Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:24])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[NH:18][CH:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH:33]1[CH2:35][CH2:34]1>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:24])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:32][CH:33]3[CH2:35][CH2:34]3)[CH:17]=[CH:16]4)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: BrCC1CC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)ccc2c1
Temperature: 70 °C
Reaction time: 24 h
Yield: 59.8 %

Procedure:
A mixture of the product of Example 11 (100 mg), potassium carbonate (174 mg) and (bromomethyl)cyclopropane (63 mg) in DMF (2 mL) was stirred at room temperature for 16 hours and at 70° C. for 24 hours. Further (bromomethyl)cyclopropane (300 mg) was added and the mixture heated at 70° C. for a further 24 hours. The reaction mixture was filtered and purified by HPLC to give the title compound (70 mg) as a solid.
Reaction SMILES: [CH2:1]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])P(=O)(OCC)OCC.[H-].[Na+].[CH:20]([C:22]1[C:23]([NH:33][C:34](=[O:55])[C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][C:43]3[N:44]=[C:45]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[O:46][C:47]=3[CH3:48])=[CH:37][CH:36]=2)=[N:24][N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:26]=1)=O.O>CN(C)C=O>[CH3:48][C:47]1[O:46][C:45]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)=[N:44][C:43]=1[CH2:42][O:41][C:38]1[CH:39]=[CH:40][C:35]([C:34]([NH:33][C:23]2[C:22](/[CH:20]=[CH:1]/[P:10](=[O:17])([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16])=[CH:26][N:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:24]=2)=[O:55])=[CH:36][CH:37]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(C(=O)Nc2nn(-c3ccccc3)cc2C=O)cc1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1NC(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)OCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 37 %

Procedure:
To a solution (5 mL) of tetraethyl methylenediphosphonate (265 mg) in N,N-dimethylformamide was added sodium hydride (60% in oil, 40 mg) and the mixture was stirred at room temperature for 20 min. A solution (5 mL) of N-(4-formyl-1-phenyl-1H-pyrazol-3-yl)-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzamide (400 mg) in N,N-dimethylformamide was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1 to 1:0, v/v) to give diethyl (E)-2-[3-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzoyl}amino)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate as colorless amorphous form (195 mg, yield 37%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10]/[C:9]/2=[N:14]\[C:15]#[N:16])=[CH:4][CH:3]=1.[Cl:17][C:18]1[S:22][C:21]([C:23]([NH:25][CH2:26][C:27]2[N:28]=[CH:29][NH:30][CH:31]=2)=[O:24])=[CH:20][CH:19]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[Cl:17][C:18]1[S:22][C:21]([C:23]([NH:25][CH2:26][C:27]2[N:28]=[CH:29][N:30]([C:2]3[CH:7]=[CH:6][C:5]([N:8]4[CH:13]=[CH:12][CH:11]=[CH:10]/[C:9]/4=[N:14]\[C:15]#[N:16])=[CH:4][CH:3]=3)[CH:31]=2)=[O:24])=[CH:20][CH:19]=1
Reactant: N#C/N=c1\ccccn1-c1ccc(I)cc1
Reactant: O=C(NCc1c[nH]cn1)c1ccc(Cl)s1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: N#C/N=c1\ccccn1-c1ccc(-n2cnc(CNC(=O)c3ccc(Cl)s3)c2)cc1
Temperature: 130 °C
Yield: 29.5 %

Procedure:
A mixture of (E)-(1-(4-iodophenyl)pyridin-2(1H)-ylidene)cyanamide (25 mg, 0.078 mmol), 5-Chloro-N-((1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 3-1 (65 mg, 0.18 mmol), 8-hydroxyquinoline (10 mg, 0.069 mmol) and K2CO3 (75 mg, 0.54 mmol) in DMSO (1 mL) was degassed with Ar before being charged with CuI (15 mg, 0.079 mmol). The mixture in a sealed tube was heated at 130° C. overnight. It was then purified by HPLC to give the titled compound (10 mg). MS 435.1 and 437.0 (M+H, Cl pattern).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N:10]=[C:11]=[S:12].[CH3:13][C:14]1[C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=[CH:16][N:15]=1.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]([NH:21][CH2:20][C:19]1[C:14]([CH3:13])=[N:15][CH:16]=[CH:17][CH:18]=1)=[S:12]
Reactant: Fc1ccc(N=C=S)c(Cl)c1Cl
Reactant: Cc1ncccc1CN
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Solvent: CC#N
Product: Cc1ncccc1CNC(=S)Nc1ccc(F)c(Cl)c1Cl

