Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH2:9][C:8]2[CH:10]=[C:11]3[O:16][CH2:15][O:14][C:12]3=[CH:13][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[N:5][N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:45]=[N+:46]=[N-:47].C(OC(N=NC(OCC)=O)=O)C>O1CCCC1.C1(C)C=CC=CC=1>[N:45]([CH2:2][C:3]1[CH2:9][C:8]2[CH:10]=[C:11]3[O:16][CH2:15][O:14][C:12]3=[CH:13][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[N:5][N:4]=1)=[N+:46]=[N-:47]
Reactant: O=[N+]([O-])c1ccc(C2=NN=C(CO)Cc3cc4c(cc32)OCO4)cc1
Reactant: [N-]=[N+]=N
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: [N-]=[N+]=NCC1=NN=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2C1)OCO3
Reaction time: 2 h
Yield: 68 %

Procedure:
A solution of 3.06 g (9.0 mmol) of 8-hydroxymethyl-5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h][2,3]-benzodiazepine (starting compound III.) and 2.58 g (9.9 mmol) of triphenylphosphine in 100 ml of dry tetrahydrofuran is mixed with 13.5 ml of a 1.2N hydrazoic acid solution in toluene, then a solution of 1.74 ml (9.9 mmol) of azodicarboxylic acid-diethyl ester is added, and the mixture is stirred for another 2 hours. The precipitated product is suctioned off and washed with tetrahydrofuran and n-hexane. 2.23 g (68%) of the title compound with a melting point of 198-200° C. is obtained.
Reaction SMILES: N1C=C[CH:3]=N1.[N:6]1[CH:11]=CC=[CH:8][C:7]=1[CH2:12][C:13]1[NH:17]N=NN=1.[N+:18]([O-:21])(O)=[O:19]>S(=O)(=O)(O)O>[N+:18]([C:12]1[C:13]([CH3:3])=[N:17][N:6]([CH3:11])[C:7]=1[CH3:8])([O-:21])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: c1cn[nH]c1
Reactant: c1ccc(Cc2nnn[nH]2)nc1
Agent: O=S(=O)(O)O
Product: Cc1nn(C)c(C)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
The pyrazole from (a) above (3.1 g; 0.028, moles) was dissolved in cold sulfuric acid (15 mL), cooled to 0° C., and then treated with fuming nitric acid (12 mL). The acidic solution was heated on a steam bath for 2 hours, cooled to room temperature, and poured over ice. The solution was made basic (pH=12) and the precipitate was collected by filtration and washed with water. Yield: 2.3 g (53%), white solid. 1H NMR (CDCl3) δ3.7 (s, 3H), 2.6 (s, 3H), 2.5 (s, 3H) ppm.
Reaction SMILES: Cl[C:2]1[C:7]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:11]=2)=[C:6]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[O:33][CH3:34])[CH:5]=[CH:4][N:3]=1.[Cl-].C[Zn+].[CH3:38]N1CCN(C)C1=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CCOC(C)=O>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:38])[C:7]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:11]=2)=[C:27]([O:33][CH3:34])[CH:28]=1
Reactant: CN1CCN(C)C1=O
Reactant: COc1cc(F)ccc1-c1ccnc(Cl)c1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Agent: C[Zn+]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1-c1ccnc(C)c1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Temperature: 50 °C

