Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:35])[C@@H:16]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[C:26]([Cl:34])[CH:25]=2)[CH2:17][C@H:18]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]2)=[N:10]1)(C)(C)C.O1CCCC1.O>C(O)(=O)C>[Cl:34][C:26]1[CH:25]=[C:24]([C@@H:16]([CH2:17][C@H:18]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]2)[C:15]([NH:14][C:11]2[CH:12]=[CH:13][N:9]([CH2:8][CH2:7][OH:6])[N:10]=2)=[O:35])[CH:29]=[CH:28][C:27]=1[S:30]([CH3:33])(=[O:32])=[O:31]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)[C@H](C[C@H]2CCC(=O)C2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc([C@@H](C[C@H]2CCC(=O)C2)C(=O)Nc2ccn(CCO)n2)cc1Cl
Temperature: 25 °C
Yield: 98.4 %

Procedure:
In a round bottom flask was placed (R)—N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionamide (85 mg, 0.15 mmol), tetrahydrofuran (2 mL), water (0.5 mL) and acetic acid (2 mL). This solution was then stirred at 25° C. until all starting material is consumed (˜4 hr). The reaction was then diluted with water (10 mL) and transferred to a separatory funnel where it was extracted with ethyl acetate (3×10 mL). The organic layers were combined and then washed with saturated aqueous sodium bicarbonate solution (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 100% ethyl acetate to 5% methanol/ethyl acetate) afforded (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-3-((R)-3-oxo-cyclopentyl)-propionamide (67 mg, 99%) as a white foam: [α]29589=−11.5° (c=0.13, methylene chloride); ES-HRMS m/e calcd for C20H24N3O5SCl (M+H)+ 454.1198, observed 454.1193; 1H NMR (300 MHz, DMSO-d6) δ 1.51 (m, 1H, CH), 1.78-2.30 (m, 8H, 4×CH2), 3.34 (s, 3H, SO2CH3), 3.67 (q, J=5.4 Hz, 2H, OCH2), 3.96 (m, 1H, ArCHCO), 4.00 (m, 2H, NCH2), 4.84 (t, J=5.4 Hz, 1H, OH), 6.41 (d, J=2.1 Hz, 1H, Ar), 7.55 (d, J=2.1 Hz, 1H, Ar), 7.62 (d, Jo=8.3 Hz, 1H, Ar), 7.73 (s, 1H, Ar), 8.02 (d, Jo=8.3 Hz, 1H, Ar), 10.85 (s, 1H, NH).
Reaction SMILES: C(O[C:4](=[O:16])[C:5](=[C:9]1[C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10]1)[O:6][CH2:7][CH3:8])C.[OH-:17].[K+].Cl>>[CH2:7]([O:6][C:5]1[C:9]([C:13]([OH:17])=[O:14])=[N:10][C:11]([OH:15])=[N:12][C:4]=1[OH:16])[CH3:8]
Reactant: CCOC(=O)C(OCC)=C1NC(=O)NC1=O
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: CCOc1c(O)nc(O)nc1C(=O)O
Temperature: 0 °C

Procedure:
(2,5-dioxo-imidazolidin-4-ylidene)-ethoxy-acetic acid ethyl ester (16.02 g, 1 eq.) was dissolved in aq. 1 N KOH (281 ml, 4 eq.) and refluxed for 3.5 hrs. The mixture was cooled to 0° C. and carefully acidified with conc. HCl. After overnight cooling (4° C.), it led to the formation of white precipitate. The mixture was filtered and the precipitate was dried in vacuo. The product obtained was a white solid (7.76 g, 55%).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:17]([CH:18]=O)[C:16]=1[OH:24]>>[Br:14][C:15]1[C:16]([OH:24])=[C:17]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1cc(Cl)cc(Br)c1O
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: O=c1cc(N2CCN(Cc3cc(Cl)cc(Br)c3O)CC2)nc[nH]1

