Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:29])([F:28])[F:27])=[N:19]3)[CH2:11][CH2:10][N:9]1[CH2:30][C:31](O)=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[O:40][NH2:41].C1CCC(N=C=NC2CCCCC2)CC1.CCOC(C)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:27])([F:29])[F:28])=[N:19]3)[CH2:11][CH2:10][N:9]1[CH2:30][C:31]([NH:41][O:40][CH:35]1[CH2:36][CH2:37][CH2:38][CH2:39][O:34]1)=[O:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NOC1CCCCO1
Reactant: COc1ccc(N2CCN(CC(=O)O)[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(N2CCN(CC(=O)NOC3CCCCO3)[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Reaction time: 3 h
Yield: 74.3 %

Procedure:
A solution of (S)-2-(2-benzyl-4-(8-methoxy-2-(trifluoromethyl)quinolin-5-yl)piperazin-1-yl)acetic acid (184 mg, 0.40 mmol) in CH2Cl2 (4 mL) at 0-5° C. was treated with O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (49 mg, 0.42 mmol), catalytic DMAP, and finally DCC (87 mg, 0.42 mmol). The reaction mixture was stirred for 3 h after which time the mixture was treated with EtOAc (5 mL), filtered and evaporated. The residue was purified by silica gel flash chromatography with 100% EtOAc, as eluant to afford intermediate 2-((S)-2-benzyl-4-(8-methoxy-2-(trifluoromethyl)quinolin-5-yl)piperazin-1-yl)-N-(tetrahydro-2H-pyran-2-yloxy)acetamide as an oil (166 mg, 74%). LC/MS (Method A) 5.76 min, [M+1]+ 559.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:14]2[C:23]([O:24][CH3:25])=[C:22]3[C:17]([C:18](=[O:34])[C:19]([C:29]([O:31]CC)=[O:30])=[CH:20][N:21]3[CH:26]3[CH2:28][CH2:27]3)=[CH:16][C:15]=2[F:35])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([O:5][C:6]([NH:8][C:9]1([C:14]2[C:23]([O:24][CH3:25])=[C:22]3[C:17]([C:18](=[O:34])[C:19]([C:29]([OH:31])=[O:30])=[CH:20][N:21]3[CH:26]3[CH2:27][CH2:28]3)=[CH:16][C:15]=2[F:35])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC)c(C3(NC(=O)OC(C)(C)C)CCCC3)c(F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(C2(NC(=O)OC(C)(C)C)CCCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 101.5 %

Procedure:
2.3 g of ethyl 7-(1-t-butoxycarbonylaminocyclo-pentyl)-l-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylate was suspended 40 ml of ethanol. Then 40 ml of a 1N aqueous solution of sodium hydroxide was added thereto and the resulting mixture was stirred at room temperature for 15 hours. After removing the solvent under reduced pressure, the mixture was acidified by adding methylene chloride and 2N HCl. The organic layer was collected, washed with water and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, 2.2 g of 7-(1-t-butoxycarbonylaminocyclopentyl)-1-cyclo-propyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecar-boxylic acid was obtained (yield: 100%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[N:17]3[CH:24]=[CH:25][N:26]=[C:16]23)=[CH:11][CH:10]=1)C1C=CC=CC=1.C1COCC1>[Pd].CO>[N:26]1[CH:25]=[CH:24][N:17]2[C:18]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[C:16]=12
Reactant: c1ccc(COc2ccc(-n3c4ncccc4n4ccnc34)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Oc1ccc(-n2c3ncccc3n3ccnc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
A mixture of 9-[4-(benzyloxy)phenyl]-9H-imidazo[1′,2′:1,2]imidazo[4,5-b]pyridine (2.48 g), 10% palladium on carbon (containing water (50%), 2.48 g), THF (50 mL) and methanol (50 ml) was stirred under a hydrogen atmosphere at room temperature for 1 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/THF) and recrystallized from ethanol to give the title compound (1.38 g).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33][N:41]5[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCl
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCN1CCN(C)CC1
Yield: 21.8 %

Procedure:
The urea intermediate from Example 65A (200 mg, 0.38 mmol) and N-methyl piperazine (0.126 mL, 1.14 mmol) were reacted as described in Example 57B to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)urea as a colorless solid (49 mg, 22%). 1H NMR (300 MHz, DMSO-d6) δ 9.58 (brs, 1H), 9.00 (brs, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.26-7.49 (m, 5H), 6.49 (s, 1H), 4.25-4.29 (m, 2H), 3.98 (s, 3H), 2.75-2.79 (m, 2H), 2.20-2.60 (m, 8H), 2.15 (s, 3H), 1.27 (s, 9H); LC-MS (ESI) m/z 592 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.C(=O)([O-])[O-].[NH4+:16].[NH4+]>S(Cl)(Cl)=O>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH2:16])=[O:11]
