Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8](O)=[O:9].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.O>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:8][OH:9]
Reactant: N[C@@H]1CCCC[C@H]1C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: N[C@@H]1CCCC[C@H]1CO
Temperature: 85 °C
Reaction time: 24 h
Yield: 72.3 %

Procedure:
To a stirred solution of (1R,2R)-2-aminocyclohexanecarboxylic acid (500 mg, 3.49 mmol) in anhydrous THF (3 mL) at 0° C. was added dropwise a solution of LAH (2M solution in THF, 7 mL, 13.99 mmol). The reaction vessel was sealed and the mixture was stirred at 85° C. for 24 h. The mixture was cooled to 0° C. and diluted with THF (6 mL). To the reaction mixture was added sequentially water (0.5 mL), 1M aq NaOH (0.5 mL), and water (1.5 mL). To the mixture was added MgSO4 and the mixture was stirred at rt for 10 min. The mixture was then diluted with THF (10 mL) and filtered, and the filtrate was concentrated under reduced pressure to afford ((1R,2R)-2-aminocyclohexyl)methanol (326 mg, 70%) as an oil. 1H NMR (300 MHz, DMSO-d6) δ 3.27-3.52 (m, 3H), 2.29 (dt, J=10.1, 4.0 Hz, 1H), 1.53-1.78 (m, 4H), 0.98-1.21 (m, 4H), 0.87 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][C:17]2[C:22]([O:23][CH3:24])=[CH:21][C:20]([O:25][CH3:26])=[CH:19][C:18]=2[O:27][CH3:28])[CH2:6][C:5]1=[O:29].CC(C)([O-])C.[K+].C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:56]=[N+:57]=[N-:58])(=O)=O)(C)C.C(=O)([O-])O.[Na+]>C1COCC1.C(O)(=O)C>[N:56]([CH:6]1[N:7]([CH2:16][C:17]2[C:18]([O:27][CH3:28])=[CH:19][C:20]([O:25][CH3:26])=[CH:21][C:22]=2[O:23][CH3:24])[C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:4]([CH2:3][C:2]([F:1])([F:30])[F:31])[C:5]1=[O:29])=[N+:57]=[N-:58]
Reactant: COc1cc(OC)c(CN2CC(=O)N(CC(F)(F)F)c3ccccc3C2=O)c(OC)c1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc(OC)c(CN2C(=O)c3ccccc3N(CC(F)(F)F)C(=O)C2N=[N+]=[N-])c(OC)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
The product from Step 4C (1 g, 0.0023 mol) was dissolved in THF (30 ml) under nitrogen, cooled to −78° C. and potassium tert butoxide (0.28 g, 0.0025 mol) as a solution in THF (5 ml) added over 10 minutes. 2,4,6-Triisopropylbenzenesulfonyl azide (1.65 g, 0.005 mol) in THF (5 ml) was added dropwise and the mixture stirred for 10 minutes. Glacial acetic acid (0.6 ml) was added and the reaction mixture allowed to attain room temperature and left to stir for 4 hours. The reaction mixture was poured into sodium hydrogen carbonate solution and extracted (ethyl acetate ×2). The combined organic layers were washed (brine), dried (MgSO4) and evaporated in vacuo to give the desired azide which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:25]([CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])=[C:24]([O:31][CH3:32])[CH:23]=[C:22]([O:33][CH3:34])[C:3]=1[C:4](=[O:21])[CH:5]=[CH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH2:16][O:17][CH3:18])=[C:9]([O:19][CH3:20])[CH:8]=1.[H][H]>[Pd].C(OCC)(=O)C>[OH:1][C:2]1[C:25]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[C:24]([O:31][CH3:32])[CH:23]=[C:22]([O:33][CH3:34])[C:3]=1[C:4](=[O:21])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH2:16][O:17][CH3:18])=[C:9]([O:19][CH3:20])[CH:8]=1
Reactant: [H][H]
Reactant: COCOc1c(OC)cc(C=CC(=O)c2c(OC)cc(OC)c(CC=C(C)C)c2O)cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCOc1c(OC)cc(CCC(=O)c2c(OC)cc(OC)c(CCC(C)C)c2O)cc1OC
Reaction time: 8 h
Yield: 92.1 %

