[O:23]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=CCc1cc(C#N)ccc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCc1cc(C#N)ccc1OC(=O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of INT 25 (10.0 g, 62.8 mmol) in dichoromethane (450 mL) was added triethylamine (7.98 g, 79 mmol), followed by dropwise addition of trichloroacetyl chloride (14.42 g, 79 mmol) and the resulting mixture was stirred at room temperature overnight. The mixture was washed with saturated aqueous ammonium chloride and saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated to give INT 26 which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.C(N(CC)CC)C.[Br:16][CH2:17][C:18](Br)=[O:19].O>ClCCl>[Br:16][CH2:17][C:18]([N:4]1[CH2:5][CH2:6][CH2:7][C:2]([CH3:8])([CH3:1])[CH2:3]1)=[O:19]
Reactant: CC1(C)CCCNC1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)CCCN(C(=O)CBr)C1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A mixture of 3,3-dimethylpiperidine (10 g) and triethylamine (12.3 ml) in dry dichloromethane (50 ml) was added dropwise to an ice-cold solution of bromoacetyl bromide (7.7 ml) in dry dichloromethane (100 ml). The mixture was stirred at 23° for 18 h then recooled to 0°. Iced water (200 ml) was added and the layers separated. The aqueous layer was further extracted with dichloromethane (2×200 ml) then the combined extracts were washed with 2N HCl (200 ml) and saturated brine (200 ml), dried and evaporated to give the title compound (17.28 g) as a brown oil.
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([N:6]3[C:11]([CH2:12][O:13]2)=[N:10][NH:9][C:8](=[O:16])[C@H:7]3[CH3:17])=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:2]1[CH:15]=[C:14]2[C:5]([N:6]3[C:11]([CH2:12][O:13]2)=[N:10][NH:9][C:8](=[O:16])[C@H:7]3[CH3:17])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(Br)ccc3N21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)ccc3N21
Temperature: 90 °C
Reaction time: 2 h
Yield: 47.6 %

Procedure:
A mixture of (R)-7-bromo-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Preparation #10, Step E, 5.0 g, 16.88 mmol), (2-fluorophenyl)boronic acid (3.54 g, 25.32 mmol), K2CO3 (4.67 g, 33.78 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (2.76 g, 3.37 mmol) in dioxane (60 mL) and water (10 mL) was stirred at 90° C. for 2 h. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (eluting with 10-50% EtOAc in petroleum ether) to give (R)-7-(2-fluoro-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (2.5 g, 46%) as a red solid. 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.51 (m, 1H), 7.43-7.13 (m, 6H), 4.83 (q, J=6.4 Hz, 1H), 4.69-4.60 (d, J=13.2 Hz, 2H), 1.33 (d, J=6.4 Hz, 3H).
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([NH:15][C:16](=[O:22])[CH2:17][CH2:18][C:19]([OH:21])=O)=[CH:7][CH:6]=1.[NH2:23][CH:24]([CH:31]=[CH2:32])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[NH2:2][N:3]=[CH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([N:15]([CH2:4][C:5]2[CH:14]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:16](=[O:22])[CH2:17][CH2:18][C:19]([NH:23][CH:24]([CH:31]=[CH2:32])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:21])=[CH:7][CH:6]=1
Reactant: C=CC(N)CC(=O)OCC
Reactant: NN=Cc1ccc(NC(=O)CCC(=O)O)c2ccccc12
Agent: Cl
Product: C=CC(CC(=O)OCC)NC(=O)CCC(=O)N(Cc1ccccc1)c1ccc(C=NN)c2ccccc12