Procedure:
The title compound was prepared from 2,3-dichloro-4-fluorophenylisothiocyanate and C-(2-methylpyridin-3-yl)methylamine using General Procedure 1. 1H NMR (DMSO-d6, 400 MHz) 2.47 (s, 3H), 4.69 (m, 2H), 7.21 (dd, 1H, J=4.9 Hz, J=7.6 Hz), 7.46 (t, 1H, J=8.9 Hz), 7.54-7.67 (bs, 1H), 7.58 (dd, 1H, J=1.4 Hz, J=7.7 Hz), 8.26-8.42 (bs, 1H), 8.33 (dd, 1H, J=1.7 Hz, J=4.8 Hz), 9.49 (s, 1H); RP-HPLC (Hypersil®-100 C18, 5 μm, 100 Å, 10 cm; 5%-100% acetonitrile-0.1M ammonium acetate over 5 min, 2 mL/min), then 100% acetonitrile isocratic 1 minutes, Rt 3.69 min. (90.8%); MS: M+H− 342.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[CH3:8][C:9](=O)[CH2:10][CH2:11][C:12](=O)[CH3:13]>>[C:2]([NH:6][N:7]=[C:9]([CH2:10][CH2:11][C:12](=[N:7][NH:6][C:2]([CH3:5])([CH3:4])[CH3:3])[CH3:13])[CH3:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(=O)CCC(C)=O
Reactant: CC(C)(C)NN
Agent: Cl
Product: CC(CCC(C)=NNC(C)(C)C)=NNC(C)(C)C
Yield: 60 %

Procedure:
The procedure of Example (a) is followed using about 67.6 g (0.54 mole) of t-butyl hydrazine hydrochloride and about 28.5 g (0.25 mole) of 2,5-hexane-di-one. The title compound is isolated as a fraction distilled at about 106° C.-114° C. under 1.0 mm Hg pressure. The yield is about 60 percent based upon the initial amount of hexane-di-one.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[NH2:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[C:9]([OH:14])[N:8]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:6][C:7]1[C:12]([F:13])=[CH:11][N:10]([CH2:2][CH:3]2[CH2:5][CH2:4]2)[C:9](=[O:14])[N:8]=1
Reactant: Nc1nc(O)ncc1F
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(=O)n(CC2CC2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a solution of (bromomethyl)cyclopropane (1.0 g, 7.4 mmol) in DMF (20 mL) was added molecular sieves (—2 g), and the resulting mixture was stirred at room temperature. After 1 h, 4-amino-5-fluoropyrimidin-2-ol (1.9 g, 14.8 mmol) and K2CO3 (5.1 g, 37 mmol) were added, and the reaction mixture was heated at 90° C. for 12 h. After cooling to room temperature, the crude reaction mixture was filtered through a Büchner funnel, and the solid residue was washed with EtOAc. The collected filtrate was concentrated in vacuo to give a residue which was purified by normal phase chromatography (isocratic, 5% MeOH/EtOAc). Following recrystallization from methyl tert-butylether, 4-amino-1-(cyclopropylmethyl)-5-fluoropyrimidin-2(1H)-one (1.12 g, 83%) was isolated as a white solid: mp 224-226° C.; 1H NMR (400 MHz, methanol-d4) δ 7.86 (d, J=6.2 Hz, 1H), 3.61 (d, J=7.2 Hz, 2H), 1.24 (ddd, J=12.8, 7.6, 4.8 Hz, 1H), 0.65-0.50 (m, 2H), 0.39 (q, J=4.8 Hz, 2H); ESIMS m/z 184 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](Cl)=[N:4][CH:3]=1.CO.[CH2:15]([NH2:17])[CH3:16]>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:17][CH2:15][CH3:16])=[N:4][CH:3]=1
Reactant: Clc1ncc(Br)c2ccccc12
Reactant: CCN
Solvent: CO
Product: CCNc1ncc(Br)c2ccccc12
Temperature: 50 °C
Yield: 88 %

