Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:23])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2F)/[N:7]([CH2:24][C@H:25]2[CH2:29][CH2:28][CH2:27][O:26]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[C:31]([NH:35][NH2:36])([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:31]([NH:35][NH:36][C:13]1[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:19])[F:20])=[CH:17][C:12]=1[C:11](/[N:10]=[C:8]1\[S:9][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:6][N:7]\1[CH2:24][C@H:25]1[CH2:29][CH2:28][CH2:27][O:26]1)=[O:23])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)s1
Reactant: CC(C)(C)NN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)NNc1ccc(C(F)(F)F)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@H]1CCCO1
Yield: 20.1 %

Procedure:
A mixture of Example 1A (300 mg, 0.7 mmol), tert-butylhydrazine hydrochloride (261 mg, 2.1 mmol) and potassium carbonate (385 mg, 2.8 mmol) in DMF (15 mL) was stirred at 40° C. for 24 hours. The mixture was poured into water and extracted with ethyl acetate. The acetate extract was washed with water, brine, dried with MgSO4, and concentrated under reduced pressure. Purification by chromatography (SiO2) afforded 70 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.08 (s, 9 H), 1.30-1.35 (m, 9H), 1.63-2.04 (m, 4 H), 3.68 (t, J=6.7 Hz, 1 H), 3.76-3.88 (m, 1 H), 4.18-4.39 (m, 3 H), 4.62 (s, 1 H), 7.28-7.32 (m, 1 H), 7.46-7.60 (m, 2 H), 8.51 (d, J=1.6 Hz, 1 H), 9.90 (s, 1 H). MS (DCI/NH3) m/z 499 (M+H)+. Anal. calculated for C24H33F3N4O2S: C, 57.81H, 6.67 N, 11.24. Found: C, 58.22H, 6.72 N, 10.98.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=2)[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[N:9]=[C:8]([C:26]([F:29])([F:28])[F:27])[CH:7]=1.[H-].[Na+].O.[CH2:33]1COCC1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=2)[CH2:14][N:15]([CH3:33])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:19])[CH3:20])[N:9]=[C:8]([C:26]([F:29])([F:27])[F:28])[CH:7]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(-n2nc(C(F)(F)F)cc2-c2ccco2)c1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CN(Cc1cccc(-n2nc(C(F)(F)F)cc2-c2ccco2)c1)C(=O)OC(C)(C)C
Temperature: 21 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
To a stirred solution of 55 (3.51 g, 8.62 mmol) in THF (43 ml) was added NaH (0.689 g, 17.23 mmol). After 15 minutes Mel (2.69 ml, 43.1 mmol) was added and the resulting suspension was allowed to stir at 0° C. for 1 h and at 21° C. for 16 h. Water was added the product was extracted with EtOAc. After the usual work-up the residue was purified via Biotage (5% to 45% EtOAc/Hexane; 40+M column) to afford 138 (3.2 g, 7.59 mmol, 88% yield) as colorless oil. LRMS (ESI): (calc.) 421.4; (found) 444.2 (MNa)+.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>[Cu].C(OCC)(=O)C>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:3]=1
Reactant: Ic1ccccc1
Reactant: Clc1ccc2c(c1)[nH]c1ccccc12
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1ccc2c3ccccc3n(-c3ccccc3)c2c1
Temperature: 25 °C
Yield: 57.4 %

Procedure:
Next, a mixed solution of 17.7 g of 2-chloro-9H-carbazole, 22 g of iodobenzene, 20 g of a copper powder, 43 g of potassium carbonate and 200 ml of dimethylformamide was heated/stirred at 140° C. for 16 hours under a nitrogen flow. The solution was cooled to room temperature, 50 ml of ethyl acetate was added, and the mixture was filtered with Celite. To the resultant filtrate was added a saturated aqueous ammonium chloride solution, and the mixture was stirred for a while, and then extracted with ethyl acetate and hexane. The extract was dried over magnesium sulfate, and then evaporated. The concentrate was purified by silica gel column chromatography and vacuum-dried to obtain 14 g of 2-chloro-9-phenyl-9H-carbazole.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[N:9]=[C:8]([C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)[C:7]=2[CH:28]=1.B(Br)(Br)Br.C(O)C.CO>C(Cl)Cl.C(OCC)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[N:9]=[C:8]([C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)[C:7]=2[CH:28]=1
Reactant: CCOC(=O)c1ccc(C2=Nc3ccccc3Oc3ccc(OC)cc32)cc1
Agent: BrB(Br)Br
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C2=Nc3ccccc3Oc3ccc(O)cc32)cc1
Reaction time: 2 h
Yield: 29.9 %

