Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])=[N:17][CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:47][CH2:48][CH2:49][N:50]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH:51]1[CH2:57][C:54]2([CH2:56][CH2:55]2)[O:53][CH2:52]1)(=O)=O>CN(C)C(=O)C>[CH2:55]1[C:54]2([CH2:57][CH:51]([N:50]([CH2:49][CH2:48][CH2:47][O:1][C:2]3[CH:11]=[C:10]4[C:5]([C:6]([O:12][C:13]5[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]6[C:23](=[O:35])[N:24]([C:29]7[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=7)[N:25]([CH3:28])[C:26]=6[CH3:27])=[O:21])=[N:17][CH:18]=5)=[CH:7][CH:8]=[N:9]4)=[CH:4][CH:3]=3)[C:58]([O:60][C:61]([CH3:63])([CH3:62])[CH3:64])=[O:59])[CH2:52][O:53]2)[CH2:56]1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(O)ccc34)cn2)c(=O)n(-c2ccccc2)n1C
Reactant: CC(C)(C)OC(=O)N(CCCOS(C)(=O)=O)C1COC2(CC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCCN(C(=O)OC(C)(C)C)C5COC6(CC6)C5)ccc34)cn2)c(=O)n(-c2ccccc2)n1C
Temperature: 40 °C
Reaction time: 48 h
Yield: 63.1 %

Procedure:
To a solution of N-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide (200.6 mg, 0.44 mmol) and cesium carbonate (684.6 mg, 2.1 mmol, Aladdin) in N,N-dimethylacetamide (1 mL) was added (N-(4-oxaspiro[2.4]heptane-6-yl)-tert butoxycarbonylamino)propyl methanesulfonate (0.63 mmol) in N,N-dimethylacetamide (5 mL). After stirring at 40° C. for 2 days, the reaction mixture was concentrated in vacuo. The residue was chromatographed with a silica gel column (1:4 (v/v) n-hexane/EtOAc) to give the title compound as a white solid (200 mg, 62.5%).
Reaction SMILES: C([O:3][C:4](=[O:18])[CH:5]([CH:11]1[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12]1)C(OCC)=O)C.O=C1C(CCC)CCC(CC(O)=O)C1>>[O:17]=[C:13]1[CH2:14][CH2:15][CH2:16][CH:11]([CH2:5][C:4]([OH:18])=[O:3])[CH2:12]1
Reactant: CCOC(=O)C(C(=O)OCC)C1CCCC(=O)C1
Agent: CCCC1CCC(CC(=O)O)CC1=O
Product: O=C(O)CC1CCCC(=O)C1
Yield: 70 %

Procedure:
Step 2 (3-Oxo-cyclohexyl)-acetic acid was prepared in 70% yield from 2-(3-oxo-cyclohexyl)-malonic acid diethyl ester by the method described above for the synthesis of (3-oxo-4-propyl-cyclohexyl)-acetic acid: 1H NMR (300 MHz, CDCl3) δ 2.58-1.92 (m, 7H), 1.80-1.61 (m, 1H), 1.52-1.42 (m, 1H); ESI MS m/z 155 [M−H]−.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C(N(CC)C(C)C)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([CH:12]=[CH:11][C:10]([O:14][CH2:15][CH3:16])=[O:13])=[C:3]([F:9])[CH:4]=1
Reactant: Nc1ccc(Br)c(F)c1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(N)cc1F
Temperature: 110 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
4-Bromo-3-fluoroaniline (5.0 g) was dissolved in a mixed solvent of DMF (18 ml) and N,N-diisopropylethylamine (18 ml). Ethyl acrylate (3.9 ml), palladium acetate (295 mg), and tris(2-methylphenyl) phosphine (3.2 g) were added to the obtained mixture in a nitrogen atmosphere, and the mixture was stirred at 110° C. for 5 hours. The reaction mixture was filtered through Celite and separated with ethyl acetate and water. The organic layer was washed with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (14-25% ethyl acetate/n-hexane). The purified material was crystallized with n-hexane to obtain Compound 2a (4.2 g, 76%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17]CC4C=CC=CC=4)[CH:12]=3)=[C:9]([CH2:25][CH3:26])[N:8]([C@@H:27]3[CH2:30][C@H:29]([CH2:31]O)[CH2:28]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:33]1([CH3:43])[CH:38]=[CH:37][C:36](S(Cl)(=O)=O)=[CH:35][CH:34]=1.[CH3:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>>[CH2:43]([O:17][C:13]1[CH:12]=[C:11]([C:10]2[C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([C@H:27]3[CH2:28][C@@H:29]([CH2:31][N:48]4[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]4)[CH2:30]3)[C:9]=2[CH2:25][CH3:26])[CH:16]=[CH:15][CH:14]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1CCNCC1
Reactant: CCc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@@H](CO)C1
Product: CCc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@@H](CN2CCN(C)CC2)C1