Procedure:
To a suspension of 4-bromo-1 chloroisoquinoline (0.831 g, 3.43 mmol) in MeOH (10.3 mL, 254 mmol) was added ethylamine (70% in water, 1.1 mL). The mixture was heated at 50° C. for 16 h. The mixture was concentrated. The residue was partitioned between water (20 mL) and DCM (20 mL). DCM layer was separated. The aqueous layer was extracted with DCM (10 mL) The combined DCM solutions were dried (Na2SO4). Filtration and concentration gave 4-bromo-N-ethylisoquinolin-1-amine (0.761 g, 88%). LCMS: M+H+=251.
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[CH2:12]([O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[OH:23])[CH2:13][CH:14]=[CH2:15]>C(Cl)Cl>[CH2:12]([O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=[O:23])[CH2:13][CH:14]=[CH2:15]
Reactant: C=CCCOC1CCCCC1O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C=CCCOC1CCCCC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of PCC (26.6 g, 123 mmol) in CH2Cl2 (160 mL) was added 2-(but-3-en-1-yloxy)cyclohexanol (7 g, 41 mmol) in CH2Cl2 (10 mL). The reaction was stirred at rt overnight. The mixture was filtered through a pad of celite and washed with CH2Cl2. The residue was purified by column chromatography to give the title compound. 1H NMR (500 MHz, CDCl3) δ 5.75-5.90 (m, 1H), 4.95-5.15 (m, 2H), 3.78 (dd, 1H, J=5.37 Hz, 9.76 Hz), 3.65-3.70 (m, 1H), 3.39-3.45 (m, 1H), 1.05-2.58 (m, 10H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.C1(C)C=CC(S([N:22]=[N+:23]=[N-])(=O)=O)=CC=1>C1COCC1.C(N(CC)CC)C>[N+:22](=[C:3]1[C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]1=[O:12])=[N-:23]
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: [N-]=[N+]=C1C(=O)Oc2ccccc2C1=O
Yield: 70.6 %

Procedure:
To a 100 mL round-bottom flask fitted with a mechanical stirrer, nitrogen inlet and bubbler was charged 4-hydroxycoumarin (3.1 g, 18.8 mmol) dissolved in dry THF (21.6 g) and triethylamine (1.8 g). A solution of p-toluenesulfonyl azide (5.3 g, 28.3 mmol) in dry THF (14.4 g) was then added to this solution dropwise over a period of 15 minutes. The reaction was continued until all of 4-hydroxycoumarin had reacted as monitored by HPLC (ca. 2.0 hours). The precipitated reaction product was filtered on a small Buchner funnel and the filtrate was packed in powdered dry ice to produce a second crop of crystals which were also isolated by filtration. The combined filtercakes were dried overnight under vacuum at 60° C. to obtain orange colored crystals of 3-diazo-4-oxo-3,4-dihydrocoumarin; yield 2.5 g (70.6% yield). The crude product was further purified by dissolving it in 75.0 g of acetone and precipitating by pouring into 150.0 g ice-water yielding pale yellow crystals. The product was characterized by 13C NMR, and DSC. A sample recrystallized from acetone-water melted at 159.5° C.; 13C-NMR in DMSO-d6 solvent showed 9 singlet lines at the following chemical shifts, in ppm: 173.748, 157.754, 153.316, 136.239, 125.231, 125.063, 118.696, 117.741, 77.022.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2([CH3:52])[C:27]3[N:23]([C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:25][N:26]=3)[C:22]3[CH:34]=[CH:35][CH:36]=[CH:37][C:21]=3[N:20]([CH2:38][C:39](=[O:50])[N:40]([CH:47]([CH3:49])[CH3:48])[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:19]2=[O:51])=[CH:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2([CH3:52])[C:27]3[N:23]([C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:25][N:26]=3)[C:22]3[CH:34]=[CH:35][CH:36]=[CH:37][C:21]=3[N:20]([CH2:38][C:39]([N:40]([CH:47]([CH3:48])[CH3:49])[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:50])[C:19]2=[O:51])=[CH:9]1
Reactant: CC(C)N(C(=O)CN1C(=O)C(C)(Cc2cn(C(=O)OC(C)(C)C)c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)N(C(=O)CN1C(=O)C(C)(Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 50 h

