Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[N:14]1([CH2:20][C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[CH2:24][NH2:25])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.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.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.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]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:25][CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[C:21]([CH2:20][N:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[CH:22]=3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: NCc1cccc(CN2CCCCC2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(Cl)c2cc(NCc3cccc(CN4CCCCC4)c3)ccc12

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (70 mg, 0.27 mmol), 3-piperidin-1-ylmethyl-benzylamine (72 mg, 0.35 mmol), Pd2(dba)3 (25 mg, 0.027 mmol), rac-BINAP (51 mg, 0.081 mmol) and NaOt-Bu (76 mg, 0.81 mmol) in DMA (6 mL) was heated at 80° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(3-piperidin-1-ylmethyl-benzylamino)-2H-phthalazin-1-one: 16 mg (15.5%): m/z (M+H)=383. 1H-NMR (DMSO-d6) δ: 12.30 (s, 1H), 7.95 (d, 1H), 7.63 (m, 1H), 7.25 (m, 3H), 7.15 (m, 2H), 6.75 (s, 1H), 4.41 (d, 2H), 3.37 (s, 2H), 2.24 (m, 4H), 1.38 (m, 4H), 1.32 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl.CN(C)C1C=CN=CC=1>[C:19]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc2c(ccn2C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-cyanoindole (1.0 g, 7.0 mmol) in dichloromethane (8 mL) was added 4-(dimethylamino)pyridine (0.171 g, 1.4 mmol), triethylamine (1.96 mL, 1.42 g, 14 mmol) and benzoyl chloride (0.89 mL, 1.08 g, 7.7 mmol). The resulting mixture was stirred for 18 hours at room temperature. The mixture was diluted with dichloromethane (80 mL) and washed consecutively with a saturated solution of sodium hydrogencarbonate (40 mL) and brine (40 mL). The organic phase was dried with magnesium sulfate (1 hour). Filtration and concentration furnished the crude material which was purified by flash chromatography on silica gel, eluting with ethyl acetate/heptanes=2:3. 1-Benzoyl-1H-indole-5-carbonitrile was obtained as a solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Br:13])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[Br:14].C[N+]1([O-])CC[O:19]CC1>C(#N)C.[Cl-].[Na+].O>[Br:14][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([Br:13])[C:3]=1[CH:2]=[O:19])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)c(CBr)c(Br)c1
Reactant: C[N+]1([O-])CCOCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(Br)c(C=O)c(Br)c1
Temperature: 50 °C

Procedure:
Methyl 3,5-dibromo-4-(bromomethyl)benzoate (INTERMEDIATE 24) (3.9 g) was dissolved in acetonitrile (100 mL) and to this was added 4 Å molecular sieves and N-methylmorpholine N-oxide (1.18 g) and the reaction heated to 50° C. for 12 h. The reaction mixture was poured into brine and extracted into ethyl acetate, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography eluting with 90% hexane:10% ethyl acetate to give the title compound. 1H NMR (500 MHz, CDCl3): δ 10.27 (s, 1H); 8.29 (s, 2H); 3.99 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])=[O:27]>>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])=[O:27])[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COCCOCCOC(=O)CCCCCCCBr
Reactant: c1ccc(-c2nc[nH]c2-c2ccccc2)cc1
Product: COCCOCCOC(=O)CCCCCCCn1cnc(-c2ccccc2)c1-c1ccccc1

