Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]=[C:14]([NH2:16])[C:13]3[CH:12]=[CH:11][S:10][C:9]=3[NH:8][C:7]=2[CH:17]=1.[CH3:18][O:19][CH2:20][CH2:21][C@H:22]1[CH2:27]N[CH2:25][CH2:24][NH:23]1.CS(C)=O.C1(C)C=CC=CC=1>C(OCC)(=O)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]=[C:14]([N:16]3[CH2:25][CH2:24][NH:23][C@@H:22]([CH2:21][CH2:20][O:19][CH3:18])[CH2:27]3)[C:13]3[CH:12]=[CH:11][S:10][C:9]=3[NH:8][C:7]=2[CH:17]=1
Reactant: NC1=Nc2ccc(F)cc2Nc2sccc21
Reactant: COCC[C@H]1CNCCN1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COCC[C@H]1CN(C2=Nc3ccc(F)cc3Nc3sccc32)CCN1
Temperature: 105 °C
Reaction time: 40 h
Yield: 25 %

Procedure:
Combine 6-fluoro-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (1.20 g, 4.45 mmol), (S)-2(2-methoxy-ethyl)-piperazine (1.60 g, 11.12 mmol), DMSO (4.0 ml), and toluene (16.0 ml). Stir and heat the mixture at 105° C. After 40 hours, cool the mixture to ambient temperature. Dilute the mixture with ethyl acetate and wash the organic layer with 0.1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using a gradient of dichloromethane to dichloromethane/methanol (90:10) to give 400.4 mg (25%) of a tan foam: mass spectrum (ion spray): m/z 361.1 (M+1).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH2:19]Cl)[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=O)=O)C=CC=CC=1.[CH3:21][O-:22].[Na+]>CO.C(OCC)(=O)C>[CH3:21][O:22][CH2:19][C:17]1[CH:18]=[C:13]2[CH:12]=[CH:11][NH:10][C:14]2=[N:15][CH:16]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(CCl)cnc21
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COCc1cnc2[nH]ccc2c1
Reaction time: 12 h
Yield: 99.7 %

Procedure:
To a mixture of 1-benzenesulfonyl-5-chloromethyl-1H-pyrrolo[2,3-b]pyridine (3.3 g, 10.76 mmol) in methanol (15 mL) was added sodium methoxide (1.74 g, 32.3 mmol) at room temperature and the resulting mixture was stirred for 12 h. The mixture was diluted with ethyl acetate (250 mL), washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 5-methoxymethyl-1H-pyrrolo[2,3-b]pyridine (1.74 g, quant.) as a light yellow solid which was used in the next step without further purification: LC/MS m/e calcd for C9H10N2O [M+H]+ 163.19, observed 162.9.
Reaction SMILES: C(N1[C:11]2=[CH:12][C:13]3[C:17](=[CH:18][C:10]2=C(C2SC(Br)=CC=2)C1=O)[N:16](CCCCCC)[C:15](=O)[C:14]=3[C:26]1S[C:28](Br)=[CH:29][CH:30]=1)CCCCC.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1.O.BrC1SC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO>[CH:28]1[C:15]2[NH:16][C:17]3[C:13](=[CH:12][CH:11]=[CH:10][CH:18]=3)[C:14]=2[CH:26]=[CH:30][CH:29]=1
Reactant: CCCCCCN1C(=O)C(c2ccc(Br)s2)=c2cc3c(cc21)=C(c1ccc(Br)s1)C(=O)N3CCCCCC
Agent: [Pd]
Agent: Brc1cccs1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 460 %

Procedure:
A mixture of 1,5-dihexyl-3,7-di-(5-bromothiophen-2-yl)-1H,5H-pyrrolo[2,3-f]indole-2,6-dione (0.150 g, 0.221 mmol), 2,7-bis(4′,4′,5′,5′-tetramethyl-1′,3′,2′-dioxaborolan-2′-yl)-N-9″i-heptadecanylcarbazole (0.152 g, 0232 mmol), Pd2(dba)3 (5.0 mg), (o-tol)3P (3.0 mg), K3PO4 (0.187 g) and toluene/H2O (20 mL/1 mL) was heated at reflux for 24 h. 2-bromothiophene (0.035 g, 0.22 mmol) in toluene (1 mL) was added and the resulting mixture was stirred for another 12 h. Then, after cooling to room temperature, the mixture was dropped into methanol to precipitate. After being filtered and dried, the precipitation was Soxhlet extracted with methanol, acetone, hexane, dichloromethane. A black solid (0.170 g, 85%) was obtained.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@H:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:10][C@H:9]1[C:19](O)=[O:20])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(Cl)Cl.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:38][NH:39][O:40][CH3:41]>CCOC(C)=O>[CH:13]1([C@H:11]2[CH2:12][N:8]([C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[C@H:9]([C:19](=[O:20])[N:39]([O:40][CH3:41])[CH3:38])[CH2:10]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](C2CCCCC2)C[C@H]1C(=O)O