Procedure:
To a stirring solution of compound 34 (1.57 g, 4.21 mmol) in DCM (30 mL) was added BBr3 (1M in DCM, 13.0 mL, 13.0 mmol) at 4° C. drop wise and the reaction mixture was stirred for 2 h. Ethanol (20 mL) was added and the mixture was stirred at room temperature for 30 min. Enough MeOH to get everything soluble was added and this mixture was poured into ethyl acetate (600 mL). This organic phase was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography with 30% ethyl acetate in hexanes to afford title compound 35 (453 mg, 30%) as a beige solid. LRMS (ESI): (calc) 359.12 (found) 360.2 (MH)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH2:16])=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH2:3][CH2:2]1.I.CS[C:20]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)=[NH:21]>C(O)C>[O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:20]([C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)=[NH:21])=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH2:3][CH2:2]1
Reactant: Nc1ccc2c(ccn2C2CCOCC2)c1
Reactant: CSC(=N)c1cccs1
Agent: I
Solvent: CCO
Product: N=C(Nc1ccc2c(ccn2C2CCOCC2)c1)c1cccs1
Temperature: 25 °C
Reaction time: 21 h
Yield: 31.5 %

Procedure:
Compound 89 (95 mg, 0.439 mmol) is charged to a small, argon purged flask fitted with a magnetic stir bar. Anhydrous ethanol (5 mL) and thiophene-2-carboximidothioic acid methyl ester hydroiodide (219.2 mg, 0.769 mmol) are added to the flask and the reaction was stirred under argon at ambient temperature for 21 hours, at which time the solvent was evaporated and the residue was partitioned between H2O and ethyl acetate and 1M sodium hydroxide solution added to adjust pH to 9. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered, concentrated and the residue purified via chromatography on silica gel (methanol:CH2Cl2, 5:95 to 7.5:92.5) to yield a pale yellow residue, 90 (45 mg, 31.5%). 1H NMR (DMSO-d6) δ 1.82-2.11 (m, 4H), 3.57 (t, 2H, J=11.0 Hz), 3.92-4.07 (m, 2H), 4.50-4.68 (m, 1H), 6.33 (brs, 2H), 6.37 (d, 1H, J=2.5 Hz), 6.71 (d, 1H, J=8.2 Hz), 7.00 (s, 1H), 7.09-7.11 (m, 1H), 7.45 (d, 1H, J=2.7 Hz), 7.52 (d, 1H, J=8.6 Hz), 7.60 (d, 1H, J=4.8 Hz), 7.72 (d, 1H, J=2.7 Hz); ESI-MS (m/z, %): 326 (MH+, 100%); ESI-HRMS calculated for C18H20N3OS (MH+): 326.1321, observed: 326.1332.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC>CO>[O:16]([CH2:15][CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2ccccc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: c1ccc(OCCC2CCNCC2)cc1
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-(2-phenoxyethyl)piperidine (220 mg, 0.72 mmol) in MeOH (2 mL) was added 2N anhydrous HCl/ether (0.5 mL, 1.0 mmol). The reaction mixture was stirred overnight. After evaporation, the residue was dissolved in deionized water. EtOAc was used to wash the aqueous layer before the pH was altered to approx. 9-10. The aqueous layer was extracted three times with CH2Cl2 and dried over Na2SO4. After evaporation, 4-(2-phenoxyethyl)piperidine (131.5 mg, 89%) was obtained as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 7.23 (m, 2H), 6.96 (m, 1H), 6.85 (m, 2H), 3.95 (m, 2H), 3.27 (m, 2H), 2.71 (m, 3H), 1.92 (m, 2H), 1.56 (m, 3H), 1.42 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])[C:13]=2[CH3:25])[CH:7]=[CH:6][C:5]=1[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[F:34].O.O.[OH-].[Li+]>CO.C1COCC1>[CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:13]=2[CH3:25])[CH:7]=[CH:6][C:5]=1[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[F:34]
Reactant: CCOC(=O)CCc1ncnc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(COc3ncnc(CCC(=O)O)c3C)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
To a solution of ethyl 3-(6-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-5-methylpyrimidin-4-yl)propanoate (180 mg) in methanol (2.0 mL) and THF (2.0 mL) were added water (2.0 mL) and lithium hydroxide monohydrate (75 mg), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative HPLC to give the title compound (88 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][NH:10][C:3]=12.[C:11]([O:15][C:16](=[O:35])[NH:17][CH:18]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:19](=[O:26])[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([CH3:14])([CH3:13])[CH3:12]>C1(C)C(C)=CC=CC=1>[C:11]([O:15][C:16](=[O:35])[NH:17][CH:18]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:19](=[O:26])[N:20]1[CH2:21][CH2:22][N:23]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[CH:9][NH:10][C:3]=23)[CH2:24][CH2:25]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: Clc1ccnc2cc[nH]c12
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCNCC1
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccnc3cc[nH]c23)CC1
Yield: 7.9 %