Procedure:
To a solution of 3-{6-[(isopropyl-phenyl-carbamoyl)-methyl]-4-methyl-5-oxo-1-phenyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulen-4-ylmethyl}-indole-1-carboxylic acid tert-butyl ester in dioxane (1 mL) was added HCl (4.0M in dioxane, 550 μL) and the reaction was stirred at room temperature for 50 hours. The volatiles were concentrated in vacuo and the residue was dissolved in CH2Cl2. The organic solution was washed with aqueous NaHCO3 (1×), dried (Na2SO4), filtered and concentrated. Purification by preparative chromatography eluting with 40% acetone in CH2Cl2 provided 17 mg of 2-[4-(1H-indol-3-ylmethyl)-4-methyl-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-phenyl-acetamide. 1H NMR (CD2Cl2) δ 8.37 (s, 1H), 7.78 (m, 1H), 7.53-7.23 (m, 13H), 7.11 (m, 2H, 7.02 (t, 1H), 6.90 (d, 1H), 5.03 (m, 1H), 4.33 (d, 1H), 3.76-3.58 (m, 1H), 2.83 (m, 2H), 1.75 (s, 3H), 1.11 (m, 6H); MS 595.2 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([N+:11]([O-])=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1>[Pd].C(O)C>[NH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][N:2]2[CH3:1]
Reactant: Cn1ccc2c([N+](=O)[O-])cccc21
Agent: [Pd]
Solvent: CCO
Product: Cn1ccc2c(N)cccc21
Reaction time: 2 h
Yield: 106 %

Procedure:
A mixture of the nitroindole (D9) (0.5 g; 2.8 mM) and 5% palladium on charcoal in ethanol (75 ml) was hydrogenated at 60 p.s.i. (4.14×105Pa) at room temperature for 2 h. Removal of the catalyst by filtration followed by evaporation of the solvent gave the title compound (0.44 g; 97%).
Reaction SMILES: [CH2:1]([N:7]([CH3:38])[C:8]([C@@H:10]1[CH2:14][C@H:13]([O:15][C:16]2[C:25]3[C:20](=[C:21]([CH3:28])[C:22]([O:26][CH3:27])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:29]3[S:30][CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[N:33]=3)[CH:17]=2)[CH2:12][NH:11]1)=[O:9])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[C:39](N1C=CN=C1)([N:41]1[CH:45]=[CH:44][N:43]=[CH:42]1)=[O:40]>ClCCl>[CH2:1]([N:7]([CH3:38])[C:8]([C@@H:10]1[CH2:14][C@H:13]([O:15][C:16]2[C:25]3[C:20](=[C:21]([CH3:28])[C:22]([O:26][CH3:27])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:29]3[S:30][CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[N:33]=3)[CH:17]=2)[CH2:12][N:11]1[C:39]([N:41]1[CH:45]=[CH:44][N:43]=[CH:42]1)=[O:40])=[O:9])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCCN(C)C(=O)[C@@H]1C[C@H](Oc2cc(-c3nc(C(F)(F)F)cs3)nc3c(C)c(OC)ccc23)CN1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: C=CCCCCN(C)C(=O)[C@@H]1C[C@H](Oc2cc(-c3nc(C(F)(F)F)cs3)nc3c(C)c(OC)ccc23)CN1C(=O)n1ccnc1
Reaction time: 0.67 h
Yield: 99 %