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CON(C)C(=O)[C@@H]1C[C@@H](C2CCCCC2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
(2S,4S)-Boc-4-cyclohexyl-pyrrolidine-2-carboxylic acid (Chem Impex Int'l, Wood Dale, Ill., 997 mg, 3.35 mmol) was treated with DCM (25 mL) followed by 1,1′-carbonyldiimidazole (598 mg, 3.69 mmol). The solution was allowed to stir at room temperature for 1.5 h then the reaction mixture was then treated with N,O-dimethyl hydroxylamine hydrochloride (360 mg, 3.69 mmol) and allowed to stir over the weekend at room temperature. The reaction mixture was diluted with EtOAc (50 mL), washed with a saturated solution of NaHCO3 (30 mL) and brine (30 mL), dried over MgSO4, filtered and concentrated affording crude (2S,4S)-tert-butyl 4-cyclohexyl-2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (1.14 g, 3.35 mmol, 99% yield) as a clear, colorless viscous oil. MS (ESI) 363.2 [M+Na]+. The crude material was used in the next step without further purification.
Reaction SMILES: [CH2:1]([CH:3]([CH2:26][CH3:27])[CH:4]([NH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)[C:5]1[S:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:2].O1CCCC1.[OH-].[Na+]>C(O)C>[CH2:26]([CH:3]([CH2:1][CH3:2])[CH:4]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=1)[C:5]1[S:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:27]
Reactant: CCC(CC)C(Nc1ccc(C(=O)OC)cc1)c1sc2ccccc2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCC(CC)C(Nc1ccc(C(=O)O)cc1)c1sc2ccccc2c1C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a mixture of methyl 4-{[2-ethyl-1-(3-methyl-1-benzothiophen-2-yl)butyl]amino}benzoate (580 mg) synthesized above, tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (10.0 mL), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was dissolved in water (20 mL), and 1N hydrochloric acid (10.0 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (529 mg, 95%) as a white solid.
Reaction SMILES: [OH:1][C:2]1([C:15](O)=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.[CH2:43]([O:50][C:51](=[O:57])[C@@H:52]1[CH2:56][CH2:55][CH2:54][NH:53]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:43]([O:50][C:51](=[O:57])[C@@H:52]1[CH2:56][CH2:55][CH2:54][N:53]1[C:15]([C:2]1([OH:1])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:16])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: O=C(O)C1(O)c2ccccc2-c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)C1(O)c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 9-hydroxy-9-fluorene carboxylic acid (5.04 g, 22.3 mmol) in N,N-dimethylformamide (30 mL), cooled to 0° C. under nitrogen, was added (O-7-azabenzotriazol-1-y)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), (9.32 g, 24.5 mmol), L-proline-benzyl ester hydrochloride (5.93 g, 24.5 mmol), and N,N-diisopropylethylamine (8.5 mL, 48.8 mmol). The mixture was stirred at 0° C. for 3 hours, then concentrated and purified on silica gel (ethyl acetate-hexane, 1:2) to give 9-hydroxy-9-fluorenylcarbonyl-L-proline benzyl ester. HPLC=96%, R.T.=3.7 min; M+1=414.1.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH:36]=O)=[CH:30][CH:29]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:38][O:39][C:40](=[O:42])[CH3:41])(=[O:3])[CH3:2].N1C=CC=CC=1.Cl.[CH3:50][O:51][NH2:52]>C(O)C>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH:36]=[N:52][O:51][CH3:50])=[CH:30][CH:29]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:38][O:39][C:40](=[O:42])[CH3:41])(=[O:3])[CH3:2]
Reactant: CON