Reactant: [NH4+]
Reactant: O=C(O)Cc1ccccc1I
Agent: O=C([O-])[O-]
Solvent: O=S(Cl)Cl
Product: NC(=O)Cc1ccccc1I
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A solution of 2-iodophenylacetic acid (20.5 g, 78.2 mmol) in thionyl chloride (70 mL) was stirred at 75° C. for 3 hours. The thionyl chloride was removed in vacuo and the resulting residue was dissolved in DCM (100 mL). Ammonium carbonate (15.03 g, 156.5 mmol) was added and the resulting mixture was stirred at 60° C. for 20 hours. The volatiles were evaporated in vacuo, water (100 mL) was added and the resulting suspension was sonicated for 1 minute, before filtering and washing the filter cake with water then Et2O. After air drying, the title compound I6 was obtained as a light cream coloured solid (12.9 g, 63%); 1H NMR (300 MHz, d6-DMSO) δ 7.82 (d, J=8.3 Hz, 1H), 7.41 (brs s, 1H), 7.30-7.37 (m, 2H), 6.95-7.01 (m, 2H), 3.55 (s, 2H). LCMS-B: rt 5.108 min; m/z 262 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([F:14])[CH:12]=2)[NH:7][CH:6]=1)[CH3:4].C[N:16](C=O)C>>[CH2:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([F:14])[CH:12]=2)[N:7]([NH2:16])[CH:6]=1)[CH3:4]
Reactant: CN(C)C=O
Reactant: CCc1c[nH]c2ncc(F)cc12
Agent: [H-]
Agent: [Na+]
Product: CCc1cn(N)c2ncc(F)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A suspension of NaH (2.7 g, 68 mmol, 60% in mineral oil) in DMF (20 mL) at 0° C. is treated with 3-ethyl-5-fluoro-1H-pyrrolo[2,3-b]pyridine (745 mg, 4.5 mmol) and stirred at 0° C. for 1 h. The mixture is treated with HOSA (2.5 g, 22.5 mmol) portion wise and warmed to rt over 2 h. The mixture is then poured over ice, filtered through a pad of Celite, and extracted with EtOAc (3×50 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 30% -50% EtOAc in heptane to afford 3-ethyl-5-fluoropyrrolo[2,3-b]pyridin-1-ylamine (685 mg, 84%). MS: 180 (M+H); 1H NMR (300 MHz, CDCl3): δ 8.16 (s, 1H), 7.56 (m, 1H), 7.14 (s, 1H), 4.93 (s, NH2, 2H), 2.697 (q, 2H), 1.28 (t, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[F:31])([C:22]#[N:23])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=[O:41].[K+].[K+].OO>CS(C)=O.CCOC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[F:31])([C:22]#[N:23])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[CH:7][CH:8]=1)(=[O:41])[NH2:2]
Reactant: CC(C)(C)CC1CN(C(=O)Nc2ccc(C#N)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)CC1CN(C(=O)Nc2ccc(C(N)=O)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To the mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid (4-cyano-phenyl)-amide (56.8 mg, 0.10 mmol) and K2CO3 (excess) in DMSO (2 mL) was added 30% H2O2 (1.0 mL, excess) and the reaction mixture was stirred at rt overnight. The reaction mixture was then diluted with EtOAc washed with sat NH4Cl, water and brine. The solvent was removed and the crude product was triturated with EtOAc and the solid was collected to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid (4-carbamoyl-phenyl)-amide (55.9 mg, 95.5%). HRMS (ES+) m/z Calcd for C30H28Cl2F2N4O2+H [(M+H)+]: 585.1630, found: 585.1631.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]1[C:8]2([CH3:12])[C:9]([CH3:11])=[CH:10][CH:5]([CH:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7]2)[N:4]1CC1C=CC=CC=1>[Pd].C(O)C>[ClH:1].[CH3:2][CH:3]1[C:8]2([CH3:12])[CH:9]([CH3:11])[CH2:10][CH:5]([CH:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7]2)[NH:4]1
Reactant: CCOC(=O)C1CC2(C)C(C)=CC1N(Cc1ccccc1)C2C
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CC2(C)C(C)CC1NC2C
Reaction time: 3.5 h

Procedure:
