Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8](I)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:19][C:20]1[CH:25]=[C:24](B(O)O)[CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O.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>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([C:24]3[CH:23]=[CH:22][N:21]=[C:20]([F:19])[CH:25]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: Fc1ccc(-c2nc3c(Cl)cccn3c2I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nc3c(Cl)cccn3c2-c2ccnc(F)c2)cc1
Temperature: 100 °C
Yield: 80.5 %

Procedure:
8-Chloro-2-(4-fluorophenyl)-3-iodoimidazo[1,2-α]pyridine (0.15 g, 0.4 mmol) was dissolved in N,N-dimethylformamide (5 mL). To this solution was added 2-fluoro-4-pyridinylboronic acid (120 mg, 0.8 mmol), dichlorobis(triphenylphosphine)palladium (II) (60 mg, 0.08 mmol) and aqueous sodium carbonate (170 mg, 1.6 mmol). The resulting solution was heated at 100° C. overnight. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic phase was dried (magnesium sulfate), filtered and concentrated to a solid. Purification by silca gel chromatography (1:1 ethyl acetate:hexane) gave 8-chloro-2-(4-fluorophenyl)-3-(2-fluoropyridin-4-yl)imidazo[1,2-α]pyridine (110 mg, 81%) as a white solid. 1H NMR (CDCl3): δ 8.41 (d, 1H), 8.09 (d, 1H), 7.62 (q, 2H), 7.42 (d, 1H), 7.29 (d, 1H), 7.07 (m, 3H), 6.87 (t, 1H); 19F NMR (CDCl3) δ −65.46 and −112.94; MS m/z 342 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:21])[CH:13]=[C:14]([C:16]([O:18]CC)=[O:17])[O:15][C:5]=3[C:4]=2[CH:3]=1.O>C(O)(=O)C.Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:21])[CH:13]=[C:14]([C:16]([OH:18])=[O:17])[O:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1cc(=O)c2c(o1)c1cc(Cl)ccc1n2C
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cn1c2ccc(Cl)cc2c2oc(C(=O)O)cc(=O)c21
Temperature: 0 °C

Procedure:
A mixture of 3.5 g (0.012 mole) of ethyl 8-chloro-4,5-dihydro-5-methyl-4-oxopyrano[3,2-b]indole-2-carboxylate in 50 ml glacial acetic acid and 10 ml conc. hydrochloric acid was stirred at reflux for 3 hr, then cooled and added to 500 g ice--H2O. The crude product was filtered, washed with 50% aqueous ethanol, and air dried. A suspension of the product in 75 ml of chloroform was stirred for 90 min at room temperature, then filtered. After recrystallization twice from DMF-water, the final product was dried for several hours under high vacuum at 100°. The yellow flakes obtained had a mpt. of 290°-dec.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl[CH2:20][CH2:21][CH2:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=1)=[O:24].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CN(C=O)C>[CH3:32][C:27]1[CH:26]=[C:25]([C:23](=[O:24])[CH2:22][CH2:21][CH2:20][N:15]2[CH2:16][CH2:17][CH:12]([C:8]3[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:18])[CH3:1])[CH:11]=[CH:10][CH:9]=3)[CH2:13][CH2:14]2)[CH:30]=[CH:29][C:28]=1[CH3:31]
Reactant: Cc1ccc(C(=O)CCCCl)cc1C
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)CCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1C
Yield: 79.7 %