Procedure:
An ethyl acetate solution of 2.8 g of the so-obtained 2'-hydroxy-3,5,4',6'-tetramethoxy-4-methoxymethoxy-3'-(3-methyl-2-butenyl)chalcone was added to 20 ml of an ethyl acetate solution of 0.4 g of palladium/carbon, in which hydrogen had been adsorbed in advance, and hydrogen was further adsorbed with strong stirring. Then, the mixture was stirred overnight, the palladium/carbon was removed by using Celite, and the residue was dissolved in ether and crystallized from hexane to obtain 2.6 g (yield=94%) of 1-(2-hydroxy-4,6-dimethoxy-3-isopentylphenyl)-3-(3,5-dimethoxy-4-methoxymethoxyphenyl)-1-propanone in the form of a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:32]=[CH:31][C:10]([CH2:11][CH:12]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][C:17](OS(C(F)(F)F)(=O)=O)=[CH:18][CH:19]=4)[O:14][CH2:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2C=CC=CC=2)C(C=O)=CC=CC=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH:69]1([C:74]([O:76][CH2:77][CH3:78])=[O:75])[CH2:73][CH2:72][CH2:71][CH2:70]1>CN(C)C=O.C(COC)OC.O.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.[Cl-].[Zn+2].[Cl-]>[C:1]1([C:7]2[CH:32]=[CH:31][C:10]([CH2:11][CH:12]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][C:17]([C:69]5([C:74]([O:76][CH2:77][CH3:78])=[O:75])[CH2:73][CH2:72][CH2:71][CH2:70]5)=[CH:18][CH:19]=4)[O:14][CH2:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccc(OS(=O)(=O)C(F)(F)F)cc2OCC1Cc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C1CCCC1
Agent: Cl[Pd]Cl
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=Cc1ccccc1-c1ccccc1
Solvent: CN(C)C=O
Solvent: N#Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1(c2ccc3c(c2)OCC(Cc2ccc(-c4ccccc4)cc2)C3=O)CCCC1

Procedure:
3-(4-Phenyl-benzyl)-7-trifluoromethylsulfonyloxy-4-chromanone (35.0 g, 91.0 mmole, prepared from the product of Example 2C with biphenyl aldehyde using the procedures of Example 2D and Example 2E, was dissolved in a mixture of dimethylformamide (230 mL) and dimethoxyethane (230 mL). To this solution was added in the following order, tris(2-methylphenyl)phosphine (7.48 g, 24.6 mmole), bis(benzonitrile)palladium (II) chloride (2.44 g, 6.37 mmole), the trimethylsilyl ketene acetal of ethyl cyclopentanecarboxylate (29.26 g, 136.5 mmole), and a 1.0M ethereal solution of zinc chloride (25 mL, 25 mmole). The resulting clear yellow solution was refluxed for about 1 hour. Additional trimethylsilyl ketene acetal (9.75 g, 45.5 mmole) was added at this point and the reflux continued for about another 1 hour. The cooled mixture was diluted with water (1 L) and extracted with ether. The combined ether extracts were washed with water (1 L) and then dried over magnesium sulfate. Filtration and concentration of the extract gave a yellow oil which was chromatographed on silica gel (8:92 ethyl acetate/hexane). This yielded 22.13 g (64%) of the title compound of this Example 5A as a white solid; m.p. 50-56 ° C.; 1H NMR (CDCl3): 1.23 (3H, t, J=7.0), 1.75 (4H, m), 1.9 (2H, m), 2.6 (2H, m), 2.70 (1H, dd, J=10.5,13.8), 2.9 (1H, m), 3.26 (1H, dd, J =4.3, 13.8), 4.08 (2H, d, J=7.0), 4.15 (1H, dd, J=8.2, 11.5), 4.35 (dd, J=4.3, 11.5), 6.95 (1H, d, J=1.7), 7.02 (1H, dd, J=1.7, 8.3), 7.2-7.4 (5H, m), 7.84 (1H, d, J=8.3).
Reaction SMILES: [Cl:1]CCl.[F:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:8][N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](O)=[O:16])[C:10]1=[O:18].C(Cl)(C(Cl)=O)=O>CN(C=O)C>[F:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:8][N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([Cl:1])=[O:16])[C:10]1=[O:18]
Reactant: ClCCl
Reactant: O=C(O)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The flask was charged with dichloromethane, 20 mg of 1-(3,4-difluorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid, DMF, (COCl)2 was added slowly via syringe. Then the resulted mixture was allowed to stir at room temperature for 3 h. After TLC show the reaction was complete, the solvent was removed under high vacuum to give 25 mg of crude product, which was used for the next step reaction without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:54]1[CH:55]=[CH:56][C:57]2[N:79]([CH:80]=1)[C:60]1[N:61]([C:70]3[CH:75]=[CH:74][C:73]([N+:76]([O-:78])=[O:77])=[CH:72][CH:71]=3)[C:62](=[O:69])[C:63]3[C:68]([C:59]=1[N:58]=2)=[CH:67][CH:66]=[CH:65][CH:64]=3.[N:81]1([CH2:86][CH2:87][NH2:88])[CH2:85][CH2:84][CH2:83][CH2:82]1>O1CCOCC1>[N+:76]([C:73]1[CH:72]=[CH:71][C:70]([N:61]2[C:60]3[N:79]4[CH:80]=[C:54]([NH:88][CH2:87][CH2:86][N:81]5[CH2:85][CH2:84][CH2:83][CH2:82]5)[CH:55]=[CH:56][C:57]4=[N:58][C:59]=3[C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[C:62]2=[O:69])=[CH:75][CH:74]=1)([O-:78])=[O:77]
Reactant: NCCN1CCCC1
Reactant: O=c1c2ccccc2c2nc3ccc(Br)cn3c2n1-c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Product: O=c1c2ccccc2c2nc3ccc(NCCN4CCCC4)cn3c2n1-c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 25.5 %