Procedure:
6-[4-(3-Bromo-5-chloro-2-hydroxy-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 3-bromo-5-chlorosalicylaldehyde (available from Aldrich). 1H NMR (400 MHz, CDCl3) δ 2.62-2.66 (m, 4H), 3.48-3.66 (m, 4H), 3.72 (s, 2H), 5.40 (s, 1H), 6.93-6.94 (m, 1H), 7.44-7.45 (m, 1H), 7.86 (s, 1H), 12.85 (br s, 1H). Mass spectrum (ES) MH+=401.
Reaction SMILES: [C:1]([C:4]1[C:8]([O:9][CH3:10])=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[N:5]=1)(O)=[O:2].[NH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.O.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:6]1[C:7]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[C:8]([O:9][CH3:10])[C:4]([C:1](=[O:2])[NH:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[N:5]1
Reactant: COc1c(C(=O)O)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Reactant: NN1CCOCC1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1c(C(=O)NN2CCOCC2)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 3-carboxy-1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-1H-pyrazole (3.5 g, compound obtained in Reference Example 1(6)) in methylene chloride (100 mL) was added N-aminomorpholine (1.47 g), water-soluble carbodiimide HCl (2.76 g) and 1-hydroxybenzotriazole hydrate (2.21 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added an aqueous sodium hydrogencarbonate solution and the mixture was stirred and extracted with chloroform. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=40/60 to 20/80) to obtain 1-(2-chloro-phenyl)-5-(4-chlorophenyl)-4-methoxy-3-(N-morpholinocarbamoyl)-1H-pyrazole (3.49 g; yield: 81%) as a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15]C.[CH:32]1(C2C(N[C@@H]3C4C(=CC=CC=4)C[C@@H]3O)=NC(C)=C(C3C=CC(Cl)=CC=3Cl)N=2)CC1>>[CH:30]1([C:11]2[C:12]([NH:17][C@@H:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][C@@H:19]3[O:27][CH2:28][CH3:29])=[N:13][C:14]([CH3:15])=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]=2)[CH2:32][CH2:31]1
Reactant: Cc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(C2CC2)nc1-c1ccc(Cl)cc1Cl
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(C)c(-c2ccc(Cl)cc2Cl)nc1C1CC1

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[3-cyclopropyl-5-(2,4-dichlorophenyl)-6-methylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.87–1.07, 1.18–1.23, 1.82, 2.27, 3.10–3.16, 3.47–3.57, 3.66–3.76, 4.40, 5.83, 5.98, 7.25–7.50; MS (ESI+) for C25H25Cl2N3O m/z 454 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=3[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:21])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:28][CH3:29].Br[CH2:31][CH2:32][CH2:33][Cl:34].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:34][CH2:33][CH2:32][CH2:31][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=3[C:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:21])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:28][CH3:29]
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
{2-[(7-Hydroxy-6-methoxy-4-quinolyl)oxy]-5-methylphenyl}-(phenyl)methanone (200 mg), 1-bromo-3-chloropropane (245 mg), and potassium carbonate (358 mg) were suspended in N,N-dimethylformamide (5 ml), and the suspension was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (210 mg, yield 87%).
Reaction SMILES: [OH-].[Na+].[CH3:3][S:4][CH2:5][C:6]1[O:11][CH2:10][N:9]([C:12]([CH3:19])([CH3:18])[C:13]([O:15]CC)=[O:14])[C:8](=[O:20])[C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C.O1CCOCC1.O>[CH3:3][S:4][CH2:5][C:6]1[O:11][CH2:10][N:9]([C:12]([CH3:19])([CH3:18])[C:13]([OH:15])=[O:14])[C:8](=[O:20])[C:7]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)C(C)(C)N1COC(CSC)=C(c2ccccc2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: CSCC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)O)CO1
Temperature: 60 °C
Yield: 38.7 %