Procedure:
The title compound is prepared in analogy to Example 116 from cis-{3-[4-amino-5-(3-benzyloxy-phenyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}-methanol of Example 124, p-toluenesulfonyl chloride and N-methyl-piperazine. Analytical HPLC-MS: tR=1.40 min (Grad 1); ES-MS: m/eo=511.45.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[N:5]=[CH:4][C:3]=1[C:14]([NH2:16])=[O:15].[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25](OC)=O.[O-]CC.[Na+].O>C(O)C.C(OCC)(=O)C>[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25]1[NH:16][C:14](=[O:15])[C:3]2[CH:4]=[N:5][N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH3:13])[C:2]=2[N:1]=1
Reactant: COC(=O)Cc1ccccc1Br
Reactant: Cc1ccccc1-n1ncc(C(N)=O)c1N
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccccc1-n1ncc2c(=O)[nH]c(Cc3ccccc3Br)nc21
Temperature: 25 °C

Procedure:
2.0 g (9.25 mmol) of 5-amino-1-(2-methylphenyl)-1H-pyrazole-4-carboxamide (Example 25A) and 9.5 g (41.62 mmol) of methyl (2-bromophenyl)acetate are dissolved in 30 ml of absolute ethanol under argon, and 3.15 g (46.6 mmol) of sodium ethoxide are added. The reaction mixture is heated to a reflux overnight. Cooling to room temperature is followed by hydrolysis with 50 ml of water and subsequent extraction with ethyl acetate (2×50 ml). The combined organic phases are dried over sodium sulphate, and the solvent is distilled off under reduced pressure. The crude product is then purified by column chromatography (silica gel; mobile phase cyclohexane/ethyl acetate, gradient 10:1→1:1). 3.01 g (82% of theory) of the product are obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[CH:14]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.N1C=CC=CC=1>O>[CH:14]1([NH:22][C:11]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[O:12])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NC1CCCCCCC1
Reactant: O=C(Cl)c1cnc2ccccc2n1
Solvent: c1ccncc1
Solvent: O
Product: O=C(NC1CCCCCCC1)c1cnc2ccccc2n1
Yield: 39.2 %

