Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl([O-])(=O)=O.[Na+].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:20](=[O:28])[CH:21]=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].N([O-])=O.[Na+].S(=O)(=O)(O)O>O.C(OCC)(=O)C.C(#N)C.CN(C)C=O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:20]([C:21]1[NH:3][N:2]=[N:1][C:22]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:28]
Reactant: CCOC(=O)C=CC(=O)c1ccc(OC)c(OC)c1
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn[nH]c1C(=O)c1ccc(OC)c(OC)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
Sodium azide (4.87 g, 75 mmol), sodium chlorate (2.90 g, 27 mmol), and a 37% aqueous ferric chloride solution (1.49 g, 3 mmol) were added to N,N-dimethylformamide (36 mL), the mixed solution was heated to 40° C., and a mixed solution previously prepared by adding ethyl 4-(3,4-dimethoxyphenyl)-4-oxo-2-butenoate (18 g, 68 mmol) to N,N-dimethylformamide (36 mL) and then dissolving them each other at 50° C. was added dropwise thereto. After the completion of the dropwise addition, a reaction was allowed to proceed at 40° C. for one hr, and a reaction was further allowed to proceed at 65° C. for one hr. After the completion of the reaction, the reaction solution was cooled to 5° C., and acetonitrile (7 mL) and an aqueous solution of sodium nitrite (1.18 g, 17 mmol) in water (25 mL) were successively added dropwise thereto. The mixture was adjusted to pH 1.5 by the addition of a 3 M aqueous sulfuric acid solution. The mixture was stirred at 5° C. for one hr, and ethyl acetate (198 ml) was then added thereto, followed by separation. The organic layer was washed three times with 5% brine, was dried over anhydrous magnesium sulfate, and was filtered. The filtrate was concentrated under the reduced pressure to precipitate crystals. Toluene (90 mL) was added to the residue of the concentration, and the crystals were aged at 5° C. for 12 hr. The crystals were collected by filtration, were then washed with toluene, and were dried under the reduced pressure to give 17.15 g of a light yellow powder (yield 82.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:12][C:13](=O)[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].O=P(Cl)(Cl)[Cl:29].CN(C)C1C=CC=CC=1>>[Cl:29][C:13]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:10]=[C:11]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2Cl)nc(-c2ccccc2)[nH]c1=O
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)c1c(Cl)nc(-c2ccccc2)nc1-c1ccc(Cl)cc1Cl
Reaction time: 4 h
Yield: 97 %

Procedure:
To a stirred solution of ethyl 4-(2,4-dichlorophenyl)-6-oxo-2-phenyl-1,6-dihydropyrimidine-5-carboxylate (372 mg, 0.91 mmol) in doixane (6 mL) was added POCl3 (0.4 mL, 4.55 mmol) and N,N-dimethylaniline (11.5 μL, 0.09 mmol). After 4 hrs at 70° C., the reaction was concentrated under reduced pressure and diluted with EtOAc (100 mL). The organic layer was extracted with saturated NaHCO3 solution (2×60 mL), brine (50 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The crude reaction product was purified by flash chromatography (silica gel, 30% EtOAc/hexane) to give ethyl 4-chloro-6-(2,4-dichlorophenyl)-2-phenylpyrimidine-5-carboxylate (360 mg, 97% for 3 steps) as a clear oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=O.[OH-].[Na+].[CH:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([CH:2]=[CH:1][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:20])=[CH:5][CH:6]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(C=Cc1ccc(O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
The photo-reactive group of the side chain was synthesized as follows. First, 10.2 g (0.075 mol) of 4-hydroxyacetophenone was dissolved into 0.7 w/v % aqueous solution of NaOH. Benzaldehyde (8 g (0.075 mol)) then was added and the resulting solution was stirred for 8 hours at a room temperature. Then, the solution was neutralized with 5N HCl to yield 4-hydroxychalcone at 50% yield as follows.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH3:12])[NH:4][C:3]=1[C:13]([O:15]CC)=[O:14].[OH-].[K+]>C(O)C.O>[CH3:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH3:12])[NH:4][C:3]=1[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)c1[nH]c(C)c(C(=O)OCC)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(C)[nH]c(C(=O)O)c1C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To a solution of 23,9 g (0.1 mol) of diethyl 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylate in 300 ml of hot ethanol was added a solution of 14 g (0.25 mol) of potassium hydroxide in 350 ml of water. The solution was boiled and the ethanol was allowed to evaporate. After 1.5 hours, the volume was reduced by 350 ml then cooled, filtered, and acidified with 2 N hydrochloric acid. A precipitate formed which was collected, washed with water, and dried to give 19 g of 3,5-dimethyl-4-ethoxycarbonyl-1H-pyrrolecarboxylic acid. This acid was disolved in quinoline, 5 g of powdered copper was added, and the mixture heated to 200° C. during which time carbon dioxide was released. The residue was distilled (0.1 mm/120°-140° C.) and the distillate recrystallized (ethyl ether/pentane) to give the title compound, m.p. 74°-76° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[O:41])=[CH:35][N:34]=1>C(Cl)Cl>[CH3:32][C:33]1[N:34]=[CH:35][C:36]([NH:39][C:40](=[O:41])[NH:1][C:2]2[C:7]3[N:8]=[C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]4)[O:10][C:6]=3[CH:5]=[CH:4][CH:3]=2)=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2nc3c(N)cccc3o2)CC1
Reactant: Cc1ccc(N=C=O)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)Nc2cccc3oc(CN4CCN(C(=O)OC(C)(C)C)CC4)nc23)cn1
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a room temperature solution of tert-butyl 4-((4-aminobenzo[d]oxazol-2-yl)methyl)piperazine-1-carboxylate (5.0 g, 15.1 mmol, 1.0 equiv) and triethylamine (2.1 g, 15.1 mmol, 1.0 equiv) in dry DCM (37 mL) was added 2-methyl-5-isocyanatopyridine (2.22 g, 16.6 mmol, 1.1 equiv) in dry DCM (37 mL) via cannula. After 1 h, the reaction mixture was filtered and washed with water (25 mL) and brine (25 mL). The solution was dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel purification (5% MeOH/95% EtOAc—15% MeOH/85% EtOAc) provided the title compound as a white foam (7.03 g, 100%). LCMS [M+H]+=467.2.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1.BrC1C=CC(N)=CC=1OCCOC1C=CC=CC=1>>[Cl:1][C:2]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(OCCCN2CCN(c3ccccc3)CC2)c1
Agent: Nc1ccc(Br)c(OCCOc2ccccc2)c1
Product: Nc1ccc(Cl)c(OCCCN2CCN(c3ccccc3)CC2)c1
Yield: 76 %