Procedure:
A solution of sodium hydroxide (16.43 g) in 10 water was added to a stirred solution of ethyl 2-(2,3-dihydro-6-methylthiomethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoate (68 g) in a mixture of ethanol and 1,4-dioxan. The solution was heated at 60° C. for 6 hours, allowed to cool and the solvent was removed under reduced pressure to give an orange oil which was dissolved in water. The aqueous solution was washed with dichloromethane, acidified to pH 1 with concentrated hydrochloric acid, extracted with dichloromethane, the extract dried (magnesium sulphate) and evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with dichloromethane/ethyl acetate to give 2-(2,3-dihydro-6-methylthiomethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoic acid (24.2 g) as a yellow solid, m.p. 136-137° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:10][NH:11][CH:12]([CH3:28])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[OH:9])[CH:5]=[CH:6][CH:7]=1>C(O)C.Cl.[Pt]=O>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:10][NH:11][CH:12]([CH3:28])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][NH:23]3)=[CH:16][CH:15]=2)[OH:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(Cc1ccc(OCc2ccccn2)cc1)NCC(O)c1cccc(Cl)c1
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: CC(Cc1ccc(OCC2CCCCN2)cc1)NCC(O)c1cccc(Cl)c1

Procedure:
3-Chloro-α-[[[2-[4-(2-pyridylmethyloxy)phenyl]-1-methylethyl]amino]methyl]benzene methanol, (2.5 g) in ethanol (40 ml) and 2M hydrochloride acid (40 ml) was hydrogenated at atmospheric pressure in the presence of platinum oxide. The reaction mixture was filtered, the filtrate neutralised with 2M sodium hydroxide solution, extracted with ethyl acetate and dried. Evaporation of the solvent gave an oil which was treated with ethereal hydrogen chloride to give 3-chloro-α-[[[2-[4-(2-piperidinylmethyloxy)phenyl]-1-methylethyl]amino]methyl] benzenemethanol, dihydrochloride m.p. 181°-198C. (methanol-ether), as a 95:5 mixture of diastereoisomers.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9](OC(C)(C)C)=O.Cl[C:17]1[C:22]([C:23]2[N:28]=[CH:27][N:26]=[C:25]([O:29][C:30]3[C:35]4[N:36]=[C:37]([NH2:39])[S:38][C:34]=4[CH:33]=[CH:32][CH:31]=3)[CH:24]=2)=[CH:21][CH:20]=[C:19]([C:40]([F:43])([F:42])[F:41])[N:18]=1>>[CH2:9]([N:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@H:3]1[CH2:2][NH:1][C:17]1[C:22]([C:23]2[N:28]=[CH:27][N:26]=[C:25]([O:29][C:30]3[C:35]4[N:36]=[C:37]([NH:39][C:25](=[O:29])[CH3:24])[S:38][C:34]=4[CH:33]=[CH:32][CH:31]=3)[CH:24]=2)=[CH:21][CH:20]=[C:19]([C:40]([F:43])([F:42])[F:41])[N:18]=1)[CH:19]([CH3:40])[CH3:20]
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)nc4Cl)ncn3)cccc2s1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CN
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)nc4NC[C@@H]4CCCCN4CC(C)C)ncn3)cccc2s1

Procedure:
The title compound was prepared from (S)-2-aminomethyl-N-Boc-piperidine (AstaTech) and 4-(6-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yloxy)-benzo[d]thiazol-2-amine, Example 1(b), analogous to the procedures described for Example 3(a-d). MS (ESI, pos. ion.) m/z: 600 (M+1).
Reaction SMILES: CCO.C([O:11][C:12]1[CH:13]=[C:14]([C:24]([O:26][CH3:27])=[O:25])[CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=1)C1C=CC=CC=1.[H][H]>[C].[Pd].C1COCC1>[OH:11][C:12]1[CH:13]=[C:14]([C:24]([O:26][CH3:27])=[O:25])[CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(-c2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1cc(O)cc(-c2ccccc2)c1