Procedure:
A mixture of 0.0500 g (0.200 mmol) of 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide, 0.100 g (0.480 mmol) of 4-chloro-3′,4′-dimethylbutyrophenone, 0.080 g (0.600 mmol) of K2CO3 and 0.090 g (0.600 mmol) of NaI in 5 mL of DMF was heated at reflux temperature for 18 hours. The reaction mixture was filtered, the filtrate was poured into 5 mL of water and washed with 3×5 mL of ethyl acetate. The combined organic extracts were dried (MgSO4), concentrated in vacuo and purified by preparative TLC (silica; 9.5:0.5, dichloromethane:methanol+1% isopropyl amine) to afford 0.067 g (80.0% yield) of the desired product: 1H NMR (400 MHz, CDCl3) δ 7.72 (d, 1H, J=8.0 Hz), 7.44 (s, 1H), 7.38 (d, 1H, J=8.0 Hz), 7.23-7.20 (m, 2H), 7.16 (s, 1H), 6.95 (d, 1H, J=6.8 Hz), 3.13-3.11 (m, 2H), 3.02 (t, 2H, J=7.0 Hz), 2.56-2.40 (m, 4H), 2.32 (s, 6H), 2.17-2.15 (m, 2H), 2.04-1.78 (m, 6H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e 421.3 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:21]([OH:23])=[O:22])=[C:6]([CH:9]([S:15][C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])[CH2:7][S:8][C@H:3]12.CN(C)C=O.[F:31][C:32]([S:35][CH2:36][C:37](O)=[O:38])([F:34])[F:33]>C(N(CC)CC)C>[F:31][C:32]([S:35][CH2:36][C:37]([NH:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:21]([OH:23])=[O:22])=[C:6]([CH:9]([S:15][C:16]3[NH:17][N:18]=[N:19][N:20]=3)[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])[CH2:7][S:8][C@H:3]12)=[O:38])([F:34])[F:33]
Reactant: O=C(O)CSC(F)(F)F
Reactant: NC(=O)CCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)CCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)CSC(F)(F)F)[C@H]2SC1

Procedure:
A suspension of 3.85 g. (0.01 mol.) of 7-amino-3-[1-(2-carbamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid in 50 ml. of dry dimethylformamide was treated with 2 ml. of triethylamine and the mixture was stirred for 15 minutes at 25°. The activated ester of trifluoromethylmercaptoacetic acid (2.57 g., 0.016 mol.) was added to the mixture and it was stirred an additional hour. The reaction mixture was evaporated to dryness and water and ethyl acetate were added to the residue. The layers were separated, ethyl acetate was added to the aqueous phase and it was acidified to pH 2.5 by addition of 6N hydrochloric acid. The mixture was filtered, the layers were separated and the aqueous phase was extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and evaporated to dryness to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:20])([C:16]([F:19])([F:18])[F:17])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[CH:5]=[C:4]([Cl:21])[C:3]=1[NH2:22].[F:23][C:24]1[C:32]([N+:33]([O-:35])=[O:34])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27].C(N(CC)CC)C.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:20])([C:16]([F:17])([F:18])[F:19])[C:9]([F:14])([F:15])[C:10]([F:11])([F:13])[F:12])[CH:5]=[C:4]([Cl:21])[C:3]=1[NH:22][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[C:32]([N+:33]([O-:35])=[O:34])[C:24]=1[F:23]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1F
Reactant: Nc1c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1Br)c1cccc([N+](=O)[O-])c1F
Temperature: 25 °C
Yield: 43.1 %

Procedure:
To a solution of 2-bromo-6-chloro-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethyl-propyl)phenylamine (Example I 8.1) (20 g, 47.1 mmol) and 2-fluoro-3-nitrobenzoic acid (17.4 g, 94.2 mmol) in dichloromethane (230 ml) was added triethylamine (19.7 ml, 141 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (“BOP-Cl”) (23.98 g, 94 mmol). The reaction mixture was heated to reflux for 6 hours. The reaction mixture was cooled to ambient temperature and quenched by the addition of aqueous hydrochloric acid (1N). The mixture was then extracted three times with dichloromethane. The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 7:3) to give N-[2-bromo-6-chloro-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)phenyl]-2-fluoro-3-nitrobenzamide (12 g, 43% yield).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:22])[CH2:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[CH:8][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12](=[O:22])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)CCC(=O)c1ccc(OCc2ccccc2F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCC(=O)c1ccc(OCc2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of tert-Butyl 4-(4-(2-fluorobenzyloxy)phenyl)-4-oxobutyrate (Step B, 1.27 g, 4.2 mmol) in dichloromethane (25 ml) was treated with trifluoroacetic acid (5 ml). The reaction mixture was stirred at ambient temperature for 3 hours and concentrated in vacuo. The purification was done by flash chromatography on silica gel column (chloroform:methanol 95:5 spiked with acetic acid) to afford the title compound as a white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:6][C:5](=[O:7])[C:4]([OH:8])=[C:3]1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=1.I[CH:21]([CH3:23])[CH3:22]>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:19])[O:6][C:5](=[O:7])[C:4]([O:8][CH:21]([CH3:23])[CH3:22])=[C:3]1[C:9]1[CH:10]=[CH:11][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][CH:14]=1
Reactant: CC(C)I
Reactant: CC1(C)OC(=O)C(O)=C1c1ccc(S(C)(=O)=O)cc1
Solvent: c1ccccc1
Product: CC(C)OC1=C(c2ccc(S(C)(=O)=O)cc2)C(C)(C)OC1=O
Reaction time: 18 h