Procedure:
An oven-dried pyrex screw-tube was charged with rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl ((rac)-BINAP) (0.3 equiv., 0.138 mmol, 0.086 g), Pd2(dibenzylidene-acetone)3 (Pd2 dba3) (0.1 equiv., 0.046 mmol, 0.042 g) and Cs2CO3 (1.4 equiv., 0.643 mmol, 0.210 g). Dry dioxane (1 ml) was added and the screw-tube was purged with Ar. The reaction mixture was heated at 80° C. for 30 min, after which it was allowed to cool to room temperature. 9-Bromo-6-(4-nitrophenyl)-pyrido[2′,1′:2,3]-imidazo[4,5-c]isoquinolin-5(6H)-one (18) (1.0 equiv., 0.460 mmol, 0.200 g) and pyrrolidineethanamine (1.0 equiv., 0.460 mmol, 0.052 g) were added and the reaction mixture was stirred at 100° C. until no starting materials were left. The progress of the reaction was monitored by LCMS. Removal of the solvent under reduced pressure, followed by column chromatography (gradient elution: dichloromethane→dichloromethane/methanol 9:1) of the resulting residue gave 6-(4-nitrophenyl)-9-(2-pyrrolidin-1-yl-ethylamino)-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5(6H)-one (67) (0.055 g, yield=26%, purity (LC)=97%).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH3:10])[NH:6][C:7]=1[CH2:8][CH3:9])[CH3:2].[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1.N1CCOCC1>C(#N)C.CO>[CH2:1]([C:3]1[N:4]=[C:5]([CH2:10][C:16]([C:15]2[CH:19]=[CH:20][C:12]([F:11])=[CH:13][CH:14]=2)=[O:17])[NH:6][C:7]=1[CH2:8][CH3:9])[CH3:2]
Reactant: CCc1nc(C)[nH]c1CC
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: C1COCCN1
Solvent: CC#N
Solvent: CO
Product: CCc1nc(CC(=O)c2ccc(F)cc2)[nH]c1CC