Procedure:
In a nitrogen atmosphere, 10% palladium-carbon (900 mg) was added to a mixed solution of EtOH (40 mL)-THF (8 mL) of methyl 5-benzyloxybiphenyl-3-carboxylate (1.55 g), and stirred in a hydrogen atmosphere at room temperature for 2 hours. The reaction liquid was filtered through Celite, and concentrated under reduced pressure to obtain the title compound as a white powder. Not purified, this was used in the next step.
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[I:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)[N:12]=[CH:11]2.CI>CN(C=O)C>[CH3:1][O:22][C:21](=[O:23])[C:20]1[CH:19]=[CH:18][C:17]([N:13]2[C:14]3[C:10](=[CH:9][C:8]([I:7])=[CH:16][CH:15]=3)[CH:11]=[N:12]2)=[CH:25][CH:24]=1
Reactant: O=C(O)c1ccc(-n2ncc3cc(I)ccc32)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(-n2ncc3cc(I)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
K2CO3 (7.35 g, 53.2 mmol) is suspended in 110 mL DMF. 4-(5-iodoindazole-1-yl)-benzoic acid (17.6 g, 48.33 mmol), dissolved in 25 mL DMF, is added dropwise. The reaction mixture is stirred for 30 min at r.t. Subsequently CH3I (3.31 mL, 53.2 mmol) is added dropwise (temperature rises to 30° C.). The reaction mixture is stirred overnight at r.t. and then poured on ice water. It is three times extracted with ethyl acetate. The combined organic extracts are washed twice with water and brine. After drying over Na2SO4 and filtration the solvent is evaporated. The residue is purified by chromatography (silicagel, eluents: ethyl acetate/hexane) yielding 14.03 g (76.8%) of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])C.Br[O-].[Na+].[OH-].[Na+].BrBr.S(=O)(O)[O-:35].[Na+]>O1CCOCC1>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:35])=[CH:5][CH:6]=2)=[CH:11][CH:12]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=S([O-])O
Reactant: CCCCCCCCCCOc1ccc(-c2ccc(C(C)=O)cc2)cc1
Agent: BrBr
Agent: [Na+]
Agent: [O-]Br
Solvent: C1COCCO1
Product: CCCCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reaction time: 2 h

Procedure:
To a solution of 4-acetyl-4'-decyloxy-1,1'-biphenyl (4.2 g, 0.012 mol) in 1,4-dioxane (20 ml), an aqueous solution of sodium hypobromite (40 ml) [freshly prepared from sodium hydroxide (7.9 g) and bromine (7.1 g)] was added dropwise at 20°-25° C., and stirring was continued for 2 h at 40° C. After cooling, sodium bisulfite was added to destroy excess sodium hypobromite and the mixture was acidified with hydrochloric acid. The resultant precipitate was filtered, washed with H2O and dried to give the title compound as a white amorphous powder; yield: 3.5 g (90.1%); mp 245.5°-250.0° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:19]1[C:20]([CH3:36])=[C:21]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=[CH:23][CH:24]=1)[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:11]=2)[NH:6][CH:5]=1.O=[CH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].C1(C)C=CC=CC=1.Cl.O1CCOCC1>O1CCOCC1.CC1C=CC(C)=CC=1.[Pd]>[CH2:28]([O:27][C:26]([NH:25][C:21]1[C:20]([CH3:36])=[C:19]([C:3]2[C:4]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([N:13]5[CH2:14][CH2:15][O:16][CH2:17][CH2:18]5)[CH:11]=4)[NH:6][C:5]=3[C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[N:1][CH:2]=2)[CH:24]=[CH:23][CH:22]=1)=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)C=O
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1C(CN)c1c[nH]c2ccc(N3CCOCC3)cc12
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccc(C)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncc(-c2cccc(NC(=O)OCc3ccccc3)c2C)c2c1[nH]c1ccc(N3CCOCC3)cc12
Temperature: 40 °C
Reaction time: 8 h
Yield: 18.8 %

