Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.C1(CC([NH:22][CH:23]2[C:54](=[O:55])[N:25]3[C:26]([C:38]([O:40][CH:41]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[O:39])=[C:27]([CH:30]=[CH:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH2:28][S:29][C@H:24]23)=O)C=CC=CC=1.CO>C(Cl)Cl>[NH2:22][CH:23]1[C:54](=[O:55])[N:25]2[C:26]([C:38]([O:40][CH:41]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[O:39])=[C:27]([CH:30]=[CH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[CH2:28][S:29][C@H:24]12
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3ccccn3)CS[C@H]12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3ccccn3)CS[C@H]12
Yield: 68.8 %

Procedure:
To a suspension of pyridine-phosphorus pentachloride complex prepared from pyridine (48 g) and phosphorus pentachloride (12.7 g) in methylene chloride (120 ml) was added benzhydryl 7-phenylacetamido-3-[2-(2-pyridyl)vinyl]-3-cephem-4-carboxylate (trans isomer) (12 g) under ice-cooling with stirring. The mixture was stirred at the same temperature for 30 minutes and poured into methanol (90 ml) at -25° C. The mixed solution was further stirred at -5° to -15° C. for 10 minutes and then was evaporated under reduced pressure. To the residue was added a mixture of tetrahydrofuran (200 ml), ethyl acetate (200 ml) and water (200 ml) and the mixture was adjusted to pH 6.5 with a saturated aqueous solution of sodium bicarbonate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated to give benzhydryl 7-amino-3-[2-(2-pyridyl)vinyl]-3-cephem-4-carboxylate (trans isomer) (6.6 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][NH:6]1.[CH3:15][C:16]([CH3:18])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.[OH-].[Na+]>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][N:6]1[CH:16]([CH3:18])[CH3:15]
Reactant: COC(=O)CC1NCc2ccccc21
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: COC(=O)CC1c2ccccc2CN1C(C)C
Reaction time: 6 h

Procedure:
To the compound obtained from Step A (0.50 g, 2.61 mmol) in dichloroethane (46 mL) was added acetone (1.76 mL, 24.01 mmol) and sodium triacetoxyborohydride (2.48 g., 11.74 mmol). After 6 hours, the mixture was diluted with 1.0N NaOH (100 mL), and the organic portion was separated. The aqueous layer was extracted with DCM (3×100 mL). The combined DCM extracts were dried (MgSO4) and concentrated to dryness to afford about 0.60 g (99%). EIS-MS 235 [M+1].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH:15]2[CH2:20][CH2:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:23][CH:22]=3)=[CH:17][CH2:16]2)[CH2:11][CH2:10]1>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:22]=[CH:23][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(C2CC=C(c3ccc(-c4ccccc4)cc3)CC2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccccc1N1CCN([C@H]2CC[C@H](c3ccc(-c4ccccc4)cc3)CC2)CC1

Procedure:
1-(2-Methoxyphenyl)-4-(1-(4-phenylphenyl)cyclohex-1-en-4-yl)piperazine (2.7 g, 5.4 mmol) was hydrogenated at 50 psi (about 3.5×105N.m-2) above atmospheric pressure at 45° C. in acetic acid (50 ml), using 10% Pd/C (2.4 g) as a catalyst for three days. The volatiles were evaporated in vacuo and the residue was partitioned between dichloromethane (150 ml) and sat. NaHCO3 (200 ml). The organic layer was separated and washed with brine and evaporated in vacuo. The residues were recrystallised from dichloromethane and again from methanol. The white solid was dissolved in ether and acidified to pH 1 with ethereal HCl. The volatiles were removed in vacuo to give the title compound as the one and a half hydrochloride; three quarters hydrate (0.281 g), m.p. 220°-225° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.C(O[CH:13]=[C:14]([S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25])[S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16])C>Cl.C1(C)C=CC=CC=1.N12CCCC1=NCCC2>[C:27]1([S:24]([C:14]([S:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])=[CH:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[CH3:9])(=[O:25])=[O:26])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCOC=C(S(=O)(=O)c1ccccc1)S(=O)(=O)c1ccccc1
Reactant: CNc1ccc(Cl)cn1
Agent: C1CN=C2CCCN2C1
Agent: Cl
Solvent: Cc1ccccc1
Product: CN(C=C(S(=O)(=O)c1ccccc1)S(=O)(=O)c1ccccc1)c1ccc(Cl)cn1

