Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:12]([C:16]1[O:20][N:19]=[C:18]([NH:21][C:22]([CH:24]2[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]2)=[O:23])[CH:17]=1)([CH3:15])([CH3:14])[CH3:13].Cl.C(N(CC)C(C)C)(C)C>CN(C=O)C.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:12]([C:16]1[O:20][N:19]=[C:18]([NH:21][C:22]([CH:24]2[CH2:29][CH2:28][CH2:27][N:26]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH2:25]2)=[O:23])[CH:17]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)c1cc(NC(=O)C2CCCNC2)no1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)C2CCCN(S(=O)(=O)c3ccc(Cl)cc3)C2)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-chlorophenylsulfonyl chloride (117.35 mg; 0.556 mmol) in DMF (2 mL) is added piperidine-3-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (160 mg; 0.556 mmol), N,N-diisopropylethylamine (0.261 mL; 1.5 mmol) and 4-dimethylaminopyridine (2 mg, 0.016 mmol). The reaction mixture is left stirring at room temperature for 18 hours. After this time, the mixture is diluted with ethyl acetate and washed with water 3 times, then brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica using methanol/methylene chloride provides the title compound, m/z 426/428 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].I[C:24]1[CH:29]=[CH:28][C:27]2[O:30][CH2:31][O:32][C:26]=2[CH:25]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.C1(C)C=CC=CC=1>[O:30]1[C:27]2[CH:28]=[CH:29][C:24]([NH:1][C:2]3[CH:14]=[C:13]([CH2:15][CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:12]=[CH:11][C:3]=3[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[CH:25][C:26]=2[O:32][CH2:31]1
Reactant: Ic1ccc2c(c1)OCO2
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1Nc1ccc2c(c1)OCO2
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To toluene 3.0 mL solution of tert-butyl 2-amino-4-phenethylbenzoate 0.10 g were added 1-iodo-3,4-methylenedioxybenzene 0.14 g,cesium carbonate 0.22 g, tris(dibenzylideneacetone)dipalladium(0) 3 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 8 mg,and it was stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature, tris(dibenzylideneacetone)dipalladium(0) 3 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 8 mg were added to it, and it was stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=4:1] to give tert-butyl 2-((benzo-1,3-dioxol-5-yl)amino)-4-phenethylbenzoate. Trifluoroacetic acid 10 mL was added to the obtained tert-butyl 2-((benzo-1,3-dioxol-5-yl)amino)-4-phenethylbenzoate, and it was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 80-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-((benzo-1,3-dioxol-5-yl)amino)-4-phenethylbenzoic acid 12 mg of white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:7][C:6](=[O:12])[CH:5]=[CH:4][C:3]1=2.[H-].[Li+].[C:15]1([CH2:21][CH2:22]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]([CH2:22][CH2:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6](=[O:12])[CH:5]=[CH:4][C:3]1=2
Reactant: BrCCc1ccccc1
Reactant: O=C1CCCc2[nH]c(=O)ccc21
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C1CCCc2c1ccc(=O)n2CCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.4 %

Procedure:
A mixture of 5,6,7,8-tetrahydro-5-oxo-2(1H)-quinolinone (7.5 g), lithium hydride (0.59 g), and dimethylformamide (300 ml) was stirred for 3 hrs at 25° C., under nitrogen. 2-Phenylethyl bromide (9.36 g) was added and the mixture was stirred for an additional eighteen hrs. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was triturated with petroleum ether to afford 3.0 g (24%) of 5,6,7,8-tetrahydro-5-oxo-1-(2-phenylethyl)-2(1H)-quinolinone.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6]C)=O.[F:10][C:11]([F:20])([F:19])[C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[F:10][C:11]([F:19])([F:20])[C:12]1[CH:13]=[CH:14][C:15]([NH:16][C:4](=[O:6])[CH2:3][C:2](=[O:1])[CH2:8][CH3:9])=[CH:17][CH:18]=1
Reactant: CCC(=O)CC(=O)OC
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: CCC(=O)CC(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
Methyl 3-oxopentanoate 10.0 g (76.8 mmol) was heated to 115° C. and 4-(trifluoromethyl)aniline 12.83 g (79.6 mmol) was added dropwise thereto for 10 minutes. After stirring at the same temperature for 25 minutes, toluene (50 mL) was added and the resulting reaction solution was further heated and stirred for 12 hours. The reaction solution was cooled to 0° C. to precipitate a solid and subjected to vacuum filtration to obtain N-[4-(trifluoromethyl)phenyl]-3-oxopentanoic acid amide as a white solid (11.22 g, isolated yield: 57%). 1H-NMR (CDCl3, 400 MHz/ppm): δ 1.13 (3H, t), 2.64 (2H, q), 3.60 (2H, s), 7.58 (2H, d), 7.69 (2H, d), 9.52 (1H, br)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18](O)=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:24]1C=CN=C1)=O.N>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([NH2:24])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C[C@@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1CCOC1
