Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[O:12][CH2:13][CH:14]1[CH2:23][CH2:22][C:17]2([O:21][CH2:20][CH2:19][O:18]2)[CH2:16][CH2:15]1)C1C=CC=CC=1>C(O)C.C1COCC1.C1CCCCC=1.[OH-].[Pd+2].[OH-]>[O:18]1[C:17]2([CH2:22][CH2:23][CH:14]([CH2:13][O:12][C:11]3[CH:10]=[C:9]([OH:8])[CH:26]=[CH:25][CH:24]=3)[CH2:15][CH2:16]2)[O:21][CH2:20][CH2:19]1
Reactant: c1ccc(COc2cccc(OCC3CCC4(CC3)OCCO4)c2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: C1=CCCCC1
Product: Oc1cccc(OCC2CCC3(CC2)OCCO3)c1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
8-{[3-(Benzyloxy)phenoxy]methyl}-1,4-dioxaspiro[4.5]decane (817 mg) was dissolved in a mixed solvent of ethanol (15 mL) and THF (15 mL), and cyclohexene (4.67 mL) and 20% palladium hydroxide-activated carbon (218 mg) were added thereto, followed by heating under reflux for 4 hours. The reaction mixture was allowed to cool to room temperature, the catalyst was removed by filtration, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=100/0-95/5) to obtain 3-(1,4-dioxaspiro[4.5]dec-8-ylmethoxy)phenol (567 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@H:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C@@H:12]([C:19]3[CH:27]=[CH:26][C:22]4[O:23][CH2:24][O:25][C:21]=4[CH:20]=3)[CH2:11][N:10]2[CH2:28][C:29]([N:31]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:32][CH2:33][CH2:34][CH2:35]O)=[O:30])=[CH:5][CH:4]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[Li+].[Br-:54]>C(OCC)C.CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@H:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C@@H:12]([C:19]3[CH:27]=[CH:26][C:22]4[O:23][CH2:24][O:25][C:21]=4[CH:20]=3)[CH2:11][N:10]2[CH2:28][C:29]([N:31]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:32][CH2:33][CH2:34][CH2:35][Br:54])=[O:30])=[CH:5][CH:4]=1
Reactant: [Br-]
Reactant: CCCCN(CCCCO)C(=O)CN1C[C@H](c2ccc3c(c2)OCO3)[C@@H](C(=O)OCC)[C@H]1c1ccc(OC)cc1
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCCCN(CCCCBr)C(=O)CN1C[C@H](c2ccc3c(c2)OCO3)[C@@H](C(=O)OCC)[C@H]1c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
To an ice cooled solution of 2.80 g (5.05 mmol) of the compound of Example 547C in 27 mL of diethyl ether was added 1.4 mL (10 mmol) of triethylamine, then 0.58 mL of methanesulfonyl chloride. A white precipitate formed, and the suspension was stirred at 0° C. for 20 min. The reaction was diluted with 75 mL of diethyl ether, then extracted with saturated aqueous NaHCO3 solution (2×25 mL), 5% NH4OH (2×25 mL), and brine (1×25 mL), dried over MgSO4, filtered, and concentrated to 3.0 g of a colorless oil. To this material in 45 mL of DMF was added 6.0 g (69 mmol) of LiBr. The reaction warmed to about 50° C., then gradually cooled. The solution was stirred at ambient temperature for 4 h, then poured into 450 mL of water, and extracted with diethyl ether (3×100 mL). The combined ether layers were back extracted with water (1×100 mL), and brine (1×100 mL), dried over MgSO4, filtered, and concentrated in vacuo to an oil. The product was purified via silica gel chromatography, eluting with 3:1 diethyl ether: petroleum ether, to give 2.65 g (90%) of a colorless oil.
Reaction SMILES: [CH2:1]([S:5](Cl)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[CH3:9][NH:10][C:11](=[O:21])[O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([CH3:20])[CH:14]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:9][NH:10][C:11](=[O:21])[O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][S:5]([CH2:1][CH2:2][CH2:3][CH3:4])(=[O:7])=[O:6])=[C:15]([CH3:20])[CH:14]=1
Reactant: CCCCS(=O)(=O)Cl
Reactant: CNC(=O)Oc1ccc(N)c(C)c1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)Nc1ccc(OC(=O)NC)cc1C

