Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].O1CCCC1.[CH3:14][CH:15]([CH3:20])[C:16]([O:18][CH3:19])=[O:17].[C:21]([C:25]1[N:26]=[C:27]([C:30]2[O:31][C:32]3[CH:38]=[CH:37][C:36]([CH2:39]Cl)=[CH:35][C:33]=3[CH:34]=2)[S:28][CH:29]=1)([CH3:24])([CH3:23])[CH3:22]>CN(C)P(=O)(N(C)C)N(C)C.CCCCCC>[C:21]([C:25]1[N:26]=[C:27]([C:30]2[O:31][C:32]3[CH:38]=[CH:37][C:36]([CH2:39][C:15]([CH3:20])([C:16]([O:18][CH3:19])=[O:17])[CH3:14])=[CH:35][C:33]=3[CH:34]=2)[S:28][CH:29]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1csc(-c2cc3cc(CCl)ccc3o2)n1
Reactant: COC(=O)C(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C(C)(C)Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled suspension of lithium diisopropylamide {(1.45 mM tetrahydrofuran and n-hexane solution), 3.7 ml} and methyl 2-methylpropionate (0.6 g), a dried hexamethylphosphoric triamide (0.5 ml) was added at -65 to -57° C. Subsequently, 4-tert-butyl-2-(5-chloromethylbenzofuran-2-yl)thiazole was added to the mixture in small portions. After being stirred for 30 minutes at the same temperature, additive hexamethylphosphoric triamide (1.5 ml) was added to the mixture. The reaction mixture was gradually elevated to -10° C. for 1 hour. The resulting mixture was poured into ice-water and extracted with diethyl ether. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to column chromatography on silica gel and eluted with a mixture of n-hexane and ethyl acetate (20:1). The fractions containing object compound were combined and concentrated under reduced pressure to give 4-tert-butyl-2-[5-(2-methyl-2-methoxycarbonylpropyl)benzofuran-2-yl]thiazole (0.43 g).
Reaction SMILES: Br[C:2]1[C:3]([O:16][C:17]2[N:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.[CH:27]1([N:30]2[CH:34]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:32]=[N:31]2)[CH2:29][CH2:28]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.CC(C1C=C(C(C)C)C(C2C=CC=C(P(C3CCCCC3)C3CCCCC3)C=2)=C(C(C)C)C=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+]>[CH:27]1([N:30]2[CH:34]=[C:33]([C:2]3[C:3]([O:16][C:17]4[N:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[N:18]=4)=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]4)[CH:32]=[N:31]2)[CH2:29][CH2:28]1
Reactant: CC1(C)OB(c2cnn(C3CC3)c2)OC1(C)C
Reactant: CC(=O)N1c2ccc(Br)c(Oc3ncc4ccccc4n3)c2CC[C@@H]1C
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2cccc(P(C3CCCCC3)C3CCCCC3)c2)c(C(C)C)c1
Agent: Nc1ccccc1-c1[c-]cccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)c(Oc3ncc4ccccc4n3)c2CC[C@@H]1C
Temperature: 100 °C
Yield: 44.8 %

Procedure:
A mixture of (S)-1-(6-bromo-2-methyl-5-(quinazolin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.025 g, 0.061 mmol), 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.017 g, 0.073 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (XPhos 2nd generation precatalyst) (2.4 mg, 0.003 mmol), and cesium carbonate (0.059 g, 0.182 mmol) in 1,4-dioxane (2.0 mL) and water (0.40 mL) was heated at 100° C. for 2 h. The reaction mixture was filtered through Celite and concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 25-100% ethyl acetate-hexane) to afford (S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-5-(quinazolin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.012 g, 45%) as a white solid. MS (ESI, pos. ion) m/z 440. