Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][NH:7][C:8](=[O:38])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Br)[CH:30]=2)[CH:10]=1.[N-:44]=[N+:45]=[N-:46].[Na+]>CN(C)C=O.O>[F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][NH:7][C:8](=[O:38])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][N:44]=[N+:45]=[N-:46])[CH:30]=2)[CH:10]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CBr)c2)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-(3-(bromomethyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (200 mg, 0.18 mmol, 1.00 equiv, 60%) in N,N-dimethylformamide (5 mL), and NaN3 (70 mg, 1.08 mmol, 5.00 equiv). The resulting solution was stirred for 2 h at 80° C. in an oil bath. The resulting solution was diluted with 25 mL of water. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:2). The product was obtained as 55 mg (49%) a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH:11]([CH3:13])[CH3:12])[CH:9]=[N:10][C:5]2=[C:4](Cl)[CH:3]=1.[NH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1>CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH:11]([CH3:13])[CH3:12])[CH:9]=[N:10][C:5]2=[C:4]([NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[CH:3]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CC(C)n1cnc2c(Cl)cc(Cl)nc21
Solvent: CC(C)O
Product: CC(C)n1cnc2c(NCCc3ccc(O)cc3)cc(Cl)nc21
Temperature: 140 °C

Procedure:
The product mixture containing 5,7-dichloro-3-isopropyl-3H-imidazo[4,5-b]pyridine (b) (40 mg, 0.17 mmol), tyramine (120 mg, 0.87 mmol), and 2-propanol (2 mL) was heated in a sealed vial at 140° C. for 72 hr. The mixture was concentrated, and the residue was purified by preparative TLC (1:2 hexanes/ethyl acetate eluant) to afford the title compound as an off-white solid. MS m/z 331.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:29](=[O:38])[CH2:30][CH2:31][NH:32]C(=O)COC)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.C1(C(O)=O)CC1>>[NH2:32][CH2:31][CH2:30][C:29]([NH:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][N:19]=[C:18]2[NH:17][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[C:2]([Cl:1])[CH:3]=1)=[O:38]
Reactant: COCC(=O)NCCC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Agent: O=C(O)C1CC1
Product: NCCC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1

Procedure:
The procedure of (20-2) of Example 20 was repeated except for using cyclopropylcarboxylic acid and 0.09 g of the compound obtained in (20-1) of Example 20 instead of methoxyacetic acid, and subjecting column chromatography (eluent-chloroform:methanol=15:1) to obtain the title compound (0.05 g, 49%).
Reaction SMILES: CN(C)C=O.[OH:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(OCC)(=O)C>[CH2:23]([O:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(COCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a 30 ml N,N-dimethylformamide solution of 2.4 g (11.15 mmol) of tert-butyl 4-hydroxymethyl-1-piperidinecarboxylate, 557 mg (60% in oil, 13.9 mmol) of sodium hydride and 1.86 ml (15.6 mmol) of benzyl bromide were added with ice cooling. The mixture was stirred at room temperature for 23 hours. Then, the reaction mixture was diluted with ethyl acetate, and the dilution was washed with water and a saturated aqueous solution of sodium chloride in this order. The washed system was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to obtain 3.5 g (quantitative) of the captioned compound.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]([NH2:8])([CH3:7])[CH3:6])=[O:3].C(O)(C(O)=O)=O.O=[CH:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]>CO>[CH3:6][C:5]1([CH3:7])[NH:8][CH:16]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:1][C:2](=[O:3])[CH2:4]1
Reactant: COC(=O)CCC=O
Reactant: CC(=O)CC(C)(C)N
Agent: O=C(O)C(=O)O
Solvent: CO
Product: COC(=O)CCC1CC(=O)CC(C)(C)N1
Temperature: 100 °C
Reaction time: 3 h
Yield: 36.7 %