Procedure:
4,5-Diphenylimidazole (2.85 g) was treated with 2-(2-methoxy-ethoxy)ethyl 8-bromooctanoate (8.63 g) as described in Example 20 to give 2-(2-methoxyethoxy)ethyl 8-(4,5-diphenylimidazole-1-yl)octanoate as a colourless oil (i.5 g, 25%). Found: C, 72.28; H, 7.91; N, 6.35% C28H36N2O4 requires: C, 72.38; H, 7.81; N, 6.03%
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:21])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][C:15]=3F)=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.Cl.Cl.[NH:25]1[C:29]2=[N:30][CH:31]=[CH:32][C:33]([CH2:34][NH2:35])=[C:28]2[CH:27]=[CH:26]1>>[CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:21])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][C:15]=3[NH:35][CH2:34][C:33]3[CH:32]=[CH:31][N:30]=[C:29]4[NH:25][CH:26]=[CH:27][C:28]=34)=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1
Reactant: NCc1ccnc2[nH]ccc12
Reactant: CC1(C)CCNc2cc(NC(=O)c3cccnc3F)ccc21
Agent: Cl
Product: CC1(C)CCNc2cc(NC(=O)c3cccnc3NCc3ccnc4[nH]ccc34)ccc21

Procedure:
The titled compound was prepared from N-(4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-2-fluoro-nicotinamide and C-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine dihydrochloride by the method described in Step A of Example 1. MS (ES+): 427 (M+H). Calc'd. for C25H26N6O—426.52.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]([NH:7][C:8]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])=[O:6].C1(C)C(C)=CC=CC=1.Cl[CH2:32][C:33]([OH:35])=[O:34]>C(N(CC)CC)C>[ClH:22].[C:33]([CH2:32][N:3]([CH3:2])[CH2:4][C:5]([NH:7][C:8]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])=[O:6])([OH:35])=[O:34]
Reactant: O=C(O)CCl
Reactant: CNCC(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: CN(CC(=O)O)CC(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Yield: 104 %

Procedure:
4.6 g of 2-(methylamino-acetamido)-5-chlorobenzophenone hydrochloride were heated in 100 mls. of dry xylene with 3 g of triethylamine and 1.9 g of chloracetic acid for 8 hours under reflux whilst stirring. After cooling, the precipitated triethylamine hydrochloride was filtered off and the filtrate was shaken 3 times with 100 mls. of water each time. After drying over potassium carbonate and filtering, it was concentrated in vacuo, the oily crude base obtained being dissolved in 100 mls. of dry ether and filtered again. By passing in dry hydrogen chloride gas, filtering under suction and drying in a vacuum desiccator, 2.8 g (71% of theory) of 2-(4-carboxy-3-methyl-3-aza-butyramido)-5-chlorobenzophenone hydrochloride were obtained with a melting point of 162°-164°.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[C:3]=1[C:4]#[N:5].C([O-])(=O)C.[K+].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]=1[C:4]#[N:5]
Reactant: OB(O)c1ccccc1
Reactant: N#Cc1c(N)cccc1Br
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: N#Cc1c(N)cccc1-c1ccccc1
Temperature: 110 °C
Reaction time: 17 h

Procedure:
2-Amino-6-bromo-benzonitrile (1.0 Kg, 5.07 moles) and toluene (10 L, 10 vol) were added to a 20 L glass-lined reactor equipped with mechanical stirrer under inert atmosphere. Potassium acetate (996 g, 10.16 moles) and phenylboronic acid (866, 7.10 moles) were added into the solution and the solution was degassed with nitrogen for 30 min. After this time, dichloro-bis(triphenylphosphine) palladium (II) (17.8 g, 0.025 moles) was added to the reaction mixture at ambient temperature. The mixture was heated to 110° C., where it stirred for 17 h. At the conclusion of this period, the reaction progress was monitored by HPLC, which indicated the reaction was completed. The reaction mixture was filtered through a celite bed. The filtrate was transferred back to the reactor and concentrated hydrochloric acid (˜35%, 2 L, 2 vol) was charged to the reactor at ambient temperature. The HCl salt of the title compound precipitated out from the reaction and was collected by filtration. The HCl salt was transferred into the 20 L reactor and then made basic with 10% NaOH solution (pH 8-9). The resulting product was extracted with ethyl acetate (10 L, 10 vol). The ethyl acetate layer was washed with water (5 L, 5 vol) and then the solvent was evaporated under vacuum to give a residue. Hexanes (5 L, 5 vol) were added to the residue at 35-40° C., and the resulting slurry was cooled to ambient temperature. Once at the prescribed temperature, the product was collected by filtration to provide a pale yellow solid (802 g, 81.4%, 99% by HPLC). 1H NMR (DMSO-D6, 400 MHz, δ ppm); 7.43-7.52 (m, 5H), 7.33-7.37 (m, 1H), 6.83 (d, J=8 Hz, 1H), 6.62 (d, J=8 Hz, 1H), 6.1 (s, 2H). ES-MS: [M++1]=194.23.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=1.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.[Cl-].[NH4+]>C1COCC1>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]([C:7]2[CH:12]=[N:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[OH:21])=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COc1ccc(Br)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccc(F)cc2)cn1
Temperature: -65 °C

