Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24](I)[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:38](N)[CH2:39]C.C[Si](C#C)(C)C>C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([C:38]#[CH:39])[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCN
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(I)c(Cl)cc3[nH]c2=O)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C#C[Si](C)(C)C
Solvent: CCOCC
Product: C#Cc1cc2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c(-c3cc(C)cc(C)c3)c(=O)[nH]c2cc1Cl
Temperature: 95 °C

Procedure:
To a suspension of 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-iodo-2-oxo- 1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (EXAMPLE 4.2 Step B, 200 mg in 3 mL N,N-dimethylformamide) was added tetrakis(triphenylphosphine)palladium (18 mg) followed by copper(I) iodide (30 mg), n-propylamine (0.26 mL) and trimethylsilylacetylene (0.45 mL) and the mixture sealed in a thick-walled tube. This was heated to 95° C. on an oil bath for 10 hours, then cooled to room temperature and diluted with diethyl ether. This was washed successively with water and brine and the combined organics dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane, 30:70; then 40:60) gave a mixture of the title compound and the corresponding trimethylsilyl derivative (155 mg). This material was converted to the title compound by treatment with 4.4 mg of potassium carbonate in 2 mL methanol. After 1 hour, the mixture was diluted with methylene chloride, washed with half-saturated sodium chloride, then brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane, 30:70; then 40:60) gave the title compound (127 mg).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18].C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:15]=[CH:14][C:13]([NH:16][S:26]([C:23]3[CH:24]=[CH:25][C:20]([CH:17]([CH3:19])[CH3:18])=[CH:21][CH:22]=3)(=[O:28])=[O:27])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCN(c2ccc(N)cn2)CC1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN1CCN(c2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.4 g (7.97 mmol) of 6-(4-allylpiperazin-1-yl)pyridin-3-ylamine from Example 1.2 and 1.74 g (7.97 mmol) of 4-isopropylbenzenesulfonyl chloride were dissolved in 30 ml of tetrahydrofuran at room temperature. 3.3 ml (23.91 mmol) of triethylamine were then added to this mixture. After that, the reaction mixture was stirred overnight at room temperature. After the solvent had been evaporated to dryness, water was added to the residue. The aqueous reaction mixture was made acid with 1N hydrochloric acid and extracted twice with diethyl ether. After that, the aqueous phase was made alkaline (pH 9-10) with a 1N aqueous solution of sodium hydroxide and then extracted twice with diethyl ether. After the combined organic phases had been dried over sodium sulfate, the drying agent had been filtered off and the solvent had been evaporated down to dryness, the resulting residue was chromatographed on silica gel using cyclohexane/ethyl acetate (45:55% to 100% ethyl acetate). The filtrate was evaporated down to dryness. The resulting residue was thoroughly stirred in 10 ml of heptane, filtered off in suction and dried, with 1.93 g (61% of theory) of the title compound being obtained.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:30]([OH:42])(=[O:41])[CH2:31][C:32]([CH2:37][C:38]([OH:40])=[O:39])([C:34]([OH:36])=[O:35])[OH:33].CO>O>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:30]([O-:42])(=[O:41])[CH2:31][C:32]([CH2:37][C:38]([O-:40])=[O:39])([C:34]([O-:36])=[O:35])[OH:33]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: O
Solvent: CO
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Temperature: 25 °C

Procedure:
Sunitinib (2.25 g, 5.65 mmol) and citric acid (1.09 g, 5.65 mmol) were dissolved while heating in the mixture of methanol (100 ml) and water (10 ml). The solution was left to cool to room temperature to give sunitinib citrate. Melting point: 168-173° C. (Form I).
Reaction SMILES: [OH-].[K+].[I:3][C:4]1[CH:5]=[C:6]([CH:9]=[O:10])[NH:7][CH:8]=1.Br[CH2:12][CH2:13][OH:14].C(O)(=O)C>O1CCOCC1>[OH:14][CH2:13][CH2:12][N:7]1[CH:8]=[C:4]([I:3])[CH:5]=[C:6]1[CH:9]=[O:10]
Reactant: OCCBr
Reactant: O=Cc1cc(I)c[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=Cc1cc(I)cn1CCO
Temperature: 60 °C
Yield: 50 %

