Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]#[N:19])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:21][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]([CH3:21])[C:18]#[N:19])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1cc(CC#N)c2ccccc21
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C#N)c1cn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 25 °C
Yield: 71 %

Procedure:
To a stirred solution of (1-tert-butoxycarbonyl indol-3-yl)acetonitrile (5.30 g, 20.7 mmol) in THF (20 mL, anhyd) chilled to −78° C. was added dropwise a 1.0M solution of LiHMDS in THF (21 mL, 21 mmol). After 40 min iodomethane (1.3 mL, 21 mmol) was added rapidly, and the reaction mixture was allowed to warm to ambient temperature. After 15 h the reaction was quenched by addition of 0.2N HCl (100 mL) and extracted with Et2O (2×100 mL). The combined extracts were washed with brine, dried (Na2SO4), concentrated and chromatographed (silica gel, 6% EtOAc/Hex) to give the title compound (4.0 g, 71%) as a light yellow oil. 1H-NMR (CDCl3): δ 8.17 (1H, br d), 7.60 (2H, m), 7.37 (1H, br d), 7.30 (1H, app t), 4.10 (1H, q), 1.76 (3H, d), 1.68 (9H, s).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:24]=[C:18]2[C:19](=O)[NH:20][CH2:21][CH2:22][N:17]2[N:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1.CCOC(C)=O>[CH2:7]([O:14][C:15]1[CH:24]=[C:18]2[CH2:19][NH:20][CH2:21][CH2:22][N:17]2[N:16]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1NCCn2nc(OCc3ccccc3)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: c1ccc(COc2cc3n(n2)CCNC3)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.9 %

Procedure:
A 1 M solution of lithium aluminum hydride in THF (0.77 mL, 0.77 mmol) was added dropwise to a stirred solution of 2-(benzyloxy)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (0.16 g, 0.65 mmol) in THF (4 mL) under nitrogen at 0° C. The mixture was stirred at room temperature for 4 hours and diluted with AcOEt. Na2SO4.10H2O was added at 0° C. and the mixture was stirred for 20 minutes at this temperature, filtered through a pad of diatomaceous earth and then washed with additional AcOEt. The filtrate was evaporated in vacuo to yield 2-(benzyloxy)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (0.14 g, 97% yield) as a yellow oil, that was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[N:9]=[C:10]=[O:11])=[CH:4][CH:3]=1.[F:13][C:14]([F:30])([F:29])[C:15]1[CH:16]=[C:17]([NH:21][C:22]2[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[CH:23]=2)[CH:18]=[CH:19][CH:20]=1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:23]3[C:24](=[O:28])[CH2:25][CH2:26][CH2:27][C:22]=3[N:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:13])([F:29])[F:30])[CH:16]=3)[C:10](=[O:11])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1C=C(Nc2cccc(C(F)(F)F)c2)CCC1
Reactant: O=C=NC(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: O=C1CCCC2=C1C(c1ccc(Br)cc1)NC(=O)N2c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A solution of 1-bromo-4-(chloro(isocyanato)methyl)benzene (4.25 g, 17.24 mmol) in dichloromethane (30 mL) is added to a solution of 3-(3-(trifluoromethyl)phenylamino)-cyclohex-2-enone (4.00 g, 15.67 mmol) in dichloromethane (60 mL) and the resulting mixture is heated at reflux for 3 h and stirred at room temperature over night. All volatiles are evaporated and the residue is purified by flash chromatography on silica (gradient dichloromethane/methanol 100:0 to 98:2). Yield: 5.10 g; ESI mass spectrum: [(79Br)-M+H]+=465, [(81Br)-M+H]+=467; Retention time HPLC: 1.44 min (V001—006).
Reaction SMILES: C([Li])CCC.I[C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=1.[O:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1.O>C1COCC1>[I:13][C:10]1[CH:11]=[CH:12][C:7]([C:17]2([OH:20])[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)=[CH:8][CH:9]=1
Reactant: Ic1ccc(I)cc1
Reactant: O=C1CCOCC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OC1(c2ccc(I)cc2)CCOCC1
Temperature: -78 °C