Procedure:
The title compound was prepared in the manner of Example 1 substituting 4-[[4-(aminoiminomethyl)naphthyl]amino]-4-oxobutanoic acid hydrochloride for 4-[[4-(aminoiminomethyl)-3-phenyl]amino]-4-oxobutanoic acid hydrochloride and using ethyl 3-amino-4-pentenoate. The product was purified by reverse phase HPLC using the conditions of Example 1 to afford the title compound. The product was verified by 13C NMR (CD3OD) δ 13.2, 30.5, 31.3, 39.0, 48.5, 60.4, 114.6, 120.3, 123.1, 123.9, 124.8, 126.6, 127.0, 128.0, 128.1, 130.3, 136.8, 137.4, 167.6, 171.0, 172.6, 173.0; Chemical Ionization Mass Spectrometry (MH+)=411
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7]Br.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K]>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH2:7][N:17]2[C:16](=[O:18])[C:15]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]3[C:13]2=[O:23])[CH:9]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=[N+]([O-])c1ccc(F)cc1CBr
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1cc(F)ccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A solution of 5-fluoro-2-nitro-benzylbromide (6.2 g) in dimethylformamide (20 ml) was dropped into a stirred suspension of potassium phthalimide (4.9 g) in the same solvent (40 ml). The mixture was heated under stirring to 90° C. for 2 hours, then cooled and diluted with water. The title compound (7.2 g) was recovered by filtration. M.p. 198°-200° C.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@H:7]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[C:16]([C:19]2[N:23]4[CH:24]=[CH:25][C:26]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:27][C:22]4=[N:21][CH:20]=2)[CH:15]=[CH:14]3)[CH2:6][N:5](C(OCC2C=CC3C(=CC=CC=3)C=2)=O)[CH2:4]1.Cl.C1COCC1.C([O-])(O)=O.[Na+]>[Pd].CCO>[CH3:32][O:31][CH2:30][CH2:29][O:28][C:26]1[CH:25]=[CH:24][N:23]2[C:19]([C:16]3[CH:15]=[CH:14][C:13]4[C:18](=[C:9]([O:8][C@H:7]5[C@H:3]([O:2][CH3:1])[CH2:4][NH:5][CH2:6]5)[CH:10]=[CH:11][CH:12]=4)[N:17]=3)=[CH:20][N:21]=[C:22]2[CH:27]=1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(O[C@@H]5CN(C(=O)OCc6ccc7ccccc7c6)C[C@H]5OC)c4n3)cnc2c1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Solvent: C1CCOC1
Product: COCCOc1ccn2c(-c3ccc4cccc(O[C@@H]5CNC[C@H]5OC)c4n3)cnc2c1
Reaction time: 3 h
Yield: 63.5 %

Procedure:
A flask was charged with (trans)-naphthalen-2-ylmethyl 3-methoxy-4-(2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-yloxy)pyrrolidine-1-carboxylate (0.054 g, 0.087 mmol), 2 N HCl (0.1 mL), THF (1 mL), EtOH (1 mL), and 10% Degussa type Pd/C (0.0186 g, 0.0175 mmol), and the reaction mixture was placed under a balloon of H2 and stirred for 3 hours. The reaction was neutralized with saturated NaHCO3 and filtered (GF/F paper). The filter cake was washed with CHCl3 and water. The layers were separated, the aqueous phase was washed with chloroform, and the organic phase was dried over Na2SO4, filtered and condensed. The residue was purified by silica gel chromatography to provide 24 mg of the desired product. MS APCI (+) m/z 435.2 (M+1) detected.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([F:27])[CH:18]=2)([NH2:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.FC(F)(C(F)(F)F)C([O:32][C:33](=O)[C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])=O>C(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([NH:16][C:33](=[O:32])[C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:20]=[C:19]([F:27])[CH:18]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: O=C(OC(=O)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Reactant: N[C@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(N[C@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1)C(F)(F)C(F)(F)F
Reaction time: 0.08 h
Yield: 65.2 %