Product: C[C@@H](C(N)=O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A mixture of (S)-2-(4-Chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.65 g, 0.012 mole) and 1,1'-carbonyldiimidazole (1.96 g, 0.0121 mole) was stirred at room temperature in dry tetrahydrofuran (100 ml) for 2.5 hours with a stream of nitrogen bubbling through it. The reaction mixture was cooled in a dry ice/acetone bath, liquid ammonia (50 ml) was added, the mixture was allowed to warm to room temperature and was stirred overnight under nitrogen. The solvents were removed under reduced pressure and the resulting solid was partitioned between water (100 ml) and ethyl acetate (100 ml). The insoluble solid was collected by filtration (1.38 g). The layers were separated, the aqueous layer was extracted once with ethyl acetate and the combined organic layers were washed twice with water, twice with a 5% potassium hydroxide solution and twice again with water, dried over magnesium sulfate, treated with charcoal, filtered, and evaporated under reduced pressure to gibe 1.9 g of solid. The 3.28 g (91 % yield) of solids were combined and dissolved in hot methanol, filtered hot, cooled to room temperature and water was added to the cloud point. The resulting solid was collected by filtration, rinsed with water and dried under high vacuum at room temperature to give 2.50 g of title compound, mp. 202°-204° C.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[S:32]1[CH:36]=[CH:35][C:34]([CH2:37][NH2:38])=[CH:33]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:29])[F:30])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:38][CH2:37][C:34]1[CH:35]=[CH:36][S:32][CH:33]=1)=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NCc1ccsc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCc1ccsc1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 35.7 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol), thiophen-3-ylmethanamine (11.8 mg, 0.104 mmol), 4-methylmorpholine (28.1 mg, 0.278 mmol), and HATU (34.4 mg, 0.090 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(thiophen-3-ylmethyl)acetamide (12.9 mg, 0.025 mmol, 35.2% yield): LCMS=527.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.16 (2 H, d, J=8.53 Hz), 7.52-7.76 (7 H, m), 7.26 (1 H, dd, J=5.02, 1.25 Hz), 6.85-7.01 (2 H, m), 5.16 (1 H, s), 4.60 (2 H, s); HPLC peak RT=3.0 min (Method E).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[C:12]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:16][C:15]([CH2:18]Br)=[CH:14][CH:13]=1>C(=O)([O-])[O-].[Ag+2].C1(C)C=CC=CC=1>[C:12]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:13]=[CH:14][C:15]([CH2:18][O:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)=[CH:16][CH:17]=1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1ccc(O)nc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(OCc2ccc(-c3ccccc3)cc2)nc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
The mixture of methyl 6-hydroxynicotinate (6 g), 4-biphenylylmethyl bromide (7.7 g), silver carbonate (4.8 g), and toluene (60 ml) was stirred at 50° C. for 12 hr. The reaction mixture was further stirred at 100° C. for 6 hr and filtrated.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=4[F:38])=[C:23]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:24]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=4[F:38])=[C:23]([CH2:25][C:26]([CH3:29])([CH3:27])[CH3:28])[CH:24]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cc(COc2cnc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)ncn1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ncc(OCc3cc(C(CC(=O)O)C4CC4)ncn3)cc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.1 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(6-(((6-(2-fluoro-5-methoxyphenyl)-5-neopentylpyridin-3-yl)oxy)methyl)pyrimidin-4-yl)propanoate (362 mg) in THF (3.0 mL) and methanol (1.5 mL) was added 1N aqueous sodium hydroxide solution (3.0 mL), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added hydrochloric acid (1N, 3.0 mL) at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give the title compound (353 mg) as a white amorphous solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[NH2:38])=[CH:28][CH:27]=1>C(Cl)Cl.C(N(CC)CC)C>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[NH:38][C:7]([C:5]2[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3][N:2]([CH3:1])[CH:6]=2)=[O:8])=[CH:30][CH:31]=1