Procedure:
A 2.5M solution of n-BuLi in THF (181 mL, 0.452 mol) was added slowly to a stirred solution of 5-bromo-2-(methyloxy)pyridine (85 g, 0.452 mol) in THF (500 mL) cooled to −65° C. The internal temperature was maintained at or below −55° C. during the addition; when the addition was complete, a solution of 4-fluorobenzaldehyde (51 g, 0.411 mol) in THF (120 mL) was added slowly maintaining the temperature at or below −50° C. Saturated ammonium chloride solution (200 mL) was added and the mixture was warmed to −15° C. and concentrated at reduced pressure. The mixture was diluted with EtOAc (1 L) and washed twice with saturated ammonium chloride solution. The aqueous layers were back-extracted with EtOAc and the combined organic layers were washed with brine, dried and concentrated to afford the product as a light amber oil: 1H NMR (CDCl3) δ 8.14 (1H, d, J=2.5 Hz), 7.54 (1H, dd, J=8.6, 2.5 Hz), 7.36 (2H, dd, J=8.6, 5.4 Hz), 7.05 (2H, m), 6.73 (1H, d, J=8.6 Hz), 5.82 (1H, s), 3.94 (3H, s), 2.40 (1H, br).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:15]=[N:14][C:13](Cl)=[CH:12][C:11]=2[CH3:17])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[NH:19][NH2:20]>C(O)CCC>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:15]=[N:14][C:13]([NH:20][NH:19][C:18]([O:22][CH2:23][CH3:24])=[O:21])=[CH:12][C:11]=2[CH3:17])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Cc1cc(Cl)nnc1-c1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)NN
Solvent: CCCCO
Product: CCOC(=O)NNc1cc(C)c(-c2cccc([N+](=O)[O-])c2)nn1

Procedure:
A 2.49 g. portion of 6-(m-nitrophenyl)-5-methyl-3-chloropyridazine and 2.18 g. of ethyl carbazate in 50 ml. of butyl alcohol are stirred at reflux for 4 hours. The reaction mixture is concentrated free of solvent and the concentrate is shaken with ether and water. The resulting solid is recovered by filtration, washed with water and ether and dried, yielding ethyl 3-[6-(m-nitrophenyl)-5-methyl-3-pyridazinyl]carbazate as a cream colored solid, m.p. 186°-187° C.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])=[CH:7][C:6]=1[CH3:19])C(C)=O.[N+:20]([O-])(O)=O.N([O-])=O.[Na+].C1C=CC=CC=1>C(O)(=O)C.[Cl-].[Na+].O>[C:13]([C:12]1[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=1[C:8]1[CH:7]=[C:6]2[C:5](=[CH:10][CH:9]=1)[NH:1][N:20]=[CH:19]2)#[N:14]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(-c2ccccc2C#N)cc1C
Agent: O=N[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: N#Cc1ccccc1-c1ccc2[nH]ncc2c1
Temperature: 45 °C