Procedure:
A mixture of 5-chloro-2-(methylamino)pyridine (0.41 g), 2-ethoxy-1,1-bis(phenylsulphonyl)ethene and concentrated hydrochloric acid (1 drop) in toluene (20 ml) was heated at reflux for 4 hours and then the mixture was treated with 1,5-diazabicyclo[4.3.0]-non-5-ene (3 drops) and heated at reflux for 18 hours. The reaction mixture was cooled and concentrated in vacuo to give an oil which was triturated with ethanol to give a brown solid which was recrystallised from toluene to give 1,1-bis(phenylsulphonyl)-2-[N-(5-chloropyrid-2-yl)-N-methylamino]ethene (0.2 g), mp. 205°-206° C.
Reaction SMILES: C([O:3][C:4](/[CH:6]=[CH:7]/[C:8]1[C:13]2[CH2:14][C:15]3([O:20][C:12]=2[C:11]([O:21][CH3:22])=[CH:10][CH:9]=1)[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:5])C.[OH-].[Na+]>C(O)C>[C:4](/[CH:6]=[CH:7]/[C:8]1[C:13]2[CH2:14][C:15]3([O:20][C:12]=2[C:11]([O:21][CH3:22])=[CH:10][CH:9]=1)[CH2:16][CH2:17][CH2:18][CH2:19]3)([OH:5])=[O:3]
Reactant: CCOC(=O)/C=C/c1ccc(OC)c2c1CC1(CCCC1)O2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(/C=C/C(=O)O)c2c1OC1(CCCC1)C2
Yield: 75 %

Procedure:
A mixture of Compound 90a (3.5 g) obtained in Step A, a 4N aqueous solution (35.0 ml) of sodium hydroxide, and ethanol (150 ml) was stirred at room temperature for 15 hours. The solvent was distilled off and the residue was dissolved in water. Concentrated hydrochloric acid was dropwise added to the solution, and a precipitate was collected by filtration, washed with water, and dried to give Compound 90b (2.38 g, 74.9%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:19]([CH3:18])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Reactant: CNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CN(c1ccccc1)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 180 °C
Reaction time: 5 h

Procedure:
4-Chloro-1-fluoro-2-nitrobenzene (20.0 g, 0.11 mol) and K2CO3 (15.7 g, 0.11 mol) were dissolved in N-methylaniline (37 mL, 0.34 mol) and subsequently heated to 180° C. After 5 h, the reaction mixture was cooled to room temperature, diluted with CH2Cl2 (750 mL) and washed with H2O (500 mL), aq. citric acid (5% 500 mL) and brine (500 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residual oil was chromatographed over silica (cyclohexane/CH2Cl2, 9/1, v/v) giving title compound containing ˜30% starting material. The compound was subsequently stirred in cold hexane and the resulting red crystals were filtered resulting in pure crystalline product (16.5 g, 57% yield). Data: melting point: 59-62° C., Rf 0.65 (cyclohexane/ethyl acetate, 4/1, v/v).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CI.[C:14](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][O:11][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc2c1CCCC2
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cccc2c1CCCC2
Reaction time: 72 h