Procedure:
The compound 26c was prepared starting from 26b following the procedure described for the synthesis of 25c in 76% yield as a white solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([NH2:23])[CH3:22])=[CH:17][CH:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].ClC(Cl)(Cl)[C:28]([N:30]=C=O)=[O:29]>C(Cl)Cl>[CH:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([NH:23][C:28]([NH2:30])=[O:29])[CH3:22])=[CH:17][CH:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(Oc2ncc(-c3ccc(C(C)N)cc3)s2)cc1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)Oc1ccc(Oc2ncc(-c3ccc(C(C)NC(N)=O)cc3)s2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.3 %

Procedure:
To a solution of Example 1F (0.15 g, 0.0004 mol) in methylene chloride (5 mL) was added trichloroacetyl isocyanate (0.08 mL, 0.0006 mol) and the mixture was stirred at room temperature for 15 minutes, and concentrated. The residue was dissolved in methanol (10 mL) and refluxed with a few drops of saturated sodium carbonate solution for 0.5 hours. The mixture was cooled to room temperature, concentrated to dryness and triturated with methanol (15 mL) and water (2 mL) to give 0.15 g of the title compound (88% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.23-1.34 (m, 9 H) 4.55-4.75 (m, 2 H) 5.42 (s, 2 H) 6.44 (d, J=8.09 Hz, 1 H) 6.97-7.05 (m, 2 H) 7.25-7.36 (m, 4 H) 7.49 (d, J=8.09 Hz, 2 H) 7.65 (s, 1 H). MS (ESI), m/z 397.9 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23](=[O:35])CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C(Cl)(=O)[O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23](=[O:35])[O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C(Cl)OCc1cccc(Cl)c1
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Product: N#Cc1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3NC(=O)OCc3cccc(Cl)c3)C2)cc1

