Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]([F:17])(S(F)(=O)=O)[C:3](F)(F)[C:4](F)(F)[C:5](F)(F)F.O[C@@H]1C[C@@]2(C)[C@@H:30]([CH2:31][CH2:32][C:33]2=[O:37])[C@H:29]2[C@H:20]1[C@@H:21]1[C:26]([CH2:27][CH2:28]2)=[CH:25][C:24](=[O:38])[CH2:23][CH2:22]1>C1(C)C=CC=CC=1.N12CCCN=C1CCCCC2.C(OCC)(=O)C>[F:17][C@H:2]1[CH2:3][C@@:4]2([CH3:5])[C@@H:30]([CH2:31][CH2:32][C:33]2=[O:37])[C@H:29]2[C@H:20]1[C@@H:21]1[C:26]([CH2:27][CH2:28]2)=[CH:25][C:24](=[O:38])[CH2:23][CH2:22]1
Reactant: C[C@]12C[C@@H](O)[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: C[C@]12C[C@H](F)[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reaction time: 0.5 h

Procedure:
4.6 ml of perfluorobutane-1-sulphonyl fluoride are added dropwise at 0° C. to 5.0 g of 11α-hydroxyoestr-4-ene-3,17-dione in 100 ml of toluene and 7.3 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene. After 30 min, the solution is diluted with ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated in vacuo. After chromatographing the crude product on silica gel using a hexane-ethyl acetate gradient, 3.8 g of 11β-fluorooestr-4-ene-3,17-dione of melting point 173-174° C. are obtained.
Reaction SMILES: C([O-])=O.[Na+].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([N+:26]([O-])=O)[CH:14]=1.C(O)(=O)C>CC(O)C.O.[C].[Pd]>[NH2:26][C:15]1[CH:14]=[C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH3:5])[CH:25]=[CH:24][C:16]=1[C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18]
Reactant: COc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: CC(=O)O
Product: COc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(N)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
Sodium formate (2.7 g) and 10% palladium-carbon (0.65 g) were sequentially added to a solution mixture of tert-butyl 4-(2-methoxyphenyl)-2-nitrobenzoate (3.3 g) in 2-propanol (40 mL), water (10 mL), and acetic acid (2.6 mL), followed by heating to reflux for 2 hours. The reaction mixture was cooled to room temperature, and then the insoluble substance was removed by filtration. The solvent was evaporated under reduced pressure, and a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 99-91% hexane/ethyl acetate] to obtain 3.0 g of tert-butyl 2-amino-4-(2-methoxyphenyl)benzoate as a white oily substance.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[CH2:6]=[CH:7][C:8]1C=CC=C[CH:9]=1.[Li][Li]>>[CH2:1]=[CH:2][C:3](=[CH2:4])[CH3:5].[CH2:6]=[CH:7][CH:8]=[CH2:9]
Reactant: C=Cc1ccccc1
Agent: [Li][Li]
Solvent: C=CC(=C)C
Product: C=CC=C

Procedure:
A method in which isoprene or an isoprene/butadiene mixture is polymerized and, then, styrene or its derivative is subjected to polymerization using an initiator consisting of a dilithium compound.
Reaction SMILES: C(OC(C[N:7]1[C:16](=[O:17])[CH:15]2[CH:10]([CH:11]3[C:18](=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:14]2[C:13]([C:32]([OH:45])([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:12]3)[C:8]1=[O:9])=O)C.[C:46]([O:52][CH2:53]Cl)(=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:45][C:32]([C:13]1[CH:14]2[C:18](=[C:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:11]([CH:12]=1)[CH:10]1[C:8]([N:7]([CH2:53][O:52][C:46](=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48])[C:16](=[O:17])[CH:15]21)=[O:9])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CCOC(=O)CN1C(=O)C2C3C=C(C(O)(c4ccccc4)c4ccccn4)C(C3=C(c3ccccc3)c3ccccn3)C2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCN1C(=O)C2C3C=C(C(O)(c4ccccc4)c4ccccn4)C(C3=C(c3ccccc3)c3ccccn3)C2C1=O
Yield: 48 %