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.81-0.91 (m, 5H), 1.07 (d, J=6.74 Hz, 3H), 1.47 (m, 1H), 2.03 (br dd, J=13.34, 6.89 Hz, 1H), 2.18 (s, 3H), 2.44 (m, 1H), 3.55-3.67 (m, 1H), 4.63 (m, 1H), 7.41 (br s, 1H), 7.51-7.70 (m, 3H), 7.72 (s, 1H), 7.91 (ddd, J=8.50, 7.04, 1.47 Hz, 1H), 8.06 (s, 1H), 8.10 (d, J=8.21 Hz, 1H), 9.54 (s, 1H). MS (ESI, pos. ion) m/z 440 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([F:22])[CH:21]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[CH:13]=2)[CH:8]=[CH:7]1.[N+:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32]Cl)([O-:25])=[O:24]>C(OCC)C>[F:22][C:20]1[CH:19]=[C:4]([CH:3]=[C:2]([F:1])[CH:21]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[CH:13]=2)[C:8]([S:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N+:23]([O-:25])=[O:24])=[CH:7]1
Reactant: CC(=O)Nc1ccc2ccn(Cc3cc(F)cc(F)c3)c2c1
Reactant: O=[N+]([O-])c1ccccc1SCl
Solvent: CCOCC
Product: CC(=O)Nc1ccc2c(Sc3ccccc3[N+](=O)[O-])cn(Cc3cc(F)cc(F)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a solution of N-[1-(3,5-Difluoro-benzyl)-1H-indol-6-yl]-acetamide (23.3 mg, 0.08 mmol) in diethyl ether (4 mL) was added 2-nitrobenzenesulfenyl chloride (14.7 mg, 0.09 mmol). The resulting yellow solution was stirred overnight at room temperature. The mixture was concentrated in vacuo and purified over a SiO2 column (heptane/ethyl acetate 9:1) to give the title compound as a yellow solid (35.0 mg, yield=96%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][O:13]1
Reactant: COC(=O)c1ccc(Br)c(O)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(Br)c(OC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.5 %

Procedure:
The title compound was prepared by adapting the method reported by Kita et al.[Kita, 1994] To a solution of methyl 4-bromo-3-hydroxybenzoate (4.0 g, 17.31 mmol) in anhydrous CH2Cl2 (30 mL) was added 3,4-dihydro-2H-pyran (3.95 mL, 43.28 mmol) and p-toluenesulfonic acid (0.01 g, 0.17 mmol) at 0° C. The mixture was stirred at this temperature for 90 min, warmed to room temperature and quenched with saturated NaHCO3 solution (50 mL). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The pale yellow residue was purified by flash column chromatography [SiO2, Et2O/n-hexane (4:6)] affording a colourless oil. The oil solidified on standing at room temperature to give methyl 4-bromo-3-(tetrahydropyran-2-yloxy)benzoate as colourless needles (4.12 g, 76%); δH (270 MHz, CDCl3) 1.59-1.77 (m, 3H), 1.86-2.13 (m, 3H), 3.6-3.64 (m, 1H), 3.8-3.85 (m, 1H), 3.88 (s, 3H), 5.6-5.62 (m, 1H), 7.52 (dd, J=8.2, 1.7, 1H), 7.59 (d, J=8.4, 1H), 7.76 (d, J=2.0, 1H); LRMS (FAB+) m/z (rel. intensity) 316.9 (30, [C13H1581BrO4+H]), 314.9 (47, [C13H1579BrO4+H]; LC-MS (APCI+):tR=1.48 min, m/z 334.13 (C13H1581BrO4+H3O+), 332.11 (C13H1579BrO4+H3O+); HPLC: tR=3.21 min (98%); HRMS (FAB+) Found 317.02290; C13H1681BrO4 requires 317.02115.