Procedure:
Diacetoneamine hydrogen oxalate (4.25 g) and methyl 4-oxobutanoate (2 g) were suspended in methanol (20 ml). The reaction mixture were stirred at 100° C. for three hours and then at room temperature overnight. It was then evaporated and the residue was purified by Combiflash chromatography (2.0 M ammonia methanol in dichloromethane=0-30%) to give methyl 3-(6,6-dimethyl-4-oxopiperidin-2-yl)propanoate (1.35 g, 37%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[C:40]([O:43][CH2:44][C:45]([CH3:59])([CH3:58])[C@@H:46]([C:55](O)=[O:56])[NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])(=[O:42])[CH3:41].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:40]([O:43][CH2:44][C:45]([CH3:59])([CH3:58])[C@H:46]([NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C:55](=[O:56])[NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[NH:19][C:20](=[O:21])[C@H:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[NH:27][C:28](=[O:31])[O:29][CH3:30])(=[O:42])[CH3:41]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: CC(=O)OCC(C)(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)COC(C)=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
To a solution of the product of Example 2C (0.275 g, 0.517 mmol) in tetrahydrofuran (0.40 mL) were added the product from Example 174E (0.15 g, 0.519 mmol), DEPBT (0.233 g, 0.779 mmol), and N,N-diisopropylethylamine (0.45 mL, 2.58 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic layer was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with a gradient starting with dichloromethane and ending with ethyl acetate to give the title compound (0.214 g, 50% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.80 (m, 15 H), 1.39 (s, 9 H), 1.47-1.56 (m, 2 H), 1.99 (s, 3 H), 2.72-2.79 (m, 3 H), 3.49 (s, 3 H), 3.62-3.65 (m, 2 H), 3.80-3.84 (m, 2 H), 4.05 (d, J=9.9 Hz, 1 H), 4.10-4.24 (m, 2 H), 4.94 (d, J=4.8 Hz, 1 H), 6.60-6.65 (m, 2 H), 7.10-7.21 (m, 8 H), 7.29-7.31 (m, 1 H), 7.52 (d, J=8.8 Hz, 1 H), 7.77 (d, J=8.5 Hz, 1 H), 7.82-7.89 (m, 4 H), 8.64 (m, 1 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]([NH2:18])[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1.CN1CCOCC1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]([NH:18][S:27]([CH3:26])(=[O:29])=[O:28])[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(-c2cnn(-c3cccnc3)c2)n1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CS(=O)(=O)Nc1cccc(-c2cnn(-c3cccnc3)c2)n1
Reaction time: 8 h

Procedure:
146 mg (585 μmol) of 6-[1-(pyridin-3-yl)-1H-pyrazol-4-yl]pyridine-2-amine and 54.0 μl (701 μmol) of N-methylmorpholine were initially charged in 10 ml of dichloromethane, and methanesulphonyl chloride was added at room temperature. The mixture was stirred overnight and the reaction mixture was filtered through silica gel (eluent: ethyl acetate). After concentration, the crude product was purified by chromatography (dichloromethane/methanol).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH2:23]([O:30][C:31]([CH:33]1[CH2:38][CH2:37][CH:36]([CH:39]([OH:41])[CH3:40])[CH2:35][CH2:34]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:23]([O:30][C:31]([CH:33]1[CH2:38][CH2:37][CH:36]([C:39](=[O:41])[CH3:40])[CH2:35][CH2:34]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(O)C1CCC(C(=O)OCc2ccccc2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)C1CCC(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.7 %

Procedure:
Dess-Martin reagent (151 mg, 0.355 mmol) was added to a solution of 4-(1-hydroxy-ethyl)-cyclohexanecarboxylic acid benzyl ester (71.6 mg, 0.273 mmol) in anhydrous dichloromethane (0.91 ml) at 0° C. The mixture was stirred at the same temperature for 10 minutes, and further warmed to room temperature and stirred for 4.5 hours. An aqueous sodium thiosulfate solution was added to the reaction solution, followed by extraction with dichloromethane. The organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4-acetyl-cyclohexanecarboxylic acid benzyl ester (60.2 mg, 85%).
Reaction SMILES: [O:1]1[CH2:6][C:5](=[O:7])[NH:4][C:3]2[N:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.C1C(=O)N([Br:19])C(=O)C1.O>CN(C=O)C>[Br:19][C:10]1[CH:9]=[N:8][C:3]2[NH:4][C:5](=[O:7])[CH2:6][O:1][C:2]=2[CH:11]=1
Reactant: O=C1COc2cccnc2N1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: O=C1COc2cc(Br)cnc2N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2H-pyrido[3,2-b][1,4]oxazin-3-one (0.75 g, 5 mmol) in DMF (18 mL) was slowly added NBS (1.07 g, 6 mmol) under N2. The mixture was stirred at rt for 16 h. HPLC indicated 75% conversion. More NBS (0.53 g, 3 mmol) was added and the mixture was stirred for another 24 h. Water (5 mL) was added and the reaction flask was chilled. The white solid which separated was filtered and washed with EtOAc, H2O, Et2O, and dried under vacuum in the presence of PBS and then used directly in the next step (687 mg, 60%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:14].O>CC(C)=O>[CH2:1]([N:8]1[CH2:12][CH:11]2[O:14][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: C1=CCN(Cc2ccccc2)C1
Solvent: CC(C)=O
Solvent: O
Product: c1ccc(CN2CC3OC3C2)cc1
Yield: 59.9 %