Procedure:
3-Chlorobenzyl (1R,2R)-2-((S)-1-(4-cyanophenyl)piperidin-3-ylamino)cyclohexylcarbamate was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (60 mg, 0.20 mmol) and 3-chlorobenzyl carbonochloridate (68 mg, 0.22 mmol) according to General Procedure H to give 20 mg (21.3%) of white solid. Anal. Calcd. for C26H31ClN4O2 m/z 466.2, found: 467.2 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 7.46 (d, J=8.8 Hz, 2H), 7.35 (m, 1H), 7.30 (m, 4H), 7.28 (m, 2H), 7.23 (m, 1H), 6.96 (d, J=3 Hz, 2H), 5.0 (m, 2H), 3.71 (m, 1H), 3.58 (m, 1H), 3.29 (m, 1H), 2.98 (m, 1H), 2.72 (m, 2H), 2.52 (m, 1H), 2.04 (m, 1H), 1.92 (m, 2H), 1.78 (m, 3H), 1.62 (m, 1H), 1.34 (m, 4H), 1.20 (m, 1H).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[O:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)=[O:6]>O.CO>[C:12]1([C:9]2[O:8][C:7]([C:5]([OH:6])=[O:4])=[CH:11][CH:10]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(-c2ccccc2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
A solution of sodium hydroxide (200 mg) in water (5 ml) was added to a stirred solution of 5-phenyl-furan-2-carboxylic acid methyl ester (7) (384 mg, 1.90 mmoles) in methanol (20 ml) and the mixture was stirred at room temperature for 4 hours. The solvent was evaporated and the residue was diluted with water (10 ml) and acidified to pH=2 with 1 M aqueous hydrochloric acid. The precipitate was collected, washed with water and the residue was triturated with cyclohexane to afford (8) (350 mg) as a white solid. LC/MS System A; Rt=3.89 mins.
Reaction SMILES: [N+](=[C:3](P(=O)(OC)OC)C(=O)C)=[N-].[CH:13]([NH:16][C:17]1[N:22]=[CH:21][C:20]([CH2:23][CH2:24][CH:25]=O)=[CH:19][CH:18]=1)([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>CO.O.CCOC(C)=O>[CH2:23]([C:20]1[CH:19]=[CH:18][C:17]([NH:16][CH:13]([CH3:15])[CH3:14])=[N:22][CH:21]=1)[CH2:24][C:25]#[CH:3]
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reactant: CC(C)Nc1ccc(CCC=O)cn1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: C#CCCc1ccc(NC(C)C)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under an argon atmosphere 361 mg (1.88 mmol) of dimethyl (1-diazo-2-oxopropyl)phosphonate in 4 mL of MeOH was added to a solution of 300 mg (1.57 mmol) of 3-(6-isopropylaminopyridin-3-yl)propionaldehyde and 434 mg (3.14 mmol) of potassium carbonate in 6 mL of MeOH and the mixture was stirred for 3 hours at RT. The reaction mixture was diluted with water and EtOAc, combined with saturated aqueous sodium hydrogen carbonate solution, and the organic phase was separated off, extracted with water, dried over magnesium sulfate, filtered, and the solvent was removed in vacuo. Yield: 220 mg (75% of theoretical); C12H16N2 (M=188.269); calc.: molpeak (M+H)+:189; found: molpeak (M+H)+:189; HPLC-MS: 4.09 minutes (method G).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.[Cl:20][CH2:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[CH2:21][Cl:20])=[CH:17][CH:18]=1
Reactant: ClCc1ccccc1CCl
Reactant: Oc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCc1ccccc1COc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 0 °C

Procedure:
A solution of (10.11 mmol) of 4-((quinolin-2-yl)methyloxy)phenol, (30.33 mmol, 3 equiv.) of 2-chloromethylbenzyl chloride and 4.2 g (30.33 mmol, 3 equiv) of K2CO3 in 100 mL of 8:1--acetone:DMF is refluxed for 24 hrs. The mixture is poured into ice-water and allowed to stand for 11/2 hours. The precipitate that forms is filtered off, redissolved in EtOAc, dried, and concentrated in vacuo. The crude product is filtered by flash column chromatography to afford 2-(4-((quinolin-2-yl)methyloxy)phenoxymethyl)benzyl chloride which is used directly in the next step.
Reaction SMILES: C(O[C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][CH2:16][C:17]2=[O:20])=[CH:12][CH:11]=1)=[O:5])C.C(N(CC)C(C)C)(C)C.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C(Cl)Cl>[N:30]1([C:4](=[O:5])[CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][CH2:16][C:17]3=[O:20])=[CH:12][CH:11]=2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: C1COCCN1
Reactant: CCOC(=O)CCCOc1ccc2c(c1)C(=O)CCC2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCCc2ccc(OCCCC(=O)N3CCOCC3)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
To a suspension of 7-(3-ethoxycarbonylpropoxy)-1-tetralone (0.925 g, 3.7 mmol), HUBT (1.415 g, 3.7 mmol), N,N-diisopropylethyl amine (1.3 mL) in CH2Cl2 (20 mL) was added morpholine (0.330 mL, 3.7 mmol) at room temperature and under argon atmosphere. The reaction mixture was then stirred at room temperature for 24 h and then concentrated. The residue dissolved in ethyl acetate (50 mL) and the organic layer was washed with dil. HCl, water, brine, and dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified on the column of silica gel using ethyl acetate-hexane (8:2) as an eluent to give 7-(4-morpholin-4-yl-4-oxo-butoxy)-1-tetralone (1.010 g, 86%): mp 88-90° C., 1H NMR (500 MHz, CDCl3): δ 2.07-2.15 (m, 4H), 2.50 (t, J=7.5 Hz, 2H), 2.61 (T, J=7.5 Hz, 2H), 2.88 (t, J=6.0 Hz, 2H), 3.46 (t, J=5.0 Hz, 2H), 3.59-3.66 (m, 6H), 4.04 (t, J=6.0 Hz, 2H), 7.01-7.03 (dd, J=3.0 and 8.5 Hz, 1H), 7.15 (d, J=8.5 Hz, 1H), 7.48 (d, J=3.0 Hz, 1H). HFABMS m/z 318.1706 (calc for C18H23NO4, MH+, 318.1705).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([CH:21]=[C:22]([C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:25])[N:23]=3)[CH:20]=2)[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1>FC(F)(F)C(O)=O>[OH:8][C:9]1[N:14]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([CH:21]=[C:22]([C:24]([NH:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[O:25])[N:23]=3)[CH:20]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Nc1ccccc1)c1cn2cc(-c3cccc(OCc4ccccc4)n3)ccc2n1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccc1)c1cn2cc(-c3cccc(O)n3)ccc2n1
Yield: 71.3 %