Reaction SMILES: S(O[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)(C1C=CC(C)=CC=1)(=O)=O.C1CCN2C(=NCCC2)CC1.C(Cl)Cl>CN(C=O)C>[N:15]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][CH:12]=[CH:13][CH2:14]1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=CCC1
Temperature: 150 °C
Yield: 85 %

Procedure:
A mixture of tert-butyl 4-(tosyloxy)piperidine-1-carboxylate (5.50 g, 15.40 mmol, 1 eq) and DBU (5.70 g, 31.00 mmol, 2 eq) in DMF (100 mL) was heated at 150° C. overnight and cooled to room temperature. To this, 100 mL of CH2Cl2 was added, and the mixture was washed with brine (20 mL×3) and water (30 mL×2). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (10:1 (v/v) PE/EtOAc) to give the title compound as pale yellow oil (2.40 g, 85.00%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 184.1 (M+1).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([S:11][CH3:12])[N:5]=1)[CH3:2].[I:13]Cl>CO>[CH2:1]([NH:3][C:4]1[C:9]([I:13])=[C:8]([CH3:10])[N:7]=[C:6]([S:11][CH3:12])[N:5]=1)[CH3:2]
Reactant: CCNc1cc(C)nc(SC)n1
Reactant: ClI
Solvent: CO
Product: CCNc1nc(SC)nc(C)c1I
Reaction time: 8 h
Yield: 67 %

Procedure:
To the solution of N-ethyl-6-methyl-2-(methylthio)pyrimidin-4-amine (20 g, 121.6 mmol) in methanol was added iodine monochloride (26.58 g, 163.7 mmol) in small portions at 0° C. Then the reaction mixture was stirred overnight. After evaporation of solvent, the residue was triturated with acetone. The product N-ethyl-5-iodo-6-methyl-2-(methylthio)pyrimidin-4-amine (25.2 g, 75% yield) was collected by filtration. 1H NMR (400 MHz, CDCl3): δ 5.37 (bs, 1H), 3.52 (q, J=7.2 Hz, 1H), 2.50 (s, 3H), 1.26 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(ON=O)(C)(C)C.[I:8]I.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[CH:19][C:20](N)=[N:21][CH:22]=2)=[CH:13][CH:12]=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[N:21][C:20]([I:8])=[CH:19][N:18]=2)=[CH:13][CH:12]=1
Reactant: II
Reactant: Nc1cnc(-c2ccc(Cl)cc2)cn1
Agent: CC(C)(C)ON=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(-c2cnc(I)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
With the exclusion of light, 4.9 mL (40.0 mmol) tert-butylnitrite and 7.6 g (30 mmol) iodine are added to a solution of 4.8 g (23.3 mmol) 5-(4-chloro-phenyl)-pyrazin-2-ylamine in 100 mL CCl4 and 50 mL DCM and the reaction mixture is stirred overnight at RT. It is combined with 100 mL water and 50 mL 10% Na2S2O3 solution, the organic phase is separated off, washed again with 50 mL 10% Na2S2O3 solution and twice with 50 mL water and dried over MgSO4. It is filtered through activated charcoal, evaporated down i.vac. and the residue is purified by chromatography (silica gel, gradient: PE to PE/EtOAc 8:2).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([CH3:51])=[C:22]([C:29]([C:31]3[CH:40]=[C:39]4[C:34]([C:35](=[O:50])[N:36]([CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:37](=[O:41])[NH:38]4)=[CH:33][CH:32]=3)=[O:30])[N:23]3[C:28]=2[CH:27]=[CH:26][CH:25]=[CH:24]3)=[CH:16][CH:15]=1.[NH2:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][OH:58].OS([O-])(=O)=O.[K+]>CN(C=O)C>[OH:58][CH2:57][CH2:56][O:55][CH2:54][CH2:53][NH:52][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([CH3:51])=[C:22]([C:29]([C:31]3[CH:40]=[C:39]4[C:34]([C:35](=[O:50])[N:36]([CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:37](=[O:41])[NH:38]4)=[CH:33][CH:32]=3)=[O:30])[N:23]3[C:28]=2[CH:27]=[CH:26][CH:25]=[CH:24]3)=[CH:16][CH:15]=1
