Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([OH:15])=O)[N:10]=[C:9]([C:16]3[N:17]=[N:18][N:19]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH:20]=3)[CH:8]=2)=[CH:4][CH:3]=1.[CH3:32][C:33]([NH2:42])([CH3:41])[CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[CH3:41][C:33]([NH:42][C:13](=[O:15])[CH2:12][N:11]1[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:31][CH:30]=2)=[CH:8][C:9]([C:16]2[N:17]=[N:18][N:19]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[CH:20]=2)=[N:10]1)([CH3:32])[CH2:34][N:35]1[CH2:36][CH2:37][O:38][CH2:39][CH2:40]1
Reactant: COc1ccc(Cn2cc(-c3cc(Cc4ccc(F)cc4)n(CC(=O)O)n3)nn2)cc1
Reactant: CC(C)(N)CN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2cc(-c3cc(Cc4ccc(F)cc4)n(CC(=O)NC(C)(C)CN4CCOCC4)n3)nn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
A mixture of {5-(4-fluorobenzyl)-3-[1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl]-1H-pyrazol-1-yl}acetic acid (1.0 g, 2.37 mmol), 1,1-dimethyl-2-morpholin-4-yl-ethylamine (0.375 g, 2.37 mmol), HATU (0.71 g, 2.85 mmol) and Et3N (0.71 g, 7.1 mol) in DMF (20 mL) was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue was treated with water (50 mL) and CH2Cl2 (50 mL). The aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organics were dried over Na2SO4 and evaporated to afford crude title compound (1.3 g, 92%) as yellow oil that was used without further purification in next step.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(N(CC)CC)C.[O:27]=[S:28]1(=[O:37])[CH2:33][CH2:32][N:31]([C:34](Cl)=[O:35])[CH2:30][CH2:29]1>C1COCC1.O>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:34]([N:31]3[CH2:32][CH2:33][S:28](=[O:37])(=[O:27])[CH2:29][CH2:30]3)=[O:35])[CH2:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)N1CCS(=O)(=O)CC1
Reactant: CC(C)(C)c1cc(NC(=O)C2CCCNC2)no1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)C2CCCN(C(=O)N3CCS(=O)(=O)CC3)C2)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of piperidine-3-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (100 mg; 0.347 mmol) in anhydrous THF (1 mL) is added triethylamine (0.098 mL; 0.7 mmol) and 1,1-dioxo-1λ6-thiomorpholine-4-carbonyl chloride (71.15 mg; 0.36 mmol). The reaction mixture is left stirring at room temperature overnight. The reaction mixture is diluted with water and extracted with ethyl acetate 3 times. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo.
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]([CH3:12])=[C:6]2[CH2:13][C:14]([OH:16])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Br:29][C:30]1[CH:31]=[C:32]([NH2:40])[C:33](=[CH:38][CH:39]=1)[C:34]([O:36][CH3:37])=[O:35].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.O1CCCC1>[Br:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[C:32]([NH:40][C:14](=[O:16])[CH2:13][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:8][C:7]=2[CH3:12])[CH:31]=1
Reactant: COC(=O)c1ccc(Br)cc1N
Reactant: COc1ccc2[nH]c(C)c(CC(=O)O)c2c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Br)cc1NC(=O)Cc1c(C)[nH]c2ccc(OC)cc12
Yield: 66.6 %

Procedure:
5-Methoxy-2-methyl-3-indole acetic acid (5 g, obtainable from Acros), carbonyidiimidazole (4.44 g) and tetrahydrofuran (120 ml) were stirred at room temperature for 30 min after which methyl 4-bromoanthranilate (5.24 g) and pyridinium tosylate (13.69 g) were added and the mixture refluxed for 14 h. After diluting with dichloromethane (200 ml), the residue was washed with 2M hydrochloric acid (200 ml), 2M sodium hydroxide (200 ml), water (200 ml) and brine (200 ml) and dried (MgSO4). After solidifying by treatment with cyclohexane and ethyl acetate, the solid was triturated with ether to afford methyl 4-bromo-2-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}benzoate (6.54 g), MH+ 433, 435; MH− 431, 433; TR 3.67 min.
Reaction SMILES: [F:1][C:2]([F:12])([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]OCC(C1C=CC=C(OC)C=1)(F)F>>[F:1][C:2]([F:12])([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][O:4][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][Br:13]
Reactant: COc1cccc(C(F)(F)COCCCCCCBr)c1
Reactant: OCC(F)(F)Cc1ccccc1
Product: FC(F)(COCCCCCCBr)Cc1ccccc1
Yield: 36 %