Procedure:
Compound 127 (18.35 g) was dissolved in anhydrous dichloromethane (37 mL) under argon. 1,1′-Carbonyldiimidazole (2 eq.) was added at room temperature. The reaction mixture was stirred for 40 min. The mixture was diluted with DCM, washed with water, dried over Na2SO4, and concentrated under vacuum. Compound 128 (19.39 g) was recovered as a pale yellow foam in 99% yield over two steps and in 98% purity (HPLC).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li]CCCC.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23](Cl)=[O:24])=[CH:15]1>C1COCC1.CCCCCC>[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]([O:8][CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:24])=[CH:15]1
Reactant: O=C(Cl)c1c[nH]c2ccccc12
Reactant: OCCN1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(OCCN1CCCC1)c1c[nH]c2ccccc12
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a dry THF solution of 2-(1-pyrrolidinyl)ethanol (1.10 g, 9.6 mmol) was dropwise added under ice-cooling a 1.5M hexane solution of n-BuLi (6.4 ml, 9.6 mmol) over a period of 10 min. followed by stirring for 30 min. The solvent was removed under reduced pressure. To the residue was added dry THF (20 ml). To the resulting pale yellow suspension was added a dry THF solution (5 ml) of indole-3-carboxylic acid chloride (1.00 g, 5.6 mmol) with stirring at room temperature over a period of 10 min. After stirring overnight, a reaction solution was then concentrated under reduced pressure. The residue was extracted with diluted hydrochloric acid followed by washing with ether. The aqueous layer was adjusted with saturated aqueous sodium bicarbonate to a pH of >10 and again extracted with ether. The organic layer was washed successively with water and saturated aqueous sodium chloride, then dried (MgSO4) and concentrated under reduced pressure to give 1.10 g of the title compound as colorless plates. m.p. 145°-146° C.;
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:10]([CH2:11][C:12]([OH:14])=[O:13])[N:9]=[N:8][N:7]=2)=[CH:2]1.S(=O)(=O)(O)O.[CH3:20][O:21][CH2:22][CH2:23]O>>[CH3:20][O:21][CH2:22][CH2:23][O:13][C:12](=[O:14])[CH2:11][N:10]1[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[N:7][N:8]=[N:9]1
Reactant: COCCO
Reactant: O=C(O)Cn1nnnc1-c1ccsc1
Agent: O=S(=O)(O)O
Product: COCCOC(=O)Cn1nnnc1-c1ccsc1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 82.3 %

Procedure:
To a solution of 2 g (9.51 mM) of [5-(3-thienyl)tetrazol-1-yl]acetic acid in 10 ml of 2-methoxyethanol was added 1 ml of sulfuric acid. After the addition, the mixture was stirred at 90° C. for 2.5 hrs. The mixture was then poured into ice-water and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent: chloroform/ethyl alcohol=30/1) for separation and purification, to give 2.1 g (yield 82.3%) of [5-(3-thienyl)tetrazol-1-yl]acetic acid 2-methoxyethyl ester.
Reaction SMILES: Cl.NCCS.C(N(CC)CC)C.[C:13]([NH:20][C@H:21]([CH:23]=[O:24])[CH3:22])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>CN(C)C=O>[C:13]([NH:20][C@H:21]([CH2:23][OH:24])[CH3:22])([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14]
Reactant: C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: Cl
Agent: NCCS
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H](CO)NC(=O)OC(C)(C)C

Procedure:
6.82 g (60 mmoles) of cysteamine hydrochloride is dissolved in 50 ml of dimethylformamide, and the solution is neutralized with 8.4 ml of triethylamine. The solution is mixed with a solution of crude Boc-L-alaninal obtained by oxidizing 8.75 g (50 mmoles) of Boc-alaninol in 50 ml of dimethylformamide, and mixture is stirred overnight at room temperature. The solvent is distilled off under reduced pressure, the formed crystals are dissolved in ethyl acetate, the solution is washed with 10% citric acid and saturated aqueous sodium bicarbonate, and the ethyl acetate layer is dried. The solvent is distilled off under reduced pressure to obtain 4.93 g (42.6%) of the desired compound 9-A as white crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][CH:10]=[C:9]([OH:20])[CH:8]=2)=[O:4].CSC.B(Br)(Br)Br.C(=O)(O)[O-].[Na+].Cl>ClC(Cl)C>[OH:20][C:9]1[CH:8]=[C:7]2[C:12]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:5]([C:3]([OH:4])=[O:2])[C:6]2=[O:21])=[CH:11][CH:10]=1
Reactant: COC(=O)C1=C(c2ccccc2)c2ccc(O)cc2C1=O
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(Cl)Cl
Solvent: CSC
Product: O=C(O)C1=C(c2ccccc2)c2ccc(O)cc2C1=O
Temperature: 90 °C
Yield: 48.6 %