Procedure:
To a suspension of the alcohol of Step 1 (100 mg, 0.354 mmol) in benzene (5.0 mL) were added an excess of 2-iodopropane (105 mL) and Ag2CO3 (294 mg, 1.06 mmol). After a period of 18 h at 45° C., the reaction mixture was filtered over celite and washed with CH2CL2. After evaporation, the crude compound was purified by flash chromatography (35% to 40% EtOAc) to provide 70 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][S:8][C:9]2[C:14]([Br:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]([NH:19]C(=O)C3C=CC=CC=3)=[S:18])[CH:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[C:14]([Br:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]([NH2:19])=[S:18])[CH:10]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(CSc2cc(NC(=S)NC(=O)c3ccccc3)ncc2Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(CSc2cc(NC(N)=S)ncc2Br)cc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
1-(4-(4-methoxybenzylthio)-5-bromopyridin-2-yl)-3-benzoylthiourea (8.50 g, 17.4 mmol) was suspended in THF (150 mL). NaOH (116 ml, 348 mmol) was added, and the reaction was stirred at 65° C. overnight. The solution was cooled and filtered, and the solids were washed with cold water. The solids were then triturated in EtOH and filtered to provide the desired product (5.3 g, 79% yield) as a tan solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[CH3:7][O:8][C:9](=[O:15])[C:10]([CH3:14])([CH3:13])[CH2:11]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:7][O:8][C:9](=[O:15])[C:10]([CH3:14])([CH3:13])[CH2:11][N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1
Reactant: Ic1cn[nH]c1
Reactant: COC(=O)C(C)(C)CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Cn1cc(I)cn1
Reaction time: 2 h
Yield: 80.8 %

Procedure:
A solution of 4-iodo-1H-pyrazole (194 mg, 1 mmol), 3-hydroxy-2,2-dimethylpropionic acid methyl ester (200 mg, 1.5 mmol) and triphenylphosphine (393 mg, 1.5 mmol) in THF (5 mL) was treated with DIAD (0.3 mL, 1.5 mmol) at room temperature. After 2 h, the reaction mixture was concentrated and the crude residue was purified by column chromatography (SiO2, 10% ethyl acetate/hexanes) to give 249 mg (81%) of desired product as an oil. 1H NMR (500 MHz, CDCl3) δ 7.59 (s, 1H), 7.46 (s, 1H), 3.69 (s, 2H), 3.55 (s, 3H), 1.18 (s, 6H).
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[O:11][CH:10]([CH3:13])[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][C:6]=2[S:5][CH:4]=1)[CH3:2]>C(OCC)(=O)C.Cl>[CH3:10][O:11][C:12]1[CH:3]=[C:1]([C:3]2[C:12]3[O:11][CH:10]([CH3:13])[CH2:9][NH:8][CH2:7][C:6]=3[S:5][CH:4]=2)[CH:2]=[CH:7][CH:6]=1
Reactant: CCc1csc2c1OC(C)CN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cccc(-c2csc3c2OC(C)CNC3)c1
Yield: 148.9 %