Procedure:
Butanesulfonyl chloride (2.6g., 0.017 mole) was added dropwise to a mixture of 3-methyl-4-aminophenyl N-methylcarbamate (3.0g., 0.017 mole), triethylamine (1.85g., 0.018 mole) and benzene (50 ml.). After refluxing for two hours, the reaction mixture was washed in a separatory funnel with water. The organic phase was dried with anhydrous magnesium sulfate and upon removal of the solvent the product was isolated as a dark oil (3.15g.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:11]2)[CH:3]=1.[CH3:27][C:28]1[C:36]2[C:31](=[CH:32][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:35]=2)[NH:30][N:29]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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].O.O1CCOCC1>[CH3:16][C@H:15]1[N:10]([C:4]2[CH:3]=[C:2]([C:33]3[CH:32]=[C:31]4[C:36]([C:28]([CH3:27])=[N:29][NH:30]4)=[CH:35][CH:34]=3)[N:7]=[C:6]([NH:8][CH3:9])[N:5]=2)[CH2:11][C@@H:12]([C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:13][CH2:14]1
Reactant: CNc1nc(Cl)cc(N2C[C@@H](C(=O)NCc3ccccc3)CC[C@H]2C)n1
Reactant: Cc1n[nH]c2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CNc1nc(-c2ccc3c(C)n[nH]c3c2)cc(N2C[C@@H](C(=O)NCc3ccccc3)CC[C@H]2C)n1
Temperature: 100 °C
Yield: 67.1 %

Procedure:
(3S,6R)-1-[6-Chloro-2-(methylamino)-4-pyrimidinyl]-6-methyl-N-(phenylmethyl)-3-piperidinecarboxamide (370 mg, 0.99 mmol), 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (383 mg, 1.48 mmol, 1.5 equiv), tricyclohexylphosphine (42 mg, 0.5 mmol, 0.15 equiv), Pd2(dba)3 (68 mg, 0.07 mmol, 0.075 equiv) and K3PO4 (357 mg, 1.68 mmol, 1.7 equiv) were charged to a 30 mL microwave vial, followed by addition of 1,4-dioxane (4 mL) and water (1.33 mL). The mixture was bubbled with argon for 10 minutes, followed by capping and heating at 100° C. for 20 hours. This mixture was combined with another run starting with 200 mg of (3S,6R)-1-[6-chloro-2-(methylamino)-4-pyrimidinyl]-6-methyl-N-(phenylmethyl)-3-piperidinecarboxamide. The combined mixture was filtered through celite, and rinsed with EtOAc (50 mL). The filtrate was concentrated in vacuo, and the resulting residue was partitioned between EtOAc (75 mL) and brine (20 mL). The organic was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography using gradient elution of 1% A in CHCl3 to 50% A in CHCl3 (where A was a mixture of 800/80/3200 CH3OH/NH4OH/CHCl3). Trituration of the purified material in a mixture of CHCl3 (1 mL) and hexane (6 mL), and drying under vacuum at 65° C. afforded the title compound (312 mg) as a tan solid. LC-MS (ES) m/z=470 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 1.30 (d, J=6.8 Hz, 3H), 1.75-1.90 (m, 3H), 1.97-2.10 (m, 1H), 2.42-2.54 (m, 1H), 2.59 (s, 3H), 2.97 (s, 3H), 3.10-3.20 (m, 1H), 4.42 (s, 2H), 4.60-4.70 (bs, 1H), 4.75-4.85 (bs, 1H), 6.49 (s, 1H), 7.25-7.37 (m, 5H), 7.65 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.3 Hz, 1H), 8.02 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[C:6]=2[CH:17]=1.[Cu](C#N)[C:19]#[N:20].CN(C)C=O.Cl>[Fe](Cl)(Cl)Cl.O>[C:19]([C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[C:6]=2[CH:17]=1)#[N:20]
Reactant: N#C[Cu]C#N
Reactant: O=C1c2ccccc2CCc2ccc(Br)cc21
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2c(c1)C(=O)c1ccccc1CC2
Reaction time: 6 h