Procedure:
6-Hydroxy-1-oxo-3-phenyl-1H-indene-2-carboxylic acid methyl ester (2.6 g, 9.28 mmol) obtained in Step 1 was dissolved in dichloroethane, and boron tribromide methyl sulfide (6.0 mL, 27.84 mmol) was added thereto. The mixture was refluxed for 2 hrs at 90° C., cooled in an ice bath, neutralized using sodium bicarbonate, and adjusted to pH 2 using 6N hydrochloric acid. The resulting mixture washed successively with dichloromethane and water. The organic layer was separated, dried over anhydrous MgSO4, concentrated under a reduced pressure and recrystallized to obtain 1.2 g of the titled compound (yield: 48.6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[C:5](/[CH:10]=[CH:11]/[C:12]([CH2:14][C:15](/[CH:17]=[CH:18]/[C:19]2[CH:27]=[C:24]([O:25][CH3:26])[C:22]([OH:23])=[CH:21][CH:20]=2)=[O:16])=[O:13])[CH:4]=1.[C:28](O)(=[O:50])/[CH:29]=[CH:30]\[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=[CH:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl.O>[C:28]([O:9][C:8]1[CH:7]=[CH:6][C:5]([CH:10]=[CH:11][C:12](=[O:13])[CH2:14][C:15](=[O:16])[CH:17]=[CH:18][C:19]2[CH:20]=[CH:21][C:22]([OH:23])=[C:24]([O:25][CH3:26])[CH:27]=2)=[CH:4][C:3]=1[O:2][CH3:1])(=[O:50])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=[CH:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]
Reactant: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)c(OC)c2)ccc1O
Reactant: CCCCCCCCCC=CC=CC=CC=CC=C/C=C\C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)Oc1ccc(C=CC(=O)CC(=O)C=Cc2ccc(O)c(OC)c2)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.5 %

Procedure:
To a solution of curcumin (300 mg, 0.81 mmol), cis-docosahexaenoic acid (275 mg, 0.83 mmol) and catalytic amount of 4-(dimethylamino)pyridine in DCM (10 mL) was added a solution of N,N′-dicyclohexylcarbodiimide (252 mg, 1.2 mmol) in DCM (5 mL) for 5 min at ice cold temperature. The mixture was stirred at rt for 16 h and diluted with water. DCM layer was separated and the aqueous layer was extracted with DCM (3×100 mL). The combined DCM layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and the residue was chromatographed over silica gel column using hexane-ethyl acetate mixture (90:10) as an eluent to give the product as oil (250 mg, 45%). IR (neat) νmax 3015, 2960, 2930, 1761, 1631, 1593, 1269, 1120, 1031, 972 cm−1; 1H NMR (CDCl3) δ 7.61 (1H, d, J=16.0 Hz, H-1), 7.60 (1H, d, J=15.6 Hz, H-7), 7.03-7.16 (5H, m, H-2′, 2″, 5′, 6′, 6″), 6.93 (1H, d, J=8.4 Hz, H-5″), 6.55 (1H, d, J=16 Hz, H-2), 6.49 (1H, d, J=16 Hz, H-6), 5.89 (1H, br s, Ar—OH), 5.83 (1H, s, H-4), 5.38-5.39 (12H, m, H-4′″, 5′″, 7′″, 8′″, 10′″, 11′″, 13′″, 14′″, 16′″, 17′″, 19′″, 20′″), 3.95 (3H, s, Ar—OCH3), 3.87 (3H, s, Ar—OCH3), 2.84-2.86 (10H, m, H-6′″, 9′″, 12′″, 15′″, 18′″), 2.58-2.66 (2H, m, H-2″), 2.22-2.23 (2H, m, H-21″), 2.05-2.09 (2H, m, H-3′″), 0.97 (3H, t, J=7.4 Hz, H-22′″); LCMS (ESI, negative ion mode): m/z 677 (M-H)−.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:11](I)=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH2:24]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][C:35]#[CH:36])[CH2:28][CH2:27]1)[CH3:25]>>[Cl:1][C:2]1[C:3]2[C:11]([C:36]#[C:35][CH2:34][CH2:33][CH2:32][N:29]3[CH2:28][CH2:27][N:26]([CH2:24][CH3:25])[CH2:31][CH2:30]3)=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: COc1c(C)cnc(Cn2cc(I)c3c(Cl)nc(N)nc32)c1C
Reactant: C#CCCCN1CCN(CC)CC1
Product: CCN1CCN(CCCC#Cc2cn(Cc3ncc(C)c(OC)c3C)c3nc(N)nc(Cl)c23)CC1

Procedure:
Sonogashira coupling of 4-chloro-5-iodo-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo [2,3-d]pyrimidin-2-amine with 1-ethyl-4-(pent-4-ynyl)piperazine, according to the general procedure A gave the title compound, as a solid. Mp=142.3-144.1° C. HPLC Rt=4.11 min.