Procedure:
Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), cyclooctylamine (123 μL, 114 mg, 0.90 mmol), pyridine (5 mL), and water (100 mL) yielding 100 mg (39%) of (228):
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12](O)([CH3:15])([CH3:14])[CH3:13].C(N(C1C=CN=CC=1)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(CC(=O)O)cc1
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN(CC)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(CC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
450 g (3 mol) of 4-methylphenyl-acetic acid (Aldrich), 1.13 l (12 mol) of tert-butanol and 90 g (0.74 mol) of 4-(N,N-diethylamino)pyridine are dissolved in 2 l of dichloromethane. After addition of 680 g (3.3 mol of dicyclohexylcarbodiimide, dissolved in 400 ml of dichloromethane, the mixture is stirred at 25° C. for 20 h, the precipitated urea is filtered off with suction and washed with 200 ml of dichloromethane, and the organic phase is washed twice each with 500 ml of 2 M hydrochloric acid and water. The organic phase is concentrated and distilled.
Reaction SMILES: [C:1]1(Cl)[C:8](Cl)=[C:7](Cl)[C:5](=O)[C:3](=[O:4])[C:2]=1Cl.[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([CH:28]=[C:29]([OH:32])[C:30]=1[OH:31])[C:24](OC)=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C[CH2:34][O:35]CC>>[CH2:13]([O:20][C:21]1[C:30](=[O:31])[C:29](=[O:32])[CH:28]=[C:23]([C:24]2[C:2]([C:3]([O:35][CH3:34])=[O:4])=[CH:1][CH:8]=[CH:7][CH:5]=2)[CH:22]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1cc(O)c(O)c(OCc2ccccc2)c1
Reactant: O=C1C(=O)C(Cl)=C(Cl)C(Cl)=C1Cl
Reactant: CCOCC
Product: COC(=O)c1ccccc1C1=CC(=O)C(=O)C(OCc2ccccc2)=C1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
To a solution of orthochloranii (1.97 g, 8.02 mmol) in 5 mL of Et2O cooled to −30° C. was added dropwise via an addition funnel over 6 h a solution of methyl 3-benzyloxy-4,5-dihydroxybenzoate (2.0 g, 7.3 mmol) in 115 mL of Et2O. The reaction was stirred for a further 0.5 h at −30° C. and then stored at −20° C. for 20 h. The precipitated red solid was collected by filtration, washed with cold Et2O and dried on a vacuum pump to afford 1.11 g (55%) of the orthoquinone. IR (CDCl3) 1727, 1671 cm−1; 1H NMR (CDCl3, 300 MHz) δ 7.41-7.26 (m. 5H), 6.74 (s. 1H), 6.73 (s, 1H1, 6.56 (s. 2H), 3.92 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 179.9, 174.2, 164.7, 152.1, 141.3, 134.3, 128.8, 128.7, 127.7, 124.4, 107.7, 71.1, 53.4; MS (−FAB) 272 (M−, 12). Anal. Calc for C15H12O5; C. 66.18; H. 4.41; Found: C, 65.75; H. 4.45.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][CH:9]([F:46])[C:10]([N:12]1[C@H:16]([CH2:17][F:18])[C@@H:15]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[CH:27][C:28]([CH:31]([NH:33][C:34](=[O:43])[O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH3:32])=[N:29][CH:30]=3)=[CH:21][CH:20]=2)[O:14]C1(C)C)=[O:11]>C(Cl)Cl>[F:46][CH:9]([F:8])[C:10]([NH:12][C@H:16]([CH2:17][F:18])[C@@H:15]([C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([CH:31]([NH:33][C:34](=[O:43])[O:35][CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH3:32])=[N:29][CH:30]=2)=[CH:23][CH:24]=1)[OH:14])=[O:11]
Reactant: CC(NC(=O)OCc1ccccc1)c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(NC(=O)OCc1ccccc1)c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
Trifluoroacetic acid (2.2 mL) is added to the product of step 2, Example 95A (1.05 g, 1.94 mmol) in CH2Cl2 (39 mL) at 0° C. After 30 minutes the ice bath is removed and the mixture stirred at room temperature for 8 hours. Saturated NaHCO3 (60 mL) is added and the mixture extracted with CH2Cl2 (40 mL). The combined organics are dried over MgSO4, filtered and evaporated to give the title product (850 mg): m/z: 501.19.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[S:17][C:13]=3[CH:12]=2)[CH:2]=1.N1C2C(=NC=CC=2)N(CC2C=CC3N=C(S(C)(=O)=O)SC=3C=2)C=1.[NH2:46][CH2:47][C:48]1([OH:54])[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16]([NH:46][CH2:47][C:48]4([OH:54])[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]4)[S:17][C:13]=3[CH:12]=2)[CH:2]=1
Reactant: NCC1(O)CCCCC1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cccnc43)cc2s1
Agent: CS(=O)(=O)c1nc2ccc(Cn3cnc4cccnc43)cc2s1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: OC1(CNc2nc3ccc(Cn4cnc5cccnc54)cc3s2)CCCCC1
Temperature: 125 °C
Reaction time: 15 h