Procedure:
To a solution of (R)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine (15 mg, 0.038 mmol), prepared by method described in Procedures 5, 6 and 7, in anhydrous DCM (0.5 mL), was added pyridine (1 drop) and 2,2,3,3,3-pentafluoropropanoic anhydride (14 mg, 0.040 mmol) at room temperature. The reaction mixture was stirred for 5 mins and the solvents removed under a stream of nitrogen. The resulting residue was diluted with MeOH (0.5 mL) and purified by preparative HPLC (YMC Sunfire 30×100 mm column, eluting with 10-90% MeOH/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm); (R)-N-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-2,2,3,3,3-pentafluoropropanamide (13.4 mg, 65% yield) was isolated as a colorless oil at a retention time of 12.44 min. LCMS: RT=2.12 min [M+H] 541.21 (LCMS Method 2); HPLC: RT=4.28 min, Purity 98% (HPLC Method 1) NMR: 400 MHz 1H (CDCl3) 9.60 ppm, 1 H, s; 8.36 ppm, 1 H, s; 7.75 ppm, 1H, d, J=8.0 Hz; 7.44 ppm, 1H, s; 7.34 ppm, 1H, d, J=8.0Hz; 7.30 ppm, 1H, d, J=8.0 Hz; 7.09 ppm, 4 H, m; 6.53 ppm, 2H, d, J=4.0 Hz; 3.38 ppm, 1H, d, J=12.0 Hz; 3.65 ppm, 1H, d, J=12.0 Hz.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][CH2:7][C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:21])[N:13]=[C:14](S(C)(=O)=O)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:47]=[CH:46][C:35]([O:36][CH2:37][C:38]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[O:39])=[CH:34][CH:33]=1>O1CCOCC1>[NH2:21][C:12]1[N:13]=[C:14]([N:43]2[CH2:44][CH2:45][N:40]([C:38](=[O:39])[CH2:37][O:36][C:35]3[CH:46]=[CH:47][C:32]([Cl:31])=[CH:33][CH:34]=3)[CH2:41][CH2:42]2)[C:15]2[N:16]=[C:8]([CH2:7][CH2:6][C:5]3[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=3)[S:9][C:10]=2[N:11]=1
Reactant: O=C(COc1ccc(Cl)cc1)N1CCNCC1
Reactant: CS(=O)(=O)c1nc(N)nc2sc(CCc3ccc(F)cc3)nc12
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Nc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(CCc3ccc(F)cc3)sc2n1
Temperature: 70 °C
Yield: 86.7 %

Procedure:
To a solution of 2-(4-fluorophenethyl)-7-(methylsulfonyl)thiazolo[5,4-d]pyrimidin-5-amine (50 mg, 0.14 mmol) and triethylamine (30 μl, 0.21 mmol) in dioxane (1 ml) was added 2-(4-chlorophenoxy)-1-(piperazin-1-yl)ethanone (51 mg, 0.21 mmol). The reaction mixture was heated at 70° C. for 3 hours. After cooling, the volatiles were removed under reduced pressure. The crude residue was purified by chromatography on silica gel (CH2Cl2/MeOH 70:1) to yield the title compound as a light yellow solid (64 mg, 85%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][OH:11])[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:27][S:28]([O:11][CH2:10][C@@H:9]([NH:12][C:13]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:19])[C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](CO)c1cc(F)cc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)c1cc(F)cc(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred solution of (S)-tert-butyl (1-(3-bromo-5-fluorophenyl)-2-hydroxyethyl)carbamate (4.8 g, 14.36 mmol) in anhydrous DCM (100 mL) at 0° C. was added triethylamine (4.00 mL, 28.7 mmol) followed by methanesulfonyl chloride (1.343 mL, 17.24 mmol). The reaction was stirred at 0° C. for 1 hr, by which time the LCMS indicated the reaction had gone to completion. The reaction mixture was poured into saturated NaHCO3 solution (100 mL). The mixture was shaken, the layers separated and the aqueous layer was extracted with DCM (2×50 mL). The combined organics were washed with NaHCO3 solution (50 mL) and brine (50 mL), dried (MgSO4), filtered and concentrated, giving (S)-2-((tert-butoxycarbonyl)amino)-2-(3-bromo-5-fluorophenyl)ethyl methanesulfonate (5.92 g, 14.36 mmol, 100% yield) as a very pale orange solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.75 (d, J=8.83 Hz, 1H), 7.43-7.55 (m, 2H), 7.31 (d, J=9.46 Hz, 1H), 4.86-5.00 (m, 1H), 4.30 (dd, J=10.09, 5.04 Hz, 1H), 4.24 (t, J=9.30 Hz, 1H), 3.16-3.23 (m, 3H), 1.36-1.44 (m, 9H).