Procedure:
A similar procedure (Hursthouse, M. B.; Khan, A.; Marson, C. M.; Porter, R. A. Tetrahedron Lett 1995, 36, 33, 5979-5982) to that described for the preparation of 207 was followed using NRB (200 mg, 0.39 mmol) in dimethylformamide (2 mL), chloromethyl pivalate (41) (59 mg, 0.39 mmol) in dimethylformamide (0.5 mL), and potassium carbonate (54 mg, 0.39 mmol). Purification by flash chromatography (hexane/ethyl acetate 1:1) afforded 8 as a colourless solid (118 mg, 0.19 mmol, 48%). mp 95-98° C.; 1H NMR (400 MHz, CDCl3) δ 1.18-1.19 (8.4H, m, tBu), 1.25-1.26 (0.6H, m, tBu), 3.38 (0.2H, dd, J=7.9 and 4.5 Hz, W/H-3), 3.45 (0.5H, dd, J=7.9 and 4.5 Hz, Y/H-3), 3.51-3.59 (0.4H, m, 0.2H U/H-2 and U/H-3, 0.2H V/H-2), 3.63-3.64 (0.2H, m, W/H-4), 3.67-3.76 (0.9H, m, 0.2H V/H-3, 0.2H W/H-2 and 0.5H Y/H-2), 3.88-3.92 (0.3H, m, 0.1H U/H-1 and 0.2H V/H-1), 4.00-4.01 (0.5H, dt, J=4.5 and 1.3 Hz, Y/H-4), 4.20-4.21 (0.1H, m, U/H-4), 4.35-4.36 (0.2H, dt, J=4.5 and 1.3 Hz, V/H-4), 4.49-4.52 (0.7H, m, 0.2H W/H-1 and 0.5H Y/H-1), 5.26-5.29 (0.7H, m, CH2), 5.31-5.62 (3H, m, 1.3H CH2, 0.2H V/H-6, 0.5H Y/H-6 and 1H OH), 6.04-6.06 (0.3H, m, 0.1H U/H-6 and 0.211 W/H-6), 6.71-7.57 (16H, m, Ar), 8.42-8.50 (0.6H, m, 0.2H 2U/αPyr and 0.4H 2VαPyr), 8.54-8.55 (0.7H, m, 0.2H W/αPyr and 0.5H Y/αPyr), 8.61-8.63 (0.7H, m, 0.2H W/αPyr and 0.5H Y/αPyr); vmax(nujol)/cm−1 1140 and 1212 (C—O ester), 1586 (C═O imide), 1715 (C═O ester); m/z (FAB+) 626 (MH+, 67%), 120 (100); (Found: MH+ 626.2644, C39H36N3O5 requires 626.2655).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[N:9]([C:17]1[C:22]([F:23])=[C:21](Cl)[N:20]=[C:19]([Cl:25])[N:18]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[CH:42]1([NH2:46])[CH2:45][CH2:44][CH2:43]1.CCOCC>CN(C=O)C>[CH3:31][C:29]([O:28][C:26]([N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:4])[CH3:3])=[O:7])[N:9]([C:17]1[C:22]([F:23])=[C:21]([NH:46][CH:42]2[CH2:45][CH2:44][CH2:43]2)[N:20]=[C:19]([Cl:25])[N:18]=1)[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[O:27])([CH3:30])[CH3:32]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Reactant: NC1CCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(NC2CCC2)c1F
Reaction time: 96 h

