Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:31][CH2:30][C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH:18][CH2:19][C:20]4[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=4)[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH:32]1(B(O)O)[CH2:34][CH2:33]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O.O.C1(C)C=CC=CC=1>[CH:32]1([C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH2:31][CH2:30][C:13]4[N:14]=[CH:15][N:16]=[C:17]([NH:18][CH2:19][C:20]5[CH:21]=[N:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=5)[C:12]=4[CH2:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])[CH2:34][CH2:33]1
Reactant: N#Cc1cc(Br)ccc1N1CCc2ncnc(NCc3ccc(C(F)(F)F)nc3)c2C1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cc(C2CC2)ccc1N1CCc2ncnc(NCc3ccc(C(F)(F)F)nc3)c2C1
Temperature: 100 °C
Yield: 59.8 %

Procedure:
To a mixture of 5-bromo-2-(4-((6-(trifluoromethyl)pyridin-3-yl)methylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzonitrile (13 mg, 0.026 mmol), cyclopropylboronic acid (3.0 mg, 0.034 mmol), potassium phosphate (20 mg, 0.093 mmol), tricyclohexylphosphine (2.5 mg, 0.0090 mmol), toluene (2.0 mL), and water (0.04 mL) under argon was added palladium acetate (1.0 mg, 0.0044 mmol). The mixture was heated at 100° C. for 3 h and then cooled to rt. Water (10 mL) and EtOAc (100 mL) were added. The organic layer was separated and washed with brine, dried (Na2SO4), and concentrated. The residue was purified by semi-preparative HPLC to yield a white solid (7 mg, 58%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([CH:23]=[O:24])=[C:21]([Cl:25])[N:20]=[C:19]2/[CH:26]=[CH:27]/[CH2:28][CH3:29])=[CH:13][CH:12]=1)([O:3][CH3:4])=[O:2].[BH4-].[Na+].[OH-].[Na+]>CO.O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([CH2:23][OH:24])=[C:21]([Cl:25])[N:20]=[C:19]2/[CH:26]=[CH:27]/[CH2:28][CH3:29])=[CH:13][CH:12]=1)([O:3][CH3:4])=[O:2]
Reactant: CC/C=C/c1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC/C=C/c1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of 0.26 g of 1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-2-(1-trans-butenyl)-4-chloroimidazole-5-carboxaldehyde in 10 mL of methanol at 0° C. was added 0.24 g of sodium borohydride portionwise over 0.5 hours. The mixture was stirred for an additional 0.5 hours at 0° C. and then poured into a solution at 10% sodium hydroxide in water. The resulting mixture was extracted with ethyl acetate, and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Column chromatography (elution:ethyl acetate/benzene) provided 0.23 g of 1-[2'-carbomethoxybiphenyl-4-yl)methyl-2-(1-transbutenyl)-4-chloro-5-hydroxymethylimidazole. NMR (200 MHz, CDCl3) δ 7.84 (d, 1H); 7.53 (t, 1H); 7.40 (t, 1H); 7.29 (m, 3H); 7.08 (d, 2H); 6.86 (d of t, 1H); 6.17 (d, 1H); 5.30 (s, 2H); 4.54 (br s, 2H); 3.63 (s, 3H); 2.23 (quint., 2H); 1.04 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]([F:25])([F:24])[F:23])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][C:19]#[N:20])=[N:16][CH:17]=3)[C:6]=2[CH:21]=1>N.C(O)C.[Ni]>[Cl:1][C:2]1[C:3]([C:22]([F:23])([F:24])[F:25])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][NH2:20])=[N:16][CH:17]=3)[C:6]=2[CH:21]=1
Reactant: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CC#N)nc1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCN)nc1
Reaction time: 8 h
Yield: 78.7 %