Procedure:
5,6,7,8-Tetrahydro-1-naphthol (9.85 g, 66 mM), methyl iodide (30.6 g, 215 mM) and potassium carbonate (15 g, 90.8 mM) in acetone (500 ml) were heated under reflux with stirring for 3 days. The mixture was evaporated and the residue was extracted with 2M sodium hydroxide and ether. The organic layer was washed and dried to give 1-methoxy-5,6,7,8-tetrahydronaphthalene as as oil.
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[C:13]([NH:18][C:19]([C:21]3[CH:29]=[C:28]4[C:24]([CH:25]=[CH:26][NH:27]4)=[CH:23][CH:22]=3)=[O:20])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH3-]C#N.[Na+].C([O-])(O)=O.[Na+]>C(O)(=O)C.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[C:13]([NH:18][C:19]([C:21]3[CH:29]=[C:28]4[C:24]([CH2:25][CH2:26][NH:27]4)=[CH:23][CH:22]=3)=[O:20])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:30][CH:31]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc3cc[nH]c3c2)cc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc3c(c2)NCC3)cc1
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a stirring solution of N2-(4-t-butylbenzoyl)-N1-(6-indolylcarbonyl)-1,2-benzenediamine (0.1 g, 0.24 mmol) in acetic acid (1 mL) was added NaBH3CN (0.046 g, 0.73 mmol). After 2 h, the mixture was diluted with water (10 mL), the pH was basified with conc aq NaHCO3 and the aqueous phase was extracted twice with ethyl acetate. The combined ethyl acetate phase was washed with water and brine, then dried with MgSO4, filtered and concentrated in vacuo to give 70 mg (70%) of white solid.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].B1C2CCCC1CCC2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:30]1[CH:31]=[C:32]([C:36]([C:45]2[CH:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:48]=[C:47]([F:55])[CH:46]=2)([NH2:44])[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:33]=[CH:34][CH:35]=1>C1COCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[NH2:44][C:36]([C:32]1[CH:33]=[C:34]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:35]=[CH:30][CH:31]=1)([C:45]1[CH:50]=[C:49]([C:51]([F:52])([F:53])[F:54])[CH:48]=[C:47]([F:55])[CH:46]=1)[CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: NC(Cc1ccccc1)(c1cccc(Br)c1)c1cc(F)cc(C(F)(F)F)c1
Reactant: C=CCCCCC(=O)OCC
Agent: [Pd]
Agent: B1C2CCCC1CCC2
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCCc1cccc(C(N)(Cc2ccccc2)c2cc(F)cc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of ethyl hept-6-enoate (156 mg, 1 mmol) in dry THF (4 mL) cooled in an ice water bath was added a solution of 9-BBN (0.5 M in THF, 2.0 mL, 1 mmol). The cooling bath was removed and the reaction mixture was stirred for 1 h at room temperature. To the reaction mixture was added an aqueous solution of potassium phosphate (3 M, 0.66 mL, 2 mmol) and stirred for an additional 5 min. To the reaction mixture was added a solution of 1-(3-bromophenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine, prepared as described in Procedure 1, (0.2 M in THF, 3 mL, 0.6 mmol), followed by tris-(dibenzylideneacetone) dipalladium(0) (45 mg, 0.04 mmol). The resulting yellow solution was heated under reflux for 20 h. The reaction mixture was cooled and concentrated under reduced pressure. The residue was extracted between water (10 mL) and ether (10 mL). The ether layer was washed twice with water, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (2% to 10% EtOAc in Heptane) to yield ethyl 7-(3-(1-amino-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)phenyl)heptanoate (169 mg, 54% yield). LCMS: RT=3.61 min, Purity 84% [M+H] 516.3 (Sunfire-S5-C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [N:1]1[N:2]2[CH:10]=[CH:9][CH:8]=[C:3]2[C:4]([NH2:7])=[N:5][CH:6]=1.P(Cl)(Cl)(Cl)=O.[C:16](=O)(O)[O-:17].[Na+].C(OCC)(=O)C>CN(C=O)C>[NH2:7][C:4]1[C:3]2=[CH:8][CH:9]=[C:10]([CH:16]=[O:17])[N:2]2[N:1]=[CH:6][N:5]=1
Reactant: O=C([O-])O
Reactant: Nc1ncnn2cccc12
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Nc1ncnn2c(C=O)ccc12
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Pyrrolo[2,1-f][1,2,4]triazin-4-amine (20.5 g, 152 mmol) was dissolved in 150 mL DMF. Under ice cooling, phosphoryl chloride (31.3 mL, 336 mmol) was added dropwise at such a rate that the internal temperature did not rise above 30° C. The mixture was then heated for 2 days at 50° C. After cooling, another portion of phosphoryl chloride (14.2 mL, 152 mmol) was added, and stirring was continued for another 24 h at 50° C. After cooling, the reaction batch was slowly poured into a mixture of 2.0 L saturated aqueous sodium bicarbonate solution and 2.0 L ethyl acetate. Solid sodium bicarbonate was added until gas evolution stopped. The layers were separated, the aqueous layer was extracted with 0.5 L ethyl acetate, and the combined organic phases were dried over sodium sulfate and concentrated. The residue was suspended in 100 mL diisopropyl ether, stirred at room temperature for 10 min and then filtered. The dried residue was stirred in 6 N hydrochloric acid (500 mL) for 1 h at 50° C. and then poured into an ice/water mixture (1000 mL). The mixture was carefully neutralized with solid sodium bicarbonate, stirred for 30 min at room temperature and then filtered again. The residue was washed with water and ligroin to yield 20.6 g (83% of th.) of white crystals which were used in the next step without further purification.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:17]=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:18]([O:21][C:22]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:23]=1[C:24](O)=[O:25])([CH3:20])[CH3:19].C(OCC)(=O)C>C(#N)C>[CH:18]([O:21][C:22]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:23]=1[C:24]([N:5]1[CH2:4][CH2:3][N:2]([C:8]2[CH:17]=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:7][CH2:6]1)=[O:25])([CH3:20])[CH3:19]
Reactant: c1ccc2nc(N3CCNCC3)cnc2c1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2cnc3ccccc3n2)CC1

