Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1[CH3:11])=[O:2].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH3:11][C:4]1[CH:5]=[C:6]([C:8]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)=[O:10])[NH:7][C:3]=1[CH:1]=[O:2]
Reactant: Cc1cc(C(=O)O)[nH]c1C=O
Reactant: CN1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N2CCN(C)CC2)[nH]c1C=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 68 %

Procedure:
To a suspension of 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (1.53 g, 10 mmol) in DMF (20 mL) was added 1-methylpiperazine (1.2 g, 12 mmol), followed by 1-ethyl-3-(3-dimethylaminopropyl)carboiimide hydrochloride (EDAC, 2.3 g, 12 mmol), 1-hydroxybenzotriazole (HOBt, 1.6 g, 12 mmol) and triethylamine (3.2 mL, 24 mmol). The reaction mixture was stirred at room temperature for 2 days. The reaction was concentrated, diluted with water and extracted with ethyl acetate (5×). The combined ethyl acetate was concentrated to a volume of 20 mL and triturated with hexane (10 mL). The resulting solid was collected by vacuum filtration to give 1.6 g (68%) of 3-methyl-5-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde as a yellow solid. 1N NMR (300 MHz, DMSO-d6) δ 12.21 (s, 1H, NH), 9.7 (s, 1H, CHO), 6.35 (s, 1H), 3.58 (m, 4H 2×CH2), 2.30 (m, 7H, 2×CH2 & CH3), 2.18 (s, 3H, CH3). MS 236 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH:18](O)[CH3:19])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:21])=[CH:13][CH:14]=2)[N:9]=1.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:46]1(=[O:56])[NH:50][C:49](=[O:51])[C:48]2=[CH:52][CH:53]=[CH:54][CH:55]=[C:47]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH:18]([N:50]2[C:46](=[O:56])[C:47]3[C:48](=[CH:52][CH:53]=[CH:54][CH:55]=3)[C:49]2=[O:51])[CH3:19])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:21])=[CH:13][CH:14]=2)[N:9]=1
Reactant: CC(O)c1cc2ccc(F)cc2nc1-c1ccccc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1cc2ccc(F)cc2nc1-c1ccccc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(2-(2-chlorophenyl)-7-fluoroquinolin-3-yl)ethanol (0.7018 g, 2.326 mmol) in tetrahydrofuran (23.26 mL, 2.326 mmol) were added triphenylphosphine (1.220 g, 4.652 mmol), phthalimide (0.6844 g, 4.652 mmol), and diisopropyl azodicarboxylate (0.9159 mL, 4.652 mmol). The reaction mixture was stirred at room temperature. After 2 h, the mixture was concentrated under reduced pressure and partitioned between EtOAc (100 mL) and brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and 50% isocratic of EtOAc in hexane for 10 min as eluent to 2-(1-(2-(2-chlorophenyl)-7-fluoroquinolin-3-yl)ethyl)isoindoline-1,3-dione as an off-white solid: LC-MS (ESI) m/z 431.0 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([N:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)[OH:22])=[O:20])=[CH:14][CH:13]=1)[CH:7]=[CH:6]2.Cl[C:35]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:36]>>[CH2:38]([O:37][C:35](=[O:36])[NH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([N:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)[OH:22])=[O:20])=[CH:16][CH:17]=1)[CH:7]=[CH:6]2)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CCCCCCCCCCOC(=O)Cl
Reactant: Nc1ccc2c(ccn2-c2ccc(NC(=O)N(O)c3ccc(Cl)c(C(F)(F)F)c3)cc2)c1
Agent: Cl
Product: CCCCCCCCCCOC(=O)Nc1ccc2c(ccn2-c2ccc(NC(=O)N(O)c3ccc(Cl)c(C(F)(F)F)c3)cc2)c1

