Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C[Al](C)C.C1(C)C=CC=CC=1.[I:16][C:17]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[C:20]([C:21](OC)=[O:22])=[CH:19][N:18]=1>ClCCl.O>[CH:1]1([NH:4][C:21](=[O:22])[C:20]2[C:25]([C:27]([F:29])([F:28])[F:30])=[CH:26][C:17]([I:16])=[N:18][CH:19]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1cnc(I)cc1C(F)(F)F
Reactant: NC1CC1
Agent: C[Al](C)C
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(NC1CC1)c1cnc(I)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cyclopropylamine (862 mg, 15.1 mmol) was dissolved in 4 ml of dichloromethane and admixed dropwise under argon with a solution of trimethylaluminium in toluene (2 M, 7.55 ml, 15.1 mmol). The mixture was stirred for 30 min, and then methyl 6-iodo-4-(trifluoromethyl)nicotinate (500 mg, 1.51 mmol) (synthesis analogous to J. Med. Chem., 2008, 51, 3133-3144 by esterification of nicotinic acid) dissolved in 3 ml of dichloromethane was added dropwise. The mixture was heated under reflux overnight and, after cooling to room temperature, water was added cautiously. The mixture was extracted with ethyl acetate, the organic phase washed with potassium sodium tartrate solution, dried over magnesium sulphate and filtered, and the filtrate concentrated under reduced pressure. The purification was effected by means of silica gel chromatography with the eluent cyclohexane/ethyl acetate (EA) (0% EA to 30% EA).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:14]2[N:15]=[C:16](Cl)[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1.C(N(C(C)C)CC)(C)C.[NH:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[CH2:34][OH:35]>C(O)CCC.CN1C(=O)CCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:14]2[N:15]=[C:16]([N:29]3[CH2:33][CH2:32][CH2:31][C@H:30]3[CH2:34][OH:35])[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1
Reactant: Clc1ccc2ncc(-c3cc4ccccc4o3)n2n1
Reactant: OC[C@@H]1CCCN1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: OC[C@@H]1CCCN1c1ccc2ncc(-c3cc4ccccc4o3)n2n1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a mixture of 40.5 mg (0.15 mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine and 25 mg (0.195 mmol) diisopropylethylamine in 1 mL of 1-butanol were added 21 mg (0.22 mmol) (2S)-pyrrolidin-2-ylmethanol in 0.3 mL NMP. The mixture is stirred at 120° C. for 8 h. 16 mg (0.16 mmol) (2S)-pyrrolidin-2-ylmethanol in 0.2 mL NMP were added and shaking at 120° C. was continued for 8 h. Again, 16 mg (0.16 mmol) (2S)-pyrrolidin-2-ylmethanol in 0.2 mL NMP were added and shaking at 120° C. was continued for 8 h.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1Cl)[N:8]=[CH:7][NH:6][C:5]2=[O:13].[H-].[Na+].[CH3:16][SH:17]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[S:17][CH3:16])[N:8]=[CH:7][NH:6][C:5]2=[O:13]
Reactant: O=c1[nH]cnc2cc(Cl)c(Cl)cc12
Reactant: CS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc2nc[nH]c(=O)c2cc1Cl
Temperature: 120 °C