Procedure:
A solution of 300 mg of 6-(6-benzyloxypyrid-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in 3 mL of trifluoroacetic acid is stirred at 25° C. for 48 hours and then evaporated to dryness under reduced pressure at 45° C. The residue is triturated with ether, filtered off and dried, and then triturated again with 2 mL of saturated sodium bicarbonate solution, washed twice with 2 mL of water and twice with 2 mL of ethyl ether and dried under reduced pressure to give 168 mg of 6-(6-hydroxypyrid-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a beige-coloured solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:9])[CH:3]=1.[I:10]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([NH2:8])=[C:6]([I:10])[CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(Cl)ccc1N
Solvent: CC(=O)O
Product: Cc1cc(Cl)cc(I)c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.4 %

Procedure:
To a solution of 4-chloro-2-methyl-phenylamine (1 g, 7.06 mmol) in acetic acid (20 ml) was added N-iodo succinimide (2.38 g, 10.59 mmol) portion wise at 25° C. under nitrogen. The reaction mixture was stirred at 25° C. for 16 h. The volatiles were removed in vacuo and the resultant crude residue was diluted with EtOAc (40 ml). The organic layer was washed with aqueous 1N NaOH solution (2×15 ml), followed by aqueous Na2S2O3 solution (2×15 ml), and brine (20 ml). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (5-10% EtOAc in hexane) to yield 4-chloro-2-iodo-6-methyl-phenylamine (1.5 g, 79%) as brown solid. GC-MS: 267 (M).
Reaction SMILES: [O:1]=[CH:2][CH:3]=[CH:4][C:5]([O:7][CH3:8])=[O:6].[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1.C(O)(C(F)(F)F)=O.C([C@@H]1N[C@H](C(C)(C)C)N(C)C1=O)C1C=CC=CC=1>C(Cl)Cl.C(O)(C)C>[CH3:8][O:7][C:5](=[O:6])[C@@H:4]([C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]([CH3:9])[CH:11]=1)[CH2:3][CH:2]=[O:1]
Reactant: COC(=O)C=CC=O
Reactant: Cn1ccc2ccccc21
Agent: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1C(C)(C)C
Solvent: CC(C)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CC=O)c1cn(C)c2ccccc12
Yield: 88.9 %