Procedure:
The title compound can be synthesized from 1-[4-(5-aminoindol-1-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)-3-hydroxyurea hydrochloride and n-decyl chloroformate by using the same techniques as in Example 41.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[CH:21]=[CH:20][N:19]=3)[CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH3:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)=[CH:31][CH:30]=2)=[O:8])=[CH:11][C:12]=1[NH:17][C:18]1[N:19]=[CH:20][CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=2)[N:23]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1Nc1nccc(-c2cccnc2)n1
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1

Procedure:
The invention provides a process for preparation of imatinib base and pharmaceutically acceptable acid addition salts thereof, comprising (a) reacting 2-methyl-5-nitroaniline with cyanamide in the presence of hydrochloric acid to obtain 1-(2-methyl-5-nitrophenyl)guanidine hydrochloride; (b) converting 1-(2-methyl-5-nitrophenyl)guanidine hydrochloride to 1-(2-methyl-5-nitrophenyl)guanidine nitrate; (c) condensing 3-acetylpyridine with N,N-dimethylformamide dimethyl acetal to obtain 3-(dimethylamino)-1-(3-pyridinyl)-prop-2-en-1-one; (d) reacting 3-(dimethylamino)-1-(3-pyridinyl)-prop-2-en-1-one with 1-(2-methyl-5-nitrophenyl)guanidine nitrate to obtain N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine; (e) reducing N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine using hydrazine in the presence of Raney nickel to obtain N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidine-amine; (f) condensing N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidine-amine with 4-chloromethylbenzoyl chloride in the presence of an inorganic base to obtain 4-chloromethyl-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide; (g) condensing 4-chloromethyl-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide with an excess of N-methylpiperazine to obtain imatinib base; adding water or a mixture of water and an organic solvent; and isolating said imatinib base; and (h) optionally, converting imatinib base to a pharmaceutically acceptable acid addition salt of imatinib base.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CON(C)C(=O)Cc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)Cc1cccc(-c2ccccc2)c1
Temperature: 80 °C
Yield: 91.6 %

Procedure:
The mixture of 2-(3-bromophenyl)-N-methoxy-N-methylacetamide (2.0 g, 7.7 mmol), phenylboronic acid (1.42 g, 11.6 mmol), 1-1′-bis(diphenylphosphino)derrocene palladium dichloride (500 mg, 0.77 mmol), and saturated aqueous sodium carbonate solution (1 mL) in N,N-dimethylformamide (20 mL) was heated at 80° C. under N2 overnight. The mixture was poured into water, extracted with EA, dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (PE:EtOAc=30:1-10:1) to afford 2-(biphenyl-3-yl)-N-methoxy-N-methylacetamide (1.8 g, yield 94.7%).
Reaction SMILES: CC1(C)[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])O1.[CH:11]([NH:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O)([CH3:13])[CH3:12].C(O)(=O)C.C(N)CN>CO>[CH:11]([N:14]1[C:15]2[C:16](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:5]([C:6]([OH:7])=[O:8])[C:4]1=[O:9])([CH3:13])[CH3:12]
Reactant: CC(C)Nc1ccccc1C=O
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: CO
Solvent: CC(=O)O
Solvent: NCCN
Product: CC(C)n1c(=O)c(C(=O)O)cc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
2,2-Dimethyl-[1,3]dioxane-4,6-dione, commonly Meldrum's acid, (166.9 g, 1.16 mol) was added to a stirred solution of 2-isopropylaminobenzaldehyde (105 g, 0.64 mol), acetic acid (73.6 mL, 1.29 mol) and ethylenediamine (43.0 mL, 0.64 mol) in methanol (1 L) at 0° C. The reaction mixture was stirred for 1 h at 0° C. and then at room temperature overnight. The resulting suspension was filtered and the solid washed with methanol and collected to yield the title intermediate, 1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (146 g, 98%) as an off-white solid. 1H NMR (CDCl3; 300 MHz): 1.72 (d, 6H, CH(CH3)2), 5.50 (bs, 1H, CH(CH3)2), 7.44 (t, 1H, ArH), 7.75-7.77 (m, 2H, ArH), 7.82 (d, 1H, ArH), 8.89 (s, H, CH).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH:12]=[CH:11]C[O:9]2)=[CH:4][CH:3]=1.[H][H]>C1(C)C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][O:9]2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(C2CC=CCO2)cc1
Reactant: [H][H]
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: Brc1ccc(C2CCCO2)cc1
Yield: 37.6 %