Procedure:
Prepared in analogy to example 1.1 (b) from 2-piperazin-1-yl-quinoxaline hydrochloride and 2-isopropoxy-5-methanesulfonyl-benzoic acid (example 2.2) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a yellowish foam.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][C@@H:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=2[S:4][CH:3]=1.[CH:20]1(B(O)O)[CH2:22][CH2:21]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.CC(C)([O-])C.[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH:20]1([C:2]2[C:11]3[O:10][C@@H:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=3[S:4][CH:3]=2)[CH2:22][CH2:21]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)Cc2scc(Br)c2O1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)Cc2scc(C3CC3)c2O1
Temperature: 80 °C
Reaction time: 14 h
Yield: 82.8 %

Procedure:
A suspension of tert-butyl (2S)-8-bromo-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (616 mg) obtained in Example 12, steps 1-4, cyclopropylboronic acid (228 mg), palladium acetate (20 mg), tricyclohexylphosphine (50 mg), potassium tert-butoxide (595 mg) and toluene (20 ml) was stirred at 80° C. for 14 hr under an argon atmosphere. The reaction solution was cooled to room temperature, and filtered through celite. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→10% ethyl acetate/hexane) to give the title compound (453 mg, 83%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[C:24]([N+:25]([O-])=O)=[CH:23][N:22]=[C:21]3[C:16]=2[CH2:17][CH2:18][CH2:19][N:20]3[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(O)=O>[Fe].O>[NH2:25][C:24]1[C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10]2)=[C:16]2[C:21](=[N:22][CH:23]=1)[N:20]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:19][CH2:18][CH2:17]2
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3c2CCCN3C(=O)OC(C)(C)C)C1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3c2CCCN3C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
Iron powder (0.26 g, 4.6 mmol) was added to a mixture containing tert-butyl 5-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6-nitro-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (0.60 g, 1.2 mmol), AcOH (9 mL), and water (1 mL). The reaction mixture was stirred at room temperature for 2 h. The solution was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL) and filtered. The filtrate was neutralized with saturated aq. NaHCO3. The organic layer was washed with brine, dried with Na2SO4 and concentrated under reduced pressure to give the sub-title compound (0.51 g, 90%). LCMS calc. for C23H38N5O4 (M+H)+: m/z=448.3. Found: 448.1.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]([C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH:7]([C:15](=[O:20])[C:16]([CH3:18])([CH3:19])[CH3:17])[CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)C(=Cc1cccnc1)Oc1ccc(Cl)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)C(Cc1cccnc1)Oc1ccc(Cl)cc1
Yield: 61.9 %

Procedure:
32 g (0.49 mol) of zinc dust were added to 48 g (0.152 mol) of 2-(4-chlorophenoxy)-4,4-dimethyl-1-pyridin-3-yl-1-penten-3-one, dissolved in 170 ml of glacial acetic acid, and the mixture was heated under reflux on an oil bath for 40 minutes. The zinc was filtered off from the solution and rinsed with glacial acetic acid and the acetic acid solution was concentrated. The residue was rendered alkaline with 1 N sodium hydroxide solution and extracted three times with ethyl acetate. From the ethyl acetate phase, 29.9 g (62% of theory) of 2-(4-chlorophenoxy)-4,4-dimethyl-1-pyridin-3-yl-pentan-3-one of melting point 77°-79° C. were obtained after recrystallization from cyclohexane.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([C:20](=[O:31])[NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=4)[CH:17]=[CH:16][C:15]=3[F:32])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[F:33][C:34]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[CH:40][C:35]=1[C:36]([O:38][CH3:39])=[O:37].C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>O.COCCOC>[F:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[F:29])[CH2:22][NH:21][C:20]([C:18]1[CH:17]=[CH:16][C:15]([F:32])=[C:14]([NH:13][C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([C:42]4[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[C:34]([F:33])[CH:43]=4)=[CH:3][C:4]3=[N:10][CH:9]=2)=[O:12])[CH:19]=1)=[O:31]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: O=C(NCc1ccc(F)c(F)c1)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2ccn3c(C(=O)Nc4cc(C(=O)NCc5ccc(F)c(F)c5)ccc4F)cnc3c2)cc1F