Procedure:
To a solution of benzyl 3-(2-amino-1-(5-morpholino-1H-indol-3-yl)ethyl)-2-methylphenylcarbamate (0.713 g, 1.471 mmol) and 50% ethyl 2-oxoacetate (0.583 mL, 2.94 mmol)/toluene in 1,4-dioxane (61.3 mL) was added 4 N hydrochloric acid/1,4-dioxane (0.736 mL, 2.94 mmol)/dioxane under nitrogen. After stirring overnight, more 50% ethyl 2-oxoacetate (0.583 mL, 2.94 mmol) was added. After 2 hr, the reaction was heated to 40° C. After another 2 hr, the reaction was cooled to room temperature, concentrated in vacuo, and dissolved in water (50 mL) and EtOAc (50 mL). The mixture was basified with saturated NaHCO3 solution to pH ˜10. The layers were separated and the aqueous layer was extracted with EtOAc (3×50 mL). The organic layers were combined, washed with brine, dried over MgSO4, and concentrated in vacuo to give crude product used in subsequent step. This was added to 10% Pd/C (0.377 g, 0.354 mmol) in p-xylene (39.4 mL), and the reaction was heated at 125° C. After 9 h, the reaction was cooled to room temperature, filtered through a wad of CELITE®, rinsed with EtOAc, and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (100 mL), washed with brine (25 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography using an ISCO 40 g column eluting with 0-50% EtOAc/CH2Cl2 to give the desired product (0.1558 g, 0.276 mmol, 23.4% yield) as a light orange foam.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH:17]([CH2:19][N:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:22][CH2:21]3)[O:16][C:15]2=[O:32])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[ClH:33]>>[ClH:33].[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:18][CH:17]([CH2:19][N:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:22][CH2:21]3)[O:16][C:15]2=[O:32])[CH2:12][CH2:13]1
Reactant: COC(=O)CCN1CCN(CC2CN(C3CCN(C(=O)OC(C)(C)C)CC3)C(=O)O2)CC1
Agent: Cl
Product: COC(=O)CCN1CCN(CC2CN(C3CCNCC3)C(=O)O2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.6 g of 3-(1-BOC-4-piperidyl)-5-[4-(2-methoxycarbonylethyl)piperazino]methyloxazolidin-2-one [obtainable according to Ex. 1] are suspended in 40 ml of 2N HCl solution based on dioxane and the mixture is stirred at room temperature for 3 hours. After removal of the solvent and customary working up, 3-(4-piperidyl)-5-[4-(2-methoxycarbonylethyl)piperazino]methyloxazolidin-2-one, hydrochloride, is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C@:6]12[CH2:14][C@H:13]1[C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:32]3[CH:33]=[N:34][C:35]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[CH:36][CH:37]=3)=[N:20][N:21]2COCC[Si](C)(C)C)=[CH:17][CH:16]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C@:6]12[CH2:14][C@H:13]1[C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:32]3[CH:33]=[N:34][C:35]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[CH:36][CH:37]=3)=[N:20][NH:21]2)=[CH:17][CH:16]=1
Reactant: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(-c4ccc(N5CCOCC5)nc4)nn(COCC[Si](C)(C)C)c3c1)C(=O)N2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(-c4ccc(N5CCOCC5)nc4)n[nH]c3c1)C(=O)N2
Yield: 53.5 %