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C#N)c(Cc3ccc(OCC=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=CCOc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2C#N)cc1
Temperature: 80 °C
Yield: 57.8 %

Procedure:
To a solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-cyano-3-(4-(2-oxoethoxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (100.0 mg, 0.17 mmol) in ethanol (4 mL) under nitrogen atmosphere, was added pyridine (0.07 mL, 0.86 mmol) and O-methylhydroxylamine hydrochloride (28.7 mg, 0.34 mmol). The reaction mixture was heated at 80° C. for 2 h. After completion of the reaction as confirmed by TLC, the solvent was evaporated. The crude compound was diluted with ethyl acetate (40 mL). The organic layer was separated, washed with 5% HCl (10 mL), water (10 mL), dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 1:49 EtOAc:Pet Ether) to afford title compound (60 mg, 43%) as solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C@H:11]3[CH2:16][C@H:15]4[C@H:17]5[C@H:27]([CH2:28][CH2:29][C@:13]4([CH3:14])[C@H:12]3[OH:31])[C@:25]3([CH3:26])[C@H:20]([CH2:21][C@@H:22]4[O:30][C@@H:23]4[CH2:24]3)[CH2:19][CH2:18]5)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[O:32]1[C:36]2([CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[O:35][CH2:34][CH2:33]1>>[O:32]1[C:36]2([CH2:41][CH2:40][N:39]([C@H:23]3[CH2:24][C@@:25]4([CH3:26])[C@@H:20]([CH2:19][CH2:18][C@@H:17]5[C@@H:27]4[CH2:28][CH2:29][C@@:13]4([CH3:14])[C@H:15]5[CH2:16][C@H:11]([N:8]5[CH2:9][CH2:10][C:5]6([O:1][CH2:2][CH2:3][O:4]6)[CH2:6][CH2:7]5)[C@@H:12]4[OH:31])[CH2:21][C@@H:22]3[OH:30])[CH2:38][CH2:37]2)[O:35][CH2:34][CH2:33]1
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCC4(CC3)OCCO4)C[C@@H]12
Reactant: C1CC2(CCN1)OCCO2
Product: C[C@]12C[C@H](N3CCC4(CC3)OCCO4)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCC4(CC3)OCCO4)C[C@@H]12
Yield: 80.1 %

Procedure:
16β-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-2α,3α-epoxy-17β-hydroxy-5α-androstane is reacted with 1,4-dioxa-8-azaspiro[4.5]decane as described in Example 3 to obtain the title compound in a yield of 80.1%, m.p.: 180°-182° C.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[CH3:11][NH:12][S:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](O)=O)(=[O:15])=[O:14].N>>[CH3:11][NH:12][S:13]([C:16]1[CH:24]=[CH:23][CH:22]=[C:18]([C:19]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:17]=1)(=[O:14])=[O:15]
Reactant: NC(=NO)c1cccnc1
Reactant: CNS(=O)(=O)c1cccc(C(=O)O)c1
Agent: N
Product: CNS(=O)(=O)c1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and the product of Example 57A. 1H NMR (300 MHz, CD3OD) δ 2.60 (s, 3 H), 7.65 (ddd, J=8.1, 5.0, 0.8 Hz, 1 H), 7.87 (t, J=8.1 Hz, 1 H), 8.15 (ddd, J=8.0, 1.9, 1.0 Hz, 1 H), 8.48 (ddd, J=7.8, 1.7, 1.0 Hz, 1 H), 8.58 (dt, J=8.1, 1.9 Hz, 1 H), 8.67 (t, J=1.5 Hz, 1 H), 8.75 (dd, J=4.7, 1.7 Hz, 1 H), 9.31 (dd, J=2.2, 0.8 Hz, 1 H) ppm; MS (DCI/NH3) m/z 317 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([N+:24]([O-:26])=[O:25])=[CH:13][C:14]2[NH:19][C:18](=[O:20])[O:17][C:16]([CH3:22])([CH3:21])[C:15]=2[CH:23]=1)(=O)=O.[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([SH:34])=[CH:30][CH:29]=1>>[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([S:34][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[C:12]([N+:24]([O-:26])=[O:25])=[CH:13][C:14]3[NH:19][C:18](=[O:20])[O:17][C:16]([CH3:21])([CH3:22])[C:15]=3[CH:23]=2)=[CH:30][CH:29]=1
Reactant: CC1(C)OC(=O)Nc2cc([N+](=O)[O-])c(OCCCCOS(C)(=O)=O)cc21
Reactant: Cc1ccc(S)cc1
Product: Cc1ccc(SCCCCOc2cc3c(cc2[N+](=O)[O-])NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 210 from 6-(4-methanesulfonyloxy-butoxy)-7-nitro-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-methyl-thiophenol.