Procedure:
The compound is prepared as described in example X (step 4) with 800 mg (5.79 mmol) of 4,5-Diethyl-2-methyl-1H-imidazole (example XXVII, step 1), 2.75 g (17.36 mmol) of 4-fluorobenzoyl chloride and 1.93 g (19.10 mmol) of TEA in 15 ml acetonitrile. The crude intermediate (1.30 g, 2.58 mmol) is dissolved in 10 ml methanol under argon. 1.12 g (12.88 mmol) of morpholine are added dropwise to the solution. The mixture is refluxed for 10 minutes. The solvent is evaporated under argon and the residue is purified over silica (eluent: dichlormethane/methanol 50:1). The solvent is evaporated under vacuum to yield 572 mg (82.6% of th.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:24][C:25]([N:27]1[CH2:30][CH:29]([O:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:28]1)=[S:26])[CH2:5][O:6][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:24][C:25]([N:27]1[CH2:28][CH:29]([O:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:30]1)=[S:26])[CH2:5][OH:6]
Reactant: COC(=O)[C@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=S)N1CC(OC(=O)c2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)[C@H](CO)NC(=S)N1CC(OC(=O)c2ccccc2)C1
Reaction time: 8 h
Yield: 93.1 %

Procedure:
To a solution of (2S)-2-{[3-(benzoyloxy)-azetidine-1-carbothioyl]amino}-3-(t-butyldiphenylsilyloxy)propionic acid methyl ester (23.3 g, 40.0 mmol) (obtained as described in Reference Example 70(3)) in tetrahydrofuran (700 ml) was added a 1.0 M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (48.4 g, 48.4 mmol) in an ice bath and the mixture was stirred overnight. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:acetonitrile (3:1) as the eluant to afford (2S)-2-{[3-(benzoyloxy)-azetidine-1-carbothioyl]amino}-3-hydroxy-propionic acid methyl ester (12.6 g, yield 92%) as a white solid.
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[O:21][C:22](=[O:29])[C@H:23]([CH2:25][CH2:26][S:27][CH3:28])[NH2:24].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:24][C@H:23]([C:22]([OH:29])=[O:21])[CH2:25][CH2:26][S:27][CH3:28])=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CSCC[C@H](NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(C)cc1)C(=O)O

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to methionine methyl ester using the procedure described in Method 3. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]#[N:13])=[CH:9]2)=[CH:4][CH:3]=1.[Cl:14]OC(C)(C)C>C(Cl)(Cl)Cl>[Cl:14][C:11]1[C:2]([OH:1])=[CH:3][CH:4]=[C:5]2[C:10]=1[CH:9]=[C:8]([C:12]#[N:13])[CH:7]=[CH:6]2
Reactant: N#Cc1ccc2ccc(O)cc2c1
Reactant: CC(C)(C)OCl
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc2ccc(O)c(Cl)c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 7-hydroxynaphthalene-2-carbonitrile (2.23 g) in chloroform (120 ml) was dropwise added tert-butyl hypochlorite (1.64 ml) with ice-cooling, and the mixture was stirred at room temperature for 15 min. After completion of the reaction, the resultant solid was collected by filtration and dried under reduced pressure to give the title compound (1.88 g).
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([C:9]([NH:11][C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:19])=[NH:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.Cl[P:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:1]([C:5]1[CH:21]=[CH:20][C:8]([C:9]([NH:11][C:12]2[C:13]([CH3:19])=[CH:14][CH:15]=[CH:16][C:17]=2[CH3:18])=[N:10][P:28]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccc(C)c1NC(=N)c1ccc(C(C)(C)C)cc1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Product: Cc1cccc(C)c1NC(=NP(c1ccccc1)c1ccccc1)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Procedure as described for NP Amidine I using the following amounts: 1.40 g of 4-t-butyl-N1-(2,6-dimethylphenyl)benzamidine (Amidine IV, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.93 mL chlorodiphenylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, the sticky residue was treated with 20 mL of pentane. After 1 hour stirring at room temperature, the pentane was removed in vacuo yielding 2.16 g (93%) of off-white solid.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:15]=[C:16]([C:33]4[O:37][C:36]([C:38]5[CH:39]=[C:40]([OH:44])[CH:41]=[CH:42][CH:43]=5)=[N:35][N:34]=4)[CH:17]=[C:18]([N:20]4[C:32]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:26]5[C:21]4=[CH:22][CH:23]=[CH:24][CH:25]=5)[CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:45]([O:50][CH2:51][CH2:52]Br)(=[O:49])[C:46]([CH3:48])=[CH2:47].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:45]([O:50][CH2:51][CH2:52][O:44][C:40]1[CH:41]=[CH:42][CH:43]=[C:38]([C:36]2[O:37][C:33]([C:16]3[CH:15]=[C:14]([N:12]4[C:11]5[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=5[C:5]5[C:13]4=[CH:1][CH:2]=[CH:3][CH:4]=5)[CH:19]=[C:18]([N:20]4[C:32]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:26]5[C:21]4=[CH:22][CH:23]=[CH:24][CH:25]=5)[CH:17]=3)=[N:34][N:35]=2)[CH:39]=1)(=[O:49])[C:46]([CH3:48])=[CH2:47]
Reactant: Oc1cccc(-c2nnc(-c3cc(-n4c5ccccc5c5ccccc54)cc(-n4c5ccccc5c5ccccc54)c3)o2)c1
Reactant: C=C(C)C(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)C(=O)OCCOc1cccc(-c2nnc(-c3cc(-n4c5ccccc5c5ccccc54)cc(-n4c5ccccc5c5ccccc54)c3)o2)c1
Reaction time: 21 h