Reactant: Cc1c(-c2ccc(OCCCCCI)cc2)c2ccccn2c1C(=O)c1ccc2c(=O)n(CC(=O)OC(C)(C)C)c(=O)[nH]c2c1
Reactant: NCCOCCO
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc(OCCCCCNCCOCCO)cc2)c2ccccn2c1C(=O)c1ccc2c(=O)n(CC(=O)OC(C)(C)C)c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.8 %

Procedure:
Potassium carbonate (0.48 g, 3.46 mmol) and tert-butyl {7-[(1-{4-[(5-iodopentyl)oxy]phenyl}-2-methylindolizin-3-yl)carbonyl]-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl}acetate (0.50 g, 0.69 mmol) are added to a solution of 2-(2-aminoethoxy)ethanol (0.73 g, 6.93 mmol) in 7 mL of DMF. The solution is stirred for 24 h at ambient temperature and then run into a molar solution of KHSO4. The precipitate formed is filtered off, washed with water and dried under vacuum to give 380 mg (yield: 79%) of a brown powder.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:12]1([Mg]Br)[CH2:16][CH2:15][CH2:14][CH2:13]1>C(OCC)C.[Cl-].[NH4+].C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ni]Cl>[CH:12]1([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Br[Mg]C1CCCC1
Reactant: Clc1ccc2ccccc2n1
Agent: Cl[Ni]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: c1ccc2nc(C3CCCC3)ccc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
To a solution of 2-chloroquinoline (8.2 g, 50 mmol) and [1,2-bis(diphenylphosphino)-ethane]dichloronickel(II) (200 mg, 0.38 mmol) in diethyl ether (20 ml) cooled in a ice/methanol bath was added cyclopentylmagnesium bromide (2 M solution in diethyl ether; 25.5 ml, 51 mmol) over a period of 15 minutes. The resulting brown solution was then stirred for 30 minutes, the ice bath removed and the mixture stirred for a further 10 minutes. The reaction mixture was then re-cooled to 0° C. and a saturated ammonium chloride solution (40 ml) added slowly. The resulting reaction mixture was poured into a separating funnel and further diluted with diethyl ether (60 ml) and saturated ammonium chloride solution (60 ml). The organics were separated and the aqueous layer washed with diethyl ether (2×100 ml). The combined organics were dried (MgSO4), filtered and the solvent removed in vacuo to leave 2-cyclopentylquinoline (9.98 g, 50.4 mmol) as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1[CH:9]=[C:10]2[CH:16]=[C:15]([C:17]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)=[CH:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[NH:14][C:11]2=[N:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1[CH:9]=[C:10]2[CH:16]=[C:15]([CH:17]([C:25]3[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=3)[CH2:18][CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[NH:14][C:11]2=[N:12][CH:13]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cnc2[nH]c(C(=CC3CCOCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cnc2[nH]c(C(CC3CCOCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Temperature: 50 °C
Yield: 99.1 %

Procedure:
A mixture of {2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-carbamic acid tert-butyl ester (520 mg, 1.05 mmol) and 10% palladium on activated carbon (0.2 g) in methanol (150 mL) was heated at 50° C. under hydrogen (5 atm) for 12 h. After cooling to room temperature, the catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo to give {2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-carbamic acid tert-butyl ester (520 mg, 100%) which was used in the next step without purification: LC/MS m/e calcd for C26H33N3O5S [M+H]+ 500.63, observed 500.2.