Procedure:
Under an argon atmosphere, a solution of n-butyllithium (2.59M, in hexane) (8.76 ml) was added dropwise to a solution of 1,4-diiodobenzene (7.49 g) in anhydrous THF (50 ml) at −78° C., and the resulting mixture was stirred at −78° C. for minutes. Tetrahydro-4H-pyran-4-one (2.09 ml) was added dropwise thereto and the resulting mixture was stirred at −78° C. for 1.5 hours. After stirring the mixture for another 3 hours at room temperature, water was added, and the resulting mixture was extracted with ethyl acetate. Organic layer was washed once with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was recrystallized from cyclohexane/ethyl acetate mixed solvent to obtain tetrahydro-4-(4-iodophenyl)-2H-pyran-4-ol (4.12 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:14][C:15]1[CH:16]=[C:17]([N:22]=[C:23]=[O:24])[CH:18]=[CH:19][C:20]=1[Cl:21]>CN(C)C=O>[Cl:14][C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:24])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccc(Cl)c(Cl)c2)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 10 g of ethyl 2-aminothiazol-4-ylglyoxylate, 10 g of 3,4-dichlorophenyl isocyanate and 100 ml of dimethylformamide. The resulting product was a pale yellow powder having the following physical properties.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([F:7])=[CH:5][N:6]=1.[C:8](Cl)(Cl)=[O:9]>C(OCC)(=O)C>[F:7][C:4]1[S:3][C:2]([N:1]=[C:8]=[O:9])=[N:6][CH:5]=1
Reactant: Nc1ncc(F)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C=Nc1ncc(F)s1
Reaction time: 3 h

Procedure:
2-Amino-5-fluorothiazole (19.0 grams) and a saturated solution of phosgene in ethyl acetate (200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 3 hours. After this time the reaction mixture is cooled and filtered to recover the desired product 5-fluorothiazol-2-yl isocyanate dimer.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:10]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:28][O:29][C:30]1[CH:36]=[C:35]([N:37]2[CH2:42][CH2:41][CH:40]([N:43]3[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]3)[CH2:39][CH2:38]2)[CH:34]=[CH:33][C:31]=1[NH2:32].CCN(C(C)C)C(C)C>C(O)CCC>[Br:1][C:2]1[C:3]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:10]=2)=[N:4][C:5]([NH:32][C:31]2[CH:33]=[CH:34][C:35]([N:37]3[CH2:42][CH2:41][CH:40]([N:43]4[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]4)[CH2:39][CH2:38]3)=[CH:36][C:30]=2[O:29][CH3:28])=[N:6][CH:7]=1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(Cl)ncc3Br)c3ccccc32)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc(Br)c(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccccc23)n1
Yield: 52.8 %

Procedure:
3-(5-Bromo-2-chloropyrimidin-4-yl)-1-tosyl-1H-indole (INTERMEDIATE 6, 372 mg, 0.83 mmol), 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (INTERMEDIATE 27, 343 mg, 0.83 mmol), and DIEA (0.145 mL, 0.83 mmol) in n-butanol (4.0 mL) were heated at 170° C. for 3 h. The reaction mixture was concentrated in vacuo and the crude residue was purified by chromatography on silica gel (10% MeOH/1% NH4OH in DCM) to give the title product (320 mg, 53.9%). m/z 718.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(Cl)cc1C(=O)O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1c(C(=O)O)cc(Cl)cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a conc. H2SO4 (90 mL) was added portionwise 5-chloro-2-methylbenzoic acid (13.2 g, 77.6 mmol) at −5-0° C. Then a mixture of conc. HNO3 (10.5 g, 1744 mmol) in conc. H2SO4 (15 mL) was added dropwise at −5-0° C. over a period of about 1.5 hr. After the addition, the mixture was stirred at this temperature for 2 hr. The mixture was poured into crashed ice with vigorous stirring and the precipitate was collected by filtration. The precipitate was dissolved in EtOAc, washed with brine, dried over anhydrous Na2SO4, and concentrated to give a crude title compound (13.2 g), which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1.O>CN(C=O)C>[CH3:8][C:3]1[C:2]([O:1][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Cc1ncccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncccc1Oc1ccc([N+](=O)[O-])cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
3-Hydroxy-2-methylpyridine (40 g, 0.37 mole) in dry DMF (1.3 L) under argon was cooled to 0° C. Sodium hydride (11.1 g of an 80% dispersion in oil, 0.37 mole) was added portionwise and the mixture stirred at 0° C. for 15 minutes and then room temperature for 3 hours. 2-Chloro-5-nitropyridine (58.6 g, 0.37 mole) was added and the mixture stirred for 18 hours at r.t. Water (50 ml) was added dropwise and the solvent was removed in vacuo. The residue was dissolved in CH2Cl2, washed with 10% aqueous sodium hydroxide, and water, dried (Na2SO4) and evaporated in vacuo to afford the title compound (81.1 g, 95%) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[S:13]([CH2:23][N+:24]#[C-:25])([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[C-]#N.[Na+]>>[C:19]1([CH3:20])[CH:18]=[CH:17][C:16]([S:13]([C@@H:23]2[C@@H:6]([C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=3)[O:7][CH:25]=[N:24]2)(=[O:14])=[O:15])=[CH:22][CH:21]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [C-]#N
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)[C@H]2N=CO[C@@H]2c2cccc(C(F)(F)F)c2)cc1