Procedure:
2-(4-Acetamino-3-methylphenyl)benzonitrile (15.2 mmole, 3.8 g) was dissolved in 50 ml acetic acid and treated for 1 hour at room temperature with a scream of gaseous N2O5 generated by the addition of nitric acid to sodium nitrite. Benzene and brine were added to the reaction. The organic layer was separated, dried and warmed gently on a rotorvap (45° C.) for 1 hour. The solution was concentrated. Ether and saturated sodium bicarbonate were added. The organic phase was dried and concentrated. The residue was chromatographed over silica gel eluded with 50% ether in hexane to yield 240 mg of 5(2-cyanophenyl)indazole. (MS)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8](=[O:10])[CH3:9].C1C(=O)N([Br:21])C(=O)C1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8](=[O:10])[CH2:9][Br:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1Cl
Solvent: CC#N
Product: O=C(CBr)c1ccc([N+](=O)[O-])cc1Cl
Temperature: 80 °C
Yield: 23.6 %

Procedure:
A stirring solution of 3-chloro-4-acetyl-nitrobenzene (1.685 g, 8.44 mmol) (prepared as described in J. Med. Chem. 2005, 48, 6066) and paratoluenesulfonic acid (2.41 g, 12.66 mmol) in acetonitrile (100 mL) was treated with NBS (1.503 g, 8.44 mmol) and heated to 80° C. for 23 h. Another gram of NBS was added after 21 h. The reaction was cooled to room temperature and concentrated in vacuo. The residue was taken up in EtOAc and the organic layer was washed with water (2×), brine, and dried over MgSO4, filtered, and adsorbed on silica. Purification on silica by flash chromatography using a gradient of 0-40% EtOAc/hexane yielded 554 mg of the titled compound as a waxy solid (23% yield): 1H NMR (400 MHz, DMSO-d6) δ 4.95 (s, 2H), 8.09 (d, 1H), 8.35 (dd, 1H), 8.44 (d, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1([C:13]2[S:14][C:15]([C:18]3[CH:19]=[C:20]([N:25]([C:33]4[N:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][N:34]=4)C(=O)OC(C)(C)C)[CH:21]=[C:22]([CH3:24])[CH:23]=3)=[CH:16][N:17]=2)[CH2:11][CH2:10][C:9](=[O:12])[NH:8][CH2:7][CH2:6]1.C(O)(C(F)(F)F)=O>C(#N)C.O>[OH:1][CH2:2][CH2:3][O:4][C:5]1([C:13]2[S:14][C:15]([C:18]3[CH:19]=[C:20]([NH:25][C:33]4[N:38]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:36]=[CH:35][N:34]=4)[CH:21]=[C:22]([CH3:24])[CH:23]=3)=[CH:16][N:17]=2)[CH2:6][CH2:7][NH:8][C:9](=[O:12])[CH2:10][CH2:11]1
Reactant: Cc1cc(-c2cnc(C3(OCCO)CCNC(=O)CC3)s2)cc(N(C(=O)OC(C)(C)C)c2nccc(C(F)(F)F)n2)c1
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(OCCO)CCNC(=O)CC3)s2)c1
Temperature: 125 °C
Yield: 79.8 %

Procedure:
A bi-phasic mixture of the product from Step 1 (15 mg, 0.02 mmol) in acetonitrile and water with 0.05% TFA (reverse-phase HPLC solvent system) was heated at 125° C. for 10 minutes. The reaction was concentrated in vacuo, and the residual oil was partitioned between EtOAc (2×40 ml) and saturated aqueous NaHCO3 (55 ml). The combined organic layers were dried over MgSO4, filtered and concentrated to afford the desired title product (8.1 mg, 77%) as a yellow oil. MS ESI: [M+H]+ m/z 508.2 1H NMR (500 MHz, DMSO) δ 10.3 (m, 1H), 8.82 (m, 1H), 8.04 (m, 1H), 7.98 (s, 1H), 7.54 (m, 1H), 7.45 (s, 1H), 7.17 (s, 1H), 4.68 (m, 1H), 3.98 (m, 2H), 3.55 (m, 2H), 3.00-2.79 (m, 2H), 2.38 (s, 3H), 2.37-1.82 (m, 3H), 1.37-1.01 (m, 3H). rhSYK activity=+++
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:9]1(=O)[O:14][C:12](=[O:13])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[C:11]3[C:10](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]2=[O:14])=[N:6][CH:7]=1
Reactant: Cc1ccc(N)nc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(N2C(=O)c3ccccc3C2=O)nc1