Procedure:
To a solution of tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (0.497 g, 1.0 mmol) in DMF (5 mL) at room temperature was added diisopropylethylamine (0.19 mL, 1.10 mmol) followed immediately by commercially available cyclobutylamine (0.085 mL, 1.0 mmol). The reaction was stirred for 4 days, then ether was added, and the mixture was washed with water and the aqueous layer was back extracted. The combined organics were dried (Na2SO4), concentrated in vacuo, and azeotroped once with MeOH to provide tris(1,1-dimethylethyl)2-[2-chloro-6-(cyclobutylamino)-5-fluoro-4-pyrimidinyl]-1,1,2-hydrazinetricarboxylate as a white solid.
Reaction SMILES: Br[C:2]1[C:3]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.Cl.[F:17][C:18]1([F:22])[CH2:21][NH:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[F:17][C:18]1([F:22])[CH2:21][N:20]([C:2]2[C:3]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=2)[CH2:19]1
Reactant: N#Cc1cc(OCC(F)(F)F)c(Br)cn1
Reactant: FC1(F)CNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: N#Cc1cc(OCC(F)(F)F)c(N2CC(F)(F)C2)cn1
Temperature: 120 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
To a solution of 5-Bromo-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carbonitrile (example 78c, 587 mg, 2.09 mmol) in dry toluene (10 ml) in a schlenk tube was added 3,3-difluoroazetidine hydrochloride (298 mg, 2.3 mmol), cesium carbonate (1.36 g, 4.18 mmol), palladium diacetate (46.9 mg, 209 μmol) and BINAP (130 mg, 209 μmol). The reaction mixture was stirred at 120° C. for 1 hour. The reaction mixture was filtered over a pad of celite and the filtrate was diluted with ethylacetate. The organic phase was extracted with a 1M aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (480 mg, 78%). MS (ESI, m/z): 294.2 (M+H+).
Reaction SMILES: [Br:1][C:2]([F:12])([F:11])[S:3]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)(=[O:5])=[O:4].[N:13]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1>N1C=CC=CC=1.O>[Br:1][C:2]([F:11])([F:12])[S:3]([C:6]1[N:10]=[CH:9][N:8]([C:18]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:19])[N:7]=1)(=[O:4])=[O:5]
Reactant: O=C(Cl)N1CCCC1
Reactant: O=S(=O)(c1nc[nH]n1)C(F)(F)Br
Solvent: c1ccncc1
Solvent: O
Product: O=C(N1CCCC1)n1cnc(S(=O)(=O)C(F)(F)Br)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.9 %

Procedure:
To a solution of 0.12 g (0.45 mmol) 3-(bromodifluoromethylsulfonyl)-1,2,4-triazole, prepared as above, in 0.5 ml dry pyridine was added 0.07 g (0.54 mmol) pyrrolidine-1-carbonyl chloride and the mixture was agitated for 16 h at room temperature. The reaction mixture was then diluted with water and extracted with ether. The resulting organic layer was washed successively with dilute hydrochloric acid, water and saturated sodium bicarbonate solution, dried over MgSO4 and evaporated to give 0.1 g (65% yield) of the desired 3-(bromodifluoromethylsulfonyl)-1-(pyrrolidinocarbonyl)-1,2,4-triazole as a pale yellow oil: 1H NMR (CDCl3) δ(ppm) 9.1 (1H), 4.0 (2H), 3.7 (2H), 2.1 (4H).
Reaction SMILES: F[B-](F)(F)F.[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(O[CH2:17][CH:18]=[CH2:19])(=O)C>C1(C)C=CC=CC=1>[CH2:19]([O:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:18]=[CH2:17].[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=CCOC(C)=O
Agent: F[B-](F)(F)F
Solvent: Cc1ccccc1
Solvent: Oc1ccccc1
Product: C=CCOc1ccccc1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
A mixture of bis(1,5-cyclooctadiene)iridium tetrafluoroborate [Ir(cod)2]+BF4− (0.01 mmol) and toluene (1.0 ml) was treated with phenol (1 mmol) and allyl acetate (5 mmol) with stirring at 100° C. The reaction mixtures after 5 hours and after 15 hours of the reaction were analyzed by gas chromatography. In the reaction mixture after 5 hours, phenyl allyl ether was formed in a yield of 21% with a conversion from phenol of 23%. In the reaction mixture after 15 hours, phenyl allyl ether was formed in a yield of 51% with a conversion from phenol of 51%.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:7]=1.[CH2:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][NH:23]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[C:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[CH2:9][O:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([N:23]2[CH2:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:22]2)[CH:7]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Br)c1
Reactant: c1ccc2c(c1)CNC2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(N2Cc3ccccc3C2)c1
Temperature: 99 °C
Yield: 67.8 %