Procedure:
A solution of 2-(4-bromophenyl)-3,6-dihydro-2H-pyran (140 mg, 0.586 mmol) in toluene/ethanol (10 mL, v/v=1/1) was charged into a hydrogenation Parr bottle followed by tris(triphenylphosphine)rhodium(I) chloride (55 mg, 0.0586 mmol). The mixture was set up for 45 psi of hydrogen at 80° C. overnight. The mixture was filtered through celite and the filtrate was concentrated. The residue was purified by silica gel chromatography to give the title compound (50 mg, 35%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.46 (d, 2H) 7.23 (d, 2H) 4.29 (d, 1H) 4.13 (m, 1H) 3.60 (t, 1H) 1.95 (m, 1H) 1.81 (d, 1H) 1.60 (m, 3H) 1.27 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(=O)C>[CH3:4][CH:3]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:2][CH2:7][CH3:6]
Reactant: Nc1ccccc1
Solvent: CC(C)=O
Product: CCCC(C)Nc1ccccc1

Procedure:
N-(1-methylbutyl)aniline was prepared from aniline and propan-2-one using the same method as in Example 2i)a).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH2:7][C:8]1[CH:9]=[C:10]([SH:14])[CH:11]=[CH:12][CH:13]=1.Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH:25]([O:28][CH3:29])[O:26][CH3:27])[CH:17]=1.O>CC(N(C)C)=O>[CH3:29][O:28][CH:25]([O:26][CH3:27])[C:18]1[CH:17]=[C:16]([S:14][C:10]2[CH:9]=[C:8]([NH2:7])[CH:13]=[CH:12][CH:11]=2)[CH:21]=[CH:20][C:19]=1[N+:22]([O-:24])=[O:23]
Reactant: Nc1cccc(S)c1
Reactant: COC(OC)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(OC)c1cc(Sc2cccc(N)c2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 2 h

Procedure:
K2CO3 (0.085 mol) was added to a mixture of 3-aminobenzenethiol (0.075 mol) in DMA (150 mL). Then 4-chloro-2-dimethoxymethyl-1-nitrobenzene (0.050 mol) was added and the reaction mixture was stirred for 2 hours at 80° C. H2O was added and the mixture was extracted with diisopropyl ether. The crude product was purified by column chromatography (eluent: 70:30 CH2Cl2/hexane up to 99:1 CH2Cl2:CH3OH). The product fractions were collected, and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:25][CH2:26][CH2:27][CH:28]=[CH2:29])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.C(O)(=[O:36])C.C1C(=O)N(Br)C(=O)C1.[OH-].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:25][CH2:26][CH2:27][CH:28]4[CH2:29][O:36]4)[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: C=CCCCN(c1cc2nn(-c3ccc(Cl)cc3)c(C(=O)NC)c2cc1C1CC1)S(C)(=O)=O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCCC3CO3)S(C)(=O)=O)cc2nn1-c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 118.7 %