Procedure:
A mixture containing 5-methylpyridin-2-amine (5.4 g, 50 mmol), phthalic anhydride (8.88 g, 60 mmol) and DIEA (19 ml, 110 mmol) in toluene (30 ml) is refluxed for 18 hours, and cooled. The solvent is removed by rotary evaporation. The crude product is purified by silica gel flash chromatography to afford 2-(5-methylpyridin-2-yl)isoindoline-1,3-dione as a dark brown oil. LC-MS m/z: 239.1 (M+1).
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:42])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:35])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:33]=[C:32]3[C:28]([CH:29]=[CH:30][NH:31]3)=[CH:27][CH:26]=2)=[O:22])=[CH:17][C:16]=1[Cl:34].[N:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=[C:45]([CH:53]=O)[CH:44]=1>ClCCl>[CH3:9][O:10][C:11](=[O:42])/[C:12](/[NH:13][C:14](=[O:35])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:33]=[C:32]3[C:28]([CH:29]=[CH:30][NH:31]3)=[CH:27][CH:26]=2)=[O:22])=[CH:17][C:16]=1[Cl:34])=[CH:53]/[C:45]1[CH:44]=[N:43][C:52]2[C:47]([CH:46]=1)=[CH:48][CH:49]=[CH:50][CH:51]=2
Reactant: O=Cc1cnc2ccccc2c1
Reactant: COC(=O)C(NC(=O)c1ccc(C(=O)NCc2ccc3cc[nH]c3c2)cc1Cl)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Solvent: ClCCl
Product: COC(=O)/C(=C/c1cnc2ccccc2c1)NC(=O)c1ccc(C(=O)NCc2ccc3cc[nH]c3c2)cc1Cl
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
1,1,3,3-Tetramethylguanidine (102 mg, 0.9 mmol) was added to a solution of rac.-N-[2-chloro-4-[[[(1H-indol-6-yl)methyl]amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 136; 300 mg, 0.6 mmol) in dichloromethane (10 mL) at ˜5° C. The solution was stirred at ˜5° C. for 30 min and then quinoline-3-carboxaldehyde (186 mg, 1.2 mmol) was added. The solution was stirred overnight at room temperature, then it was washed with cold 1N hydrochloric acid solution and brine, dried, filtered and evaporated to give a mixture (230 mg) of (Z)-2-[[2-chloro-4-[[[(1H-indol-6-yl)methyl]amino]carbonyl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid methyl ester and unreacted quinoline-3-carboxaldehyde. This mixture was dissolved in tetrahydrofuran/methanol (3:1; 4 mL) and the solution was added to a solution of lithium hydroxide monohydrate (28 mg, 0.7 mmol) in water (1 mL). The solution was allowed to stir at room temperature for 5 days and then concentrated to remove tetrahydrofuran and methanol. The remaining solution was diluted with water and acidified with 1N hydrochloric acid solution. The resulting mixture was extracted with ethyl acetate and the organic extracts were washed with brine, dried (MgSO4), filtered, concentrated and purified by reverse phase HPLC (5-95% acetonitrile/water with 0.1% trifluoroacetic acid). The appropriate fractions were combined and evaporated and the purified acid was lyophilized to give (Z)-2-[[2-chloro-4-[[[(1H-indol-6-yl)methyl]amino]carbonyl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid (37 mg, 12% yield).
Reaction SMILES: [C:1]([C:5]1[CH:29]=[CH:28][C:8]([C:9]([NH:11][C:12]2[C:13]([O:26]C)=[N:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=3)[CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[C:13](=[O:26])[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=3)[CH:17]=2)=[O:10])=[CH:28][CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ncc(-c2ccnc(SC)n2)cc1NC(=O)c1ccc(C(C)(C)C)cc1
Solvent: O
Solvent: C1COCCO1
Product: CSc1nccc(-c2c[nH]c(=O)c(NC(=O)c3ccc(C(C)(C)C)cc3)c2)n1
Temperature: 25 °C
Yield: 25.3 %