Procedure:
Prepared according to the general procedure from methyl 4-oxo-butenoate (171 mg, 1.50 mmol), 1-methyl-1H-indole (64 μL, 0.50 mmol), TFA (7.7 μL, 0.10 mmol) and (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-imidazolidin-4-one (24.6 mg, 0.100 mmol) in CH2Cl2 (0.90 mL) and isopropanol (0.10 mL) at −85° C. for 21 h to provide, after silica gel chromatography (5:47:47 acetone/CH2Cl2/hexanes), the title compound as a colorless oil (109 mg, 89% yield, 91% ec). IR (film) 2937, 2833, 2729, 1732, 1623, 1545, 1477, 1436, 1379, 1332, 1228, 1171, 1042, 1016, 980, 773, 742 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.81 (s, 1H, CHO), 7.67 (d, J=8.4 Hz, 1H, ArH), 7.33-7.23 (m, 2H, ArH), 7.15 (ddd, J=1.2, 7.6, 7.8 Hz, 1H, ArH), 6.98 (s, 1H, NCH), 4.44 (dd, J=5.4, 9.3 Hz, 1H, ArH), 3.76 (s, 3H, NCH3), 3.69 (s, 3H, OCH3), 3.47 (dd, J=9.3, 18.6 Hz, 1H, CH2CO); 2.94 (dd, J=5.1, 18.3 Hz, 1H, CH2CO); 13C NMR (75 MHz, CDCl3) δ 200.1, 173.8, 137.0, 126.9, 126.5, 122.1, 119.5, 119.1, 110.8, 109.6, 52.5, 46.8, 36.5, 33.0; HRMS (CI) exact mass calcd for (C14H15NO3) requires m/z 245.1048, found m/z 153.1151. [α]D=−123.6 (c=1.0, CHCl3). The enantiomeric ratio was determined by HPLC analysis of the alcohol, obtained by NaBH4 reduction of the aldehyde, using a Chiracel AS and AS guard column (3:97 isopropanol/hexanes, 1 mL/min); S isomer tr=71.7 min and R isomer tr=76.3 min.
Reaction SMILES: CN(C=O)C.[CH:6]1[C:23]2[C:22]3[CH:21]=[C:20]4[C:15]([CH:16]=[CH:17][CH:18]=[CH:19]4)=[CH:14][C:13]=3[CH:12]=[CH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.C1C(=O)N([Br:31])C(=O)C1.BrC1CC(=O)NC1=O>O>[Br:31][C:14]1[C:13]2[CH:12]=[CH:11][C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:23]=3[C:22]=2[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[CH:19]2
Reactant: c1ccc2cc3c(ccc4ccccc43)cc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C1CC(Br)C(=O)N1
Solvent: CN(C)C=O
Solvent: O
Product: Brc1c2ccccc2cc2c1ccc1ccccc12
Yield: 91.6 %

Procedure:
Into 300 ml of DMF, N,N-dimethylformamide, 40 g of commercial benzanthracene was dispersed, and 35.6 g of NBS, bromosuccinimide, was added to the resultant suspension at the room temperature. After the resultant mixture was stirred for 3.5 hours, 600 ml of water was added, and the formed crystals were separated by filtration and washed with methanol. The obtained crude crystals were purified using a silica gel column with toluene and filtered with hexane, and 49.3 g of 7-bromobenzanthracene was obtained as cream crystals (the yield: 91%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:5]=[C:4]([S:21][CH3:22])[N:3]=1.[NH2:23][NH2:24]>C1COCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:6]2[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:2]([NH:23][NH2:24])[N:3]=[C:4]([S:21][CH3:22])[N:5]=2)=[CH:15][CH:16]=1
Reactant: NN
Reactant: CSc1nc(Cl)c(-c2ccccc2)c(-c2ccc(Cl)cc2)n1
Solvent: C1CCOC1
Product: CSc1nc(NN)c(-c2ccccc2)c(-c2ccc(Cl)cc2)n1
Temperature: 60 °C

Procedure:
To a stirred solution of 4-chloro-6-(4-chlorophenyl)-2-(methylthio)-5-phenylpyrimidine (1.22 g, 3.52 mmol) in THF (15 mL) at room temperature under argon was added H2NNH2 (340 mg, 10.5 mmol). The reaction mixture was heated at 60° C. under argon for 2 h. Analysis by HPLC/MS indicated that the reaction was complete. The solvent was evaporated, and the resulting residue was coevaporated with toluene (2×5 mL) and then dichloromethane (2×10 mL), then dried under vacuum. The crude title compound was used directly in the next step. HPLC/MS: retention time=2.73 min, [M+H]30 =343.
Reaction SMILES: [OH:1]O.[C:3]1([S:9][C:10]2[N:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(=O)C>[C:3]1([S:9]([C:10]2[N:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=2)=[O:1])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: OO
Reactant: Clc1cnc(Sc2ccccc2)nc1
Solvent: CC(=O)O
Product: O=S(c1ccccc1)c1ncc(Cl)cn1
Reaction time: 60 h
Yield: 50 %

Procedure:
30% hydrogen peroxide solution (0.8 g) was added to a solution of 2-phenylthio-5-chloropyrimidine (5 mmol) in acetic acid (4 ml) and left at room temperature for 60 h). The solution was then diluted (25 ml) and the precipitate purified by thick-layer (2 mm) chromatography on silica gel 60F (Merck). The plates were developed with EtOAc; yield 50% m.p. 115° C. (ligroin). 1H NMR (CDCl3): δ7.4 and 7.8 (Ph), 8.71 (H-4, H-6).