Procedure:
Obtained from Intermediate 91 (0.75 g, 4.36 mmol) by the procedure described in Intermediate 69. Purification by column chromatography with silica gel eluting with n-hexane/ethyl acetate (from pure n-hexane to 40:1) gave the title compound (0.53 g, 36%) as oil.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([NH2:19])[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([CH:30]=1)[C:27](O)=[O:28]>>[CH:1]1([C:7]2[CH:8]=[C:9]([NH:19][C:27](=[O:28])[C:26]3[CH:30]=[C:22]([O:21][CH3:20])[CH:23]=[N:24][CH:25]=3)[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:16])([F:17])[F:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Reactant: COc1cncc(C(=O)O)c1
Product: COc1cncc(C(=O)Nc2cnc(OCC(F)(F)F)c(C3CCCCC3)c2)c1
Yield: 56.3 %

Procedure:
This compound was prepared following the same procedure as described for Example 3 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (Example 8b) (100 mg, 0.36 mmol) and 5-methoxy-nicotinic acid (50.5 mg, 0.33 mmol) as starting materials. The title compound (76 mg, 51.0%) was isolated as off white solid; MS (ESI): 410 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[Cl:7][C:8]1[CH:25]=[CH:24][C:11]([O:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CCOCC>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][N:15]([CH2:16][CH2:17][CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[CH2:2][C:3]([O:5][CH3:6])=[O:4])=[CH:24][CH:25]=1
Reactant: Clc1ccc(OCCNCCCn2ccnc2)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: COC(=O)CN(CCCn1ccnc1)CCOc1ccc(Cl)cc1
Reaction time: 18 h

Procedure:
Methyl bromoacetate (2.1 g) was added to a stirred mixture of N- [2-(4-chlorophenoxy)ethyl]-3-(imidazol-1-yl)propylamine (3.87 g) and anhydrous potassium carbonate (5.73 g) in dry acetone (180 ml). The mixture was stirred and boiled under reflux for 7 hours, then left to stand at ambient temperature for 18 hours then hot filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica using ethyl acetate/triethylamine, 9 to 1 as the mobile phase. The product was obtained as an oil which was dissolved in ether, and extracted into 5M hydrochloric acid. The acid extracts were basified with 5M sodium hydroxide solution and the product extracted into ether to give methyl N-[2-(4-chlorophenoxy)ethyl)-N-[3-(imidazol-1-yl)propyl]glycinate as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)[CH2:7][CH2:6]2.[H][H].[ClH:25]>C(O)C.O.[Pd]>[ClH:25].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[CH2:7][CH2:6]2
Reactant: [H][H]
Reactant: COc1cc2c(cc1OC)N(c1ccc([N+](=O)[O-])cc1)CC2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc2c(cc1OC)N(c1ccc(N)cc1)CC2
Yield: 84.9 %

Procedure:
5,6-Dimethoxy-1-(4-nitrophenyl)-indoline was hyrogenated overnight with Pd (5%) on carbon in ethanol/water (8:2) in a shaking “duck”. When the uptake of hydrogen had come to an end, 10% hydrochloric acid was added, the catalyst was filtered off and the remainder was concentrated to dryness. The residue was dried in vacuo at 45° C. The product 4-(5,6-dimethoxyindolinyl)-phenylamine hydrochloride was obtained in a yield of 84.9% (melting point: 143-145° C.).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3([C:36]4[C:27](=[CH:28][C:29]5[O:34][CH2:33][CH2:32][O:31][C:30]=5[C:35]=4[F:37])[O:26][CH2:25]3)[C:17]2=[O:38])=[N:13][CH:14]=1)C1C=CC=CC=1>[Pd].C(O)(=O)C.CO>[F:37][C:35]1[C:30]2[O:31][CH2:32][CH2:33][O:34][C:29]=2[CH:28]=[C:27]2[O:26][CH2:25][C:18]3([C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:16]([CH2:15][C:12]4[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][N:13]=4)[C:17]3=[O:38])[C:36]=12
Reactant: O=C1N(Cc2ccc(OCc3ccccc3)cn2)c2ccccc2C12COc1cc3c(c(F)c12)OCCO3
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1N(Cc2ccc(O)cn2)c2ccccc2C12COc1cc3c(c(F)c12)OCCO3
Reaction time: 5 h
Yield: 46 %