Procedure:
To a solution of N-(2-chloro-4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-N-methyl-3-(methylsulfonyl)-5-(trifluoromethyl)benzamide (0.1 g, 193 μmol, Example 212) in THF (3 mL) were added methylzinc(II)chloride (193 μL, 387 μmol), 1,3-dimethyl-2-imidazolidinone (DMI) (0.6 mL) and PEPPSI-IPr (CAS 905459-27-0) (2.7 mg, 3.87 μmol) and the reaction mixture was heated at 50° C. for 3 hours. The reaction mixture was poured on 10% aqueous citric acid solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered and evaporated. The compound was purified by silica gel chromatography on a 10 g column using an MPLC (ISCO) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). The product was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). The product was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.05% triethylamine) (20:80 to 60:40). Colorless solid (0.035 g; 36%). MS (ESI): m/z=497.12 [M+H]+.
Reaction SMILES: C([Mg]Br)(C)C.[C:6]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:7][C:8]([O-:10])=O.[CH3:15][C:16]1[O:21][CH2:20][N:19]([C:22](C)([CH3:26])[C:23](O)=O)[C:18](=[O:28])[C:17]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N-]1C=CN=C1>O1CCCC1.CCOCC>[CH3:15][C:16]1[O:21][CH2:20][N:19]([C:22]([CH3:26])([CH3:23])[C:8](=[O:10])[CH2:7][C:6]([O:12][CH2:13][CH3:14])=[O:11])[C:18](=[O:28])[C:17]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)O)CO1
Agent: CC(C)[Mg]Br
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[n-]cn1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)CC(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
Isopropyl magnesium bromide (0.7M solution in tetrahydrofuran) was added to a solution of mono-ethyl malonate(1.44 g) in tetrahydrofuran at 0° C. The mixture was stirred at 20° C. for 0.5 hour and at 40° C. for 0.5 hour. 2-(2,3-Dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropionic acid (2 g) and carbonyldiimidazole(1.42 g) was stirred in tetrahydrofuran for 8 hours and the resulting imidazolide solution then added to the above mixture at 0° C., stirred at 20° C. for 3 hours and refluxed for 2 hours. The mixture was diluted (ether), washed (5% hydrochloric acid), dried (MgSO4),evaporated and the residue purified by column chromatography (ethyl acetate/hexane 1:2) to give ethyl 4-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-4-methyl-3-oxo-pentanoate (1.4 g), NMR 1.25(3H, t), 1.47(6H, s), 1.94(3H, s), 3.60(2H, s), 4.15(2H, q), 5.26(2H, s), 7.2-7.4(5H, m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])=[C:6]([C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(C(C)(C)C)c1
Reactant: CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1C(C)(C)C

Procedure:
A mixture of 30.0 g 3-(1,1-dimethylethyl)-4-hydroxybenzoic acid methyl ester, 42.9 ml of 1-bromotetradecane, 47.8 g of potassium carbonate and 700 ml of acetone is refluxed for 48 hours. The cooled reaction is filtered, concentrated in vacuo and purified by column chromatography (silica ge1:0-3% ethyl acetate/hexane) to give 38.8 g of the desired product as colorless prisms.
Reaction SMILES: F[C:2]1[C:3]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:4][C:5]([CH3:17])=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:7]=1.[Cl:22]C1C=CC(C)=CC=1O>>[Cl:22][C:2]1[C:3]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:4][C:5]([CH3:17])=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:7]=1
Reactant: Cc1ccc(Cl)c(O)c1
Reactant: Cc1cc(S(C)(=O)=O)c(F)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1cc(S(C)(=O)=O)c(Cl)cc1B1OC(C)(C)C(C)(C)O1

Procedure:
The title compound was prepared by a method analogous to that described for 2-(5-fluoro-2-methyl-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Steps 1-5 of Example 223), using 2-chloro-5-methylphenol as the starting material. MS (ESI, pos. ion) m/z: 353.0 (M+Na).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C@@:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][C@@:6]23[CH2:17][CH2:16][CH2:15][C:13]4[C:14]2=[C:9]([CH:10]=[CH:11][CH:12]=4)[NH:8][C:7]3=[O:18])[CH2:29][CH2:28]1
Reactant: O=C1Nc2cccc3c2[C@@]1(CCCCBr)CCC3
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccccc1N1CCN(CCCC[C@@]23CCCc4cccc(c42)NC3=O)CC1
Yield: 83.4 %

Procedure:
(S)-2a-(4-bromobutyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (308 mg, 1.0 mmol), 4-(2-methoxyphenyl)piperazine (415 mg, 2.1 mmol) and potassium carbonate (280 mg, 2.0 mmol) in anhydrous N,N-dimethylformamide (10 ml) were stirred at room temperature for 18 hours. Then, ethyl acetate (80 ml) was added to the resulting reaction mixture, which was washed with water and saturated saline solution, successively dried over anhydrous sodium sulfate, followed by evaporating the solvent under reduced pressure. The resulting product was separated and purified by means of silica gel column chromatography, whereby 350 mg (yield 84%) of the above-described object compound could be obtained.
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[CH2:24]([NH2:30])[C:25]1[O:29][CH:28]=[CH:27][CH:26]=1.CCN(CC)CC>CCO>[O:29]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:24][NH:30][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:9][C:10]([F:11])([F:12])[F:13])[CH2:14][C:15]([F:16])([F:17])[F:18])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22]
Reactant: NCc1ccco1
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(c1ccc(NCc2ccco2)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F