Procedure:
Potassium hydroxide (3.1 g, 54.3 mmol) was added to a stirred solution of 4-iodo-1H-pyrrole-2-carbaldehyde (4.0 g, 18.1 mmol) in dioxane (20 mL). 2-Bromo-ethanol (2.56 mL, 36.2 mmol) was added to the reaction mixture and heated at 60° C. for 16 h. The reaction mixture was cooled to room temperature and the pH was adjusted to ˜6 by the addition of acetic acid. The reaction mixture was then concentrated in vacuo to give a residue which was partitioned between water and ethyl acetate. The organic phase was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue which was purified by column chromatography over silica gel (100-200 mesh) using 10% ethyl acetate in petroleum ether as eluent to afford 1-(2-hydroxyethyl)-4-iodo-pyrrole-2-carbaldehyde (2.4 g, 50%) as a colourless solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([OH:19])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CO>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([O:19][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)[C@@H]1C[C@H](O)C(=O)[C@@H]2[C@@]3(C)C[C@@H](c4ccoc4)OC(=O)[C@H]3CC[C@]21C
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](OC(=O)c2ccccc2)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Yield: 93.3 %

Procedure:
A solution of 8a (0.05 g, 0.13 mmol), benzoyl chloride (0.09 g, 0.92 mmol) and a catalytic amount of DMAP in CH2Cl2 (20 mL) was stirred at room temperature for 2 h. Absolute MeOH (15 mL) was added and the solvent was removed under reduced pressure. CH2Cl2 (25 mL) was added to the residue and the solution was washed with 10% HCl (3×20 mL) and saturated NaCl (3×20 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure afforded 13 (0.06 g, 98%) as a white solid, mp 165-170° C.; 1H NMR (CDCl3): δ 1.18 (3H, s, H-19); 1.47 (3H, s, H-20); 1.50-1.75 (4H, m, H-6β, H-7α,β and H-11β); 1.84 (1H, ddd, J=3.0, 3.0, 9.9 Hz, H-6α); 2.11 (1H, dd, J=2.4, 10.8 Hz, H-8); 2.26 (1H, s, H-10); 2.47 (2H, m, H-3α,β); 2.55 (1H, dd, J=5.1, 13.5 Hz, H-11α); 2.84 (1H, dd, J=6.9, 9.9 Hz, H-4); 3.75 (3H, s, CO2CH3); 5.40 (1H, dd, J=9.6, 10.5 Hz, H-2); 5.52 (1H, dd, J=2.1, 11.7 Hz, H-12); 6.39 (1H, dd, J=0.9, 1.8 Hz, H-14); 7.40 (1H, dd, J=1.5, 1.8 Hz, H-15); 7.42 (1H, dd, J=0.9, 1.5 Hz, H-16); 7.48 (2H, dt, J=7.2, 7.5 Hz, Ar-meta-H); 7.60 (1H, tt, J=1.2, 7.5 Hz, Ar-para-H); 8.09 (2H, dt, J=1.2, 7.2 Hz, Ar-ortho-H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=1.[CH:20]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[CH3:1][O:2][C:3]1[C:8]([CH3:20])=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:5][C:4]=1[C:13]1[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=1
Reactant: CC(C)[N-]C(C)C
Reactant: COc1cc(C(F)(F)F)ccc1C1=NC(C)(C)CO1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1c(C2=NC(C)(C)CO2)ccc(C(F)(F)F)c1C
Reaction time: 0.17 h

Procedure:
To a solution of 5.465 g (20 mmol) 2-(2-methoxy-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole in 60 ml dry THF were added at <−60° C. 11.0 ml (22 mmol) lithium diisopropylamide solution 2M in THF/heptanes/ethylbenzene and the mixture stirred for 1.5 h at <−60° C. To the resulting dark brown solution were added 2.5 ml (40 mmol) iodomethane drop wise over 10 min (exothermal, Ti<−48° C.). The resulting light brown solution was stirred at <−50° C. for 2.5 h then quenched with sat. aq. NH4Cl solution and extracted three times with tert-butyl methyl ether. The combined organic phases were washed 3× with brine, dried over Na2SO4, filtered and evaporated: 7.002 g yellow solid: which was purified by flash-chromatography on silica gel with heptane and 5 to 10% AcOEt over 25 min and heptane/AcOEt 90:10 for 20 min to provide the title compound as a light yellow oil. MS (m/e): 288.12 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)O)=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[NH4+].[Cl-]>C(Cl)Cl.O>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([C:16]([F:19])([F:17])[F:18])[CH:4]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: OC(c1ccccc1)c1ccc(Br)c(C(F)(F)F)c1
Agent: CC[SiH](CC)CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1cc(Cc2ccccc2)ccc1Br
Temperature: 25 °C
Yield: 84 %