Procedure:
7.2 g. of 3-bromo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one, together with 2.7 g. of copper cyanide and 10 ml. of dimethylformamide, are heated to boiling under reflux conditions for 6 hours. The resulting hot solution is poured into a solution containing 10 g. of iron trichloride in 15 ml. of water and 3 ml. of concentrated hydrochloric acid, stirred at 70° C. for 20 minutes and extracted with toluene. The toluene extract is washed first with 3N hydrochloric acid and then with 3N caustic soda, dried over sodium sulfate and evaporated. The 3-cyano-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one which is obtained, is purified by adsorption on the 10-fold amount of Kieselgel (eluting agent: toluene); melting point 104°-106° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.O[C:49]1[C:54]([CH3:55])=[CH:53][CH:52]=[CH:51][C:50]=1[CH2:56][CH2:57][NH:58][C:59](=[O:61])[CH3:60]>>[C:59]([NH:58][CH2:57][CH2:56][C:50]1[CH:49]=[C:54]([CH3:55])[CH:53]=[CH:52][C:51]=1[O:33][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=3[O:2][CH3:1])=[CH:12][CH:13]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]1)(=[O:61])[CH3:60]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CC(=O)NCCc1cccc(C)c1O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccc(C)cc2CCNC(C)=O)cc1

Procedure:
Analogously to Method G, 0.45 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.26 g of N-[2-(2-hydroxy-3-methylphenyl)ethyl]acetamide are reacted. The title compound is obtained as a yellow oil. Rf=0.60 (EtOAc); Rt=5.78.
Reaction SMILES: [C:1]1([C:13]2[CH2:17][NH:16][C:15](=[O:18])[C:14]=2[C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[Mg].CO.Cl>CCOC(C)=O.O>[C:1]1([CH:13]2[CH2:17][NH:16][C:15](=[O:18])[CH:14]2[C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: O=C1NCC(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2ccccc12
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1NCC(c2cn3c4c(cccc24)CCC3)C1c1c[nH]c2ccccc12
Temperature: 60 °C

Procedure:
A mixture of 4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-(1H-indol-3-yl)-1,5-dihydro-pyrrol-2-one (95 mg, 270 μmol), magnesium turnings (1.3 g, 54 mmol) and methanol (15 mL) was heated at 60° C. for 3 h. Water was added to the reaction mixture and the pH adjusted to 1 with concentrated HCl. The mixture was extracted into EtOAc and washed with saturated sodium carbonate solution. The organics were dried (MgSO4), filtered and evaporated to yield a tan solid, which was titurated in hot EtOAc, yielding 4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-(1H-indol-3-yl)-pyrrolidin-2-one as a white solid (15 mg, 16%, cis/trans: 1/3.7 from 1H NMR). 1H NMR (400 MHz, CD3OD) trans-δ: 7.42 (d, J=7.2 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H), 7.06 (m, 1H), 7.00 (s, 1H), 6.95 (s, 1H), 6.93 (m, 1H), 6.82 (m, 2H), 4.14-4.05 (m, 4H), 3.85 (m, 1H), 3.71 (m, 1H), 2.90 (t, J=6.0 Hz, 2H), 2.12 (m, 2H). LCMS: m/e 356.13 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[C:16]([CH:18]=[CH2:19])[N:15]=[C:14]([CH3:20])[N:13]=2)[N:10]=[C:9]([CH3:21])[N:8]=1.Cl[CH:28](Cl)[B:29]1[O:33][C:32]([CH3:35])([CH3:34])[C:31]([CH3:37])([CH3:36])[O:30]1.[I-].[Li+]>O1CCCC1.[Cl-].[Cr+2].[Cl-]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[C:16]([CH:18]3[CH2:19][CH:28]3[B:29]3[O:33][C:32]([CH3:35])([CH3:34])[C:31]([CH3:37])([CH3:36])[O:30]3)[N:15]=[C:14]([CH3:20])[N:13]=2)[N:10]=[C:9]([CH3:21])[N:8]=1
Reactant: C=Cc1cc(-n2nc(C)nc2Cc2ccc(OC)c(OC)c2)nc(C)n1
Reactant: CC1(C)OB(C(Cl)Cl)OC1(C)C
Agent: [Cr+2]
Agent: [Cl-]
Agent: [I-]
Solvent: C1CCOC1
Product: COc1ccc(Cc2nc(C)nn2-c2cc(C3CC3B3OC(C)(C)C(C)(C)O3)nc(C)n2)cc1OC
Reaction time: 0.33 h