A mixture of ethyl 3,4,8-trimethyl-2-(phenylmethyl)-2-azabicyclo[2.2.2]oct-7-ene-6-carboxylate hydrochloride (26.5 g, mmol), 10% palladium on carbon (2.6 g) and ethanol (200 mL) were placed on a Parr hydrogenator at 50 psi for 3.5 hours. The catalyst was removed by filtration and the solvent was removed in vacuo to afford crude ethyl 3,4,8-trimethyl-2-azabicyclo[2.2.2]-octane-6-carboxylate hydrochloride as a yellow oil, which was used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:14]=1[C:15]([O:17]C)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1>O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:14]=1[C:15]([OH:17])=[O:16])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1ccc(OC)cc1OCCCNC(=O)OC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)c(OCCCNC(=O)OC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
Methyl 2-(3-tert-butoxycarbonylaminopropoxy)-4-methoxybenzoate (18.61 g, 54.8 mmol) was suspended in 3:1 tetrahydrofuran:water (100 mL), then solid LiOH monohydrate (5.06 g, 121 mmol) was added and the mixture was stirred at 50° C. for 24 hours. The mixture was diluted with water (350 mL) and washed with diethyl ether (2×250 mL). The aqueous layer was acidified to pH 1-2 with 1 N sodium bisulfate and the resulting slurry was extracted with EtOAc (2×300 mL). The combined EtOAc layers were washed with brine, dried, then concentrated in vacuo to give a solid white mass. Recrystallization from EtOAc provided 2-(3-tert-butoxycarbonylaminopropoxy)-4-methoxybenzoic acid as white needles (15.52 g, 87%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)=[C:19]([O:37][CH3:38])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][CH2:22][CH2:23][N:24]4[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]4)=[C:19]([O:37][CH3:38])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1CCCN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc2c(c1CCCN1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
A solution of tert-butyl (Z)-4-(3-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}propyl)piperazine-1-carboxylate (0.0393 g, 0.0758 mmol) in methylene chloride (3 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the precipitated solid was collected by filtration. The solid was washed with water, and then dried under reduced pressure to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-[3-(piperazin-1-yl)propyl]benzofuran-3(2H)-one (0.0273 g, 86%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:21]>CC#N>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:18][CH2:19][C:20]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)=[O:21])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: O=C(CCCl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H](NCCC(=O)c1ccc(F)cc1)c1ccc(Br)cc1
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a solution of (S)-1-(4-bromophenyl)ethanamine (20 g, 0.1 mol) and K2CO3 (28 g, 0.2 mol) in MeCN (200 mL) was added a solution of 3-chloro-1-(4-fluorophenyl)propan-1-one (18.6 g, 0.1 mol) in MeCN (20 mL). The mixture was stirred overnight. The solid was filtered, and the filtrate was concentrated to give (S)-3-(1-(4-bromophenyl)ethylamino)-1-(4-fluorophenyl)propan-1-one (30 g, 86%), which was used for the next step without purification. 1H NMR (CDCl3): δ=1.29 (m, 3H), 2.56-2.91 (m, 2H), 3.11 (m, 2H), 3.68 (q, 1H), 7.11 (m, 2H), 7.21 (m, 2H), 7.43 (m, 2H), 7.99 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)O.Cl.[CH3:13][CH:14]([CH2:16][CH2:17][CH2:18][CH:19]([CH2:21][CH2:22][CH2:23][CH:24]([CH2:26][CH2:27][CH2:28][C:29]([OH:33])([CH:31]=[CH2:32])[CH3:30])[CH3:25])[CH3:20])[CH3:15]>C1(C)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[CH3:10][C:4]1[C:5]([CH3:9])=[C:6]2[C:8]([CH2:32][CH2:31][C:29]([CH2:28][CH2:27][CH2:26][CH:24]([CH2:23][CH2:22][CH2:21][CH:19]([CH2:18][CH2:17][CH2:16][CH:14]([CH3:13])[CH3:15])[CH3:20])[CH3:25])([CH3:30])[O:33]2)=[C:2]([CH3:1])[C:3]=1[OH:11]
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Temperature: 85 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