Procedure:
To a solution of (4-bromo-3-(trifluoromethyl)phenyl)(phenyl)methanol (168 mg, 0.507 mmol) in 0.34 mL of anhydrous DCM (C=1.5M), were successively added dropwise trifluoroacetic acid (195 μL, 5 eq) and triethylsilane (243 μL, 3 eq). After 1 h45 of stirring at r.t., the reaction mixture was hydrolyzed with a saturated NH4Cl solution (5 mL). The layers were diluted with 20 mL of DCM and 20 mL of water and then separated. The aqueous layer was extracted with DCM (3×10 mL) The combined organic phase was washed with a saturated NaHCO3 solution (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel flash chromatography (cyclohexane) to afford the desired product in 84% yield (135 mg) as uncoloured oil. 1H NMR (300 MHz, CDCl3) δ 7.62 (d, J=8.2 Hz, 1H), 7.54 (d, J=2.0 Hz, 1H), 7.34 (tt, J=7.9, 1.8 Hz, 2H), 7.26 (t, J=7.3 Hz, 1H), 7.22-7.15 (m, 3H), 4.00 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 141.0 (C), 139.5 (C), 135.1 (CH), 133.6 (CH), 130.2 (q, J=31.3 Hz, C), 129.0 (CH), 128.9 (CH), 128.4 (q, J=5.4 Hz, CH), 126.8 (CH), 123.1 (q, J=273.4 Hz, C), 117.5 (q, J=1.9 Hz, C), 41.3 (CH2).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:23]=[CH:22][C:6]([C:7]([C:9]2[C:17]([Cl:18])=[C:16]([Cl:19])[C:15]([Cl:20])=[C:14]([Cl:21])[C:10]=2[C:11]([OH:13])=O)=[O:8])=[CH:5][CH:4]=1.[CH2:25]([N:27]([CH2:39][CH3:40])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])[CH:29]=1)[CH3:26].C(OC(=O)C)(=O)C>CO>[CH2:35]([N:34]([CH2:37][CH3:38])[C:30]1[CH:29]=[C:28]([N:27]([CH2:25][CH3:26])[CH2:39][CH3:40])[CH:33]=[CH:32][C:31]=1[C:7]1([C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:24])[CH3:1])=[CH:23][CH:22]=2)[C:9]2[C:10](=[C:14]([Cl:21])[C:15]([Cl:20])=[C:16]([Cl:19])[C:17]=2[Cl:18])[C:11](=[O:13])[O:8]1)[CH3:36]
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Reactant: CN(C)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)cc1
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc(C2(c3ccc(N(C)C)cc3)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c(N(CC)CC)c1
Temperature: 91 °C