Reaction SMILES: Cl[C:2](=[CH2:7])[C:3]([O:5][CH3:6])=[O:4].[Cl-].C([N+](CC)(CC)CCCC)C.C(=O)([O-])[O-].[K+].[K+].[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[NH:34][C:35]2[C:40]([C:41]=1[CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)=[CH:39][CH:38]=[C:37]([C:48]([O:50][CH3:51])=[O:49])[CH:36]=2.C[Si](C=[N+]=[N-])(C)C>CC#N>[CH:42]1([C:41]2[C:40]3[CH:39]=[CH:38][C:37]([C:48]([O:50][CH3:51])=[O:49])=[CH:36][C:35]=3[N:34]3[C:33]=2[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[NH:26][CH:2]([C:3]([O:5][CH3:6])=[O:4])[CH2:7]3)[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]1
Reactant: C=C(Cl)C(=O)OC
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3N)[nH]c2c1
Agent: CCCC[N+](CC)(CC)CC
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)OC)Nc1ccccc1-3
Temperature: 60 °C
Yield: 45 %

Procedure:
Methyl chloroacrylate (1.7 eq), triethylbutyl ammonium chloride (0.2 eq) and potassium carbonate (6 eq) were added to a solution of methyl 2-(2-aminophenyl)-3-cyclohexyl-1H-indole-6-carboxylate in dry MeCN (0.02 M). The mixture was heated at 60° C. overnight. The mixture was allowed to cool to RT, filtered and concentrated in vacuo. The residue was taken up in MeOH and 5 eq of trimethylsilyldiazomethane (2 N solution in hexanes) added dropwise. Volatiles were then removed in vacuo and the crude product was purified by flash chromatography (SiO2; 2:8 EtOAc/PE) to afford the title compound as a solid (45%). MS (ES+) m/z 433 (M+H)+.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][C:8]([O:11][C:12]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[CH:15]=[C:14]([C:23](=[O:31])[NH:24][C:25]3[CH:29]=[CH:28][N:27]([CH3:30])[N:26]=3)[CH:13]=2)=[CH:7][N:6]=1)=[O:4].[NH:32]1[CH2:35][CH2:34][CH2:33]1>CC(O)=O>[CH3:30][N:27]1[CH:28]=[CH:29][C:25]([NH:24][C:23]([C:14]2[CH:13]=[C:12]([O:11][C:8]3[CH:7]=[N:6][C:5]([C:3]([N:32]4[CH2:35][CH2:34][CH2:33]4)=[O:4])=[CH:10][N:9]=3)[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[CH:15]=2)=[O:31])=[N:26]1
Reactant: COC(=O)c1cnc(Oc2cc(C(=O)Nc3ccn(C)n3)cc3c2CC(C)(C)O3)cn1
Reactant: C1CNC1
Solvent: CC(=O)O
Product: Cn1ccc(NC(=O)c2cc(Oc3cnc(C(=O)N4CCC4)cn3)c3c(c2)OC(C)(C)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 1, from 5-[2,2-dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-pyrazine-2-carboxylic acid methyl ester (396a) and azetidine. 1H NMR (400 MHz, CDCl3) δ 8.86 (d, J=1.26 Hz, 1 H) 8.35 (d, J=1.26 Hz, 1 H) 8.30 (s, 1 H) 7.23-7.32 (m, 1 H) 7.18 (d, J=1.26 Hz, 1 H) 7.12 (d, J=1.26 Hz, 1 H) 6.79 (d, J=2.27 Hz, 1 H) 4.70 (t, J=7.83 Hz, 2 H) 4.27 (t, J=7.83 Hz, 2 H) 3.81 (s, 3 H) 2.85 (s, 2 H) 2.31-2.46 (m, 2 H) 1.49 (s, 6 H); LCMS for C23H24N6O4 m/z 449.20 (M+H+); Anal. Calcd. for C23H24N6O4.0.18 AcOH: C, 61.09; H, 5.43; N, 18.30. Found: C, 61.21; H, 5.64; N, 18.31.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:10]=[C:11]([C:16]2[C:17]([CH:25]([NH2:27])[CH3:26])=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=23)[CH:12]=[C:13]([F:15])[CH:14]=1.Br[C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[N:31]=[CH:32][NH:33]2.C(N(CC)C(C)C)(C)C>C(O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:10]=[C:11]([C:16]2[C:17]([CH:25]([NH:27][C:29]3[N:37]=[CH:36][N:35]=[C:34]4[C:30]=3[N:31]=[CH:32][NH:33]4)[CH3:26])=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=23)[CH:12]=[C:13]([F:15])[CH:14]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: CC(N)c1nn2ccccc2c1-c1cc(F)cc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CC(Nc1ncnc2[nH]cnc12)c1nn2ccccc2c1-c1cc(F)cc(F)c1