Reactant: Nc1ccccc1-c1ccc(Cl)cc1
Reactant: Cn1cc(C(=O)O)c(C(F)(F)F)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)Nc2ccccc2-c2ccc(Cl)cc2)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.4 %

Procedure:
A solution of 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (0.68 g) and oxalyl chloride (0.49 g) in methylene chloride (30 ml) is stirred for 2 hours at room temperature in the presence of a catalytic amount of DMF. The resulting acid chloride solution is then added to a solution of 4′-chlorobiphenyl-2-ylamine (0.71 g) and triethylamine (0.36 g) in 15 ml of methylene chloride at 0° C. The reaction mixture is then stirred for 4 hours at room temperature. After distilling off the solvent in a water-jet-vacuum, the residue is taken up in ethylacetate/water. The ethylacetate phase is extracted twice with water. After drying of the organic phase with Na2SO4, the solvent is distilled off in a water-jet-vacuum and the residue purified by column chromatography (silica gel; eluant: ethylacetate/hexane=1:1). 0.8 g of 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (4′-chlorobiphenyl-2-yl) amide are obtained in the form of slightly brownish crystals having a melting point of 144–146° C.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]21[CH2:24][C:13]1=[CH:14][C:15]3[N:16]=[C:17]([CH:22]=O)[CH:18]=[N:19][C:20]=3[CH:21]=[C:12]1[CH2:11]2.[NH:25]1[C:35]2[C:36]3[CH:27]([CH2:28][C:29](=[O:37])[NH:30][C:31]=3[CH:32]=[CH:33][CH:34]=2)[CH2:26]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[O:37]=[C:29]1[CH2:28][CH:27]2[CH2:26][N:25]([CH2:22][C:17]3[CH:18]=[N:19][C:20]4[CH:21]=[C:12]5[CH2:11][C:3]6([C:4]7[C:5](=[N:6][CH:7]=[CH:8][CH:9]=7)[NH:10][C:2]6=[O:1])[CH2:24][C:13]5=[CH:14][C:15]=4[N:16]=3)[C:35]3[C:36]2=[C:31]([CH:32]=[CH:33][CH:34]=3)[NH:30]1
Reactant: O=Cc1cnc2cc3c(cc2n1)CC1(C3)C(=O)Nc2ncccc21
Reactant: O=C1CC2CNc3cccc(c32)N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C1CC2CN(Cc3cnc4cc5c(cc4n3)CC3(C5)C(=O)Nc4ncccc43)c3cccc(c32)N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of (±)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoxaline-7,3′-pyrrolo[2,3-b]pyridine]-2-carbaldehyde from Step B (16 mg, 0.051 mmol), 1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-one, enantiomer B (11 mg, 0.061 mmol, described in Intermediate 19), and AcOH (0.029 mL, 0.51 mmol) in DCE (0.4 mL) was added sodium triacetoxyborohydride (16 mg, 0.076 mmol) and the mixture was stirred for 4 h at ambient temperature. The solvent was removed in vacuo and the residue was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Saturated aqueous NaHCO3 (1 mL) was added to the tubes in the fraction collector in order to rapidly neutralize to eluted solvent. The pure, product-containing fractions were combined and extracted with CH2Cl2, and the organic extract was dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound. MS: m/z=475 (M+1). HRMS: m/z=475.1878; calculated m/z=475.1877 for C28H23N6O2.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][C:5]([NH2:8])=[CH:6][CH:7]=1.C(N(CC)CC)C.C1COCC1.[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C(Cl)Cl>[NH2:9][C:3]1[N:4]=[C:5]([NH:8][C:25]([C:24]2[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=2[F:22])=[O:26])[CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: O=C(Cl)c1ccccc1F
Reactant: Nc1ccc(Br)c(N)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1nc(NC(=O)c2ccccc2F)ccc1Br
Temperature: -78 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
A solution of 3-bromo-2,6-diaminopyridine (60) (564 mg, 3 mmol), triethyl amine (0.54 ml) in DCM (6 ml)/THF (4 ml) was cooled down to −78° C. A solution of 2-fluorobenzoyl chloride (362 μl, 3.03 mmol) in 2 ml DCM was added dropwise within 10 min. The resulting reaction mixture was stirred at −78° C. for 1 h before slowly warm up to r.t. After stirred at r.t. for 3 h, the reaction quenched with aq NaHCO3 solution. 200 ml EA were added. Org. phase was washed with brine, dried over sodium sulfate, concentrated. The light yellow solid residue was triturated with DCM (ca. 15 ml), filtered and dried to give 530 mg N-(6-amino-5-bromo(2-pyridyl))(2-fluorophenyl)carboxamide (61) as white solid. (purity>95%, yield: 57%).