Procedure:
Following the general procedure for Intermediate 2 using 4-fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (100 mg, 0.287 mmol) and furfurylamine (0.028 mL, 0.315 mmol) in 3 mL of EtOH containing Et3N (0.080 mL, 0.574 mmol). The product was purified by flash chromatography on silica gel using 4:1/hexanes:EtOAc as eluent. Yield: 115 mg (94%); 1H NMR (CDCl3) 4.23 (q, J=8.40 Hz, 4H), 4.56 (d, J=5.66 Hz, 2H), 6.31 (d, J=3.12 Hz, 1H), 6.35 (m, 1H), 7.04 (d, J=8.98 Hz, 1H), 7.39 (s, 1H), 7.53 (d, J=8.89 Hz, 1H), 8.28 (s, 1H), 8.55 (s, 1H); MS (ESI) 426.21 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10](=O)[C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CS(C)=O.O.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH2:10][C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2Cc1ccccc1
Agent: NN
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)CC(=O)N2Cc1ccccc1
Reaction time: 3 h
Yield: 85.8 %

Procedure:
A solution of 1-benzyl-5-methoxyindoline-2,3-dione (6.1 g, 23 mmol) and hydrazine hydrate (50-60% grade, 2.9 mL, ca. 2 eq) in DMSO (15 mL) is heated to 140° C. in an oil bath. After 3 h, the mixture was cooled, diluted with water and EtOAc, the layers separated and the aqueous extracted with EtOAc three times (30 mL). The combined organic portions were washed with 2M H2SO4, brine, and dried over MgSO4, filtered and concentrated to afford the crude product as a viscous brown oil. The crude product was purified by silica gel chromatography (20-50% EtOAc in hexane) to yield the title compound as a brown oil (5.0 g, 85%). 1H NMR (400 MHz, CDCl3) δ 7.34-7.23 (m, 5H), 6.89 (s, 1H), 6.69 (d, J=8.3 Hz, 1H), 6.61 (d, J=8.5 Hz, 1H), 4.91 (s, 2H), 3.76 (s, 3H), 3.62 (s, 2H). MS ESI 254.0 [M+H]+, calcd for [C16H1sNO2+H]+ 254.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[CH2:20]([O:12][C:11](=[O:13])[C@@H:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
To a solution of 11.19 g (59.1 mmol) of (R)—N-tert-butoxycarbonylalanine in 70 mL of N,N-dimethylformamide was added 6.7 g (48.5 mmol) of K2CO3, and 6.9 mL (58.0 mmol) of benzyl bromide. The reaction was stirred at 80° C. for 40 min, then poured into 350 mL of H2O. The aqueous mixture was extracted with diethyl ether (3×50 mL), then the combined ether layers were back extracted with H2O (2×50 mL), and brine (1×50 mL), dried over MgSO4, filtered, and concentrated in vacuo to furnish the titled compound as a colorless oil. MS (ESI) m/z=280 (M+H)+, 297 (M+NH4)+, 302 (M+Na)+: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.25 (d, J=7.5 Hz, 3H) 1.37 (s, 9H) 4.06 (m, 1H) 5.07 (d, J=12.9 Hz, 1H) 5.15 (d, J=12.5 Hz, 1H) 7.34 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21]>C(#N)C>[CH2:21]([O:12][C:3]1[C:2]([F:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[C:5]([F:11])[CH:4]=1)[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: O=[N+]([O-])c1cc(F)c(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1cc(F)c([N+](=O)[O-])cc1F
Yield: 44.2 %

Procedure:
The product of step (a) (3.4 g, 20 mmol), 50 ml acetonitrile, 3.3 g potassium carbonate and 3 g allyl bromide were combined, heated to reflux for one hour and stripped. The mixture was extracted with dichloromethane, treated with water and separated. The organics were dried over magnesium sulfate and stripped to yield 1.9 g of 4-allyloxy-2,5 difluoro nitrobenzene product.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1Cl)=[CH:8][CH:7]=[CH:6][CH:5]=2.[F:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20].S(=O)(=O)(O)O.CCOCC>[N+](C1C=CC=CC=1)([O-])=O>[O:14]=[C:3]1[C:2]2[N:1]=[C:19]([C:18]3[CH:22]=[CH:23][CH:24]=[C:16]([F:15])[CH:17]=3)[O:20][C:11]=2[C:10](=[O:13])[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: NC1=C(Cl)C(=O)c2ccccc2C1=O
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)c2oc(-c3cccc(F)c3)nc21
Reaction time: 0.08 h
Yield: 7.1 %