Procedure:
A solution of (1R*,2S*)-5′-methoxy-2-(3-(6-morpholinopyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one (10 mg, 0.02 mmol) in THF (2.0 mL) was treated with TBAF (0.10 mL, 1M in THF) and refluxed for 3 h. The reaction was diluted with EtOAc and the organic layer was washed with brine (4×) and then dried over MgSO4. The solvent was removed and the crude product was purified by silica gel chromatography using EtOAc as eluent followed by trituration (EtOAc: Hexanes, 1:1) to give the title compound as a yellow powder (5 mg, 13%). 1H NMR (400 MHz, CD3OD) δ 8.70 (d, J=2.4 Hz, 1H), 8.14 (dd, J=8.8, 2.4 Hz, 1H), 7.89 (d, J=8.5 Hz, 1H), 7.50 (s, 1H), 7.04 (d, J=7.5 Hz, 1H), 6.98 (d, J=8.9 Hz, 1H), 6.83 (d, J=8.5 Hz, 1H), 6.62 (dd, J=8.5, 2.6 Hz, 1H), 5.61 (d, J=2.5, 1H), 4.63 (s, 1H), 3.84 (t, J=4.8 Hz, 4H), 3.58 (t, J=5.0 Hz, 4H), 3.40-3.35 (m, 1H), 3.29 (s, 3H), 2.28-2.25 (m, 1H), 2.21-2.18 (m, 1H); MS ESI 468.3 [M+H]+, calcd for [C27H25N5O3+H]+ 468.20.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[F:23]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:19]3[CH:20]=[CH:21][C:22]([F:23])=[C:17]([Cl:16])[CH:18]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1ccc(F)c(Cl)c1

Procedure:
The title compound, MS: m/e=347.2 (M+H+), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 3-chloro-4-fluoro-benzene boronic acid.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([NH:20][C:21](=[O:24])[CH2:22]Cl)[CH:9]=1)(=[O:3])[CH3:2].[CH3:25][O:26][C:27]1[CH:39]=[CH:38][C:30]([CH2:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C.C1COCC1>C(#N)C>[C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([NH:20][C:21](=[O:24])[CH2:22][N:35]2[CH2:36][CH2:37][CH:32]([CH2:31][C:30]3[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:39][CH:38]=3)[CH2:33][CH2:34]2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCNc1cc(NC(=O)CCl)nc(-c2ccccc2)n1
Reactant: COc1ccc(CC2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccc(CC2CCN(CC(=O)Nc3cc(NCCNC(C)=O)nc(-c4ccccc4)n3)CC2)cc1

Procedure:
A solution of chloroacetamide 6 (41 mg; 0.118 mmol), piperidine 7.8 (27 mg; 0.132 mmol) and DIPEA (30 μL; 0.172 mmol) in 2.5 mL of 3:2 acetonitrile:THF was reacted at rt for 8 days; whereupon the reaction was concentrated on a rotary evaporator then purified on silica gel (20 mL) with 12:1 EtOAc:i-PrOH yielding a glassy material. A solution of the product in DCM plus hexanes was evaporated leaving a white solid (23 mg; 38%). LC (method B) tR=12.8 min; 1H NMR (200 MHz, CDCl3) δ 9.53 (brs, 1H), 8.37 (m, 2H), 7.48 (m, 3H), 7.22 (s, 1H), 7.08 (m, 2H), 6.84 (m, 3H), 6.62 (brs, 1H), 5.50 (brt, J=5.5 Hz, 1H), 3.79 (s, 3H), 3.68 (m, 2H), 3.53 (m, 2H), 3.10 (s, 2H), 2.88 (m, 2H), 2.54 (m, 2H), 2.20 (m, 2H), 1.85 (s, 3H), 1.80-1.20 (m, 5H); ESIMS 517.0 (28) [MH+], 259.1 (100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O1CCOCC1>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cncc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)c2cncc(Br)c2)CC1
Reaction time: 72 h

Procedure:
5-Bromonicotinic acid (0.020 g, 0.10 mmol), 1-methylpiperazine (0.015 g, 0.15 mmol), HATU (0.046 g, 0.12 mmol), DIPEA (0.052 g, 0.40 mmol), and dioxane (2 mL) were added to a 20 mL vial. The vial was sealed and placed on a heater/shaker for 3 days at 40° C. The reaction mixture, containing the title compound, was used without purification.