Procedure:
A 4:1 mixture of 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole and 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfonyl)benzo[d]thiazole (50 mg) from Step 2 of Example 63 was dissolved in anhydrous DMA (1.5 mL), and then 1-(aminomethyl)cyclohexanol (79 mg, 0.608 mmol) from Step 1 of this Example and DIEA (98 mg, 0.760 mmol) were added. The reaction vessel was sealed and the mixture was heated with stirring at 125° C. for 15 h. LCMS analysis indicated that the reaction was not complete. Further amounts of 1-(aminomethyl)cyclohexanol (79 mg, 0.608 mmol) from Step 1 of this Example and DIEA (98 mg, 0.760 mmol) were added and the mixture stirred at 125° C. for further 5 h. After cooling to rt, the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs Diphenyl column as the stationary phase to afford 1-(((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)methyl)cyclohexanol (10 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.38 (dd, J=1.1, 4.7 Hz, 1H), 8.09 (dd, J=1.2, 8.0 Hz, 1H), 7.96 (t, J=5.6 Hz, 1H), 7.67 (s, 1H), 7.19-7.33 (m, 3H), 5.48 (s, 2H), 4.42 (br s, 1H), 1.12-1.62 (m, 12H). LCMS (ESI) m/z 394 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:2].[H-].[Na+].Br[CH2:18][C:19]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:20]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:18][C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Reactant: O=C(CBr)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1ccc(OCC(=O)N2CCOCC2)cc1
Reaction time: 0.25 h
Yield: 64.7 %

Procedure:
A mixture of 4-hydroxy-alpha-oxobenzeneacetic acid ethyl ester (0.71 g) in dimethylformamide (7 mL) under argon was treated with 55% sodium hydride (0.16 g), stirred for 15 minutes and then 4-(bromoacetyl)morpholine (0.76 g) in dimethylformamide (5 mL) was added. The mixture was stirred at room temperature for 18 hours and worked up as in Example 20. The crude product was purified by HPLC (toluene-hexane; 3:1 ) and then crystallized twice from ethyl acetate-hexane to provide 0.76 g of 4-[2-(4-morpholinyl)-2-oxoethoxy]-alpha-oxobenzeneacetic acid ethyl ester, mp 103°-106 ° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[O:9])=[CH:3][CH:2]=1.BrCBr.[C:20](=[S:22])=[S:21].[C:23](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([C:8](=[O:9])[C:7](=[C:20]2[S:22][CH2:23][S:21]2)[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:15][CH:14]=1
Reactant: S=C=S
Reactant: O=C(Cc1ccncc1)c1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: BrCBr
Solvent: CC(C)=O
Product: O=C(C(=C1SCS1)c1ccncc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.7 %