Procedure:
tert-Butyl 8-ethyl-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (190 mg) was stirred in 4N hydrogen chloride-ethyl acetate solution (5 mL) for 20 min. The reaction solution was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give 8-ethyl-2-methyl-2,3,4,5-tetrahydrothieno[2,3-f][1,4]oxazepine 1 hydrochloride (131 mg, 88%) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:14][C:15]1[CH:21]=[CH:20][C:18]([OH:19])=[CH:17][C:16]=1O.C(=O)([O-])[O-].[Na+].[Na+]>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]2[O:8][C:16]3[CH:17]=[C:18]([OH:19])[CH:20]=[CH:21][C:15]=3[N:14]=2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Oc1ccc2nc(-c3ccc(C(F)(F)F)cc3)oc2c1

Procedure:
1.5 ml (10 mmol) of 4-trifluoromethylbenzoyl chloride were heated to 190° C. in an oil bath and 1.6 g (10 mmol) of 4-aminoresorcinol were added in portions. After 1 hour the reaction mixture was introduced into 100 ml of 10% strength sodium carbonate solution and heated. The unreacted acid chloride was hydrolyzed during this procedure. The product was then extracted with ethyl acetate and purified by column chromatography (silica gel 60, ethyl acetate or chloroform/glacial acetic acid 9:1).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(Cl)(Cl)Cl>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:19](=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccccc1C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-trifluoromethylphenol (20.00 g) was dissolved in chloroform (160 mL), and triethylamine (34.0 mL) and acetic anhydride (12.4 mL) were added to the solution, and then the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (23.76 g) as a pale yellow oily substance.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=S)[NH:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:3].CO.OO>N>[O:3]=[C:2]1[C:4]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:10][C:11]([NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:1]1
Reactant: NC(=O)c1ccccc1NC(=S)NC(=O)c1ccccc1
Agent: N
Agent: OO
Solvent: CO
Product: O=C(Nc1nc(=O)c2ccccc2[nH]1)c1ccccc1
Reaction time: 8 h
Yield: 40.1 %

Procedure:
To a stirred mixture of 4.5 g of the above benzamide in a mixture of 120 ml of methanolic ammonia plus 100 ml of methanol, was added dropwise, 3.6 ml of 30% hydrogen peroxide. This mixture was stirred overnight, the solid collected, partially dissolved in 500 ml of hot acetonitrile and filtered. The filtrate was chilled and the solid collected, giving 1.6 g of the desired product as white crystals, mp 227°-228° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][CH3:12])=[C:4]([F:13])[CH:3]=1.CC1(C)COB(B2OCC(C)(C)CO2)OC1.CC([O-])=O.[K+].ClCCl.Cl[C:39]1[N:44]=[C:43]([O:45][CH3:46])[C:42]([C@@:47]2([CH3:54])[CH2:52][CH2:51][CH2:50][NH:49][C:48]2=[O:53])=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH2:11]([N:8]1[C:9]2[C:5](=[C:4]([F:13])[CH:3]=[C:2]([C:39]3[N:44]=[C:43]([O:45][CH3:46])[C:42]([C@@:47]4([CH3:54])[CH2:52][CH2:51][CH2:50][NH:49][C:48]4=[O:53])=[CH:41][CH:40]=3)[CH:10]=2)[CH:6]=[N:7]1)[CH3:12]
Reactant: COc1nc(Cl)ccc1[C@@]1(C)CCCNC1=O
Reactant: CCn1ncc2c(F)cc(Br)cc21
Agent: CC(=O)[O-]
Agent: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCn1ncc2c(F)cc(-c3ccc([C@@]4(C)CCCNC4=O)c(OC)n3)cc21
Temperature: 110 °C
Yield: 80.6 %