Procedure:
To a stirring slurry of chromium(II) chloride (630 mg, 5.12 mmol, 8.0 eq.) in dry tetrahydrofuran (10 ml) under nitrogen at 23° C. was added n,n,n′,n′-tetramethylethylenediamine (0.768 ml, 5.12 mmol, 8.0 eq.). The resulting blue reaction mixture was allowed to stir for 20 min. To the reaction mixture was added a solution of 4-(5-(3,4-dimethoxybenzyl)-3-methyl-1H-1,2,4-triazol-1-yl)-2-methyl-6-vinylpyrimidine (3-1, 225 mg, 0.640 mmol, 1.0.eq.) in tetrahydrofuran (2 mL) followed by a solution of 2-(dichloromethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (270 mg, 1.281 mmol, 2.0 eq.) and lithium iodide (343 mg, 2.56 mmol, 4.0 eq) in tetrahydrofuran (2 mL). The resulting greenish blue reaction mixture was allowed to stir for 72 h. The reaction mixture was filtered, concentrated, and partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated to afford 4-(5-(3,4-dimethoxybenzyl)-3-methyl-1H-1,2,4-triazol-1-yl)-2-methyl-6-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)pyrimidine (3-2). The crude material was carried forward with no purification. LRMS m/z (M+H) 492.5 found, 492.3 required
Reaction SMILES: O1CCCC1.[CH2:6]([C:9]1[C:10]([NH:35][C@H:36]2[CH2:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]2)=[N:11][C:12]2[N:13]([N:32]=[CH:33][CH:34]=2)[C:14]=1[N:15]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=1)[CH:7]=C.I([O-])(=O)(=O)=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>[Os](=O)(=O)(=O)=O.O>[C:28]([O:27][C:25]([N:15]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH3:24])=[CH:20][CH:21]=1)[C:14]1[N:13]2[C:12](=[CH:34][CH:33]=[N:32]2)[N:11]=[C:10]2[C:9]=1[CH:6]=[CH:7][N:35]2[C@H:36]1[CH2:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]1)=[O:26])([CH3:29])([CH3:30])[CH3:31]
Reactant: C=CCc1c(N[C@H]2CCCN(C(=O)OC(C)(C)C)C2)nc2ccnn2c1N(C(=O)OC(C)(C)C)c1ccc(OCC)cc1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c3ccn([C@H]4CCCN(C(=O)OC(C)(C)C)C4)c3nc3ccnn23)cc1