Procedure:
In a manner analogous to Preparation 1, 3-(trifluoromethyl)benzaldehyde (0.16 g, 1.47 mmol), tosylmethylisocyanide (0.27 g, 1.40 mmol) and NaCN (6.9 mg, 0.14 mmol) gave the desired compound as a tan solid. 1H NMR (300 MHz, CDCl3) δ 2.44 (s, 3H), 4.98-5.04 (dd, 1H), 6.08-6.12 (dd, 1H), 7.3-7.42 (d, 2H), 7.50-7.62 (m, 5H), 7.78-7.86 (d, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([N+:12]([O-:14])=[O:13])[C:6]=1[NH2:15].[N-:16]=[N+:17]=[N-:18].[Na+].O>CN(C)C=O>[N:16]([CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([N+:12]([O-:14])=[O:13])[C:6]=1[NH2:15])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1c(OCCCl)cc(Cl)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOc1cc(Cl)cc([N+](=O)[O-])c1N
Temperature: 60 °C

Procedure:
A solution of 2-(2-chloro-ethoxy)-4-chloro-6-nitro-phenylamine (3.07 g, 12.2 mmol), sodium azide (1.59 g, 24.4 mmol) in anhydrous N,N-dimethylformamide (30 ml) was allowed to heat at 60° C. for 18 hours. The reaction was poured into water (150 ml) and extracted with ethyl ether (2×100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum to afford an orange solid. The solid was washed with ethyl ether (5 ml) to afford an orange crystalline solid: mp 113-114° C.
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[OH-].[Na+].[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].Cl>CC(C)=O.O>[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH:1][CH:2]([CH2:3][CH2:4][S:5][CH3:6])[C:7]([OH:9])=[O:8])=[O:16]
Reactant: CSCCC(N)C(=O)O
Reactant: O=C(Cl)c1ccccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CSCCC(NC(=O)c1ccccc1F)C(=O)O

Procedure:
To a clear solution of D,L-methionine (10 g, 67.02 mmol) and NaOH (4.0 g, 100.53 mmol) in acetone (100 ml)/ H2O (100 ml) was added 2-fluorobenzoyl chloride dropwise with stirring between each addition. Basicity was maintained by adding 2N NaOH when necessary. After addition was completed, the reaction mixture was acidified to pH 2 with 6N HCl and extracted into EtOAc. The organic layer was dried with Na2SO4, filtered, and concentrated to give provide 2-(2-fluorobenzoylamino)-4-methylsulfanyl-butyric acid (intermediate XIIa, 13.6 g) as an oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.C(OC1C=CC(C(F)(F)F)=CC=1C1[S:31][C:30]([NH:32][C:33](=[O:42])[C:34]2[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=2[F:41])=[N:29][C:28]=1[C:43]([O:45][CH3:46])=[O:44])C=C>>[F:41][C:35]1[CH:36]=[CH:37][CH:38]=[C:39]([F:40])[C:34]=1[C:33]([NH:32][C:30]1[S:31][C:1]([C:3]2[CH:12]=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=2)=[C:28]([C:43]([O:45][CH3:46])=[O:44])[N:29]=1)=[O:42]
Reactant: C=CCOc1ccc(C(F)(F)F)cc1-c1sc(NC(=O)c2c(F)cccc2F)nc1C(=O)OC
Reactant: COC(=O)c1cccc(C=O)c1
Product: COC(=O)c1cccc(-c2sc(NC(=O)c3c(F)cccc3F)nc2C(=O)OC)c1

Procedure:
Compound 114 was prepared as from methyl 3-formylbenzoate as described for the preparation of Compound 63.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:22][N:23](C)[C:24](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:38]>C(OCC)(=O)C.CC(O)C>[ClH:38].[F:1][C:2]1[C:3]([CH2:22][NH:23][CH3:24])=[CH:4][N:5]([S:14]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccco2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2ccco2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77 %

Procedure:
To a mixed solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(2-furylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (243 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL), and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 160 mg, 77%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[Cl:12].[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15].[Cl-].[Li+]>C1(C)C=CC=CC=1>[CH2:15]([C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[Cl:12])[CH:14]=[CH2:13]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1OCc2c1ccc(Br)c2Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1ccc2c(c1Cl)COC2=O