Procedure:
To a solution of 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridine (89 mg, 0.25 mmol) and isoindoline (31 μL, 0.28 mmol, 1.1 equiv.) in anhydrous toluene (2 mL) were added successively sodium tert-butoxide (36 mg, 0.38 mmol, 1.5 equiv.), tris(dibenzylideneacetone)dipalladium(0) (4.6 mg, 5.0 μmol, 0.02 equiv.), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; 8.7 mg, 15 μmol, 0.06 equiv.). The mixture was degassed and purged with Ar (3 cycles), then warmed to 98-100° C. for 4 h. After cooling to room temperature, the mixture was diluted with EtOAc, and the solution was washed with brine, dried over Na2SO4, and evaporated. The residue was purified by CC (SiO2, CH2Cl2/EtOAc 4:1, then 3:2). The product (67 mg) was obtained as a pale yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.73 (m, 2H), 7.27 (m, 4H), 6.63-6.41 (m, 1H), 4.85 (s, 4H), 4.10 (m, 2H), 3.96 (m, 1H), 3.41 (m, 2H), 2.02 (m, 3H), 1.85 (m, 1H), 1.47 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:26]=[O:27]>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]2[N:6]([C:8]([CH:26]=[O:27])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: Cc1cc(Br)cn2cc(-c3ccc(F)cc3)nc12
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(Br)cn2c(C=O)c(-c3ccc(F)cc3)nc12
Yield: 85 %

Procedure:
6-Bromo-2-(4-fluorophenyl)-8-methylimidazo[1,2-a]pyridine (6 g, 0.021 moles) was treated was treated with phosphorous oxychloride (2.8 mL) in N,N-dimethylformamide in a similar manner as described in Example 2 to give 6-bromo-2-(4-fluorophenyl)-8-methylimidazo[1,2-a]pyridine-3-carbaldehyde (5.7 g, 85%) as a white solid. 1H NMR (CDCl3): δ 10.04 (s, 1H), 9.73 (s, 1H), 7.86 (q, 2H), 7.53 (s, 1H), 7.25 (t, 2H), 2.75 (s, 3H); 19F NMR (CDCl3) δ −111.0; MS m/z 334 (M+1).
Reaction SMILES: [NH2:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([C:12](O)=[O:13])([CH2:5]3)[CH2:3]1)[CH2:9]2.B(F)(F)F.CCOCC.B.[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([CH2:12][OH:13])([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: NC12CC3CC(C1)CC(C(=O)O)(C3)C2
Agent: B
Agent: FB(F)F
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: NC12CC3CC(C1)CC(CO)(C3)C2
Temperature: 100 °C

Procedure:
To a solution of 5.98 g of 3-amino-1-adamantanecarboxylic acid in 40 ml of dry tetrahydrofuran stirred under a nitrogen atmosphere is added 6.5 ml of boron trifluoride etherate. Stirring is continued as 35 ml of a 1 M solution of borane in tetrahydrofuran is added at a rate which maintains reflux. The reaction mixture is refluxed for 4.5 hours then cooled and 20 ml of a 4 N solution of sodium hydroxide is added dropwise. The upper phase, which contains the tetrahydrofuran and the borate ester of the product, is separated. The tetrahydrofuran is removed under reduced pressure, and the residue is heated with 40 ml of a 4 N sodium hydroxide solution for 24 hours at 100° C. The solution is extracted three times with 200 ml of chloroform. The combined chloroform extracts are dried over potassium carbonate and the solvent is removed under reduced pressure. The residue is stirred with diethyl ether to give a crystalline product, 3-amino-1-adamantanemethanol which is represented by the following structure ##STR69##
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].C(Cl)(=O)C([Cl:18])=O.CN(C)C=O>O1CCCC1>[F:1][C:2]([F:14])([F:13])[C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:18])=[O:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(C(=O)O)cccc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1c(C(=O)Cl)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-trifluoromethyl-2-methylbenzoic acid 5.00 g, oxalyl dichloride 3.42 g, N,N-dimethylformamide about 50 mg and tetrahydrofuran 200 mL was stirred at 25° C. for one hour. The reaction mixtures were concentrated under reduced pressure to give 3-trifluoromethyl-2-methylbenzoic acid chloride.
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][O:13][C:14]=2[CH3:15])[CH:5]=1.[C:17]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH3:18].[Li]>>[C:21]([O:20][C:17](=[O:19])[CH2:18][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][O:13][C:14]=2[CH3:15])[CH:5]=1)=[O:16])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)c1cccc(-c2ncoc2C)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Product: Cc1ocnc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1