13.5 g of trimethyl hydroquinone are dissolved in 100 ml of toluene, and 13.5 g of silica-alumina, 6.0 g of zinc chloride and 0.5 g of concentrated hydrochloric acid (35% hydrochloric acid) are added thereto under nitrogen flow. The reaction system is warmed to 85° C. and then 25.0 g of isophytol are added dropwise over about 20 minutes. After completion of the addition, stirring is continued for about 4 hours at the same temperature and then the reaction system is allowed to cool. Then, 100 ml of toluene are added to the reaction mixture and the insoluble material is filtered off. The filtrate is washed in succession with 3% caustic soda, 1% sodium hydrosulfite, water and saturated aqueous salt solution and dehydrated with anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure to give 36.2 g of dl-α-tocopherol (yield 99.8%). 25.0 g of dl-α-tocopherol thus obtained are dissolved in 50 ml of acetic anhydride and 12.5 g of sodium acetate and 1.25 g of metallic zinc powder are added thereto. The reaction mixture is acetylated by stirring at 95°-100° C. for about 3.5 hours and then extracted with 200 ml of n-hexane. The extract is washed in succession with 1% caustic soda, water and saturated aqueous salt solution and dried over magnesium sulfate. Thereafter, n-hexane is distilled off under reduced pressure to give 26.2 g of crude dl-α-tocopherol acetate. The crude dl-α-tocopherol acetate thus obtained is subjected to vacuum distillation to give 20.5 g of the main fraction of 165°-175° C./8×10-3 mmHg. The purity of this product is 97.3% and the distillation yield is 78.0%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:11][CH:10]=[C:9]([CH2:12][OH:13])[CH:8]=1.C[N+]1([O-])CCOCC1>C(#N)C.C(OCC)(=O)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=1
Reactant: OCc1c[nH]c(-c2ccccn2)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=Cc1c[nH]c(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.5 %

Procedure:
To a solution (50 mL) of [5-(pyridin-2-yl) -1H-pyrrol-3-yl]methanol (0.96 g) in acetonitrile were added tetra-n-propylammonium perruthenate (194 mg), N-methylmorpholine N-oxide (2.98 g) and molecular sieves 4A powder (5 g), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→1:1) to give the title compound as colorless crystals (yield 270 mg, 29%).
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH3:6])[CH2:3][CH2:4][OH:5].N1C=CC=CC=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.Cl>C(Cl)Cl>[OH:7][C:2]([CH3:6])([CH3:1])[CH2:3][CH2:4][O:5][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:14])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: CC(C)(O)CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
10.0 ml (93.7 mmol) of 3-methylbutane-1,3-diol and 7.60 ml (94.9 mmol) pyridine are dissolved in 100 ml DCM. The mixture is cooled in an ice bath. 15.0 g (78.7 mmol) of 4-methylbenzenesulfonyl chloride are added portionwise. The reaction mixture is stirred at r.t. for 16 h. The reaction mixture is poured into 100 ml of 1N aq. HCl and stirred for 10 min. Then the layers are separated. The aq. layer is extracted with DCM. The combined organic layers are washed with brine and dried. The solvent is evaporated and the residue is chromatographed on silica gel (PE/EtOAc) to give the title compound. Yield: 15.3 g; Mass spectrum (ESI+): m/z=276 [M+NH4]+.
Reaction SMILES: [CH3:1]CCCCC.[H-].[Na+].[Br:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13]([OH:15])=[O:14]>CN(C=O)C.CCOC(C)=O>[Br:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13]([O:15][CH3:1])=[O:14]
Reactant: CCCCCC
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(Br)c1
Temperature: 25 °C
Yield: 63 %

Procedure:
To a mixture of hexane washed 60% disp. NaH (2.28 g, 57 mmol) in DMF (250 mL), 0 C., was added 3-bromo-4-methylbenzoic acid (10.03 g, 46.6 mmol) After 30 min, the reaction was warmed to room temperature, diluted with EtOAc (1.25 L) and washed with H2O (5×250 mL). The organic layer was MgSO4 dried and concentrated. The residue was chromatographed (˜375 g silica, 10% EtOAc/CH2Cl2) to give the desired product as a solid (16.68 g, 63%); IR(CHCl3): 1260, 1294, 1437, 1721 cm−1; NMR(300 MHz, CDCl3): 2.46 (s, 3H); 3.92 (s, 3H); 7.31 (d, 1H, J=7.8 Hz); 7.88 (d, 1H, J=7.8 Hz); 8.21 (s, 1H); MS(FD): 228.0.