Temperature: 110 °C
Yield: 11.3 %

Procedure:
1-[3-(3,5-Difluorophenyl)pyrazolo[1,5-a]pyridin-2-yl]ethanamine trifluoroacetate (16 mg, 0.07 mmol), 6-bromo-9H-purine (13 mg, 0.07 mmol, Aldrich 104981) and N,N-diisopropylethylamine (12 mL, 0.07 mmol) were stirred in ethanol (0.47 mL) and heated to 110° C. for 16 hours. Purification by preparative LCMS (H2O with 0.1% TFA (pH 2), 5% acetonitrile to 24% acetonitrile over 1 minute, 24% to 48% acetonitrile over 12 minutes, Waters Sunfire C18, 5 μM particle size, 30×100 mm, RT=8.75 min.) gave the desired compound (4.0 mg, 12%). LCMS for C20H17F2N7 (M+H)+: m/z=392.0. 1H NMR (300 MHz, DMSO-d6): 8.75 (m, 1H), 8.39 (m, 1H), 8.28 (m, 1H), 7.64 (m, 1H), 7.31 (m, 1H), 7.23 (m, 2H), 7.17 (m, 1H), 6.98 (m, 1H), 5.84 (m, 1H), 1.62 (m, 3H).
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17])[CH:12]=O.N1CCCCC1>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:7]2[S:1][C:2](=[S:3])[NH:4][C:5]2=[O:6])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17]
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
A solution containing 2.1 g (0.0157 mol) of rhodanine, 2.76 g (0.0151 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.15 ml of piperidine in 10 ml of acetic acid was heated for 7-8 h at 100° C. After cooling the crystalls were filtered and washed with 2-propanol. Yield 4.0 g (89%), mp>350° C. (decomp.).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]3[CH:34]=[C:33]([C:35]([CH3:41])([CH3:40])[C:36]([F:39])([F:38])[F:37])[O:32][N:31]=3)=[O:28])=[C:22]([F:42])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10]CC1C=CC(OC)=CC=1)[CH3:2]>Cl>[CH2:1]([O:3][C:4]1[C:9](=[O:10])[NH:8][CH:7]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]3[CH:34]=[C:33]([C:35]([CH3:41])([CH3:40])[C:36]([F:39])([F:37])[F:38])[O:32][N:31]=3)=[O:28])=[C:22]([F:42])[CH:21]=2)[CH:5]=1)[CH3:2]
Reactant: CCOc1cc(-c2ccc(CC(=O)Nc3cc(C(C)(C)C(F)(F)F)on3)c(F)c2)cnc1OCc1ccc(OC)cc1
Agent: Cl
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(C(C)(C)C(F)(F)F)on3)c(F)c2)c[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
A mixture of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide (20 mg, 0.034 mmol) and HCl (4 mol/L in dioxane, 20 mL) was stirred at 25° C. for 2 h. The mixture was concentrated and the crude material was purified by preparative HPLC (MeCN/H2O as eluants, acidic condition) to give a white solid of 2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide (7.9 mg, 0.017 mmol, 49.7% yield): 1H NMR (400 MHz, CD3OD) δ: 7.42-7.36 (m, 1H), 7.35 (s, 2H), 7.29 (d, J=2.2 Hz, 1H), 7.22 (d, J=2.2 Hz, 1H), 6.87 (s, 1H), 4.12 (q, J=7.0 Hz, 2H), 3.81 (s, 2H), 1.56 (s, 6H), 1.46 (t, J=6.8 Hz, 3H); ES-LCMS m/z 468 (M+1).