Reaction SMILES: N[C@H:2]([CH3:13])[CH2:3][C:4]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7].Cl.[OH-:15].[Na+]>>[Br:12][C:10]1[CH:11]=[C:4]2[C:5](=[CH:8][CH:9]=1)[C:6](=[O:15])[NH:7][C@H:2]([CH3:13])[CH2:3]2
Reactant: C[C@@H](N)Cc1cc(Br)ccc1C#N
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: C[C@@H]1Cc2cc(Br)ccc2C(=O)N1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
480 mg (1.7 mmol) (R)-2-(2-amino-propyl)-4-bromo-benzonitrile (as hydrochloride salt) are dissolved in 5 ml 10 N sodium hydroxide solution and stirred for 16 hours at 80° C. Then the reaction mixture is acidified with hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac. The residue is purified by RP-HPLC.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH2:10][NH:11][C:12](=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>C(O)C.[Fe]>[CH2:1]([O:8][C:9](=[O:23])[CH2:10][NH:11][C:12](=[O:22])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CNC(=O)c1cccc([N+](=O)[O-])c1)OCc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1cccc(C(=O)NCC(=O)OCc2ccccc2)c1
Yield: 74.5 %

Procedure:
To a solution of N-(3-nitrobenzoyl)glycine benzyl ester (5.98 g) in 90% aqueous ethanol (150 ml) was added ammonium chloride (3.56 g). To the mixture was added portionwise iron powder (5.31 g) under stirring and refluxing. After the addition was completed, the mixture was refluxed for 2 hours under stirring. The reaction mixture was hot-filtered. The filtrate and the washings were combined and evaporated in vacuo. To the aqueous residue were added water and ethyl acetate under stirring. The separated organic layer was washed with water twice and dried over magnesium sulfate. Removal of the solvent gave N-(3-aminobenzoyl)glycine benzyl ester (4.03 g) as a viscous oil, which was used in a following reaction without further purification.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][C@H:3]([C:7]([O:9]CC)=[O:8])[N:2]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].O[Li].O>O1CCOCC1.O>[C:15]([O:14][C:12]([N:2]1[CH:3]([C:7]([OH:9])=[O:8])[CH2:4][CH:5]2[CH:1]1[CH2:6]2)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)[C@H]1CC2CC2N1C(=O)OC(C)(C)C
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1C(C(=O)O)CC2CC21
Reaction time: 18 h
Yield: 91 %

Procedure:
To a mixture of (3R)-2-tert-butyl 3-ethyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (D26) (diastereoisomer mixture) (3.4 g, 13.3 mmol) in dioxane (15 ml) and water (15 ml), LiOH H2O (2.2 g, 53 mmol). The mixture was stirret at RT for 18 h. Dioxane was evaporated off and water was washed with Et2O (2×40 ml) then the pH was adjusted to ˜4 by addition of citric acid and the resulting aqueous phase was extacted with DCM (200 ml), washed with water (20 ml), dried over Na2SO4 and evaporated in vacuo to afford the title compound (D27) (2.75 g) as diastereoisomer mixture with syn-anti ratio 10/2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([O:15][CH3:16])[CH3:14])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.CN1CCOCC1.[BH4-].[Na+]>C1COCC1.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C@H:13]([O:15][CH3:16])[CH3:14])[CH2:10][OH:11])([CH3:2])([CH3:4])[CH3:3]
Reactant: CO[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: CO[C@H](C)[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
To a round bottom flask containing a stir bar and (2S,3R)-2-((tert-butoxycarbonyl)amino)-3-methoxybutanoic acid (2.5 g, 10.7 mmol) in THF (80 mL) under nitrogen was cooled to −30° C. in a dry ice/acetone bath. To this cold solution was added isobutyl chloroformate (1.7 mL, 12.9 mmol) followed by the addition of N-methylmorpholine (1.4 mL, 12.9 mmol). Mixture was stirred for 15 min at −30° C. N-Methylmorpholine salt develops and was filtered from mixture. Mother liquor was cooled to −30° C. where upon sodium borohydride (0.61 g, 16.1 mmol) was added followed by the addition of water (10 mL) immediately afterwards. Reaction mixture allowed to stir for 15 min at −20° C. then gradually allowed to warm to room temperature. Reaction mixture was stirred for 30 min at room temperature. Reaction mixture was then diluted with water and extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated to afford tert-butyl((2R,3R)-1-hydroxy-3-methoxybutan-2-yl)carbamate (2.0 g, 9.1 mmol, 85% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.18 (d, J=6.26 Hz, 3H) 1.45 (s, 9H) 3.33 (s, 3H) 3.55-3.84 (m, 4H). LCMS m/z 220.2 (M+H)+, Rt 0.57 min.