Procedure:
To a solution of 15.9 g (0.1 mol) of 1-benzyl-3-pyrroline, 12.0 g (0.12 mol) of 98% sulfuric acid, 15.0 g of water, and 60.0 g of acetone in a quartz round flask reactor, 45.6 g (0.20 mol) of (NH4)2S2O8 (ammonium peroxydisulfate produced by Mitsubishi Gas Chemical Industry Co., Ltd.) was added with stirring and allowed to react for 10 hours at room temperature with irradiation by 500 W Xe lamps (UXL-500D xenon lamp produced by Ushio). After completion, acetone was evaporated under reduced pressure, neutralized by NaOH (aq), and extracted with toluene and water. After the solvent was evaporated under reduced pressure, 10.5 g of 1-benzyl-3,4-epoxypyrrolidine (yield 54.4%) was obtained and 6.4 g (yield 40.0%) of 1-benzyl-3-pyrroline was recovered.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=3)[NH:12][N:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.C([O-])=O.[NH4+].ClCCl>[OH-].[Pd+2].[OH-].O>[NH2:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:8]([NH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[O:9]
Reactant: O=C(NC1CCCCC1)c1n[nH]c2ccc([N+](=O)[O-])cc12
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Nc1ccc2[nH]nc(C(=O)NC3CCCCC3)c2c1
Yield: 83.2 %

Procedure:
5-Amino-N-cyclohexyl-1H-indazole-3-carboxamide can be obtained in the following way: a suspension of 1.57 g of N-cyclohexyl-5-nitro-1H-indazole-3-carboxamide, of 80 ml of methanol, of 1.37 g of ammonium formate and of 0.314 g of palladium hydroxide is brought to reflux for two hours. The reaction medium is then brought back to a temperature in the region of 25° C. and filtered through Celite® through a sintered glass funnel. The solid obtained is washed with methanol and the filtrate is concentrated by evaporation under reduced pressure. The oil thus obtained is taken up with 80 ml of dichloromethane and 80 ml of water. The organic phase is washed with two times 60 ml of distilled water and the aqueous phases thus obtained are extracted with 80 ml of dichloromethane. The pooled organic phases are dried over magnesium sulfate, filtered and concentrated by evaporation under reduced pressure. 1.17 g of 5-amino-N-cyclohexyl-1H-indazole-3-carboxamide are thus obtained in the form of a pale pink solid (Rf=0.40, silica gel thin layer chromatography, eluent: dichloromethane/methanol (9/1 by volume)).
Reaction SMILES: [C:1]([NH:4][C@:5]1([C@@H:54]([CH2:56][CH3:57])[CH3:55])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:11]([NH:13][C@@H:14]([CH2:36][C:37]2[CH:42]=[C:41]([F:43])[CH:40]=[C:39]([F:44])[CH:38]=2)[C@@H:15]([C@H:17]2CCCC[N:18]2[CH:23](C2C=CC=CC=2)[C:24]2[CH:29]=CC=CC=2)[OH:16])=[O:12])[C:6]1=[O:53])(=[O:3])[CH3:2].FC1C=C(C=C(F)C=1)C[C@H]1[C@@H]([C@H]2C[C@H]([O:73][C:74]3[CH:79]=[CH:78][CH:77]=[CH:76][N:75]=3)CN2C(C2C=CC=CC=2)C2C=CC=CC=2)OC(=O)N1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.FC1C=C(C=C(F)C=1)C[C@H]1[C@@H]([C@H]2C[C@@H](O)CN2C(C2C=CC=CC=2)C2C=CC=CC=2)OC(=O)N1.OC1C=CC=CN=1>C1COCC1.C(OCC)(=O)C.CCCCCC>[C:1]([NH:4][C@:5]1([C@@H:54]([CH2:56][CH3:57])[CH3:55])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:45][CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:11]([NH:13][C@@H:14]([CH2:36][C:37]2[CH:38]=[C:39]([F:44])[CH:40]=[C:41]([F:43])[CH:42]=2)[C@H:15]([OH:16])[C@H:17]2[CH2:29][C@H:24]([O:73][C:74]3[CH:79]=[CH:78][CH:77]=[CH:76][N:75]=3)[CH2:23][NH:18]2)=[O:12])[C:6]1=[O:53])(=[O:3])[CH3:2]
Reactant: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@H](Oc3ccccn3)CN2C(c2ccccc2)c2ccccc2)O1
Reactant: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2CCCCN2C(c2ccccc2)c2ccccc2)C1=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@@H](O)CN2C(c2ccccc2)c2ccccc2)O1
Agent: Oc1ccccn1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2C[C@H](Oc3ccccn3)CN2)C1=O
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 52 %