Procedure:
Under a nitrogen atmosphere in a flame dried flask equipped with a magnetic stirrer and a reflux condenser, a mixture of 1.00 g (0.00465 mol) of 6,7-dichloroquinazolin-4(3H)-one and 18 ml of dimethylformamide was treated at room temperature with 0.56 g (0.012 mol) of 50% sodium hydride in mineral oil. Foaming began immediately and most of the solids dissolved. When the foaming had subsided, 1.8 ml (0.0176 mol) of 47% methyl mercaptan in dimethyl formamide was added to the stirred mixture. The mixture was heated at 120° C. for six hours. When the reaction mixture was again at room temperature, a small amount of insoluble matter was filtered, and was rinsed with a few ml of dimethylformamide. The filtrate was washed three times with 10 ml portions of hexane. The filtrate was then poured into 300 ml of ice and water. By the addition of 2N hydrochloric acid, the aqueous solution was adjusted to pH 2. There formed a fine colorless precipitate which was filtered, washed with water, air dried and pressed on a clay plate to furnish the title compound: yield 0.97 g (92%); m.p. 292°-295° C. (dec.); mass spectrum m/e 226 (parent peak and molecular ion with expected isotope pattern), 193 (-33) among others; 1H-NMR(DMSO-d6) 2.6 ppm (singlet, 3H, SCH3), 7.45 (singlet, 1H, aromatic H), 8.0 (singlet, 1H, aromatic H), 8.15 (singlet, 1H, N=CH-N).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][C:7](=[O:9])[CH2:8][CH:4]2[CH2:3][NH:2]1.[I-].CN1C=C[N+]([C:17]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])=C1.C(N(CC)CC)C.O>ClCCl>[N:19]1([C:17]([N:2]2[CH2:3][CH:4]3[CH2:8][C:7](=[O:9])[CH2:6][CH:5]3[CH2:1]2)=[O:18])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C1CC2CNCC2C1
Reactant: Cn1cc[n+](C(=O)N2CCCCC2)c1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C1CC2CN(C(=O)N3CCCCC3)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
Hexahydro-cyclopenta[c]pyrrol-5-one triflutate 1f (478 mg, 2 mmol) was dissolved in 20 mL of dichloromethane, and 1-methyl-3-(piperidine-1-carbonyl)-1H-imidazol-3-ium iodide (0.96 g, 3 mmol) and triehtylamine (0.84 mL, 6 mmol) were then added to the solution. Upon completion of the addition, the reaction mixture was stirred overnight at room temperature, 20 mL of water was then added to the mixture to quech the reaction, and the mixture was extracted with dichloromethane (50 mL×3). The combined organic extracts were washed with 10% citric acid solution (50 mL) and 50 mL of saturated brine successively, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 2-(piperidine-1-carbonyl)-hexahydro-cyclopenta[c]pyrrol-5-one 4a (0.41 g, yield 87%) as a colorless oil.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[N+:5](=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N-:6]>ClC(Cl)Cl>[CH2:11]([O:10][C:8]([C:7]1[NH:5][N:6]=[C:2]([CH2:1][OH:4])[CH:3]=1)=[O:9])[CH3:12]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C#CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(CO)n[nH]1

Procedure:
A solution of 2 g Prop-2-yn-1-ol and 3 g Ethyl diazoacetate in 16 ml trichloromethane was stirred at 70° C. for 24 h. Then the solvent was removed under reduced pressure and the residue was purified on silica gel eluting with a gradient n-heptane/ethyl acetate 1:1->1:2. The fractions containing the product were collected and evaporated under reduced pressure.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH2:11])=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.[CH3:30][O:31][CH:32]([O:43][CH3:44])[C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[C:35](F)[CH:34]=1>O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:35]2[CH:34]=[C:33]([CH:32]([O:43][CH3:44])[O:31][CH3:30])[CH:38]=[CH:37][C:36]=2[N+:39]([O-:41])=[O:40])=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(N)nc1-c1cccc(Cl)c1
Reactant: COC(OC)c1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1sc(Nc2cc(C(OC)OC)ccc2[N+](=O)[O-])nc1-c1cccc(Cl)c1
Yield: 71.1 %

Procedure:
A mixture of 2.82 g (10 mmole) of 2-amino-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid ethyl ester, 9.75 g (30 mmole) of cesium carbonate, 20 mL of dimethylformamide, and 2.15 g (10 mmole) of 4-dimethoxymethyl-2-fluoro-1-nitro-benzene was heated at 80 degrees for 1 hour. The cooled mixture was diluted with 200 mL of water and extracted three times with 100 mL of dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified with silica gel chromatography, eluting with ethyl acetate-hexanes (gradient 0:100-10:90) to give 3.4 g of 4-(3-chloro-phenyl)-2-(5-dimethoxymethyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid ethyl ester (VI.41a) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:8])[CH:7]=1.[Mg].[CH2:11]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1)[CH2:12][CH3:13].Cl>C1COCC1>[OH:20][C:17]1([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)[CH2:18][CH2:19][CH:14]([CH2:11][CH2:12][CH3:13])[CH2:15][CH2:16]1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: CCCC1CCC(=O)CC1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCC1CCC(O)(c2cc(F)cc(F)c2)CC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 132.1 %