Procedure:
To a flask charged with 5-bromo-4-chloro-2-benzofuran-1(3H)-one (190 mg, 0.77 mmol) and a stir bar was added allyl tri-n-butyltin (0.36 mL, 1.2 mmol), PdCl2(dppf)-DCM complex, lithium chloride (0.098 mg, 2.3 mmol), and toluene (5 mL). The flask was fitted with a condensor, purged three times with nitrogen, and heated to reflux for 6 hours. When LC showed complete reaction, the crude material was purified by MPLC to provide 5-allyl-4-chloro-2-benzofuran-1(3H)-one. LC-MS (IE, m/z): 209 [M+1]+;
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH:13]3[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Cl[C:21]1[C:30]2[C:25](=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:27]=[CH:28][CH:29]=2)[N:24]=[C:23]([C:35]([F:38])([F:37])[F:36])[CH:22]=1.C(N(CC)CC)C>CN1CCCC1>[F:37][C:35]([F:36])([F:38])[C:23]1[CH:22]=[C:21]([NH:19][C@H:16]2[CH2:15][CH2:14][C@@H:13]([NH:12][C:6]3[C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=[CH:8][CH:7]=3)[CH2:18][CH2:17]2)[C:30]2[C:25](=[C:26]([C:31]([F:32])([F:33])[F:34])[CH:27]=[CH:28][CH:29]=2)[N:24]=1
Reactant: FC(F)(F)c1cc(Cl)c2cccc(C(F)(F)F)c2n1
Reactant: NC1CCC(Nc2ccnc3cc(Cl)ccc23)CC1
Agent: CN1CCCC1
Solvent: CCN(CC)CC
Product: FC(F)(F)c1cc(N[C@H]2CC[C@@H](Nc3ccnc4cc(Cl)ccc34)CC2)c2cccc(C(F)(F)F)c2n1
Temperature: 150 °C
Reaction time: 18 h

Procedure:
A solution of N-(7-chloroquinolin-4-yl)-cyclohexane-1,4-diamine (20 mg, 0.07 mmol) in N-methylpyrrolidine (0.5 mL) at 150° C. was treated with 4-chloro-2,8-bis(trifluoromethyl)quinoline (21 mg, 0.07 mmol), and triethylamine (10 μl, 0.07 mmol). The mixture was stirred at 150° C. for 18 hours then concentrated under reduced pressure. The compound was purified by reverse phase HPLC to provide the desired compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([F:23])[CH:22]=1)[CH2:6][NH:7][CH:8]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:9]([O:11][C:12](C)(C)[CH3:13])=[O:10])#[N:2].[NH2:24][OH:25]>C(O)C.O>[NH2:2][C:1](=[N:24][OH:25])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([F:23])[CH:22]=1)[CH2:6][NH:7][CH:8]([CH2:16][CH:17]([CH3:18])[CH3:19])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CC(C)CC(NCc1cc(F)cc(C#N)c1)C(=O)OC(C)(C)C
Reactant: NO
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(CC(C)C)NCc1cc(F)cc(C(N)=NO)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 75.2 %

Procedure:
To tert-butyl 2-[(3-cyano-5-fluorobenzyl)amino]-4-methylpentanoate (3.0 g, 9.4 mmol) in ethanol (30 mL) was added hydroxylamine (1.2 mL, 0.019 mol) and it was stirred at 0° C. for 16 hrs. The reaction mixture was diluted with water (250 mL) and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried and concentrated. The crude product was purified by chromatography using petroleum ether/ethyl acetate as eluent, affording the title compound as a white solid (2.3 g, 70%). 1H NMR (DMSO-d6, 400 MHz): δ 9.73 (s, 1H), 7.46 (s, 1H), 7.30 (d, J=9.6 Hz, 1H), 7.13 (d, J=9.6 Hz, 1H), 5.84 (s, 2H), 3.75 (d, 1H), 3.55 (d, 1H), 2.98 (s, 1H), 2.38 (brs, 1H), 1.76-1.69 (m, 1H), 1.40 (s, 9H), 1.37 (dd, 2H), 0.96 (d, 3H), 0.87 (d, 3H). LC/MS (Method B) 354.3 (M+H)+. HPLC (Method A) Rt: 2.96 min (Purity 98.3%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[C:5]2[Cl:25].[Li]CCCC.[CH:31]([CH:33]1[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34]1)=[O:32]>C1COCC1>[C:40]([O:39][C:37]([N:35]1[CH2:36][CH:33]([CH:31]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([O:12][CH3:13])[C:6]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=2)=[C:5]3[Cl:25])[OH:32])[CH2:34]1)=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CC(C=O)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)C3CN(C(=O)OC(C)(C)C)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -75 °C
Reaction time: 0.03 h