Procedure:
To a solution of 7-Chloro-1H-pyrrolo[3,2-b]pyridine (40 mg, 0.262 mmol) in xylene (4 mL) and TEA (1 mL) was added [1-(4-chlorobenzyl)-2-oxo-2-piperazin-1-yl-ethyl]-carbamic acid tert-butyl ester (0.1 g, 0.27 mol). The mixture was refluxed for 6 days. The solvent was removed under vacuum and the residue was subject to purification by HPLC to afford {1-(4-chlorobenzyl)-2-oxo-2-[4-(1H-pyrrolo[3,2-b]pyridin-7-yl)-piperazin-1-yl]-ethyl}-carbamic acid tert-butyl ester (10 mg, 8%). 1H NMR (CDCl3, 400 Hz) δ 11.81 (s, 1H), 7.95 (d, J=6.4 Hz, 1H), 7.40 (s, 1H), 7.15 (d, J=8.00 Hz, 2H), 6.46 (d, J=6.8 Hz, 2H), 5.42 (d, J=8.4 Hz, 1H), 4.82 (d, J=7.2 Hz, 1H), 3.87-3.28 (m, 8H), 2.98 (d, J=6.4 Hz, 2H), 1.41 (s, 9H). MS (ESI+) [M+H]+ 484.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:17]([F:28])[CH:16]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.[BH4-].[Na+].[NH4+].[Cl-]>CO.C1COCC1>[NH2:1][C:2]1[C:3]([C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])=[C:17]([F:28])[CH:16]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2nc(C3CCC(=O)CC3)cnc2N)cc1F
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2nc(C3CCC(O)CC3)cnc2N)cc1F
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 98.4 %

Procedure:
A solution of tert-butyl 4-(3-amino-6-(4-oxocyclohexyl)pyrazin-2-yl)-2-fluorobenzoate (9 g, 23.35 mmol) in methanol (125 mL) and THF (125 mL) was cooled down to −78° C., and then NaBH4 (2.297 g, 60.7 mmol) was added portion wise. The reaction mixture was then stirred at −78° C. for 40 min, and LCMS indicated the reaction was completed. Some over-reduction product was observed. The ratio of trans to cis was about 8:1. 100 mL of sat. NH4Cl was added slowly at −78° C., and then the mixture was warmed up gradually to room temperature. The reaction mixture was quenched by sat. NaHCO3, and extracted by EtOAc (2×200 mL). The organic layers were combined, dried over Na2SO4, filtered off, concentrated and dried under high vacuum to provide tert-butyl 4-(3-amino-6-(4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzoate (8.9 g, 22.97 mmol, 98%), which was used in next step without further purification. LCMS (m/z): 388.2 (MH+), 0.86 min.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C[O:12][C:13]1[CH:30]=[CH:29][C:28]2[C@@H:27]3[C@H:18]([C@H:19]4[C@@:23]([CH2:25][CH2:26]3)([CH3:24])[C@@H:22]([OH:31])[CH2:21][C:20]4([CH3:33])[CH3:32])[CH2:17][CH2:16][C:15]=2[CH:14]=1.[Cl-].[NH4+].Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:32][C:20]1([CH3:33])[C@H:19]2[C@H:18]3[C@H:27]([CH2:26][CH2:25][C@:23]2([CH3:24])[C@@H:22]([OH:31])[CH2:21]1)[C:28]1[CH:29]=[CH:30][C:13]([OH:12])=[CH:14][C:15]=1[CH2:16][CH2:17]3
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1C(C)(C)C[C@@H]2O
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1(C)C[C@H](O)[C@@]2(C)CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@H]12
Temperature: 0 °C
Yield: 90 %