Procedure:
To a solution of (i) (156 mg, 0.32 mmol) and acetic acid (37 μL, 0.64 mmol) in anhydrous 1,4-dioxane (15 mL) and water (20 mL) at 0° C. was added NBS (68 mg, 0.13 mmol) in a single portion. The reaction mixture was allowed to warm slowly to room temperature over 1 h 25 min whereupon aq. 1M NaOH solution (3 mL) was added and the reaction followed LCMS analysis. After 30 min, the reaction mixture was diluted with water (10 mL), extracted with EtOAc (3×10 mL) and the combined organics then dried (MgSO4) and concentrated in vacuo to obtain (ii) (191 mg, >100%). The crude product was used without further purification in the next step. ESI-MS m/z calculated for [M+H]+: 503.2. found: 503.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:5]=[CH:4][C:3]=1[OH:20].[C:21](N)(=O)[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)[OH:24]>>[OH:24][C:23]1[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=1[C:21]1[O:20][C:3]2[CH:4]=[CH:5][C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][C:2]=2[N:1]=1
Reactant: CCCCCCCCCCCCc1ccc(O)c(N)c1
Reactant: NC(=O)c1ccccc1O
Product: CCCCCCCCCCCCc1ccc2oc(-c3ccccc3O)nc2c1
Temperature: 220 °C

Procedure:
A three-neck flask fitted with a thermometer, mechanical stirrer and condenser with Dean-Stark trap was charged with 692.5 g. (2.5 moles) of 2-amino-4-dodecylphenol and 411 g. (3.0 moles) of salicylamide. The mixture was heated with stirring to 220° C. After 6 hours of heating, the collection of water in the Dean-Stark trap ceased. At that point, the reaction mixture was cooled to room temperature and about 3 liters of cyclohexane was added. The mixture was then filtered and the filtrate was stripped of volatiles under reduced pressure. The yield of residue was 741.5 g. (2.0 moles). Infrared and nuclear magnetic resonance (nmr) analyses confirmed the structure of the product as 2-(2-hydroxyphenyl)-5-dodecylbenzoxazole, a dark oil. A gas liquid chromatography (glc) analysis indicated the product was 95+% pure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]([S:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)(=[O:28])=[O:27])[CH:22]=[CH:23][C:24]=1[Cl:25]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([N:32]2[CH2:31][CH2:30][N:29]([S:26]([C:21]3[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=3)(=[O:27])=[O:28])[CH2:34][CH2:33]2)=[O:16])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(Cl)c(Cl)c1)N1CCNCC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)O
Agent: Cl
Product: Cc1noc(-c2ccc(Br)cc2)c1C(=O)N1CCN(S(=O)(=O)c2ccc(Cl)c(Cl)c2)CC1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid and 1-[(3,4-dichlorophenyl)sulfonyl]piperazine hydrochloride.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([NH:17]C(OCC2C=CC=CC=2)=O)=[CH:9][C:8]=1[NH:28][C:29]([C:31]1[NH:32][C:33]2[C:38]([CH:39]=1)=[CH:37][C:36]([O:40][CH3:41])=[C:35]([O:42][CH3:43])[C:34]=2[O:44][CH3:45])=[O:30])(=[O:3])[CH3:2]>C1COCC1.[Pd]>[C:1]([O:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([NH2:17])=[CH:9][C:8]=1[NH:28][C:29]([C:31]1[NH:32][C:33]2[C:38]([CH:39]=1)=[CH:37][C:36]([O:40][CH3:41])=[C:35]([O:42][CH3:43])[C:34]=2[O:44][CH3:45])=[O:30])(=[O:3])[CH3:2]
Reactant: COc1cc2cc(C(=O)Nc3cc(NC(=O)OCc4ccccc4)c4ccccc4c3CCOC(C)=O)[nH]c2c(OC)c1OC
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc2cc(C(=O)Nc3cc(N)c4ccccc4c3CCOC(C)=O)[nH]c2c(OC)c1OC
Reaction time: 72 h
Yield: 83.8 %