Procedure:
To a mixed solution of tetrahydrofuran (3.2 mL) and water (0.8 mL) containing tert-butyl (S)-3-{6-allyl-7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]pyrazolo[1,5-a]pyrimidin-5-ylamino}piperidine-1-carboxylate (375 mg, 0.632 mmol), sodium periodate (405 mg, 1.89 mmol) and osmium tetraoxide (2.5w/v % tert-butanol solution, 793 μL, 0.063 mmol) were added, and the mixture was stirred. After the reaction, aqueous sodium sulfite was added to the solution, and the mixture was extracted with ethyl acetate. The combined ethyl acetate layer was washed with brine and dried over sodium sulfate. After the sodium sulfate was filtered off, and the solvent was distilled off to obtain the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]([CH:10]([C:23]1[CH:24]=[C:25]([Si:28]([CH2:33][CH3:34])([CH2:31][CH3:32])[CH2:29][CH3:30])[O:26][CH:27]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[N+]=[N-]>C1COCC1>[NH2:7][CH:10]([C:23]1[CH:24]=[C:25]([Si:28]([CH2:33][CH3:34])([CH2:31][CH3:32])[CH2:29][CH3:30])[O:26][CH:27]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCC(N=[N+]=[N-])c1coc([Si](CC)(CC)CC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(N)c1coc([Si](CC)(CC)CC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of lithium aluminum hydride (a 1.0M solution in THF; 4.22 ml, 4.22 mmol) was added slowly to a solution of 4-(1-azidotridecyl)-2-triethylsilylfuran (1.55 g, 3.84 mmol) at 0 degrees C. under argon. After stirring at room temperature for 2 hours, the mixture was cooled to 0 degrees C. and quenched with 2M sodium hydroxide. Anhydrous sodium sulfate was added to coagulate the aluminum salt and the mixture was extracted thoroughly with ethyl acetate. Evaporation of the dried (magnesium sulfate) extracts gave an oil, which was purified by flash chromatography on silica using 5% methanol/dichloromethane to give the titled amine.
Reaction SMILES: C(O[C:4]([C:6]1[C:15](=S)[C:14]2[C:9](=[C:10]([Cl:17])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:21][CH:20]=2)[N:7]=1)=[O:5])C.C(=O)([O-])[O-].[K+].[K+].[CH3:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[NH:43][NH2:44]>COCCOC.O>[Cl:17][C:10]1[C:9]2[N:8]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([N:25]4[CH:29]=[CH:28][CH:27]=[N:26]4)=[CH:23][CH:24]=3)[N:7]=[C:6]3[C:4](=[O:5])[N:43]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[CH3:36])[N:44]=[C:15]3[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccccc1NN
Reactant: CCOC(=O)c1nn(Cc2ccc(-n3cccn3)cc2)c2c(Cl)cccc2c1=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccccc1-n1nc2c3cccc(Cl)c3n(Cc3ccc(-n4cccn4)cc3)nc-2c1=O
Temperature: 92 °C

Procedure:
Ethyl-8-chloro-1-[4-(1H-pyrazol-1-yl)benzyl]-4-thioxo-1,4-dihydrocinnoline-3-carboxylate (48 mg, 0.113 mmol), potassium carbonate (78 mg, 0.56 mmol, 5 equiv), and 2-methylphenyl hydrazine (23 mg, 0.19 mmol, 1.7 equiv) were combined in 1,2-dimethoxyethane (2 mL) and heated to 92° C. for 2 hours. The mixture was cooled to ambient temperature, diluted with water (20 mL) and extracted with ethyl acetate (3×40 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (100:0 to 94:6; chloroform:methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.24 (1H, d, J=7.2 Hz), 7.88 (1H, s), 7.71-7.61 (4H, m), 7.47-7.42 (3H, m), 7.37-7.30 (3H, m), 7.29 (1H, s), 6.4 (1H, m), 6.34 (2H, s), 2.36 (3H, s), ppm; high resolution mass spectrometry (ES+) m/z 467.1388 [(M+H)+; calculated for C26H20ClN6O: 467.1382].
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1.[CH3:32][O-:33].[Na+].O>CO>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:22]2[S:23][CH:24]=[C:20]([CH2:19][S:18][C:4]3[C:5]([C:16]#[N:17])=[C:6]([N:10]4[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]4)[C:7]([C:8]#[N:9])=[C:2]([O:33][CH3:32])[N:3]=3)[N:21]=2)=[CH:26][CH:27]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1N1CCCCC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(N2CCCCC2)c1C#N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
100.0 mg (0.21 mmol) of the compound from Example 4A are initially charged in 2 ml of dry methanol. 12.2 mg (0.23 mmol) of sodium methoxide are added to this solution, and the mixture is stirred at +65° C. for 20 h. After cooling to RT the reaction mixture is stirred into 2 ml of water and stirred at RT for 1 h. The precipitate that is formed is filtered off with suction and washed with 1 ml of cold water. Purification is carried out by preparative HPLC (column: YMC GEL ODS-AQ S-5, 15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([CH:13]=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].Br[C:18]1[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:20][N:21]([CH3:23])[CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:23][N:21]1[CH:22]=[C:18]([C:13]2[N:8]3[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]3=[N:15][C:14]=2[CH3:16])[C:19]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:20]1
Reactant: CCC(CC)c1cc(C)nn2cc(C)nc12
Reactant: Cn1cc(Br)c(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCC(CC)c1cc(C)nn2c(-c3cn(C)nc3-c3ccccc3)c(C)nc12
Temperature: 130 °C
Yield: 6.4 %