Procedure:
Step 10 (A): (4S,5S)-4-(3,5-difluorobenzyl)-5-((2R,4S)-1-benzhydryl-4-(pyridin-2-yloxy)pyrrolidin-2-yl)oxazolidin-2-one. To a solution of triphenylphosphine (58 mg, 0.22 mmol) in THF (2.5 mL) at rt was added DEAD (0.035 mL, 0.22 mmol). After 1 min, a solution of (4S,5S)-4-(3,5-difluorobenzyl)-5-((2R,4R)-1-benzhydryl-4-hydroxypyrrolidin-2-yl)oxazolidin-2-one (Preparation J, 85 mg, 0.183 mmol) in THF (2.5 mL) was added. After 2 min, 2-hydroxypyridine (17.4 mg, 0.183 mmol) was added and the mixture was stirred at rt for 3.5 h. pH 7 buffer was added and the mixture was extracted with ethyl acetate. The combined organic phases were washed with sat. aqueous NaCl, dried (MgSO4), and concentrated in vacuo. Flash chromatography (silica gel, 0-100% ethyl acetate/hexane) gave 50.7 mg (52% yield) of the title compound: 1H NMR (CDCl3, 300 MHz) δ 2.22 (1H, m), 2.38-2.55 (3H, m), 2.87 (1H, d, J=12 Hz), 3.32 (1H, dd, J=6, 12 Hz), 3.56-3.63 (2H, m), 4.70 (1H, d, J=9 Hz), 4.96 (1H, s), 5.42 (1H, s), 5.51 (1H, s), 6.47-6.53 (2H, m), 6.62-6.73 (3H, m), 6.81 (1H, t, J=6 Hz), 7.13-7.28 (5H, m), 7.37-7.42 (4H, m), 7.54 (1H, m), 8.08 (1H, m). HPLC retention time: 1.73 min (method C). MS (ESI) (M+H)+ 542.31.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[NH:15][C:16]1[N:24]=[C:23]2[C:19]([NH:20][C:21](=[O:37])[N:22]2[C@H:25]2[C:34]3[C:29](=[C:30]([F:36])[CH:31]=[C:32]([F:35])[CH:33]=3)[O:28][CH2:27][CH2:26]2)=[CH:18][N:17]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[NH2:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[NH:15][C:16]1[N:24]=[C:23]2[C:19]([NH:20][C:21](=[O:37])[N:22]2[C@H:25]2[C:34]3[C:29](=[C:30]([F:36])[CH:31]=[C:32]([F:35])[CH:33]=3)[O:28][CH2:27][CH2:26]2)=[CH:18][N:17]=1
Reactant: COc1ccc(CNc2ccc(C#N)cc2Nc2ncc3[nH]c(=O)n([C@@H]4CCOc5c(F)cc(F)cc54)c3n2)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(N)c(Nc2ncc3[nH]c(=O)n([C@@H]4CCOc5c(F)cc(F)cc54)c3n2)c1