Procedure:
To a solution of 3-(5-(3,5-dicarbazol-9-ylphenyl)-1,3,4-oxadiazol-2-yl)phenol (0.7 g, 1.23 mmol) and 2-bromoethyl methacrylate (0.25 g, 1.30 mmol) in DMF (20.0 ml) was added K2CO3 (2.0 g, 14.47 mmol) at room temperature under stirring. The reaction was carried out at room temperature for 21 h. Water (100.0 ml) was added. Brown solid product was obtained by filtration and washed with methanol. The crude product was purified by silica gel column chromatography using dichloromethane/ethyl acetate (9.5:0.5) as eluent. After removal of solvent, white glass-like solid product was dissolved in THF (10.0 ml). Methanol (120.0 ml) was added into THF solution. White solid product was obtained and collected by filtration. After vacuum dry, the product as white solid in 0.7 g (83.3%) was obtained. 1H NMR (400 MHz, CDCl3, δ): 8.47 (d, 5=1.6 Hz, 2H), 8.16 (d, J=8.0 Hz, 4 Hz), 8.01 (d, J=1.6 Hz, 1H), 7.71 (dt, J1=8.0 Hz, J2=1.6 Hz, 1H), 7.67 (m, 1H), 7.57 (d, J=8.4 Hz, 4H), 7.49-7.40 (m, 5H), 7.34 (m, 4H), 7.10 (m, 1H), 6.11 (t, 5=1.2 Hz, 1H), 5.55 (m, 1H), 4.49 (t, J=4.4 Hz, 2H, OCH2), 4.29 (t, J=4.4 Hz, 2H, OCH2), 1.92 (t, J=1.2 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3, δ): 167.24, 165.05, 163.35, 159.01, 140.51, 140.32, 135.85, 130.43, 128.12, 127.36, 126.43, 126.16, 124.60, 123.84, 123.77, 120.82, 120.61, 119.95, 119.09, 112.50, 109.52, 66.24, 62.81, 18.26. [M]+ calcd for C44H32N4O4, 680.2.2. found 680.2. Anal. Calcd for C44H32N4O4: C, 77.63; H, 4.74; N, 8.23. Found: C, 77.49; H, 4.69; N, 8.21.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([Br:12])=[CH:10][N:9]=[C:8](S(C)(=O)=O)[N:7]=1)=[O:5])[CH3:2].[CH3:17][O:18][CH2:19][CH2:20][NH2:21]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:11]([Br:12])=[CH:10][N:9]=[C:8]([NH:21][CH2:20][CH2:19][O:18][CH3:17])[N:7]=1)=[O:5])[CH3:2]
Reactant: COCCN
Reactant: CCOC(=O)c1nc(S(C)(=O)=O)ncc1Br
Solvent: ClCCl
Product: CCOC(=O)c1nc(NCCOC)ncc1Br
Temperature: 45 °C