Procedure:
Representative Procedure: Diisobutylaluminum hydride (0.5 ml; 1.5M; 0.75 mmol) was added to a solution of the 15,15-dimethyl-17β-alcohol (12) in dry toluene (5 ml). The solution was heated to refluxing temperature for 24 h. The mixture was cooled to 0° C., saturated aqueous ammonium chloride was added, and the aqueous phase was further acidified with dilute HCl. The standard work-up (ethyl acetate) gave 15,15-dimethylestra-1,3,5 (10)-triene-3,17β-diol (16) (43 mg; 90%), m.p. 167-170 (from ethyl acetate); [α]D +49° (C 1.1 ethanol) (Found; C, 79.6; H, 9.3%; M+, 300. C20H28O2 requires C, 80.0; H, 9.4%; M, 300).
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.Br[CH2:39][C:40]([N:42]1[CH2:47][CH2:46][CH2:45][C:44]([CH3:49])([CH3:48])[CH2:43]1)=O>>[CH3:48][C:44]1([CH3:49])[CH2:45][CH2:46][CH2:47][N:42]([CH2:40][CH2:39][O:10][C:8]2[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[CH:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:6][CH:7]=2)[CH2:43]1
Reactant: CC1(C)CCCN(C(=O)CBr)C1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN3CCCC(C)(C)C3)cc2)c1
Yield: 157.1 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-bromo-1-(3,3-dimethylpiperidin-1-yl)ethanone (19 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (17 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][C@@H:10]([CH2:13][OH:14])[N:9]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([O:26]CC)=[O:25])=[C:17]3[N:16]=2)[CH:5]=[N:6][CH:7]=1.[OH-].[Na+].Cl.O1CCOCC1>CO>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][C@@H:10]([CH2:13][OH:14])[N:9]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[C:17]3[N:16]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CCOC(=O)c1cnn2ccc(N3[C@H](CO)CC[C@@H]3c3cncc(F)c3)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)c1cnn2ccc(N3[C@H](CO)CC[C@@H]3c3cncc(F)c3)nc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 90.6 %

Procedure:
A mixture of ethyl 5-((2R,5S)-2-(5-fluoropyridin-3-yl)-5-(hydroxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.250 g, 0.649 mmol) and 2M sodium hydroxide (3.24 mL, 6.48 mmol) in MeOH (10 mL) was stirred at ambient temperature for 4 days followed by 50° C. for 5 hours. The reaction was cooled to ambient temperature and 4M HCl in dioxane (1.78 mL, 7.14 mmol) was added. The mixture was concentrated and the residue was purified by reverse phase column chromatography (0-40% acetonitrile/water) to afford 5-((2R,5S)-2-(5-fluoropyridin-3-yl)-5-(hydroxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (210 mg, 90% yield) as a white solid. MS (apci) m/z=358.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([NH2:16])[CH:5]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:32][CH2:33][C:34](=O)[CH2:35][CH3:36].CC(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([NH:16][CH:34]([CH2:35][CH3:36])[CH2:33][CH3:32])[CH:5]=1
Reactant: CCC(=O)CC
Reactant: COC(=O)c1cc(N)cc(N2CCCC2=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC(CC)Nc1cc(C(=O)OC)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 40 %

Procedure:
To a solution of 3-amino-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (D4a) (200 mg, 0.87 mmol, 1 equiv) in (CH2Cl)2 (5 ml) were added sodium triacetoxyborohydride (1.536 g, 5.22 mmol, 6 equiv), 3-pentanone (0.546 ml, 5.22 mmol, 6 equiv) and AcOH (0.050 ml, 0.87 mmol, 1 equiv). The resulting mixture was stirred at room temperature for 48 h, diluted with CH2Cl2 (20 ml), washed with saturated aqueous NaHCO3 solution (20 ml), dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane/AcOH: 3/2) gave 3-(1-ethyl-propylamino)-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (B43) (106 mg, 40%) as a colourless oil. [M+H]+=305.0 RT=3.19
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].Cl[C:9]1[CH:19]=[CH:18][C:12]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[CH:11][C:10]=1[N+:20]([O-:22])=[O:21]>C(OCC)(=O)C>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][C:9]1[CH:19]=[CH:18][C:12]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[CH:11][C:10]=1[N+:20]([O-:22])=[O:21]
Reactant: CN(C)C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN(C)CCCN
Solvent: CCOC(C)=O
Product: CN(C)CCCNc1ccc(C(=O)N(C)C)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 2 h
Yield: 100.8 %