Procedure:
To a solution of {5-[6-chloro-2-ethyl-5-(trifluoromehyl)-1H-benzimidazol-1-yl]-2-pyridinyl}acetonitrile (step 4, 1.0 g, 2.8 mmol), in ammonia-ethanol (30 ml) was added Raney-Ni and stirred for 8 h under hydrogen atmosphere (3.0 kgf/cm2) The catalyst was filtered off and the solvent was removed. The residue was diluted with ethyl acetate, washed with brine, dried (MgSO4) and concentrated to give 813 mg of title compound as black solid. MS (EI) m/z: 368 (M+).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH2:15])[CH2:6][C@@H:5]1[CH3:16])(=[O:3])[CH3:2].CC1(C)C(C)(C)OB([C:25]2[CH:26]=[CH:27][C:28]([C:31]([O:33][CH3:34])=[O:32])=[N:29][CH:30]=2)O1.C(N(CC)CC)C.CO>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([O:33][CH3:34])=[O:32])=[N:29][CH:30]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:15])[CH2:6][C@@H:5]1[CH3:16])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](N)C[C@@H]1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: COCCOC
Solvent: CO
Product: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](N)C[C@H](C)N3C(C)=O)cn1
Yield: 87 %

Procedure:
In a separate vial, (2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation, see Intermediate 1) (50 mg, 0.156 mmol), methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate (49.4 mg, 0.188 mmol), PdCl2(dppf) (17.17 mg, 0.023 mmol) and triethylamine (0.065 mL, 0.469 mmol) were combined in DME (0.5 mL) and MeOH (1 mL) and the mixture heated under microwave irradiation to 110° C. for 45 mins. The two crude reaction mixtures were combined and concentrated in vacuo. The residue was purified by chromatography (100 g column, EtOAc/cyclohexane followed by 2M methanolic ammonia/DCM gradient). The appropriate fractions were combined, concentrated in vacuo and dried in a vacuum oven to give a residue. This residue was partitioned between sat. aq. sodium bicarbonate (100 mL) and DCM (3×100 mL). The organic layers were combined, dried by passing through a hydrophobic frit and concentrated in vacuo to give methyl 5-((2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)picolinate (555 mg, 1.64 mmol, 87% yield).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[N:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>C1COCC1>[CH:1]1([N:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)C1CC1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a stirred solution of cyclopropyl magnesium bromide in THF (104 mL, 52.1 mmol) under Ar was added di-tert-butyl azodicarboxylate (12 g, 52.1 mmol) in THF (50 mL) at −78° C. The reaction mixture was stirred for 30 min at this temperature, quenched with a saturated aq. NH4Cl solution, and extracted with EtOAc. The combined organic layers were washed with saturated aq. NH4Cl solution, dried over Na2SO4 and evaporated. The crude material was purified by silica gel column chromatography (hexane/EtOAc 2-10%) to afford the title product (11.84 g, 43.5 mmol, 83% yield) as a white solid. Rf=0.12 (CPS stain) (hexane/EtOAc 9:1)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].CCN(C(C)C)C(C)C.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28](O)=[O:29].O=P(Cl)(Cl)Cl.NCCNCCN.CCN(C(C1C=CC=C(C)C=1)=O)CC.[OH-]>ClCCCl.CC(N(C)C)=O>[Cl:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:1][C:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=2)=[O:29])[CH:11]=1