Procedure:
To a flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (1.0 g, 2.32 mmol, Intermediate 5: step d) was added THF (30 mL) at room temperature which resulted in a colorless homogeneous mixture. The solution was cooled to −75° C. and then n-BuLi (2.5 M in hexanes, 1.08 mL, 2.69 mmol) was added dropwise. After 2 minutes, tert-butyl 3-formylazetidine-1-carboxylate (545 mg, 2.94 mmol in 3 mL THF) was introduced. After 5 minutes, the reaction mixture was transferred to an ice-water bath and stirring was continued for 30 minutes. The reaction mixture was quenched with aqueous NH4Cl solution and the aqueous portion was extracted with EtOAc (5×40 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness. The crude material was chromatographed on silica gel (20% EtOAc-hexanes increasing to 50% EtOAc) to provide the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([O:10][C:11](=[O:16])[C:12](Br)([F:14])[F:13])[CH3:9].C(OC(C)C)(=O)C>CN(C=O)C>[CH2:8]([O:10][C:11](=[O:16])[C:12]([F:14])([F:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:9]
Reactant: Brc1ccccn1
Reactant: CCOC(=O)C(F)(F)Br
Solvent: CC(=O)OC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(F)(F)c1ccccn1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
2-Bromopyridine (4.5 g, 28.5 mmol) and 2-bromo-2,2-difluoroacetic acid ethyl ester (6 g, 29.6 mmol) were dissolved in DMF (25 ml) and Cu (4.5 g, 71.2 mmol) was added. The reaction mixture was heated at 50° C. for 18 h and after adding isopropyl acetate (30 ml) the reaction mixture was quenched with a solution of potassium dihydrogen phosphate (8 g) in water (50 ml). The resultant solution was stirred for 30 min, filtered and washed with isopropyl acetate. The organic layer was separated, washed with water and brine. After drying the organic layer was dried over MgSO4, it was filtered and concentrated to give 2,2-difluoro-2-pyridin-2-ylacetic acid ethyl ester (4.3 g) as a brown liquid.
Reaction SMILES: Br[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:14]1([NH2:17])[CH2:16][CH2:15]1>C1COCC1.CCOC(C)=O>[CH:14]1([NH:17][C:2]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:16][CH2:15]1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Br
Reactant: NC1CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1cccc([N+](=O)[O-])c1NC1CC1
Temperature: 60 °C

Procedure:
A mixture of 2-bromo-3-nitrobenzoic acid (1.0 g, 4.1 mmol), cyclopropanamine (0.85 mL, 12.2 mmol) in THF (10 mL) under N2 was heated at 60° C. for 1 day. The reaction mixture was diluted with EtOAc, washed with water, brine, and dried over magnesium sulfate. The organic phase was concentrated in vacuo. The residue, as a crude 2-(cyclopropylamino)-3-nitrobenzoic acid: LC-MS (ESI) m/z 223.0 [M+H]+. The crude product was subjected to the next reaction without further purification.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([F:22])[CH2:21][NH:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[CH:32][C:5]=2[N:4]=1)[CH3:2].[CH3:33][C:34]1([CH3:37])[CH2:36][O:35]1>>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([F:22])[CH2:21][N:20]([CH2:33][C:34]([CH3:37])([OH:35])[CH3:36])[CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[CH:32][C:5]=2[N:4]=1)[CH3:2]
Reactant: CC1(C)CO1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(F)CNC3)n(C)c2n1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(F)CN(CC(C)(C)O)C3)n(C)c2n1
Temperature: 80 °C
Yield: 21 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-8-(3-fluoroazetidin-3-yl)-9-methyl-6-morpholin-4-yl-9H-purine (90 mg, 0.21 mmol) and 2,2-dimethyloxirane (1 mL) in IMS (2 mL) was heated to 80° C. for 24 h then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-5%) then triturated with Et2O. The resulting residue was further purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient acetonitrile 5-95%) affording 839 (22 mg, 21%). LCMS (method I): RT 2.63 min, [M+H]+ 509.3. 1H NMR (DMSO, 400 MHz): δ 8.04-8.03 (1 H, m), 7.65-7.62 (1 H, m), 7.26-7.25 (2 H, m), 4.28 (4 H, brd s), 4.14 (2 H, dd, J=18.78, 9.71 Hz), 3.82-3.74 (9 H, m), 3.31-3.29 (4 H, m), 1.34 (3 H, t, J=7.43 Hz), 1.07 (6 H, s)