Procedure:
Following the procedure as described in EXAMPLE 5.25 and making non-critical variations using 5-(benzyloxy)-2-(chloromethyl)pyridine hydrochloride to replace 2-(bromomethyl)pyridine hydrobromide, 1′-{[5-(benzyloxy)pyridine-2-yl]methyl}-9-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (59%) was obtained as a colorless solid: MS (ES+) m/z 511.0 (M+1). A mixture of the 1′-{[5-(benzyloxy)pyridine-2-yl]methyl}-9-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one from the last step, palladium on carbon (10% w/w, 0.2 g), methanol (50 mL) and acetic acid (1 drop) was hydrogenated at a pressure of 50 psi at ambient temperature for 5 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography and eluted with a 0% to 70% gradient of ethyl acetate in dichloromethane to afford 9-fluoro-1′-[(5-hydroxypyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.37 g, 46%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ9.88 (s, 1H), 8.00 (d, J=2.6 Hz, 1H), 7.25-7.09 (m, 4H), 7.01-6.87 (m, 2H), 6.12 (d, J=1.8 Hz, 1H), 4.88 (ABq, 2H), 4.82 (ABq, 2H), 4.29-4.09 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ176.0, 152.8, 145.2, 142.6, 141.5, 141.4, 138.7, 138.0, 137.1, 134.8, 133.4, 133.2, 131.0, 128.8, 123.5, 123.0, 122.8, 122.4, 122.2, 109.5, 106.0, 80.2, 64.3, 63.6, 57.5, 44.2; MS (ES+) m/z 421.1 (M+1).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Sn](C)(C)C)=[CH:17][CH:16]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:25][C:26]1[CH:27]=[C:28]([N:33]2[CH2:37][C@H:36]([CH2:38][NH:39][C:40](=[O:42])[CH3:41])[O:35][C:34]2=[O:43])[CH:29]=[CH:30][C:31]=1I>O1CCOCC1>[Si:1]([O:8][CH2:9][CH:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:31]3[CH:30]=[CH:29][C:28]([N:33]4[CH2:37][C@H:36]([CH2:38][NH:39][C:40](=[O:42])[CH3:41])[O:35][C:34]4=[O:43])=[CH:27][C:26]=3[F:25])=[CH:17][CH:16]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC1CC(c2ccc([Sn](C)(C)C)cc2)=NO1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Solvent: C1COCCO1
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(C4=NOC(CO[Si](C)(C)C(C)(C)C)C4)cc3)c(F)c2)C(=O)O1
Temperature: 90 °C
Reaction time: 16 h
Yield: 33.4 %