Procedure:
4-tert-Butyl-N-[2-methoxy-5-(2-methylsulfanyl-pyrimidin-4-yl)-pyridin-3-yl]-benzamide (120 mg, 0.29 mmol) was dissolved in 1,4-dioxane (6 mL) and water (1.2 mL). Concentrated Hcl (600 μL) was added and the reaction mixture was heated to reflux for 30 minutes. The reaction mixture was cooled down to room temperature and water was added. The obtained precipitate was isolated by filtration and dried under vacuum. The crude solid was purified by flash chromatography to give the title compound as a fawn solid (29 mg, 25% yield). MS (ES+) m/e=395. 1H NMR (DMSO-d6) δH 1.33 (9H, s), 2.58 (3H, s), 7.59 (2H, d), 7.64 (1H, d), 7.88 (2H, d), 8.21 (1H, s), 8.58 (1H, d), 9.11 (1H, s), 9.30 (1H, s), 12.72 (1H, br s).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH3:12][Si](Cl)(C)C>CO>[CH3:12][O:2][C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)=[O:3]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
The 4-carboxybenzaldehyde is of commercial origin. It is dissolved (3 g; 20 mmol) in a trimethylsilyl chloride solution (10 g; 92 mmol) in 100 ml of MeOH. The mixture is kept stirred for 40 h at room temperature. After evaporation, a white solid corresponding to 4-methoxycarbonylbenzaldehyde 24 is isolated, characterized by NMR and used as it is for the next reaction.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl.N1CCCCC1.[OH-].[Na+]>ClCCl>[O:19]1[CH2:18][CH:17]1[CH2:15][O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(c2cccc(O)c2)=NN1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCNCC1
Product: O=C1CCC(c2cccc(OCC3CO3)c2)=NN1
Yield: 60.9 %

Procedure:
A mixture of finely powdered 6-(3-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (21.6 g, 0.11 mole), epichlorohydrin (90 ml, 1.1 mole), and piperidine (1 ml) was heated on a steam bath for 90 minutes. Evaporation of the solution under reduced pressure gave an oil which was dissolved in dichloromethane and stirred with dilute sodium hydroxide solution (60 ml). The organic phase was washed with water, dried, and evaporated under reduced pressure to a viscous oil (27 g, 96%). Purification on a silica column by eultion with chloroform gave 6-[3-(2,3-epoxypropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (16.5 g, 59%) as an oil which, when treated with ether, gave a white solid (13.7 g, 49%, m.p. 108°-112° C). The pure epoxide, recrystallised from methanol-petroleum ether (b.p. 60°-80° C), had m.p. 110°-112° C. (Found: C, 63.96; H, 5.70; N, 11.43; M+ , 246. C13H14N2O3 requires: C, 63.39; H, 5.73; N, 11.38%; M, 246).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][O:7][CH2:8][C:9]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][NH:12][C:11](=O)[CH2:10]1>C(OCC)C>[F:30][C:2]([F:1])([F:31])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][O:7][CH2:8][C:9]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: O=C1CC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CCCN1
Solvent: CCOCC
Product: FC(F)(F)c1cc(COCC2(c3ccccc3)CCCNCC2)cc(C(F)(F)F)c1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
The mixture of Isomer A of 4-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-4-phenylazepan-2-one (90 mg, 0.20 mmol) in borone.THF complex solution (1.5 M in diethyl ether, 1.08 mL) was stirred at room temperature overnight and then at 65° C. for 1 hr. After cooling down, the mixture was concentrated under vacuum and methanol (0.4 mL) and 1N HCl solution (0.4 mL) was added and the mixture was stirred at 65° C. for 2 hr. After cooling down, the mixture was concentrated under vacuum and neutralized with 1N NaOH solution and extracted with dichloromethane 3 times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum to give the product as a clear colorless sticky oil (quantitative yield).