Procedure:
A solution of 2-[4-(N-benzyloxycarbonylamino)-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl]ethyl acetate (0.1 g, 0.16 mmol) in THF (10 mL) was added to a suspension of 10% Pd/C (0.1 g) in chilled THF (10 mL) and the suspension was hydrogenated under H2 atmosphere at room temperature for 3 days. The suspension was filtered over Celite and the filtrate was concentrated in reduced pressure. The residue was crystallized with diisopropylether to yield 2-[4-amino-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl]ethyl acetate (0.064 g, 84%) as a white solid: mp 182-186° C. (decomp.); 1H NMR (CDCl3, 500 MHz) δ 9.40 (s, 1H), 8.65 (s, 1H), 7.94 (d, 8.5, 1H), 7.86 (d, 8.5, 1H), 7.57 (s, 1H), 7.55 (t, 8.0, 1H), 7.46 (t, 8.0, 1H), 7.19 (brs, 1H), 6.88 (s, 1H), 4.39 (t, 7.0, 2H), 4.23 (brs, 2H), 4.10 (s, 3H), 3.96 (s, 3H), 3.93 (s, 3H), 3.41 (t, 7.0, 2H), 2.10 (s, 1.5, 3H); FABMS (NBA) m/z 478 (M+H+), IR (neat) νmax 3341, 1727, 1639, 1591, 1536, 1505, 1466, 1410, 1304, 1243, 1106, 1046, 758 cm−1.
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH2:14][OH:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C>CS(C)=O.C(Cl)Cl>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([CH:14]=[O:15])[C@@H:10]([CH3:11])[CH2:12][CH3:13])([CH3:5])([CH3:7])[CH3:6]
Reactant: CC[C@H](C)[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 103 %

Procedure:
To an ice cold solution of Boc-isoleucinol (3.89 g, 17.9 mmol) in DMSO (15 mL) and DCM (200 mL) was added DIEA (9.7 mL, 55.5 mmol), followed by dropwise addition of a solution of Py.SO3 (8.83 g, 55.5 mmol) in DMSO (50 mL, +10 mL to rinse the funnel). The reaction mixture was stirred at rt for 2 h. After removal of the DCM, the residue was diluted with Et2O (400 mL) and washed with H2O (2×100 mL) and brine (150 mL). The aqueous layer was back extracted with Et2O (100 mL). The combined Et2O layer was washed with saturated NaHCO3 (150 mL) and dried (Na2SO4). The solvent was removed to give the titled compound (3.97 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[N:3]=1.[C:9]1(=O)[O:14][C:12](=[O:13])[C:11]2[CH2:15][CH2:16][CH2:17][CH2:18][C:10]1=2.C(O)(=O)C>C(Cl)(Cl)Cl>[OH:8][C:4]1[N:3]=[C:2]([N:1]2[C:12](=[O:13])[C:11]3[CH2:15][CH2:16][CH2:17][CH2:18][C:10]=3[C:9]2=[O:14])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(O)n1
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cccc(O)n1

Procedure:
A mixture of 2-amino-6-hydroxypyridine (2.2 g), 3,4,5,6-tetrahydrophthalic anhydride (3.0 g) and acetic acid (40 ml) is heated to reflux for about 18 hours. The reaction is then cooled and stripped. The concentrate is taken up in CHCl3 (100 ml), washed with water, dried and stripped to yield N-(6-hydroxy-2-pyridyl)-3,4,5,6-tetrahydrophthalimide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)=[CH:16][CH:15]=1)[C:10](O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC)=O.C([N:35](CC)CC)C.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.N1C=CC=CC=1>C1COCC1>[C:10]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)=[CH:16][CH:15]=1)#[N:35]
Reactant: Cc1cccc(-c2ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc2)c1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cccc(-c2ccc(C[C@@H](C#N)NC(=O)OC(C)(C)C)cc2)c1
Reaction time: 0.5 h