Procedure:
N,N-Dimethy-1,3-propanediamine (1.95 g) was added to 4-chloro-N,N-dimethyl-3-nitrobenzamide (2.18 g) and stirred for 2 hours at 90° C. The reaction mixture, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution, water and saturated brine successively, dried over sodium sulfate anhydride, and concentrated, thereby yielding the entitled compound (2.83 g) as yellowish orange oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:11]1[N:12]([CH3:36])[C:13]2[C:18]([N:19]=1)=[C:17]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[NH:28][C:27]3=[O:35])[CH2:22][CH2:21]1)[N:16]=[CH:15][N:14]=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:36][N:12]1[C:11]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:19][C:18]2[C:13]1=[N:14][CH:15]=[N:16][C:17]=2[N:20]1[CH2:21][CH2:22][CH:23]([N:26]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[NH:28][C:27]2=[O:35])[CH2:24][CH2:25]1
Reactant: OB(O)c1cccnc1
Reactant: Cn1c(Br)nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1c(-c2cccnc2)nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc21
Temperature: 150 °C
Yield: 29.3 %

Procedure:
To a solution of pyridin-3-ylboronic acid (50 mg, 0.41 mmol, Maybridge) in dioxane (0.75 mL) and water (0.1 mL) were added 1-(1-(8-bromo-9-methyl-9H-purin-6-yl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (50 mg, 0.12 mmol), Pd(dppf)Cl2 (20 mg, 0.02 mmol), and tribasic potassium phosphate (75 mg, 0.36 mmol). The reaction mixture was heated in a microwave reactor to 150° C. for 20 min. The product was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to give 15 mg (29.3% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 10.84 (s, 1H), 9.03 (m, 1H), 8.72 (dd, 1H), 8.32 (m, 1H), 8.25 (m, 1H), 7.59 (ddd, 1H), 7.15 (m, 1H), 6-91 (m, 3H), 4.55 (t, 1H), 3.85 (s, 3H), 2.35 (m, 2H), 1.84 (d, 2H); MS (EI) for C23H22N8O: 427.4 (MH+).
Reaction SMILES: C(=O)([O-])O.[Na+].FC(F)(F)S(O[C:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=1)(=O)=O.[C:27]([O:31][C:32]([NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[NH:41][C:42](=[O:58])[C:43]1[CH:48]=[CH:47][C:46](B2OC(C)(C)C(C)(C)O2)=[CH:45][CH:44]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:27]([O:31][C:32]([NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[NH:41][C:42]([C:43]1[CH:48]=[CH:47][C:46]([C:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=2)=[CH:45][CH:44]=1)=[O:58])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 74.3 %

Procedure:
A saturated solution of sodium hydrogen carbonate (3 ml) was added to a stirred solution of t-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate (Method 72, 200 mg, 0.60 mmol) in 1,2-dimethoxyethane (3 ml). N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Method 13) (318 mg, 0.72 mmol) was added followed by tetrakis(triphenylphosphine) palladium (100 mg, 0.09 mmol) and the mixture stirred at 80° C. for 18 hours. The cooled mixture was partitioned between ethyl acetate and water. The organic phase was separated, then washed with water and dried over magnesium sulfate, filtered and evaporated. The resultant residue was purified by flash column chromatography (eluting with 0-15% methanol in dichloromethane) to give the title compound (220 mg, 74%); NMR Spectrum: (DMSO-d6) 1.42 (s, 9H), 1.43 (s, 9H), 2.48 (m, 2H), 3.55 (m, 2H), 4.02 (m, 2H), 6.31 (s, 1H), 7.17 (m, 2H), 7.52 (m, 2H), 7.58 (d, 2H), 7.92 (d, 2H), 8.62 (s, 1H), 9.79 (s, 1H); Mass Spectrum: M+H+ 494.