Procedure:
To a solution of 2-(4-pyridyl)-1-(4-chlorophenyl)ethanone (70.0 g, 0.3 mol) prepared in a similar manner as the compound of Step 1 of Example A-19, dibromomethane (200 mL) and carbon disulfide (25.9 g, 0.34 mol) in acetone (800 mL) was added potassium carbonate (83.0 g, 0.6 mol). The reaction mixture was stirred at room temperature for 24 hours. An additional two equivalents of potassium carbonate and one equivalent of carbon disulfide was added and the stirring was continued for another 24 hours. Solvent was removed and the residue was partitioned between dichloromethane and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was stirred with 1000 mL of a mixture of ethyl acetate and ether (1:9) to give 78.4 g of pure product, 1-(4-chlorophenyl)-2-(1,3-dithietan-2-ylidene)-2-(4-pyridinyl)ethanone, as a yellow solid (82%), mp: 177-179° C. Anal. Calc'd. for C15H10ClNOS2: C, 56.33; H, 3.15; N, 4.38. Found: C, 55.80; H, 2.84; N, 4.59.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:40][OH:41])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([NH:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])=[CH:30][CH:31]=[C:26]4[C:25]([C:38]#[N:39])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C([OH:44])C>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:40][OH:41])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([NH:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])=[CH:30][CH:31]=[C:26]4[C:25]([C:38]([NH2:39])=[O:44])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)CCNc1ccc2c(C#N)cn(-c3cccc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)c2n1
Reactant: CCO
Solvent: O
Product: CN(C)CCNc1ccc2c(C(N)=O)cn(-c3cccc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)c2n1
Temperature: 45 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
In a 25 mL round-bottomed flask, 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-6-(2-(dimethylamino)ethylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (19 mg, 34.3 μmol, Eq: 1.00) and [hydrogen bis(dimethylphosphinito-kP)]platinum (II) (1.47 mg, 3.43 μmol, Eq: 0.1) were combined with Ethanol (271 μl) and Water (271 μl) to give a colorless solution. The reaction mixture was heated to 45° C. and stirred for 1 h. The crude reaction mixture was concentrated in vacuo, then diluted with acetonitrile and water and filtered. The resultant filtrate was lyophilized to give 1-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-6-(2-dimethylamino-ethylamino)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid amide (14.2 mg, 71%, [M+H]+ 572).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[OH:15].[C:16](Cl)(=[O:18])[CH3:17].O>ClCCl>[C:16]([O:15][C:9]1[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=1[CH3:7])(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(O)c(C)c1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C)cc1C
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
83 ml (1.02 mol) of pyridine are added to a solution of 120 ml (1 mol) of 2,4-dimethylphenol in 400 ml of dichloromethane cooled to 5° C. After stirring for 15 minutes and cooling the reaction mixture to -10° C., 73 ml (1.02 mol) of acetyl chloride in solution in 100 ml of dichloromethane are added dropwise. The reaction mixture is then brought to reflux for 2 hours, then cooled and treated by the addition of 200 ml of water, and then acidified to a pH of 1. The organic phase is extracted, dried over MgSO4 and filtered on a silica bed, to lead to the production of a yellow oil: 2,4-dimethylphenyl acetate: yield 98%.
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=[CH:12][C:11]=2[CH2:19][C:20]([OH:22])=O)=[C:7]([CH2:25][CH2:26][CH3:27])[CH:6]=1)([O:3][CH3:4])=[O:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[C:40]([C:44]1[CH:49]=[CH:48][C:47]([S:50]([NH2:53])(=[O:52])=[O:51])=[CH:46][CH:45]=1)([CH3:43])([CH3:42])[CH3:41].C1CCN2C(=NCCC2)CC1>C1COCC1>[C:40]([C:44]1[CH:49]=[CH:48][C:47]([S:50]([NH:53][C:20](=[O:22])[CH2:19][C:11]2[CH:12]=[CH:13][C:14]3[O:18][CH2:17][O:16][C:15]=3[C:10]=2[O:9][C:8]2[CH:23]=[CH:24][C:5]([C:1]([O:3][CH3:4])=[O:2])=[CH:6][C:7]=2[CH2:25][CH2:26][CH3:27])(=[O:51])=[O:52])=[CH:46][CH:45]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CCCc1cc(C(=O)OC)ccc1Oc1c(CC(=O)O)ccc2c1OCO2
Reactant: CC(C)(C)c1ccc(S(N)(=O)=O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCCc1cc(C(=O)OC)ccc1Oc1c(CC(=O)NS(=O)(=O)c2ccc(C(C)(C)C)cc2)ccc2c1OCO2
Temperature: 50 °C