Reaction SMILES: [C:1]([Si:5]([C:11]([CH3:14])([CH3:13])[CH3:12])([C:7](O)([CH3:9])C)C)([CH3:4])([CH3:3])[CH3:2].[C:15]([Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([F:21])[F:20])([CH3:18])([CH3:17])[CH3:16].[CH2:26]([O:28]C=C[Li])[CH3:27].C[Li]>C1COCC1>[C:22]([Si:19]([C:15]([CH3:18])([CH3:17])[CH3:16])([F:21])[F:20])([CH3:25])([CH3:24])[CH3:23].[C:11]([SiH:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:7][C:9]([O:28][CH2:26][CH3:27])=[CH2:15])([CH3:12])([CH3:13])[CH3:14]
Reactant: [Li]C=COCC
Reactant: CC(C)(C)[Si](C)(C(C)(C)C)C(C)(C)O
Agent: CC(C)(C)[Si](F)(F)C(C)(C)C
Agent: [Li]C
Solvent: C1CCOC1
Product: C=C(C[SiH](C(C)(C)C)C(C)(C)C)OCC
Yield: 14 %

Procedure:
Di-tert-butyldifluorosilane was prepared according to the procedure of B. Rempfer et al., J. Am. Chem. Soc. 1986, 108, 3893-3897. Following the general procedure of Example 7, di-tert-butyl(1-hydroxy-1-methylethyl)methylsilane was prepared from di-tert-butyldifluorosilane (11.8 g, 65.4 mmol), ethoxyvinyl lithium (prepared from ethyl vinyl ether (4.68 g, 64.9 mmol) and tert-butyl lithium (1.6 M in pentane, 40.6 ml, 65.0 mmol)) in THF (100 ml)) and methyl lithium (1.6 M in Et2O, 280 ml, 448 mmol). The crude product was distilled twice to furnish at 57° C./1.7 mbar 2.10 g (14%) of di-tert-butyl(1-ethoxyvinyl)methylsilane, of which 2.00 g (8.76 mmol) were hydrolysed with acetone/1 N HCl (2:1, 10 ml). Purification by silica-gel chromatography (silica-gel 35-70 μm, hexane/EtOAc, 9:1) followed by bulb-to-bulb distillation (120° C., 80 mbar) afforded 0.93 g (53%) of acetyl(di-tert-butyl)methylsilane (m.p. 35° C.), of which 0.90 g (4.49 mmol) was reacted with methyl lithium (1.6 M in Et2O, 60.0 ml, 96.0 mmol) according to Example 1 to furnish after purification by repeated silica-gel flash chromatography (silica-gel 15-40 μm, hexane/EtOAc, 9:1) 204 mg (21%) of the odoriferous title compound (m.p. 122-123° C.).
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[C:48]([N:85]2[CH2:90][CH2:89][N:88]([CH2:91][C@H:92]([OH:94])[CH3:93])[CH2:87][CH2:86]2)=[N:49][CH:50]=[C:51]([C:53]2[CH:54]=[C:55]3[C:61]([C:62]4[CH:63]=[N:64][N:65]([CH2:67][C:68]5[CH:73]=[CH:72][CH:71]=[C:70]([F:74])[CH:69]=5)[CH:66]=4)=[CH:60][N:59](S(C4C=CC(C)=CC=4)(=O)=O)[C:56]3=[N:57][CH:58]=2)[CH:52]=1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[C:48]([N:85]2[CH2:90][CH2:89][N:88]([CH2:91][C@H:92]([OH:94])[CH3:93])[CH2:87][CH2:86]2)=[N:49][CH:50]=[C:51]([C:53]2[CH:54]=[C:55]3[C:61]([C:62]4[CH:63]=[N:64][N:65]([CH2:67][C:68]5[CH:73]=[CH:72][CH:71]=[C:70]([F:74])[CH:69]=5)[CH:66]=4)=[CH:60][NH:59][C:56]3=[N:57][CH:58]=2)[CH:52]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cnc(N5CCN(C[C@@H](C)O)CC5)c(F)c4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)CN1CCN(c2ncc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cc2F)CC1
Yield: 57 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, (R)-1-(4-(3-fluoro-5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl) piperazin-1-yl) propan-2-ol (146 mg, 0.213 mmol) was hydrolyzed with lithium hydroxide (89 mg, 2.137 mmol) in THF/methanol/water (12/4/4 mL) to yield 64 mg (57% yield) after purification by prep TLC using 8% methanol in chloroform as eluent. 1H NMR (CD3OD, 300 MHz): δ 8.45-8.44 (d, 1H), 8.35-8.32 (m, 2H), 8.32 (s, 1H), 7.94 (s, 1H), 7.83-7.78 (dd, 1H), 7.65 (s, 1H), 7.40-7.33 (m, 1H), 7.12-7.00 (m, 3H), 5.43 (s, 2H), 4.02-3.95 (m, 1H), 3.56-3.53 (t, 4H), 2.77-2.63 (m, 4H), 2.47-2.33 (m, 2H), 1.18-1.16 (d, 3H). MS: m/z=530.2 (M+1), HPLC: 98.70% in method A.