Reactant: COC(=O)c1ccc(Cl)cc1N
Reactant: O=C(O)c1ccccn1
Agent: CCN(CC)C(=O)c1cccc(C)c1
Agent: NCCNCCN
Agent: [OH-]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Nc1cc(Cl)ccc1C(=O)O)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 2 mL vial, methyl 2-amino-4-chlorobenzoate (7.4 mg, 40 μmol) was dissolved into a mixture of 655 μL DCE and 120 μL DMA, followed by addition of DIPEA (600 μmol, 15 eq.). Picolinic acid (14.8 mg, 120 μmol, 3 eq.) and POCl3 (18.2 mg, 120 μmol, 3 eq.) were added. The reaction mixture was capped and stirred at room temperature overnight. Another 700 μL of DCE was added to the reaction mixture along with the following resin bound reagents: a resin bound diethylene triamine (PL-DETA, Polymer Labs, 297 μmol, 7.4 eq.) and a hydroxide ion exchange resin (PL-MP Hydroxide, Polymer Labs, 800 μmol, 20 eq.). The vial was recapped and shaken at room temperature overnight. The resin in the reaction mixture was filtered off, rinsed with 300 μL of MeOH and discarded. The combined filtrates were concentrated down in vacuo. The residue was re-dissolved into 1 mL of DMA and 280 μL of 1M aqueous NaOH. The solution was stirred at room temperature overnight. The desired product was isolated directly from this solution via reverse phase C18 preparative HPLC (water/acetonitrile w/0.1% formic acid, 30%-100% eluant gradient) to yield the final product (3.0 mg, 95% purity). MS (EI) for C13H9ClN2O3: 277 (M+H).
Reaction SMILES: C([O:8][NH:9][C:10](=[O:38])[CH:11]([CH2:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH2:12][CH2:13][CH2:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])C1C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)C>[OH:8][NH:9][C:10](=[O:38])[CH:11]([CH2:26][S:27]([C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)(=[O:29])=[O:28])[CH2:12][CH2:13][CH2:14][S:15]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)(=[O:16])=[O:17]
Reactant: COc1ccc(S(=O)(=O)CCCC(CS(=O)(=O)c2ccc(OC)cc2)C(=O)NOCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)CCCC(CS(=O)(=O)c2ccc(OC)cc2)C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-benzyloxy-2-[(4-methoxybenzenesulfonyl)methyl]-5-(4-methoxybenzenesulfonyl)-pentanamide (0.3 g, 0.5 mmol), Pearlman's catalyst (0.11 g), and absolute ethyl alcohol is agitated under hydrogen (15 psig) overnight at room temperature. The mixture is filtered and the filtrate is concentrated in vacuo. The concentrate is chromatographed over silica gel with chloroform/ethyl acetate/methyl alcohol/acetic acid (50/40/10/1) and the eluate concentrated in vacuo to afford the title compound as a white solid.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([CH2:13][OH:14])[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])[CH2:9]1)C1C=CC=CC=1.CO>[Pd]>[OH:14][CH2:13][C@H:11]1[CH2:12][NH:8][CH2:9][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21]
Reactant: OCC1CN(Cc2ccccc2)CC1c1ccccc1O
Agent: [Pd]
Solvent: CO
Product: OC[C@H]1CNC[C@H]1c1ccccc1O
Reaction time: 8 h