Procedure:
3-(5-methyl-oxazol-4-yl)-benzoic acid methyl ester (0.87 g) was treated with lithium tert.-butyl acetate according to the general procedure K (method b) to give crude 3-[3-(5-methyl-oxazol-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (1.46 g) as a pale-yellow oil.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].C(O[CH2:14][O:15][CH2:16][CH2:17][O:18][C:19](=[O:21])[CH3:20])(=O)C.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.Cl[Sn](Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[C:19]([O:18][CH2:17][CH2:16][O:15][CH2:14][N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3])(=[O:21])[CH3:20]
Reactant: CC(=O)OCCOCOC(C)=O
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(=O)OCCOCn1cc(C)c(=O)[nH]c1=O
Temperature: 25 °C
Yield: 36 %

Procedure:
Thymine (0.63 g, 5 mmol) was added to 2-acetoxyethyl acetoxymethyl ether (1.32 g, 7.5 mmol) dissolved in CH2Cl2 (15 mL). The reaction mixture was stirred at room temperature and N,O-bis(trimethylsilyl)acetamide (2.96 mL, 12 mmol) was added dropwise. After 3 hours of stirring, the clear solution was cooled to 0° C., and SnCl4 (0.12 mL, 1 mmol) was added. The reaction mixture was allowed to come to room temperature and stirred overnight. A mixture of saturated aqueous NaHCO3 (25 mL) and CHCl3 (50 mL) was prepared and cooled in ice. The reaction mixture was added slowly with vigorous stirring; a white foam formed immediately. After filtration, the aqueous layer was further extracted with ethyl acetate (3×25 mL) and CHCl3 (25 mL), and the combined organic layers were dried over anhydrous Na2SO4. After filtration of drying agent and removal of solvents in vacuo, an oily liquid was obtained. It was purified on a silica gel column using 2:1 CHCl3/CH3COCH3 as the eluent to give the desired product. Yield 36%; Wt. 4.0 g; mp 105°-107° C.; 1H NMR (DMSO-d6) 1.8 (s, CH3 C5 thymine), 2.0 (s, CH3 CO), 3.65 (m, CO O CH2 CH2), 4.1 (m, CO O CH2 CH2), 5.05 (s, O CH2 N), 7.55 (s, H C6 thymine), 11.3 (s, HN thymine ).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[N:7]([CH2:9][C:10]1[CH:11]=[N:12][C:13]([F:33])=[CH:14][C:15]=1[C:16]1[C:21]2[S:22][C:23]([C:25]3[C:30]([F:31])=[CH:29][N:28]=[C:27](Cl)[N:26]=3)=[CH:24][C:20]=2[CH:19]=[CH:18][CH:17]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.FC(F)(F)C(O)=O.[NH2:49][CH2:50][CH2:51][N:52]1[CH:56]=[CH:55][NH:54][C:53]1=[O:57]>C(O)CCC>[F:33][C:13]1[N:12]=[CH:11][C:10]([CH2:9][N:7]([CH3:8])[C:6](=[O:34])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[C:15]([C:16]2[C:21]3[S:22][C:23]([C:25]4[C:30]([F:31])=[CH:29][N:28]=[C:27]([NH:49][CH2:50][CH2:51][N:52]5[CH:56]=[CH:55][NH:54][C:53]5=[O:57])[N:26]=4)=[CH:24][C:20]=3[CH:19]=[CH:18][CH:17]=2)[CH:14]=1
Reactant: NCCn1cc[nH]c1=O
Reactant: CN(Cc1cnc(F)cc1-c1cccc2cc(-c3nc(Cl)ncc3F)sc12)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CCCCO
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1cnc(F)cc1-c1cccc2cc(-c3nc(NCCn4cc[nH]c4=O)ncc3F)sc12)C(=O)OC(C)(C)C
Temperature: 120 °C
Yield: 45.4 %