Procedure:
7-Bromo-N-(5-(3,4-difluorobenzylcarbamoyl)-2-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxamide (Intermediate 3A) (500 mg, 0.993 mmol), methyl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (306 mg, 1.093 mmol) and cesium carbonate (1295 mg, 3.97 mmol) in water (2 ml)/DME (5 ml) were mixed to give a suspension. The mixture was degassed with nitrogen and PdCl2(dppf).CH2Cl2 adduct (40.6 mg, 0.050 mmol) was added. The reaction mixture was heated using microwave radiation at 100° C. for 1 hr and partitioned between EtOAc and water. The organic portion was separated, dried (MgSO4) and concentrated in vacuo. The crude product was triturated with MeOH/diethyl ether to afford the title compound;
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([N:29]3[CH2:34][CH2:33][CH:32]([S:35]([C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[CH:39]=4)(=[O:37])=[O:36])[CH2:31][CH2:30]3)=[C:20]([NH:25][CH:26]([CH3:28])[CH3:27])[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[F:44][C:40]1[CH:39]=[C:38]([S:35]([CH:32]2[CH2:33][CH2:34][N:29]([C:19]3[N:18]=[C:17]4[CH2:16][NH:15][CH2:24][CH2:23][C:22]4=[N:21][C:20]=3[NH:25][CH:26]([CH3:28])[CH3:27])[CH2:30][CH2:31]2)(=[O:36])=[O:37])[CH:43]=[CH:42][CH:41]=1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(S(=O)(=O)c3cccc(F)c3)CC1)CN(Cc1ccccc1)CC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1nc2c(nc1N1CCC(S(=O)(=O)c3cccc(F)c3)CC1)CNCC2
Reaction time: 2 h

Procedure:
To a solution of 6-benzyl-3-(4-((3-fluorophenyl)sulfonyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (68 mg, 0.107 mmol) in THF (1333 μL) was added Pd(OH)2 (20 wt %, 22.5 mg, 0.032 mmol). The flask was purged with nitrogen then allowed to stir under an atmosphere of hydrogen (balloon) for 2 h. The reaction mixture was filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR) and washed with EtOAc. The crude material was concentrated in vacuo to give 3-(4-((3-fluorophenyl)sulfonyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine as a TFA salt (58 mg) as a yellow film.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])=[C:12]([OH:22])[C:11]=2[C:23]([F:26])([F:25])[F:24])=[CH:6][CH:5]=1.[CH3:29][N:30]1[CH:34]=[C:33]([C:35](O)=[O:36])[N:32]=[CH:31]1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1.O>[OH:22][C:12]1[C:11]([C:23]([F:24])([F:25])[F:26])=[C:10]([CH:15]=[CH:14][C:13]=1[C:16](=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])[O:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:35]([C:33]2[N:32]=[CH:31][N:30]([CH3:29])[CH:34]=2)=[O:36])=[CH:28][CH:27]=1
Reactant: Cn1cnc(C(=O)O)c1
Reactant: CC(C)CC(=O)c1ccc(OCc2ccc(CN)cc2)c(C(F)(F)F)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC(=O)c1ccc(OCc2ccc(CNC(=O)c3cn(C)cn3)cc2)c(C(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
Mix 1-[4-(4-aminomethyl-benzyloxy)-2-hydroxy-3-trifluoromethyl-phenyl]-3-methyl-butan-1-one hydrochloride (120 mg, 287.2 μmol), 1-methyl-1-H-imidazole-4-carboxylic acid (43.5 mg, 344.6 μmol), 1-hydroxybenzotriazole hydrate (52.8 mg, 344.6 μmol) in anhydrous tetrahydrofuran (4.5 mL). Add triethylamine (72.7 mg, 718 μmol, 100 μL) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (66.1 mg, 344.6 μmol) to the mixture. Stir the reaction mixture at room temperature overnight. Dilute the reaction mixture with water. Extract the mixture with ethyl acetate (3×). Combine the organic layers, wash with brine, dry over sodium sulfate, and concentrate under reduced pressure. Purify the crude residue by flash chromatography (silica gel) eluting with 5% methanol/ethyl acetate followed by reverse phase chromatography using 90/10 to 20/80 (water/0.1% trifluoroacetic acid)/acetonitrile to provide the product as a white solid (75 mg, 153 μmol, 53.4% yield). MS (m/z): 490 (M+1).