Procedure:
A mixture of 2-[1-benzyl-4-(hydroxymethyl)pyrrolidin-3-yl]phenol (101.4 mg, 0.0003580 mol) and palladium (10% on carbon, 75 mg) in methanol (5.0 mL, 0.12 mol) was stirred under hydrogen (balloon) overnight. The mixture was filtered and the filtrate was concentrated. The residue was used in next step without further purification.
Reaction SMILES: S(=O)(=O)(O)O.N[C:7]1[CH:16]=[C:15]2[C:10]([C:11]([Br:21])=[N:12][N:13]([CH:18]([CH3:20])[CH3:19])[C:14]2=[O:17])=[CH:9][CH:8]=1.N([O-])=O.[Na+].NC(N)=O.O(CC)C([S-])=[S:32].[K+].[OH-].[Na+].Cl>CC(O)=O.O.C(Cl)Cl>[SH:32][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([Br:21])=[N:12][N:13]([CH:18]([CH3:20])[CH3:19])[C:14]2=[O:17])=[CH:9][CH:8]=1
Reactant: CC(C)n1nc(Br)c2ccc(N)cc2c1=O
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: NC(N)=O
Agent: O=N[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)n1nc(Br)c2ccc(S)cc2c1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 48.6 %

Procedure:
Concentrated sulfuric acid (5 ml) was added dropwise to a solution of 7-amino-2-isopropyl-4-bromo-2H-phthalazin-1-one (1.5 g, 5.3 mmol) in HOAc (15 ml) and the solution was cooled to 0° C. A solution of sodium nitrite (0.5 g, 7.4 mmol) in water (2.5 ml) was added dropwise and the reaction mixture was stirred at 0° C. for 20 min, after which time urea (0.17 g, 2.8 mmol) was added in one portion. The reaction mixture was then added dropwise to a solution of potassium ethyl xanthate (6 g, 37.7 mmol) in water (7.5 ml) and the mixture was heated to 80° C. for 30 min. After this time, the reaction mixture was cooled to RT and DCM (100 ml) was added. The organic layer was separated, dried (MgSO4), filtered and concentrated under vacuum. The residue was taken up in THF (10 ml), NaOH (4.95 g, 0.12 mmol) was added in one portion and the mixture was heated to reflux for 24 hours. The mixture was then cooled to RT and the suspension was acidified to pH 2 with concentrated HCl. DCM (100 ml) was added, the organic layer was separated and was subsequently washed with HCl (1M, 20 ml) and water (20 ml). The organic layer was extracted with NaOH (1M, 200 ml), the aqueous layer was separated and acidified to pH 1 with concentrated HCl. The mixture was extracted with DCM (2×50 ml), the organic layers were combined, dried (MgSO4), filtered and concentrated under vacuum to give the title compound (0.77 g, 48% yield) as a light brown solid which was taken on directly without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:22])[CH:5]=1)([O-])=O.C(O)C.[H][H]>[Pd].CN(C)C=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:22])[CH:5]=1
Reactant: Cc1ccc2c(c1)C(=O)N(c1cc([N+](=O)[O-])ccc1C)C2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1ccc2c(c1)C(=O)N(c1cc(N)ccc1C)C2=O

Procedure:
The mixture of 4.28 g of N-(4-nitro-o-tolyl)-4-methylphthalimide, 200 ml of 95% aqueous ethanol and 0.21 g of 5% palladium on charcoal is hydrogenated at 3.1 atm and 45° until the hydrogen uptake ceases. The resulting suspension is diluted with the minimum amount of dimethylformamide to solubilize the organic material, filtered and evaporated. The residue is taken up in chloroform, the mixture filtered, evaporated and the residue recrystallized from methanol, to yield the N-(4-amino-o-tolyl)-4-methylphthalimide melting at 144°-147°.
Reaction SMILES: [CH2:1]([O:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([O:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][O:16][S:27]([CH3:26])(=[O:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(CCO)CCOCOCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CCOCOCc1ccccc1)CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.99 g (3.92 mmol) of 1-benzyloxymethoxy-3,3-dimethyl-5-pentanol and 0.60 ml (4.3 mmol) of triethylamine in 15 ml of dichloromethane, 0.33 ml (4.3 mmol) of methanesulfonyl chloride was added at 0° C., followed by stirring at room temperature for 30 minutes, after which saturated aqueous sodium hydrogen carbonate was added. The mixture was extracted with dichloromethane and dried, after which the solvent was distilled off to yield 1-benzyloxymethoxy-3,3-dimethyl-5-methanesulfonyloxypentane.
Reaction SMILES: CC1C=CC(NC(C2C=CC(CN3CCN(C)CC3)=CC=2)=O)=CC=1NC1N=CC=C(C2C=CC=NC=2)N=1.CO[C:40](=[O:55])[C:41]1[CH:46]=[CH:45][C:44]([CH2:47][N:48]2[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]2)=[CH:43][CH:42]=1.[N+:56]([C:59]1[CH:60]=[C:61]([CH:63]=[CH:64][C:65]=1[CH3:66])[NH2:62])([O-:58])=[O:57]>>[CH3:66][C:65]1[CH:64]=[CH:63][C:61]([NH:62][C:40](=[O:55])[C:41]2[CH:42]=[CH:43][C:44]([CH2:47][N:48]3[CH2:49][CH2:50][N:51]([CH3:54])[CH2:52][CH2:53]3)=[CH:45][CH:46]=2)=[CH:60][C:59]=1[N+:56]([O-:58])=[O:57]
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Reactant: COC(=O)c1ccc(CN2CCN(C)CC2)cc1
Agent: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1[N+](=O)[O-]