Procedure:
Combine {4-[2-(2-chloro-5-fluoro-pyrimidin-4-yl)-benzo[b]thiophen-7-yl]-6-fluoro-pyridin-3-ylmethyl}-methyl-carbamic acid tert-butyl ester (0.52 g, 1.04 mmol) and triethylamine (0.87 mL, 6.24 mmol) in n-butanol (10.0 mL). Add 1-(2-amino-ethyl)-1,3-dihydro-imidazol-2-one; compound with trifluoro-acetic acid (0.75 g, 3.12 mmol). Heat the reaction mixture at 120° C. for 54 hours for completion, then cool to room temperature. Remove solvent on a rotovap to obtain the crude product. Purify the crude by column chromatography (0.5% to 6% 2 M NH3 in methanol solution in dichloromethane) to afford the desired product (0.28 g). MS (ES) m/z 594 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:25])[C:10]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C@H:13]1[C:21]([O:23][CH3:24])=[O:22])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Rh]>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:25])[C:10]([N:12]1[C@@H:20]2[C@@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:14][C@H:13]1[C:21]([O:23][CH3:24])=[O:22])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1Cc2ccccc2N1C(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: [Rh]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2N1C(=O)[C@H](C)NC(=O)OC(C)(C)C

Procedure:
The residue obtained in Example 1 (1 kg) is dissolved in methanol and transferred to a hydrogenator, and then 0.10 kg of 5% rhodium-on-carbon is added.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]23[CH2:30][CH2:29][CH2:28][C:26]4[C:27]2=[C:22]([CH:23]=[CH:24][CH:25]=4)[NH:21][C:20]3=[O:31])[CH2:11][CH2:10]1.B(Br)(Br)Br.CO.C(OCC)(=O)C>C1C=CC=CC=1>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]23[CH2:30][CH2:29][CH2:28][C:26]4[C:27]2=[C:22]([CH:23]=[CH:24][CH:25]=4)[NH:21][C:20]3=[O:31])[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(CCCCC23CCCc4cccc(c42)NC3=O)CC1
Agent: BrB(Br)Br
Solvent: CO
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: O=C1Nc2cccc3c2C1(CCCCN1CCN(c2ccccc2O)CC1)CCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.3 %

Procedure:
2a-[4-{4-(2-Methoxyphenyl)piperazinyl}butyl]-2a,3,4,5-tetrahydrobenz[cd]indole-2(1H) -one (100 mg, 0.24 mmol) was dissolved in benzene (2 ml) to which was subsequently added dropwise boron tribromide (240 mg, 0.96 mmol), and the resulting mixture was stirred at room temperature for 2 hours and then at 60° C. for 24 hours. The reaction solution was mixed with methanol and ethyl acetate, washed with water and saturated brine and dried with anhydrous sodium sulfate. Then the solvent was evaporated under a reduced pressure to obtain 57 mg of the title compound (0.14 mmol, 59% in yield).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[CH:8]=2)[NH:3]1>C(O)(C(F)(F)F)=O>[NH:14]1[CH2:13][CH2:12][CH:11]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[CH2:10]3)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)CC(=O)N3)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C1Cc2cc(C3CCNCC3)ccc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
To a solution of TFA (10 ml) was added tert-butyl 4-(2-oxoindolin-5-yl)piperidine-1-carboxylate (789 mg, 2.49 mmol) and stirred at room temperature for 30 min. The reaction mixture was concentrated. The residue was diluted with 1N HCl and extracted with CHCl3. The aqueous layer was added with 28% NH3 aq until pH 8 and extracted with CHCl3/EtOH (3/1). The organic layer was dried over Na2SO4 and concentrated to give 5-(piperidin-4-yl)indolin-2-one (409 mg, 76%).