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:10]([NH2:12])=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=2)[N:4]=1)[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][O:40][C:41]2[CH:46]=[CH:45][N:44]3[C:47]([C:50](OCC)=[O:51])=[CH:48][N:49]=[C:43]3[CH:42]=2)[CH2:34][CH2:33]1.[Cl-].[NH4+]>C1COCC1>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:50]([C:47]2[N:44]3[CH:45]=[CH:46][C:41]([O:40][CH2:39][CH2:38][N:35]4[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]4)=[CH:42][C:43]3=[N:49][CH:48]=2)=[O:51])[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=2)[N:4]=1)[CH3:2]
Reactant: CCOC(=O)c1cnc2cc(OCCN3CCN(C)CC3)ccn12
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(N)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(OCCN5CCN(C)CC5)ccn34)c12
Temperature: 0 °C

Procedure:
To a cooled (ice/water bath) solution of 3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (0.080 g; 0.30 mmol) in anhydrous THF (2 mL) under nitrogen was added drop wise LHMDS (1.0 M solution in THF; 0.32 mmol). The mixture was stirred with cooling for 10 minutes and then added to a solution of ethyl 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (Preparation D) in anhydrous THF (2 mL) with ice/water cooling. An excess of saturated aqueous ammonium chloride solution was added to quench the reaction. The mixture was extracted with DCM. The aqueous phase was then rendered basic by the addition of saturated aqueous sodium carbonate solution and extracted multiple times with DCM and EtOAc. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica, eluting with DCM/MeOH/NH4OH (100:8:1). Purification by thin layer chromatography of the isolated material was repeated under the same conditions to provide N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide (53 mg). MS (ES+APCI) m/z=553.1 (M+H).
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([CH3:19])[CH:13]=[C:12](Cl)[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.CCO.[Pd]>[NH:1]([C:8]1[N:9]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([CH3:19])[CH:13]=[CH:12][N:11]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(Cl)nc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccnc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Yield: 97.6 %

Procedure:
A solution of 2-anilino-7-chloro-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (95.0 mg, 0.263 mmol), TEA (0.65 mmol), and 10% Pd/C in EtOAc (2.5 mL) and EtOH (2.5 mL) was stirred under H2 (1 atm) for 3.5 h. The reaction mixture was filtered through a pad of Celite using EtOH and EtOAc to rinse. The combined filtrates were concentrated in vacuo, and purified with Biotage silica gel chromatography using 1:1 EtOAc:Hex to afford 2-anilino-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (84 mg, 98%) as a pale yellow solid. LCMS RT: 2.26 min, MH+: 328.4, Rf=0.1 (1:1 EtOAc:Hex),
Reaction SMILES: C[O:2][C:3](=[O:16])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1)[CH2:5][CH2:6][CH2:7][Cl:8].O[Li].O.Cl>C1COCC1.CO>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([CH:4]([CH2:5][CH2:6][CH2:7][Cl:8])[C:3]([OH:16])=[O:2])=[N:10][CH:11]=1
Reactant: COC(=O)C(CCCCl)c1ccc(Br)cn1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(CCCCl)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(5-Bromo-pyridin-2-yl)-5-chloro-pentanoic acid methyl ester (2.0 g, 6.5 mmol) in THF/MeOH (5/1) 30 mL, LiOH.H2O (1.092 g, 26 mmol.) was added. After the solution was stirred at room temperature for 16 h, the solution was neutralized with 2N HCl to pH 5-6. The mixture was evaporated to dryness under reduced pressure, then EtOAc (50 mL) was added. The organic layer was washed with brine, dried with Na2SO4, filtered, and evaporated to obtain of an oil product without further purification. MS: calc'd 291 (MH+), exp 291 (MH+).