Procedure:
U.S. Pat. No. 5,521,184 and application WO 03/066613 describe several synthetic routes for preparing Imatinib. One synthetic process, described in Scheme 1, comprises reacting 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid methyl ester with 3-nitro-4-methyl-aniline to obtain N-(4-methyl-3-nitrophenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide, which is subsequently reduced to obtain N-(3-amino-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide. The latter is reacted with cyanamide (NH2CN) in a mixture of concentrated hydrochloric acid solution and n-butanol to produce N-(3-guanidino-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-benzamide, which is subsequently reacted with 3-dimethylamino-1-pyridin-3-yl-propenone to obtain Imatinib.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[NH:3]1.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C([O:52][C:53](=[O:73])[C@H:54]([OH:72])[CH2:55][C@H:56]([NH2:71])[CH2:57][C:58]1[CH:63]=[CH:62][C:61]([C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([Cl:70])[CH:65]=2)=[CH:60][CH:59]=1)C.CCO.[Li+].[OH-].O>CN(C=O)C>[Cl:70][C:66]1[CH:65]=[C:64]([C:61]2[CH:60]=[CH:59][C:58]([CH2:57][C@@H:56]([NH:71][C:13]([C:4]3[NH:3][C:2](=[O:1])[N:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[N:5]=3)=[O:15])[CH2:55][C@@H:54]([OH:72])[C:53]([OH:73])=[O:52])=[CH:63][CH:62]=2)[CH:69]=[CH:68][CH:67]=1
Reactant: O=C(O)c1nn(-c2ccccc2)c(=O)[nH]1
Reactant: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C[C@@H](O)C(=O)O)c1nn(-c2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 3.6 %

Procedure:
5-Oxo-1-phenyl-4,5-dihydro-1H-[1,2,4]triazole-3-carboxylic acid (42.3 mg, 206 μmol) and HCTU (128 mg, 310 μmol) were combined in DMF, and stirred for 10 minutes at room temperature. DIPEA (72 μL, 413 μmol) and (2R,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid ethyl ester (50 mg, 0.1 mmol) were added, and the resulting mixture was stirred at room temperature overnight. The mixture was combined with EtOH (402 μL, 6.9 mmol) and 1 M LiOH in water (1.1 mL, 1.1 mmol). The mixture was stirred at room temperature for 1 hour, evaporated under reduced pressure, and purified by preparative HPLC to yield the title compound (1.8 mg) as a TFA salt. MS m/z [M+H]+ calc'd for C26H23ClN4O5, 507.14. found 507.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=O)[CH2:14][CH2:13]1)=[O:11].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl.[CH3:41][O:42][C:43](=[O:48])[CH:44]([CH2:46][OH:47])[NH2:45]>ClCCl>[CH3:41][O:42][C:43](=[O:48])[CH:44]([CH2:46][OH:47])[NH:45][C:18]([CH:15]1[CH2:14][CH2:13][N:12]([C:10](=[O:11])[CH2:9][C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[CH3:1])[CH2:17][CH2:16]1)=[O:20]
Reactant: COC(=O)C(N)CO
Reactant: Cc1ccc(C)c(CC(=O)N2CCC(C(=O)O)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)C(CO)NC(=O)C1CCN(C(=O)Cc2cc(C)ccc2C)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1-[(2,5-dimethylphenyl)acetyl]-4-piperidinecarboxylic acid (i.e. the product of Example 9, Step B) (1.44 g, 5.23 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.1 g, 5.75 mmol), and N-methylmorpholine (529 mg, 5.23 mmol) in 5 mL of dichloromethane was stirred at room temperature for 15 minutes. DL-Serine methyl ester hydrochloride (814 mg, 5.23 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction was partitioned between 1 N aqueous hydrochloric acid (10 mL) and dichloromethane (10 mL), and the organic layer was washed with 1 N aqueous hydrochloric acid, water and brine, dried over MgSO4 and concentrated under reduced pressure to give 1.61 g of the title compound.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH:8]=[C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[C:12]([C:27]2[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=2)[N:13]3[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:6]([C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=2)=[N:5]1)[CH3:3].[CH2:44]([NH:46][CH2:47][CH2:48][OH:49])[CH3:45]>>[CH2:44]([N:46]([CH2:31][C:30]1[CH:29]=[CH:28][C:27]([C:12]2[N:13]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:19])=[O:20])[C:14]3[C:10]([CH:11]=2)=[C:9]([C:7]2[C:6]([C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=4)=[N:5][N:4]([CH:2]([CH3:3])[CH3:1])[CH:8]=2)[CH:17]=[CH:16][CH:15]=3)=[CH:34][CH:33]=1)[CH2:47][CH2:48][OH:49])[CH3:45]
Reactant: CCNCCO
Reactant: CC(C)n1cc(-c2cccc3c2cc(-c2ccc(C=O)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Product: CCN(CCO)Cc1ccc(-c2cc3c(-c4cn(C(C)C)nc4-c4ccc([N+](=O)[O-])cc4)cccc3n2S(=O)(=O)c2ccccc2)cc1