Procedure:
A mixture of 2-(4-(dimethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid (16.28 g.), N,N,N',N'-tetraethyl-m-phenylenediamine (9.68 g.) and acetic anhydride (10 ml.) was heated (at 91° C.) during two hours. Addition of methanol (20 ml., then 12 ml., then 10 ml.) afforded 3-(2,4-bis(diethylamino)phenyl)-3-(4-(dimethylamino)phenyl)-4,5,6,7-tetrachlorophthalide (I: X= (CH3CH2)2N, Y2 = H, Y4 = (CH3)2N, Z4 = Z5 = Z6 = Z7 = Cl) in three fractions (m.p. 174°- 176° C., m.p. 180° -181° C. and m.p. 180° -181° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.Cl[C:37]1[CH:38]=[CH:39][C:40]2[O:53][CH2:52][N:43]3[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:49]=4[C:50]([F:51])=[C:42]3[C:41]=2[N:54]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.CCOC(C)=O.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]>[F:51][C:50]1[C:49]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[N:43]2[CH2:52][O:53][C:40]3[CH:39]=[CH:38][C:37]([C:18]4[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][C:10]5[O:9][C:8]([C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=6)=[C:12]([C:13]([NH:15][CH3:16])=[O:14])[C:11]=5[CH:17]=4)=[N:54][C:41]=3[C:42]=12
Reactant: Fc1c2n(c3ccccc13)COc1ccc(Cl)nc1-2
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3c(F)c5ccccc5n3CO4)cc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a degassed solution of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (110 mg, 0.22 mmol), 2-chloro-12-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (60 mg, 0.220 mmol) and K3PO4 (176 mg, 0.66 mmol) in dioxane/H2O (0.8 mL/0.2 mL) was added Pd2(dba)3 (10 mg, 0.01 mmol) and X-Phos (10 mg, 0.02 mmol) under N2. The mixture was heated to 80° C. and then stirred for 1 hour. The reaction mixture was cooled to RT, diluted with EtOAc and filtered. The filtrate was washed with H2O, brine, dried over Na2SO4. After concentrated, the resulting residue was purified using prep-TLC (petroleum ether:EtOAc=1:1) to provide the desired product of compound 58 (60 mg, yield: 44.4%). 1H-NMR (CDCl3, 400 MHz) δ 7.94˜8.00 (m, 3H), 7.66˜7.68 (m, 2H), 7.46 (s, 2H), 7.29˜7.35 (m, 2H), 7.19 (t, J=8.4 Hz, 3H), 6.02 (s, 1H), 5.91 (s, 2H), 3.39 (s, 3H), 2.98 (d, J=4.8 Hz, 3H), 2.70 (s, 3H). MS (M+H)+: 615.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([N:15]3[CH2:21][CH:20]4[N:22]([CH3:23])[CH:17]([CH2:18][CH2:19]4)[CH2:16]3)=[O:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:24]([N:26]=[C:27]=[O:28])[CH3:25].[OH-].[Na+]>CO>[CH2:24]([NH:26][C:27]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([N:15]3[CH2:21][CH:20]4[N:22]([CH3:23])[CH:17]([CH2:18][CH2:19]4)[CH2:16]3)=[O:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)=[O:28])[CH3:25]
Reactant: CCN=C=O
Reactant: CN1C2CCC1CN(C(=O)c1ccc(-c3ccc(N)cc3)o1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCNC(=O)Nc1ccc(-c2ccc(C(=O)N3CC4CCC(C3)N4C)o2)cc1

Procedure:
To a mixture of [5-(4-amino-phenyl)-furan-2-yl]-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-methanone (0.44 g, 1.41 mmol) and methanol (30 ml) was added: ethylisocyanate (291 mg, 4.08 mmol) at −50° C. and then allowed to reach room temperature. Aqueous sodium hydroxide (5 ml, 1M) was added and the mixture was extracted twice with dichloromethane (2×10 ml). Chromatography on silica gel with dichloromethane, 10% methanol and 1% aqueous ammonia as solvent gave the title compound. Yield 519 mg (96%). The corresponding salt was obtained by addition of a diethyl ether and methanol mixture (9:1) saturated with fumaric acid. Mp. 183.6-186.4° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[S:10][CH:9]=2)=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:20][CH2:21][CH3:22]>CN(C)C=O>[CH2:20]([N:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[C:8]1[C:16]2[C:11](=[CH:12][N:13]=[CH:14][CH:15]=2)[S:10][CH:9]=1)[CH2:21][CH3:22]
Reactant: CCCBr
Reactant: c1cc(Nc2csc3cnccc23)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(c1ccncc1)c1csc2cnccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
3-(4-Pyridinylamino)thieno[2,3-c]pyridine (4 g) was added portionwise as a powder to a suspension of sodium hydride (60% oil dispersion, 0.8 g washed with heptane) in 50 mL of dimethylformamide. After anion formation was completed 1-bromopropane (2.2 g) was added. After stirring one hour the reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic extract was washed with water saturated sodium chloride, and then was dried (anhydrous magnesium sulfate), filtered and evaporated to 5 g of a dark oil. Elution through silica with 5% methanol in ethyl acetate via flash column chromatography afforded 3.5 g of a yellow solid. Elution through alumina with ether via column chromatography afforded 2.8 g of a yellow solid. Recrystallization from heptane afforded 2.6 g (54.8%) of yellowish crystals, m.p. 119°-120° C.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:8]=1[C:9](N(OC)C)=[O:10]>C1COCC1.C(OCC)C>[Cl:6][C:7]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:8]=1[C:9]([CH:1]1[CH2:3][CH2:2]1)=[O:10]
Reactant: Br[Mg]C1CC1
Reactant: CON(C)C(=O)c1ccc(C)cc1Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)C2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.7 ml (7.65 mmol) of a 1N cyclopropylmagnesium bromide solution in THF were added to 1.09 g (5.10 mmol) of the compound from Example 121A in 19 ml of diethyl ether, and the mixture was stirred at RT overnight. A further 7.7 ml (7.65 mmol) of a 1N cyclopropylmagnesium bromide solution in THF were added, and the mixture was stirred at RT overnight. The reaction mixture was added to ice-water and extracted with dichloromethane, the organic phase was dried over magnesium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient) to result in 326 mg (33% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([I:13])=[N:10][C:9]=1[C:14]([OH:16])=O.C1C=CC2N(O)N=[N:23]C=2C=1.CCN=C=NCCCN(C)C.[NH4+].[OH-]>C(Cl)Cl.CN(C=O)C.O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([I:13])=[N:10][C:9]=1[C:14]([NH2:23])=[O:16]
Reactant: O=C(O)c1nc(I)oc1-c1ccccc1Cl
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)c1nc(I)oc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of 5-(2-chlorophenyl)-2-iodo-1,3-oxazole-4-carboxylic acid (20.0 g, 57.3 mmol) in DCM (400 mL) and DMF (200 mL) were added HOBt (8.0 g, 60.0 mmol) and EDCI (15.0 g, 80.0 mmol). The reaction mixture was allowed to stir at rt for 2 h and then NH4OH (20 mL) in 1,4-dioxane (400 mL) was added. The reaction mixture was allowed to stir at rt overnight and then was diluted with EtOAc and washed with brine. The organic solution was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give 5-(2-chlorophenyl)-2-iodo-1,3-oxazole-4-carboxamide (18.0 g, 85%).
Reaction SMILES: [CH2:1]([C:5]1([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[OH:15])[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4].Cl[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([C:5]1([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCCC)CCc2c(O)cccc2C1=O
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC1(CCCC)CCc2c(OCc3ccc4ccccc4n3)cccc2C1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 77.7 %