Reaction SMILES: COC([C:5]1[O:16][C:15]2[C:14]3[CH:13]=[C:12]([O:17][CH3:18])[CH:11]=[CH:10][C:9]=3[N:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:7]=2[C:6]=1[OH:25])=O.O.[OH-].[Na+]>CN(C)C=O>[CH3:18][O:17][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:7]3[C:6](=[O:25])[CH2:5][O:16][C:15]=3[C:14]=2[CH:13]=1
Reactant: COC(=O)c1oc2c3cc(OC)ccc3n(-c3ccccc3)c2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c1c(n2-c2ccccc2)C(=O)CO1
Yield: 47.1 %

Procedure:
A mixture of 39.0 g (0.12 mole) of 3-hydroxy-7-methoxy-4-phenyl-4H-furo[3,2-b]indole-2-carboxylic methyl ester (Preparation described in U.S. patent application Ser. No. 369,448 now issued as U.S. Pat. No. 4,503,236) in 195 ml of N,N-dimethylformamide and 80 ml of water was treated with 40 ml of 50% aqueous sodium hydroxide, After heating on the steam bath for two hours, the product was isolated as described in Example V above. Recrystallization from 2-methoxyethanol/N,N-dimethylformamide yielded 15.8 g (49% yield) of the product, mp 175° C.-dec. An additional recrystallization as above raised the mp to 185°-187° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.Cl.[N:23]1([CH:28]2[CH2:31][NH:30][CH2:29]2)[CH:27]=[CH:26][N:25]=[N:24]1.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:30]2[CH2:31][CH:28]([N:23]3[CH:27]=[CH:26][N:25]=[N:24]3)[CH2:29]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: c1cn(C2CNC2)nn1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: Nc1c(F)c(N2CC(n3ccnn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1

Procedure:
A solution of 75 mg (0.25 mmol) of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 3-(1,2,3-triazol-1-yl)azetidine hydrochloride (99.7 mg, 0.625 mmol) in 3 ml of pyridine in the presence of 95 mg of DBU was heated at 75° C. overnight. The resulting suspension was evaporated to dryness and to the residue, water was added and the separated yellow solid was collected (99 mg, 98%), m.p. >330° C. (dec). 1H NMR (TFA) δ: 9.1 (s, 1H), 8.74 (s, 1H), 8.6 (s, 1H), 6.2-5.98 (m, 1H), 5.55-5.05 (m, 4H), 4.45-4.15 (m, 1H), 1.65-1.2 (m, 4H). Anal. calcd. for C18H16F2N6O3 : C, 53.74; H, 4.01; N, 20.88. Found: C, 53.63; H, 3.99; N, 20.20.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH:11]([NH:20][C:21]([N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[CH2:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[NH:31][C:30]4=[O:39])[CH2:25][CH2:24]3)=[O:22])[C:12](=[O:19])[N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:40][CH:41]([CH2:44][CH3:45])[CH:42]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH:11]([NH:20][C:21]([N:23]3[CH2:24][CH2:25][CH:26]([N:29]4[CH2:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[NH:31][C:30]4=[O:39])[CH2:27][CH2:28]3)=[O:22])[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:40][CH:41]([CH3:42])[CH2:44][CH3:45])[CH2:15][CH2:14]3)=[O:19])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CCC(C)C=O
Reactant: O=C(NC(Cc1ccc2[nH]ncc2c1)C(=O)N1CCNCC1)N1CCC(N2Cc3ccccc3NC2=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CCC(C)CN1CCN(C(=O)C(Cc2ccc3[nH]ncc3c2)NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)CC1
Reaction time: 1 h
Yield: 50 %

Procedure:
A stirred solution of 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1-(1H-indazol-5-ylmethyl)-2-oxo-2-piperazin-1-yl-ethyl]-amide (100 mg, 0.188 mmol) in methanol (25 mL) was treated with 2-methyl-butyraldehyde (0.03 ml, 0.376 mmol). After 1 h at room temperature, sodium triacetoxyborohydride (80 mg, 0.316 mmol) was added. The mixture was allowed to stir overnight. The solution was filtered through an SCX cartridge. The cartridge was eluted first with methanol and then with a 1M solution of ammonia in methanol. The solvent was removed in vacuo to give the desired product in 50% yield. LC/MS: tR=1.31 min, 601(MH)+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH:9]2[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:12][O:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:23]=[N:24][CH:25]=2)[C:21]=1Cl)=[O:15].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH3:12][O:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:23]=[N:24][CH:25]=2)[C:21]=1[NH:4][C:3]1[CH:5]=[CH:6][C:7]([CH:9]2[CH2:11][CH2:10]2)=[CH:8][C:2]=1[F:1])=[O:15]
Reactant: COC(=O)c1ccc2cncn2c1Cl
Reactant: Nc1ccc(C2CC2)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cncn2c1Nc1ccc(C2CC2)cc1F
Temperature: -70 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a solution of 2-fluoro-4-cyclopropyl aniline (395 mg, 2.61 mmol) and 5-chloro-imidazo[1,5-a]pyridine-6-carboxylic acid methyl ester (500 mg, 2.37 mmol) in THF under nitrogen at −70° C. (20 mL) was added lithium bis(trimethylsilyl) amide (4.98 mL, 1M solution, 4.98 mmol) dropwise. After stirring for 1 hour at −70° C. the reaction mixture was allowed to warm and then quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate (150 mL), the organic extract dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0-50% ethyl acetate in cyclohexane) to yield the title compound (573 mg, 60%). LCMS (Method B): RT=3.60 min, M+H+=326.