Procedure:
A solution of (R)-4-(2,4-dimethoxybenzylamino)-3-(9-(6,8-difluorochroman-4-yl)-8-oxo-8,9-dihydro-7H-purin-2-ylamino)benzonitrile (230 mg) in DCM (5 mL) was treated with TFA (5 mL) and triethylsilane (1 mL) for 16 h. The mixture was concentrated in vacuo to provide the intermediate (R)-4-amino-3-(9-(6,8-difluorochroman-4-yl)-8-oxo-8,9-dihydro-7H-purin-2-ylamino)benzonitrile. The intermediate was dissolved in 5 mL THF and treated with 3 mL trimethylorthoformate followed by p-toluenesulfonic acid (3 mg). After 1 hour, the mixture was diluted with EtOAc (100 mL) and washed once with saturated aqueous sodium bicarbonate (100 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo. Column chromatography (50→100% EtOAc/hexanes) provided 78 mg of the title compound. 1H-NMR (300 MHz, 5% CD3OD in CDCl3) δ 8.8 (s, 1H), 8.7 (s, 1H), 8.2 (s, 1H), 7.8 (d, 1H), 7.6 (dd, 1H), 6.8 (td, 1H), 6.4 (dd, 1H), 5.8 (dd, 1H), 4.6 (m, 1H), 4.4 (td, 1H), 2.9 (m, 1H), 2.3 (m, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][NH:35]4)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2].[CH:40]1([CH:43]=O)[CH2:42][CH2:41]1>>[C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][N:35]4[CH2:43][CH:40]4[CH2:42][CH2:41]4)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)C4CCCCN4)ncn3)cccc2s1
Reactant: O=CC1CC1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)C4CCCCN4CC4CC4)ncn3)cccc2s1

Procedure:
N-(2-(6-(2-Acetamidobenzo[d]thiazol-4-yloxy)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)piperidine-2-carboxamide from step (a) above (0.40 g, 0.72 mmol) was reacted with cyclopropanecarboxaldehyde (0.16 mL, 2.2 mmol, Aldrich) under the conditions of Example 3(d) to give the title compound as an off-white solid. MS (ESI, pos. ion.) m/z: 611 (M+1). Mp: 212.3-213.5° C.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:24]2[C:19](=[N:20][CH:21]=[C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([CH3:34])=[CH:31][CH:32]=4)[N:27]([CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])[N:26]=3)[N:23]=2)[NH:18][CH:17]=1)=[O:15])([CH3:12])[CH3:11])(C(C)(C)C)(C)C.[ClH:40]>CO.C1COCC1>[ClH:40].[CH3:39][N:37]([CH3:38])[CH2:36][CH2:35][N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=2)[C:25]([C:22]2[N:23]=[C:24]3[C:16]([C:14]([NH:13][C:10]([CH3:11])([CH3:12])[CH2:9][OH:8])=[O:15])=[CH:17][NH:18][C:19]3=[N:20][CH:21]=2)=[N:26]1
Reactant: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)c4n3)nn(CCN(C)C)c2c1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC(C)(C)CO)c4n3)nn(CCN(C)C)c2c1
Reaction time: 3 h

Procedure:
To a solution of N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(1-(2-(dimethylamino)ethyl)-6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (127 mg, 0.23 mmol) in 5 mL of methanol and 1 mL of THF was added 1 mL of concentrated HCl, then stirred for 3 hours. The precipitate was filtered and filter cake was washed with 2-methoxy-2-methylpropane (5 mL) to give 25 mg of 2-(1-(2-(dimethylamino)ethyl)-6-methyl-1H-indazol-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide hydrochloride. LCMS: (M+H)+=436; 1H NMR (300 MHz, DMSO): δ 12.85 (s, 1H), 10.19 (s, 1H), 9.18 (s, 1H), 8.47 (d, 1H, J=8.1 Hz), 8.37 (s, 1H), 7.92 (s, 1H), 7.68 (s, 1H), 7.17 (d, 1H, J=8.4 Hz), 4.93 (s, 2H), 3.70-3.63 (m, 4H), 2.89 (s, 6H), 2.50 (s, 3H), 1.45 (s, 6H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[CH:12]=1)[CH2:2]2.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=1)[CH2:2]2
Reactant: OB(O)c1ccccc1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(N[C@H]1CN2CCC1CC2)c1cccc(-c2ccccc2)c1

Procedure:
Prepared by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-yl)(3-bromobenzamide) and phenylboronic acid, using tetrakis(triphenylphosphine)palladium(0) and sodium carbonate in a mixture of tetrahydrofuran, ethanol, and water. The compound was purified by flash chromatography on silica gel and eluted with 3%-10% 3.5N methanolic ammonia/chloroform mixtures. Evaporation of solvent gave the title compound as a colourless solid; MS (ES+) 307 (MH+).