Procedure:
An oven dried vial was charged with 6-bromo-1-ethyl-4-fluoro-1H-indazole (900 mg, 3.7 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (1000 mg, 4.4 mmol), oven dried KOAc (1450 mg, 14.8 mmol), anhydrous dioxane (5 mL) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (75.9 mg, 0.093 mmol). The mixture was purged with nitrogen gas for 5 min. The reaction vial was sealed and heated at 110° C. for 1.5 h. After being cooled to r.t., to the reaction mixture was added (R)-3-(6-chloro-2-methoxypyridin-3-yl)-3-methylpiperidin-2-one (943 mg, 3.7 mmol), an aqueous solution of sodium carbonate (2 M, 4.6 mL, 9.3 mmol) and an additional [1,1′-Bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) complex with dichloromethane (75.9 mg, 0.093 mmol). The reaction mixture was degassed with nitrogen, and heated at 100° C. for 3 h. The reaction mixture was cooled to r.t., diluted with EtOAc, and the organic layer was washed with brine and water, dried over MgSO4, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (0-20% EtOH/DCM) to afford (R)-3-(6-(1-ethyl-4-fluoro-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-3-methylpiperidin-2-one (1140 mg, 81%). 1H NMR (600 MHz, CDCl3) δ 1.57 (t, 3H), 1.67-1.71 (m, 1H), 1.74 (s, 3H), 1.84 (d, 1H), 1.97-2.07 (m, 1H), 2.35-2.44 (m, 1H), 3.44 (br. s., 1H), 3.55 (br. s., 1H), 4.12 (s, 3H), 4.50 (q, 2H), 5.92 (br. s., 1H), 7.41 (d, 1H), 7.48 (d, 1H), 7.69 (d, 1H), 7.84 (s, 1H), 8.06 (s, 1H). MS (AP+)(M+H) 383.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)=[N:3]1>[Pd].C(O)C>[CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[N:3]1
Reactant: Cn1nnc(-c2ccc([N+](=O)[O-])cc2)n1
Agent: [Pd]
Solvent: CCO
Product: Cn1nnc(-c2ccc(N)cc2)n1
Reaction time: 17 h
Yield: 95.7 %

Procedure:
A mixture of 2-methyl-5-(4-nitro-phenyl)-2H-tetrazole (0.260 g, 1.27 mmol) and palladium on charcoal (53.6 mg) in ethanol (50 mL) is stirred in high pressure reactor under H2 at 4 bars for 17 hours. The catalyst is removed by filtration through Celite 521, washing with EtOH. The filtrates are combined and concentrated in vacuo to afford the title compound as a white solid (0.213 g, 96%). HPLC (254 nm) 1.50 min (89%)
Reaction SMILES: [CH:1]1([C:4]2[C:14]3[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=3[CH:7]=[C:6]3[O:22][CH2:23][CH2:24][N:25]([CH2:26][C@@H:27]([O:40][CH3:41])[CH2:28]OS(C4C=CC(C)=CC=4)(=O)=O)[C:5]=23)[CH2:3][CH2:2]1.[F-:42].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])O.[Na+]>C1COCC1>[CH:1]1([C:4]2[C:14]3[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=3[CH:7]=[C:6]3[O:22][CH2:23][CH2:24][N:25]([CH2:26][C@@H:27]([O:40][CH3:41])[CH2:28][F:42])[C:5]=23)[CH2:3][CH2:2]1
Reactant: [F-]
Reactant: CO[C@@H](COS(=O)(=O)c1ccc(C)cc1)CN1CCOc2cc3c(c(C4CC4)c21)CCN(C(=O)OC(C)(C)C)CC3
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H](CF)CN1CCOc2cc3c(c(C4CC4)c21)CCN(C(=O)OC(C)(C)C)CC3
Temperature: 60 °C
Reaction time: 13 h