Procedure:
To a solution of 5.00 g (24 mmol) of 2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene in 50 mL of nitrobenzene, 14.6 mL (120 mmol) of 3-fluorobenzoic acid chloride are added; after 5 min of stirring, 0.50 mL of concentrated sulfuric acid is then added with protection from light. After 24 h of reflux and complete cooling, 200 mL of ether are added to the reaction mixture. The precipitate formed is filtered, then redissolved in 200 mL of dichloromethane, to which 100 mL of a glacial sodium hydroxide solution are added. After 6 h of stirring at this temperature, the organic phase is extracted, washed several times with water and dried over calcium chloride. The solid obtained after evaporation of the solvent is purified on a medium-pressure column (support: silica; conditioning heptane; eluant: dichloromethane/heptane, 50/50). The yellow crystals so obtained are uncolored and recrystallized in a dichloromethane/heptane mixture (volume/volume) to produce 0.50 g of 4,9-dihydro-4,9-dioxo-2-(3-fluorophenyl)-naphtho[2,3-d]oxazole in the form of yellow crystals.
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:18])=[C:12]2[S:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Na+].[Na+].I[CH2:33][CH2:34][N:35]1[CH:39]=[CH:38][CH:37]=[CH:36]1>O.ClCCl>[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:18])=[C:12]2[S:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:33][CH2:34][N:35]2[CH:39]=[CH:38][CH:37]=[CH:36]2)[CH2:22][CH2:21]1
Reactant: Cc1[nH]c2ccc(Cl)cc2c1SC1CCNCC1
Reactant: ICCn1cccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1[nH]c2ccc(Cl)cc2c1SC1CCN(CCn2cccc2)CC1

Procedure:
A toluene solution (100 ml) of 5-chloro-2-methyl-3-(piperidin-4-ylthio) -1H-indole (1.09 g, prepared in Example 15), sodium carbonate (0.78 g) and 1-(2-iodoethyl) -1H-pyrrole (0.92 g, prepared according to GALEAZZI, E.; GUZMAN, A.; PINEDO, A.; SALDANA, A.; TORRE, D.; MUCHOWSKI, J. M., Can. J. Chem. (1983) 61, 454-60) is refluxed for 15 hours. The reaction mixture is taken up in a water/dichloromethane mixture. The organic phase is dried over magnesium sulfate and concentrated. The residue is chromatographed on silica gel (eluent: CH2Cl2 /MeOH : 90/10) to give 5-chloro-2-methyl -3-[[1-[2-(1H-pyrrol-1-yl)ethyl]piperidin-4-yl]thio]-1H-indole (0.9 g).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@@H:13]([OH:16])[CH2:14]C)=[CH:7][C:5]=2[N:6]=1.[N:17]1(C(OC(C)(C)C)=O)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.FC(F)(F)C(O)=O.C(Cl)Cl>CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@@H:13]([OH:16])[CH2:14][N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:7][C:5]=2[N:6]=1
Reactant: CC[C@H](O)COc1ccc2sc(C)nc2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2cc(OC[C@@H](O)CN3CCNCC3)ccc2s1
Reaction time: 8 h

Procedure:
A solution of (2S)-1-(2-methylbenzothiazol-5-yloxy)butan-2-ol, tert butyl piperazinecarboxylate, a compound of formula (5) (2.0 g, 4.9 mmol), and 25% trifluoroacetic acid/methylene chloride (20 ml) was allowed- to stir at room temperature overnight. The solvent was evaporated (in vacuo) to yield an oil. The oil was diluted with acetone (20 ml) and solid potassium carbonate was added until the foaming stopped. The resulting mixture was allowed to stir overnight. The solution was filtered through Celite 512, and the filtrate was evaporated (in vacuo), to yield an oil. The oil was placed under high vacuum overnight, to yield (2S)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazinylpropan-2-ol, as a clear viscous oil (3.4 g. 6.3 mmol).
Reaction SMILES: [Na].[I:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[CH2:11][CH2:12][OH:13].[Cl-].[NH4+]>C(O)C>[I:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:11][CH2:12][OH:13])=[CH:5][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: OCCCl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCO
Product: OCCOc1ccc(I)cc1
Yield: 50 %