Procedure:
Following the procedure described for Intermediate 101 using 4-[4-[1-(1-methylethyl)-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-indol-2-yl]benzaldehyde and 2-(ethylamino)ethanol (18.8 mmol) provided the title compound. ESMS [M+H]+: 665.4.
Reaction SMILES: C([O:3][C:4]1[C:8]([CH3:9])=[C:7]([C:10]([OH:12])=[O:11])[O:6][N:5]=1)C>Br>[OH:3][C:4]1[C:8]([CH3:9])=[C:7]([C:10]([OH:12])=[O:11])[O:6][N:5]=1
Reactant: CCOc1noc(C(=O)O)c1C
Agent: Br
Product: Cc1c(O)noc1C(=O)O
Yield: 23.8 %

Procedure:
3-Ethoxy-4-methylisoxazole-5-carboxylic acid (15 g, 88 mmol) and 47% HBr (aq) (150 mL) was boiled under reflux for 6 h. The solution was cooled and crystalline title compound was collected by filtration (8.7 g, 69%): mp 257-259° C. The acidic filtrate was added water (100 mL), and extracted with diethyl ether (6×400 mL). The organic extracts were washed with brine (100 mL), dried (MgSO4) and concentrated in vacuo to give crude title compound (3.0 g, 24%). Overall yield of 93%. A mixture of the two crops were used in the next step.
Reaction SMILES: [Li+].[Cl-].[CH3:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11](OS(C(F)(F)F)(=O)=O)=[CH:12]2)=[CH:7][CH:6]=1.[CH2:23]([Sn](CCCC)(CCCC)C=C)[CH2:24]CC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:13](=[CH:12][C:11]([CH:23]=[CH2:24])=[CH:10][CH:9]=2)[CH:14]=1
Reactant: COc1ccc2ccc(OS(=O)(=O)C(F)(F)F)cc2c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Product: C=Cc1ccc2ccc(OC)cc2c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
To a mixture of (Ph3P)2PdCl2 (1.752 g), LiCl (6.36 g), and trifluoromethanesulfonic acid 7-methoxy-naphthalen-2-yl ester (15.3 g) was added dropwise tributyl(vinyl)tin (19.02 g). The resulting mixture was stirred over 4 h at 90° C. The reaction was quenched with water and extracted with CH2Cl2. The organic layer was washed with water and dried over MgSO4. After concentration, the crude product was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to give the title compound as an oil (9 g).
Reaction SMILES: C1(S[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:15]=2)([CH3:13])[C:9]([O:11][CH3:12])=[O:10])C=CC=CC=1>C(O)(=O)C.C(OCC)(=O)C.[Zn]>[O:20]([C:16]1[CH:15]=[C:14]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])[CH:19]=[CH:18][CH:17]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)C(C)(Sc1ccccc1)c1cccc(Oc2ccccc2)c1
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)C(C)c1cccc(Oc2ccccc2)c1

Procedure:
330 mg of methyl 2-phenylthio-2-(3-phenoxyphenyl)propionate obtained in Example 8 was dissolved in 2 ml of acetic acid and the solution was heated while refluxing for 1 hour in the presence of 300 mg of zinc powder. After allowing the reaction mixture to cool, it was diluted with ethyl acetate and the remaining zinc powder was removed by filtration. The filtrate was concentrated to obtain methyl 2-(3-phenoxyphenyl)propionate in a quantative yield.