Procedure:
To the product of Step A (57.2 mg, 0.154 mmol) in dry THF (0.75 mL) was added CDI (76.0 mg, 0.469 mmol) and the reaction heated to 50° C. for 2.5 hr. To this solution was added a solution of p-t-butylphenyl-sulfonamide (131.7 mg, 0.618 mmol) and DBU (92.1 μL, 0.594 mmol) in dry THF (0.75 mL). The reaction continued to be stirred at 50° C. monitoring by thin layer chromatography until all of the mono-acid was consumed (approx. 3 hr). The reaction was concentrated in vacuo and the residue was taken up in 50:50/Et2O:EtOAc. The organic phase was washed with 10% citric acid (2×), water and brine then dried over MgSO4, filtered and the solvent removed. Purification was accomplished by radial chromatography eluting with 3:2/Hex:EtOAc. Yield=74.3 mg (0.131 mmol, 85%) rf=0.32 (80:10:1/CHCl3 :MeOH:NH4OH) FAB mass spectrum, m/e 590.0 (M+Na calculated for C30H33 NSO8 590). See Drummond, J. T.; Johnson, G. Tetrahedron Lett., 1988, 29, 1653.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH:7]2[CH:8]3[CH2:22][CH2:21][CH:20]=[CH:19][C:9]3=[C:10]3[C:18]([CH2:17][C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]3=4)=[C:6]2[C:5](C)([CH3:23])[C:4]([CH3:26])([CH3:25])[C:3]1([CH3:28])[CH3:27].[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)=[C:38]2[CH:42]=[CH:41][CH:40]=[CH:39]2)=[CH:33][CH:32]=1.[CH3:50]CCCCC.C([Li])CCC.CN1CCN(C)C1=O>O1CCCC1>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]([C:43]2[CH:44]=[CH:45][C:46]([Cl:49])=[CH:47][CH:48]=2)([CH:38]2[CH:39]=[CH:40][CH:41]=[CH:42]2)[C:7]2([CH3:50])[C:6]3[C:5]([CH3:23])([CH:12]4[CH2:13][CH2:14][CH:15]=[CH:16][C:11]4=[C:10]4[C:18]=3[CH2:17][C:19]3[CH:20]=[CH:21][CH:22]=[CH:8][C:9]4=3)[C:4]([CH3:26])([CH3:25])[C:3]([CH3:28])([CH3:27])[C:2]2([CH3:1])[CH3:29])=[CH:35][CH:36]=1
Reactant: CC1(C)C2=C3Cc4ccccc4C3=C3C=CCCC3C2C(C)(C)C(C)(C)C1(C)C
Reactant: CCCCCC
Reactant: Clc1ccc(C(=C2C=CC=C2)c2ccc(Cl)cc2)cc1
Agent: [Li]CCCC
Solvent: CN1CCN(C)C1=O
Solvent: C1CCOC1
Product: CC12C(=C3Cc4ccccc4C3=C3C=CCCC31)C(C)(C(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)C1C=CC=C1)C(C)(C)C(C)(C)C2(C)C
Temperature: 0 °C
Yield: 17 %

Procedure:
A reaction vessel equipped with a dropping funnel was charged with 40 ml of dehydrated tetrahydrofuran and 2.35 g (6.08 mmol) of octamethyloctahydrodibenzofluorene synthesized by a method described in (i) of Synthetic Example 1 under nitrogen atmosphere, and 4.62 ml (7.30 mmol) of a hexane solution of n-butyllithium of 1.58 mol/L was added dropwise and stirred while cooling the above solution at 0° C. 1,3-Dimethyl-2-imidazolidinone 0.86 ml (7.90 mmol) was added to the above solution and stirred for 30 minutes. Then, a solution prepared by dissolving 2.00 g (6.68 mmol) of 6,6-di(p-chlorophenyl)fulvene in 30 ml of dehydrated tetrahydrofuran was [put] placed in the dropping funnel and added dropwise while cooling at −78° C., and the solution was stirred for one day while slowly allowing it to return to room temperature. This reaction solution was extracted with diethyl ether, and the separated organic layer was washed with 1N hydrochloric acid, a saturated sodium hydrogen carbonate aqueous solution and a saturated salt solution and dried over anhydrous magnesium sulfate. Then, magnesium sulfate was removed by filtration, and the solvent contained in the filtrate was removed by distillation under reduced pressure by means of a rotary evaporator. The residue was purified through a silica gel column and then recrystallized from toluene to obtain a targeted product (amount obtained: 0.714 g, yield: 17%). The targeted product was identified by means of 1H-NMR and FD-MS spectra.
Reaction SMILES: [C:1]([C:3]([CH3:15])([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]CC)[CH3:4])#[N:2].N[CH2:17][CH2:18][OH:19]>C(O)CCC.O.O.C([O-])(=O)C.[Cd+2].C([O-])(=O)C>[CH3:15][C:3]([C:1]1[O:19][CH2:18][CH2:17][N:2]=1)([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:4]
Reactant: NCCO
Reactant: CCCCCCCCCCC(C)(C)C#N
Agent: CC(=O)[O-]
Agent: [Cd+2]
Solvent: CCCCO
Solvent: O
Product: CCCCCCCCC(C)(C)C1=NCCO1

Procedure:
100 mmoles of 2-cyano-2-methyldodecane is reacted with 120 mmoles of 2-aminoethanol in 50 ml of 1-butanol in presence of 2.5 mmoles of cadmium acetate dihydrate as outlined under Example 1 to give 2-(2-methyl-2-decyl)-2-oxazoline.