Procedure:
Sodium (0.53 g) was dissolved in ethanol (50 ml) under nitrogen and 4-iodophenol (5.0 g), and 2-chloroethanol (3.93 g), were added successively. The mixture was refluxed for 18 h, treated with saturated aqueous ammonium chloride (50 ml) and evaporated. The aqueous residue was extracted with ER (3×100 ml) and the dried extract was evaporated onto silica (Merck 9385; 50 ml) and purified by [C] eluted with cyclohexane-ER (7:3) followed by cyclohexane-ER (1:1) to give the title compound (3.0 g) m.p. 76°-77°.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9]([C:11]([NH2:14])([CH3:13])[CH3:12])=[CH:8][C:6]=2[N:7]=1.CCN(CC)CC.Cl.[C:29](Cl)(=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1.CC1(C)C(C)(C)OB([C:48]2[CH:56]=[CH:55][CH:54]=[C:53]3[C:49]=2[CH:50]=[N:51][NH:52]3)O1>C(Cl)Cl>[NH:52]1[C:53]2[C:49](=[C:48]([C:2]3[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]4[S:10][C:9]([C:11]([NH:14][C:29](=[O:38])[C:30]5[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=5)([CH3:13])[CH3:12])=[CH:8][C:6]=4[N:7]=3)[CH:56]=[CH:55][CH:54]=2)[CH:50]=[N:51]1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CC(C)(N)c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)NC(C)(C)c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-amine (150 mg, 0.5 mmol) in CH2Cl2 (10 mL) was added Et3N (230 μL, 1.6 mmol) and the HCl salt of p-anisoyl chloride (160 mg, 0.9 mmol). The resulting mixture stirred at room temperature overnight. The reaction was quenched by the addition of saturated aqueous NaHCO3. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. A portion (0.2 mmol) of the resulting crude material was utilized in a Suzuki coupling using General Procedure A with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide 412 after reverse phase HPLC purification (30 mg). MS (Q1) 529 (M)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:17]3[C:16]4[CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[NH:14][C:13]=3[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(N(CC)CC)C>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:17]3[C:16]4[CH2:18][N:19]([C:22](=[O:24])[CH3:23])[CH2:20][CH2:21][C:15]=4[NH:14][C:13]=3[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Fc1cccc(Nc2ccnc3[nH]c4c(c23)CNCC4)c1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(=O)N1CCc2[nH]c3nccc(Nc4cccc(F)c4)c3c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.5 %

Procedure:
(3-Fluoro-phenyl)-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (15 mg, 0.05 mmol), acetic anhydride (53 μL, 0.05 mmol), and triethylamine (22 μL, 0.16 mmol) were dissolved in 1,2-dichloroethane (2 mL), and stirred for 30 min at room temperature. The reaction was quenched with H2O, and the resulting material was filtered through an Extrelut column. The Extrelut column was washed with EtOAc, and the filtrate was concentrated. The crude material was purified via Biotage eluting with a gradient of 0 to 10% MeOH in DCM. Lyophilization of the purified product provided 61 (3 mg, 15% yield) as an oily residue. LC-MS (M+H=325, obsd.=325).
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Br:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Br:13])[C:10]=1[CH:11]=O>CC(O)C>[Br:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Br:13])[C:10]=1[CH:11]=[N:3][NH:2][CH3:1]
Reactant: CNN
Reactant: O=Cc1c(Br)cncc1Br
Solvent: CC(C)O
Product: CNN=Cc1c(Br)cncc1Br
Reaction time: 3 h

Procedure:
Methylhydrazine (1.06 mL, 19.3 mmol) was added to a solution of 3,5-dibromopyridine-4-carbaldehyde (3.4 g, 13 mmol) in 2-propanol (20 mL). After 3 hours at room temperature, the reaction mixture was concentrated in vacuo, dissolved in ethyl acetate, and washed with saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the product as a solid. Yield: 3.20 g, 10.9 mmol, 84%. 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 2H), 7.24-7.26 (m, 1H), 2.89-2.91 (m, 3H).