Procedure:
5-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-3-[4-(trimethylstannyl)phenyl]4,5-dihydroisoxazole (427 mg, 0.94 mmol), N-{[(5S)-3-{3-fluoro-4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide (355 mg, 0.96 mmol) and 2-trifurylphosphine (22 mg, 0.094 mmol) were dissolved in dry 1,4-dioxane (10 ml) and the reaction mixture placed under an atmosphere of argon. Tris(dibenzylidineacetone)dipalladium (0) chloroform adduct (49 mg, 0.05 mmol) was added and the reaction mixture stirred for 16 hours at 90° C. A second portion of 5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-[4-(trimethylstannyl)phenyl]-4,5-dihydroisoxazole (427 mg, 0.94 mmol), 2-trifurylphosphine (22 mg, 0.094 mmol) and tris(dibenzylidineacetone)dipalladium (0) chloroform adduct (49 mg, 0.05 mmol) were added and the reaction mixture stirred for another 20 hours at 90° C. Silica gel (2 g) was added and the mixture concentrated in vacuo. Purification by column chromatography (20 g silica gel bond elut: 30% to 100% ethyl acetate/hexanes) yielded 170 mg (33%) of the desired compound.
Reaction SMILES: [CH2:1]([Li])CCC.[F:6][C:7]1[C:12]([CH:13]=O)=[C:11]([OH:15])[C:10]([O:16][CH3:17])=[CH:9][CH:8]=1.Cl.C(OCC)(=O)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[F:6][C:7]1[C:12]([CH:13]=[CH2:1])=[C:11]([OH:15])[C:10]([O:16][CH3:17])=[CH:9][CH:8]=1
Reactant: COc1ccc(F)c(C=O)c1O
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=Cc1c(F)ccc(OC)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 50 g of methyltriphenylphosphonium bromide in 300 ml of toluene there was added dropwise 45 ml of n-butyllithium (2.55 M, hexane solution) at 0° C. under a nitrogen atmosphere. The mixture was stirred at room temperature for 2 hours and allowed to stand. Next, 150 ml of the supernatant was added to a solution of 5 g of 6-fluoro-2-hydroxy-3-methoxybenzaldehyde [CAS No. 457628-15-8] in 90 ml of toluene. The mixture was stirred at room temperature for 1 hour, 1N hydrochloric acid was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give 3-fluoro-6-methoxy-2-vinylphenol (4.33 g).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]=[N+:18]=[N-:19])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>CO.C(Cl)Cl>[N:17]([CH2:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[N+:18]=[N-:19]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCN=[N+]=[N-])CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: [N-]=[N+]=NCCCN1CCNCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3.5 g 1-Boc-4-(3-azidopropyl)-piperazine was dissolved in 30 ml MeOH/DCM (3/1) and 10 ml TFA were added. The reaction mixture was stirred at room temperature for 20 min and the product precipitated by the addition of 150 ml tert-Butyl-methyl ether. Yield 2.3 g.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:41])[CH2:7][C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH2:38][CH3:39])([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]([OH:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:25]([CH3:37])[CH:24]=3)[CH2:21][CH3:22])=[CH:16][C:15]=2[CH3:40])=[N:12][CH:13]=1)C.Cl>CO>[CH2:21]([C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:11]2[N:10]=[CH:9][C:8]([CH2:7][C:6]([OH:41])=[O:5])=[CH:13][N:12]=2)=[C:15]([CH3:40])[CH:16]=1)([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]([OH:36])[C:32]([CH3:34])([CH3:35])[CH3:33])=[C:25]([CH3:37])[CH:24]=1)[CH2:38][CH3:39])[CH3:22]
Reactant: CCOC(=O)Cc1cnc(-c2ccc(C(CC)(CC)c3ccc(CCC(O)C(C)(C)C)c(C)c3)cc2C)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ncc(CC(=O)O)cn2)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.9 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.06 mL) was added to a solution of [2-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-pyrimidin-5-yl]-acetic acid ethyl ester (Example 64-(2); 15.0 mg, 0.0283 mmol) in methanol (0.38 mL) at room temperature, and the mixture was stirred at room temperature for three hours. The mixture was acidified with dilute hydrochloric acid aqueous solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the title compound (14.5 mg, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])#[N:11]>C1C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[C:12](\[C:10]#[N:11])/[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)CC#N
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)/C(C#N)=C/c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-bromobenzaldehyde (1 eq), t-butyl cyanoacetate (1 eq) and NH4OAc (1 eq) in benzene (1M) was reflux for 4 h while removing water with a Dean-Stark trap. The mixture was cooled to rt, diluted with hexane and triturated. The title compound was isolated after filtration as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28](=[O:30])[CH3:29])=[CH:21][C:15]=3[N:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CCOC(C)=O>C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8](/[CH:11]=[CH:12]/[C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH:28]([OH:30])[CH3:29])=[CH:21][C:15]=3[N:14]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1ccccc1-c1ccc2[nH]c(/C=C/c3ccc(C(C)(C)C)cc3)nc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(O)c1ccccc1-c1ccc2[nH]c(/C=C/c3ccc(C(C)(C)C)cc3)nc2c1
Reaction time: 3 h