Procedure:
A mixture of 2,2-dibutyl-3,4-dihydro-5-hydroxy-1(2H)-naphthalenone (2.643 g), 2-chloromethylquinoline (1.7 g), and potassium carbonate (1.67 g) in N,N-dimethylformamide (16 ml) was stirred at 80° C. for 4 hours. The cooled mixture was poured into water. The separated oil was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried, and concentrated in vacuo. The crude product was chromatographed on silica gel using 25% ethyl acetate in n-hexane as eluent to yield 2,2-dibutyl-3,4-dihydro-5-(2-quinolylmethoxy)-1(2H)-naphthalenone (3.09 g) as a pale yellow syrup.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH3:23])([CH3:22])[C:15](=[O:21])[N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>ClCCl.C(OCC)C>[ClH:24].[CH3:23][C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)([CH3:22])[C:15]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCN(C(C)(C)C(=O)N2CCCC2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C(=O)N1CCCC1)N1CCNCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-(1,1-dimethyl-2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.745 g) in dichloromethane (10 mL) was added 2M hydrogen chloride in diethyl ether (4 mL) and the mixture stirred at room temperature for 12 hours. The solvent was evaporated to give 2-methyl-2-piperazin-1-yl-1-pyrrolidin-1-yl-propan-1-one hydrochloride salt as a beige solid. Reductive amination with 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde using the standard method in the presence of triethylamine gave the title compound as a white solid (0.355 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(N(CC)CC)C.[CH3:17][N:18]1[C:22]([C:23](Cl)=[O:24])=[CH:21][C:20]([CH3:26])=[N:19]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O.CO>[OH:9][C:4]1[CH:3]=[C:2]([NH:1][C:23]([C:22]2[N:18]([CH3:17])[N:19]=[C:20]([CH3:26])[CH:21]=2)=[O:24])[CH:7]=[C:6]([CH3:8])[CH:5]=1
Reactant: Cc1cc(N)cc(O)c1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: Cc1cc(O)cc(NC(=O)c2cc(C)nn2C)c1
Yield: 96.4 %

Procedure:
To a solution of 3-amino-5-methylphenol (4.32 g, 35.1 mmol) and triethylamine (5.20 mL, 37.4 mmol) in tetrahydrofuran (40 mL) was added dropwise with stirring under ice-cooling a solution of 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (5.85 g, 36.9 mmol) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 10 hr. Methanol (40 mL), water (40 mL) and saturated aqueous sodium carbonate solution (20 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 7 hr. The reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=100/0→50/50) to give the title compound (8.30 g, 96%) as a pale-yellow oil.