Reaction SMILES: [NH2:1][C:2](=[O:36])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:25]=[N:26][N:27](C(OC(C)(C)C)=O)[CH:28]=2)[N:14]=1)[CH3:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:26]1[CH:25]=[C:24]([NH:23][C:15]2[N:14]=[C:13]([C:12]#[C:11][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[CH:3]([CH3:4])[C:2]([NH2:1])=[O:36])[C:18]([C:19]([F:21])([F:20])[F:22])=[CH:17][N:16]=2)[CH:28]=[N:27]1
Reactant: CC(C(N)=O)c1ccccc1C#Cc1nc(Nc2cnn(C(=O)OC(C)(C)C)c2)ncc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C(N)=O)c1ccccc1C#Cc1nc(Nc2cn[nH]c2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 4-((4-((2-(1-amino-1-oxopropan-2-yl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazole-1-carboxylate A62 (0.31 g, 0.62 mmol) and TFA (0.90 mL, 12 mmol) in DCM (3.0 mL) was stirred for 2 hours at room temperature. The mixture was concentrated under reduced pressure and diluted with water (50 mL) before extracting with DCM (2×50 mL) and EtOAc (50 mL). The combined organic residues were concentrated and purified using silica gel column chromatography (50-100% EtOAc in petroleum benzine 40-60° C. then 0-10% MeOH in EtOAc) to give the title compound A63 (0.211 g, 85%). LCMS-D: rt 3.162 min; m/z 401.2 [M+H]+.
Reaction SMILES: [OH-].[Na+].O.[CH3:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20]C(=O)C)=[CH:16][CH:15]=2)=[O:13])[CH2:7][CH2:6]1>C(O)C>[CH3:4][N:5]1[CH2:6][CH2:7][N:8]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)=[O:13])[CH2:9][CH2:10]1
Reactant: CC(=O)Nc1ccc(C(=O)CN2CCN(C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1CCN(CC(=O)c2ccc(N)cc2)CC1
Temperature: 85 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
1.8 g of sodium hydroxide dissolved in 10 ml of ethanol and 10 ml of water were added to 4.0 g of 2-(4-methylpiperazin-1-yl)-1-(4-acetylamino-phenyl)-ethanone which was obtained in the same manner as in Example 1, and stirred at 85° C. for 2 hours in a nitrogen atmosphere. Then, ethanol was distilled off, the deposited oily product was extracted with chloroform, washed with water, dried over anhydrous sodium sulfate and further concentrated to solid to obtain 2.7 g of 2-(4-methylpiperazin-1-yl)-1-(4-aminophenyl)-ethanone.
Reaction SMILES: [CH2:1]([C:4]1[N:12]=[C:11]([O:13][CH3:14])[C:10]([NH:15][C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[CH:25]=3)[CH2:20][CH2:19]2)=[O:17])=[CH:9][C:5]=1[C:6](O)=[O:7])[CH2:2][CH3:3].[CH:34]1[C:47]2[C:38](=[N:39][C:40]3[C:45]([C:46]=2[NH:48][C:49]2[CH:50]=[C:51]([NH:57][C:58](=[O:62])[CH:59]([NH2:61])[CH3:60])[CH:52]=[C:53]([CH2:55][OH:56])[CH:54]=2)=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:37]=[CH:36][CH:35]=1>>[CH:44]1[C:45]2[C:40](=[N:39][C:38]3[C:47]([C:46]=2[NH:48][C:49]2[CH:50]=[C:51]([NH:57][C:58]([CH:59]([NH:61][C:6]([C:5]4[CH:9]=[C:10]([NH:15][C:16]([N:18]5[CH2:19][CH2:20][N:21]([C:24]6[CH:25]=[C:26]([O:32][CH3:33])[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=6)[CH2:22][CH2:23]5)=[O:17])[C:11]([O:13][CH3:14])=[N:12][C:4]=4[CH2:1][CH2:2][CH3:3])=[O:7])[CH3:60])=[O:62])[CH:52]=[C:53]([CH2:55][OH:56])[CH:54]=2)=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:41]=[CH:42][CH:43]=1
Reactant: CC(N)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Reactant: CCCc1nc(OC)c(NC(=O)N2CCN(c3cc(OC)cc(OC)c3)CC2)cc1C(=O)O
Product: CCCc1nc(OC)c(NC(=O)N2CCN(c3cc(OC)cc(OC)c3)CC2)cc1C(=O)NC(C)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Yield: 41.2 %

Procedure:
The same reaction procedure to the example 1 were carried out using 2-propyl-5-{[4-(3,5-dimethoxyphenyl)-piperazine-1-carbonyl]-amino}-6-methoxy-nicotinic acid and N-[3-(acridine-9-yl-amino)-5-hydroxymethyl-phenyl]-2-aminopropaneamide to give the titled compound.