Procedure:
A solution of (E)-1-(2-{2-[2-(4-tert-butyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-ethanone Cpd 1 (0.005 g, 0.01 mmol) in ethanol (0.5 mL) was treated with NaBH4 (0.003 g, 0.08 mmol). After 3 h, the reaction mixture was applied to a preative TLC plate (2000 microns, silica gel, 20×20) and developed using EtOAc:hexanes, 1:1. The desired band was extracted and concentrated to give the title compound (0.002 g). 1H-NMR (400 MHz, CD3OD) δ (ppm) 7.69 (m, 1H) 7.62 (m, 3H) 7.50 (m, 3H) 7.41 (ddd, 2H, J=2.5 Hz, J=10.1 Hz, J=14.1 Hz) 7.32 (dt, 1H, J=1.4 Hz, J=7.5 Hz) 7.23 (m, 2H) 7.17 (d, 1H, J=16.5 Hz) 4.99 (q, 1H, J=6.3 Hz) 1.38 (s, 9H) 1.35 (d, 1.5H, J=6.1 Hz) 1.33 (d, 1.5H, J=6.1 Hz). MS (ESI, pos. ion) m/z: 397.2 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].CCN(CC)CC.[O:20](C(OC(C)(C)C)=O)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=O.CCCCCC>C(Cl)Cl>[O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])[CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CCOC(=O)C1CNCCC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCCCCC
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a solution of ethyl 4-oxopiperidine-3-carboxylate (180.0 g, 0.87 mol, 1.0 eq.) in DCM (2.7 L) was added Et3N (352.14 g, 3.48 mol, 4.0 eq.) dropwise at 15° C. and stirred for 30 min followed by addition of (BOC)2O (210.0 g, 0.96 mol, 1.10 eq.) maintaining the temperature below 10° C. The resulted mixture was stirred at rt overnight, and concentrated to give a crude product that was stirred with hexane (3.5 L) for 1 h and filtered. The filtered cake was washed with hexanes. The combined organic phase was concentrated to furnish the title compound (226.0 g, 0.83 mol, 95.4%).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([Sn](CCCC)(CCCC)CCCC)=[N:6][C:7]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.I[C:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[NH:44][N:43]=1>>[NH:44]1[C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:42]([C:5]2[N:4]=[C:3]3[C:8]([N:9]=[C:10]([CH2:11][N:12]4[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]4)[N:2]3[CH3:1])=[C:7]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:6]=2)=[N:43]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Reactant: Ic1n[nH]c2ccccc12
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-c3n[nH]c4ccccc34)nc21

Procedure:
2-(1-((9-Methyl-6-morpholino-2-(tributylstannyl)-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (0.5 g) was reacted with 3-iodo-1H-indazole via General Procedure G to give 68.3 mg of 162 as a white solid following reverse phase purification. MS (Q1) 491.2 (M)+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)[C:10]=1[SH:11])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C)C=O>C(#N)C>[CH2:24]([S:11][C:10]1[N:9]([C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)[CH:8]=[N:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)c1ncn(-c2nc(C)cs2)c1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOC(=O)c1ncn(-c2nc(C)cs2)c1SCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture consisting of 4.2 g of 4-ethoxycarbonyl-1-(4-methylthiazol-2-yl)imidazole-5-thiol, 3.2 g of anhydrous potassium carbonate, 2.2 g of benzyl chloride, 20 ml of dimethylformamide and 100 ml of acetonitrile was stirred at room temperature for 2 hours. After the reaction, solid materials were separated by filtration, and the filtrate was condensed under reduced pressure to obtain crude 5-benzylthio-4-ethoxycarbonyl-1-(4-methylthiazol-2-yl)imidazole as oily product. The resulting oily product was dissolved in 100 ml of chloroform and after addition of 13 g of conc. hydrochloric acid and 30 ml of water, 28 g of a 10% sodium hypochlorite solution was added dropwise to the mixture at -10° C. to -5° C. over 15 minutes. After the reaction mixture was stirred at 0° C. or lower for 20 minutes, an organic layer was separated and an aqueous layer was extracted with chloroform. After the organic layers were combined and washed with water, 60 ml of tetrahydrofuran was added to the organic layer and then 20 ml of a 28% aqueous ammonia was added dropwise under icc-cooling, and the mixture was stirred at room temperature for 1.5 hours. After the reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added thereto, an organic layer was separated and an aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried, and then concentrated under reduced pressure to obtain oily product. The resulting oily product was identified as 5-benzylsulfinyl-4-ethoxycarbonyl-1-(5-chloro-4-methylthiazol-2-yl)imidazole by NMR and MS analyses.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][Cl:27])=[CH:24][CH:23]=1)([CH3:21])[CH3:20]>CCO>[ClH:27].[CH:19]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][S:18][C:9]2[NH:8][C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C@H:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:10]=2)=[CH:24][CH:23]=1)([CH3:21])[CH3:20]
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Reactant: CC(C)c1ccc(CCl)cc1
Solvent: CCO
Product: CC(C)c1ccc(CSC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)cc1
Product: Cl
Temperature: 25 °C
Yield: 74.9 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 4-isopropylbenzyl chloride (264 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 249 mg of the product 239. 1H NMR (DMSO-d6) δ 11.24 (s, 2 H), 7.52 (d, 2 H), 7.32 (d, 2 H), 7.20-6.90 (m, 6 H), 6.90-6.70 (m, 4 H), 5.77 (s, 2 H), 4.78 (s, 2 H), 3.02-3.85 (m, 1 H), 1.22 (d, 6 H); MS: m/z 387 (M++1).