Procedure:
To 400 mg of t-butyl 5-cyclopropyl-4-[(2R)-2-methoxy-3-{[(4-methylphenyl)sulfonyl]oxy}propyl]-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate was added 7 ml of a 1 M solution of tetrabutylammonium fluoride in THF, followed by heating and stirring at 60° C. for 13 hours under an argon atmosphere. The reaction mixture was cooled to room temperature and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate twice. The combined organic layer was dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 257 mg of t-butyl 5-cyclopropyl-4-[(2R)-3-fluoro-2-methoxypropyl]-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate as a white foamed solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10](B(O)O)=[CH:9][CH:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2].Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=2)=[C:17]([F:28])[CH:16]=1>>[F:28][C:17]1[CH:16]=[C:15]([C:10]2[C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:20]=[CH:19][C:18]=1[C:21]1[N:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=1
Reactant: CC(C)Oc1ncccc1B(O)O
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Product: CC(C)Oc1ncccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 369 using (2-isopropoxypyridin-3-yl)boronic acid and 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine in Step B. MS (ESI): mass calcd. for C18H17FN4O, 324.14; m/z found, 325.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.63-8.57 (m, 1H), 8.18-8.13 (m, 1H), 8.12 (d, J=1.4, 1H), 7.99-7.90 (m, 1H), 7.69-7.62 (m, 1H), 7.58-7.41 (m, 2H), 6.98-6.91 (m, 1H), 5.49-5.35 (m, 1H), 4.68 (s, 2H), 1.37 (d, J=6.2, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]([CH3:15])=[CH:13][C:12](O)=[CH:11][C:10]1=[O:17].[F:18][C:19]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22]>>[F:18][C:19]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=1[CH2:21][NH:22][C:12]1[CH:13]=[C:14]([CH3:15])[N:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])[C:10](=[O:17])[CH:11]=1
Reactant: NCc1ccc(F)cc1F
Reactant: Cc1cc(O)cc(=O)n1-c1c(F)cccc1F
Product: Cc1cc(NCc2ccc(F)cc2F)cc(=O)n1-c1c(F)cccc1F

Procedure:
1-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one (0.3 g, 1.26 mmol) and 2,4-difluoro benzylamine (1 mL, 8.4 mmol) were combined in a nitrogen flushed culture tube. The tube was capped and heated at 180 C for 24 h. The excess amine was distilled in vacuo and the residue was chromatographed on silica (1:1 hexanes:ethyl acetate). The compound was approximately 50% pure and was carried on without further purification (0.633 g). 1H NMR (400 MHz, CD3OD) δ 7.53 (m, 1H), 7.41 (m, 1H), 7.16 (t, J=8.8 Hz, 2H), 6.93 (m, 2H), 6.00 (s, 1H), 5.42 (s, 1H), 5.42 (s, 1H), 4.37 (s, 2H), 1.93 (s, 3H) ppm. LC/MS, tr=4.65 minutes (5 to 95% acetonitrile/water over 8 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 363 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:37][CH:38]=[CH2:39])=[C:5]([CH:30]=[CH:31][C:32]=1[C:33]([NH:35][CH3:36])=[O:34])[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:26]=[CH:25][C:14]2[CH2:15][CH2:16][CH:17]([CH2:19][CH2:20][C:21]([O:23]C)=[O:22])[O:18][C:13]=2[C:12]=1[CH2:27][CH2:28][CH3:29].[OH-].[Li+]>CO>[CH3:1][O:2][C:3]1[C:4]([CH2:37][CH:38]=[CH2:39])=[C:5]([CH:30]=[CH:31][C:32]=1[C:33]([NH:35][CH3:36])=[O:34])[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:26]=[CH:25][C:14]2[CH2:15][CH2:16][CH:17]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[O:18][C:13]=2[C:12]=1[CH2:27][CH2:28][CH3:29]
Reactant: C=CCc1c(OCCCOc2ccc3c(c2CCC)OC(CCC(=O)OC)CC3)ccc(C(=O)NC)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: C=CCc1c(OCCCOc2ccc3c(c2CCC)OC(CCC(=O)O)CC3)ccc(C(=O)NC)c1OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The compound of Example 8 (250 mg, 0.4629 mmol) was dissolved in 2.0 ml of methanol and 694 μl of 1M lithium hydroxide was added. The reaction mixture was stirred at room temperature for about two days. The solvent was removed under vacuum and 20 ml of water was added. The aqueous residue was acidified with 10% hydrochloric acid. Filtration of the resultant suspension yielded the product as white solid.