Procedure:
A solution of 5-bromo-2-methanesulfonyl-pyrimidine-4-carboxylic acid ethyl ester (86 mg, 0.27 mmol) in dichloromethane (2 ml) was treated with 2-methoxyethylamine (124 μl, 1.44 mmol) under argon atmosphere and heated to 45° C. for 2 h. All volatiles were removed and the product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as colorless oil (72 mg, 82%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:15][CH3:16])=[C:12]([OH:14])[CH:13]=1.Cl>CCO>[CH2:15]([C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:13][C:12]=1[OH:14])[CH3:16]
Reactant: CCc1ccc(N)cc1O
Reactant: Brc1nccs1
Agent: Cl
Solvent: CCO
Product: CCc1ccc(Nc2nccs2)cc1O
Temperature: 90 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
Following the general procedure for the synthesis of 2-R-5-(thiazol-2-ylamino)phenol, 2-bromothiazole (0.35 mL, 3.86 mmol), 5-amino-2-ethylphenol (265 mg, 1.93 mmol) and 37% HCl solution (0.32 mL, 3.86 mmol) in 10% aqueous EtOH solution (10 mL) was stirred at 90° C. for 24 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 6/4) in 69% yield (292 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]=[CH:6][C:7]1[N:15]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:14]2[CH:13]=[C:12]([Cl:24])[N:11]=[CH:10][C:9]=2[CH:8]=1)[CH3:2]>CCOC(C)=O.O=[Pt]=O>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][C:7]1[N:15]([CH2:16][C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C:14]2[CH:13]=[C:12]([Cl:24])[N:11]=[CH:10][C:9]=2[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cc2cnc(Cl)cc2n1CC(=O)OC(C)(C)C
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc2cnc(Cl)cc2n1CC(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
A mixture of 0.08 g of 3-(1-tert-butoxycarbonylmethyl-6-chloro-1H-pyrrolo[3,2-c]pyridin-2-yl)acrylic acid ethyl ester and 0.015 g of PtO2 in 12 mL of EtOAc was stirred under a balloon pressure of H2 for 16 h. The mixture was filtered through celite and concentrated to give crude product (0.08 g, white solid) MS (ESI): 367.2 (M+1)
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:9][C:10]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[CH:15][C:16]([Br:23])=[CH:17][CH:18]=3)[C:13](=[O:24])[C:12]=2[CH:11]=1>>[Br:9][C:10]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[CH:15][C:16]([Br:23])=[CH:17][CH:18]=3)[C:13]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([OH:24])[C:12]=2[CH:11]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: O=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Product: OC1(c2ccccc2)c2cc(Br)ccc2-c2ccc(Br)cc21

Procedure:
from phenylmagnesium chloride and 2,7-dibromo-9-fluorenone;
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]([C:25]([F:28])([F:27])[F:26])=[C:23]([C:29](O)=[O:30])[CH:22]=[N:21]2)=[CH:16][CH:15]=1.N=C=N>C(Cl)Cl>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][C:29]([C:23]1[CH:22]=[N:21][N:20]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[C:24]=1[C:25]([F:28])([F:26])[F:27])=[O:30]
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1cnn(-c2ccc(F)cc2)c1C(F)(F)F
Agent: N=C=N
Solvent: ClCCl
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1cnn(-c2ccc(F)cc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3-Trifluoromethyl benzylamine (0.014 mL, 0.100 mmole) was added to a suspension of 1-(4-fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (0.030 g; 0.109 mmol) and PS-Carbodiimide (0.2 g) in methylene chloride (2 mL). The reaction mixture was shaken at room temperature for 12 h at which time the reaction mixture was filtered and concentrated to give 1-(4-fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 3-trifluoromethyl-benzylamide. LCMS m/z=432.3 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[C:15]2[CH2:23][NH:24][CH3:25])=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[C:15]2[CH2:23][NH:24][CH3:25])=[CH:26][CH:27]=1
Reactant: CNCc1cc2ccccc2n1Cc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CNCc1cc2ccccc2n1Cc1ccc(O)cc1
Reaction time: 4 h
Yield: 89 %

Procedure:
To a solution of 1-(4-benzyloxybenzyl)-2-(methylaminomethyl)indole (27.1 g, 75.9 mmole) in methanol (75 mL) at RT in a Parr hydrogenation flask was added 10% Pd/C (0.5 g). The reaction mixture was shaken under 45 psi of H2 for 4 hr. The suspension was filtered through celite®, and the filter pad was washed with methanol. The filtrate was concentrated on the rotavap, and the residue was dried under high vacuum to afford the titled compound (18.0 g, 89%) as an off-white solid: MS (ES) m/e 268 (M+H)+.