Procedure:
8-(1-Ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (160 mg, 0.73 mmol), 4-bromo-1-methyl-3-phenyl-1H-pyrazole (250 mg, 1.1 mmol) and cesium carbonate (490 mg, 1.50 mmol) are stirred in DMF (5 ml) and degassed by bubbling a stream of nitrogen through the mixture. PdCl2(PPh3)2 (15 mg) is added and the mixture is heated to 130° C. overnight. The mixture is added to water and extracted twice with ethyl acetate. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude product is purified by chromatography using a hexane-ethyl acetate gradient (100% hexane to 50% ethyl acetate in hexane) to elute the title compound (17.5 mg, 4% yield). ES-MS (m/z): calc'd for C23H27N5: 373.5; found 374.2 (M+H)+. 1H NMR (400 mHz, CDCl3): δ 7.68 (s, 1H), 7.37 (m, 2H), 7.20 (m, 3H), 6.59 (s, 1H), 4.04 (s, 3H), 3.36 (m, 1H), 2.38 (s, 3H), 2.15 (s, 3H), 1.82 (m, 4H), 0.86 (t, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]3[CH:21]=[C:20](Cl)[N:19]=[C:18]([CH3:23])N=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].N1C=CC=C[CH:25]=1>C1COCC1.[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]3[CH:23]=[CH:18][N:19]=[C:20]([CH3:25])[CH:21]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: c1ccncc1
Reactant: COC(=O)c1cccc2cc(Oc3cc(Cl)nc(C)n3)ccc12
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1cccc2cc(Oc3ccnc(C)c3)ccc12

Procedure:
9.7 g (29.5 mMol) 6-(6-chloro-2-methyl-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid methyl ester in 950 ml THF and 24 ml (0.30 Mol) pyridine is hydrogenated in presence of 1.9 g Pd/C (10%, Engelhard 4505) during 15 h. The mixture is filtered, the solid washed extensively with THF and the filtrate concentrated. The residue is re-dissolved in EtOAc and 5% citric acid, the aq. layer separated off and extracted with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated to the title compound: HPLC: tRet=12.8.
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[F:14][C:15]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:16]=1[CH2:17][Mg]Cl>[Pd]>[F:14][C:15]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:16]=1[CH2:17][CH:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: Fc1ccc(C[Mg]Cl)c(F)c1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Agent: [Pd]
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(F)cc1F

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.50 g, 2.8 mmol) was reacted with 2,4-difluorobenzylmagnesium chloride (0.25 M in diethyl ether, 28 mL, 7 mmol) according to General Procedure 3. The resulting exo-olefin ((E)-methyl 4-(2,4-difluorobenzylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate) was then converted to the title compound by hydrogenation according to General Procedure 6 (with 5% Pd/C). The crude product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-20% EtOAc/heptane to afford the title compound: 0.062 g. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.05-2.15 (m, 1H), 2.55-2.65 (m, 1H), 2.65-2.75 (m, 2H), 2.79 (d, J=7.4, 2H), 3.25-3.35 (m, 1H), 3.81 (s, 3H), 6.38 (d, J=1.4 Hz, 1H), 6.78-6.90 (m, 2H), 7.10-7.15 (m, 1H).