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)-3-(3′-methylbiphenyl-4-yl)propanoic acid (1.37 g, 3.85 mmol) in THF (25 mL) were added ethyl chloroformate (0.407 mL, 4.24 mmol) and triethylamine (0.591 mL, 4.24 mmol) at room temperature. After being stirred for 0.5 hours, the resultant precipitate was removed by filtration. The filtrate was treated with ammonium hydroxide (10 mL) and stirred for 1.5 hours at room temperature. The reaction mixture was diluted with EtOAc and washed with H2O and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was dissolved in THF (25 mL). TFAA (0.817 mL, 5.81 mmoL) and pyridine (0.935 mL, 11.56 mmol) were added at −10° C. and stirred for 2 hours. The reaction was quenched with saturated NaHCO3 aqueous solution. The mixture was extracted with EtOAc and washed with brine. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel flash column chromatography (EtOAc/heptane) to give (S)-tert-butyl 1-cyano-2-(3′-methylbiphenyl-4-yl)ethylcarbamate. 1H NMR (400 MHz, CDCl3) δ 1.45 (s, 9H), 2.42 (s, 3.04-3.19 (m, 2H), 4.68-4.94 (m, 2H), 7.17 (d, J=7.58 Hz, 1H), 7.31-7.41 (m, 5H), 7.59 (d, J=8.08 Hz, 2H); MS: m/z (MH+) 337; Retention time=1.60 min. (condition A).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:9]([CH2:13][CH:14]([O:31]C(=O)C)[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=2)[CH:10]=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+]>CO>[C:1]([O:5][C:6]([C:8]1[N:9]([CH2:13][CH:14]([OH:31])[CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:21][CH:22]=2)[CH:10]=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCCc1ccc(OCC(Cn2cccc2C(=O)OC(C)(C)C)OC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCc1ccc(OCC(O)Cn2cccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.150 g (0.318 mmol) tert-butyl-1-[2-acetoxy-3-(4-octylphenoxy)propyl]pyrrole-2-carboxylate is dissolved in 10 ml absolute methanol, mixed with 1.26 ml (0.630 mmol) of a 0.5M sodium methanolate solution and stirred at room temperature for 15 min. Following concentration to half the volume on the rotary evaporator, the batch is diluted with diethyl ether. Washing of the organic phase with semi-saturated and with saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator yield the product as a yellowish oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([NH:10][C:11](=[O:26])[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:14][CH:13]=2)[CH:6]=[CH:7][C:8]=1[CH3:9])=O.ClCCl.[NH2:30][C:31]1[CH:32]=[C:33]2[CH:39]=[C:38]([C:40]([O:42][CH3:43])=[O:41])[NH:37][C:34]2=[N:35][CH:36]=1.C(O[BH3-])(=O)C.[Na+]>C(O)(=O)C>[CH3:25][N:22]1[CH2:21][CH2:20][N:19]([CH2:18][C:15]2[CH:14]=[CH:13][C:12]([C:11]([NH:10][C:5]3[CH:6]=[CH:7][C:8]([CH3:9])=[C:3]([CH:4]=3)[CH2:1][NH:30][C:31]3[CH:32]=[C:33]4[CH:39]=[C:38]([C:40]([O:42][CH3:43])=[O:41])[NH:37][C:34]4=[N:35][CH:36]=3)=[O:26])=[CH:17][CH:16]=2)[CH2:24][CH2:23]1
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1C=O
Reactant: COC(=O)c1cc2cc(N)cnc2[nH]1
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1cc2cc(NCc3cc(NC(=O)c4ccc(CN5CCN(C)CC5)cc4)ccc3C)cnc2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 10.1 %

Procedure:
A reactor is charged with 120 mg (0.34 mmol) of the solid obtained in step 2, 15 ml of anhydrous dichloromethane, 78 mg (0.41 mmol) of methyl 5-amino-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, 216 mg (1.02 mmol) of sodium acetoxyborohydride and a catalytic amount of acetic acid. The mixture is stirred at room temperature for 24 hours. The solvent is then evaporated under reduced pressure and the residue is taken off in 100 ml of water. The aqueous phase is extracted by 3*30 ml ethyl acetate. The aqueous phases are combined, dried on sodium sulphate and then evaporated under reduced pressure. The raw product obtained is purified by preparative HPLC and 18 mg of a solid is obtained (10%).