Procedure:
In a nitrogen atmosphere, a solution prepared by dissolving 75.85 g of 3,5-difluorobromobenzene in 150 mL of THF was added at a rate that caused gentle reflux to a solution prepared by suspending 10.03 g of magnesium in 50 mL of THF, followed by stirring at 40° C. for 1 hour. After the resultant mixture was allowed to cool to room temperature, a solution prepared by dissolving 60.62 g of 4-propylcyclohexanone in 120 mL of THF was added to the mixture at such a rate that the inside temperature did not exceed 35° C., followed by stirring at room temperature for 2 hours. Then, 10% hydrochloric acid was added until the reaction system became acidic, and an organic layer was separated from the mixture. Further, an aqueous layer was subjected to extraction with toluene, and the toluene extract was combined with organic layer and washed with saturated brine. The resultant mixture was dried by adding sodium sulfate, and then the solvent was distilled off under reduced pressure to yield 132 g of crude 1-(1-hydroxy-4-propylcyclohexyl)-3,5-difluorobenzene.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)=[NH:4].[NH4+:11].[Cl-]>CCO.O>[N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]([NH2:11])=[NH:4]
Reactant: COC(=N)c1ccccn1
Reactant: [NH4+]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: N=C(N)c1ccccn1

Procedure:
To a solution of pyridine-2-carboximidic acid methyl ester (1 eq, 176 mmol, 24 g) in EtOH (150 ml), a solution of NH4Cl (1 eq, 176 mmol, 9.5 g) in water (40 ml) is added. The resulting mixture is refluxed for 5 h. The solvents are evaporated and the residue is recrystallized from EtOH yielding the title compound; [M+H]+=122.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:40])[CH2:15][C:16]1[CH:17]=[C:18]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[CH:19]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:52][C:53]([CH3:55])=[CH2:54]>C1COCC1>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:40])[CH:15]([C:16]1[CH:17]=[C:18]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:34][CH:35]=2)[CH:19]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=1)[CH2:54][C:53]([CH3:55])=[CH2:52])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)CBr
Reactant: O=C(Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1)N1C(=O)OCC1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
To a colorless solution of 4-benzyl-3-[2-(5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetyl]-oxazolidin-2-one (6.0 g, 11.00 mmol) in dry THF (22 mL) at −78° C. was added NaHMDS (1 M in THF solution, 12.11 mL, 12.11 mmol), drop-wise, maintaining the internal temperature below −75° C. The resulting red solution was stirred at −78° C. for 30 minutes. To this was added 3-bromo-2-methyl propene (4.44 mL, 44 mmol) maintaining the temperature below −75° C. When the addition was at near completion, the system turned to green. At this point the dry-ice bath was quickly removed and replaced with wet-ice bath and completed the addition. The reaction mixture was stirred further at 0° C. for 30 min and quenched with saturated aqueous NH4Cl solution. The system was diluted with EtOAC (100 mL) and the organic phase washed with saturated aqueous NaHCO3 solution (3×50 mL) and dried (MgSO4). Solvent was removed in vacuo and the crude mixture was purified by ISCO silica gel column to yield 4-benzyl-3-[2-(5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pent-4-enoyl]-oxazolidin-2-one (6.3 g, 95%).
Reaction SMILES: C(O[C:9](=O)[N:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:14][C:13]=1[CH3:26])C)C1C=CC=CC=1>[Pd].CO>[C:22]([Si:19]([CH3:21])([CH3:20])[O:18][C:15]1[CH:16]=[CH:17][C:12]([NH:10][CH3:9])=[C:13]([CH3:26])[CH:14]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1N(C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CNc1ccc(O[Si](C)(C)C(C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
The mixture of [4-(tert-butyl-dimethyl-silanyloxy)-2-methyl-phenyl]-methyl-carbamic acid benzyl ester (14.0 g, 36.0 mmol) and palladium on carbon (10 wt %, 0.5 g) in methanol (100.0 mL) is stirred under an atmosphere of hydrogen at room temperature overnight. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure to a residue. The residue is purified by flash chromatography to afford the title compound as oil (7.4 g, 81%). LC-ES/MS m/e 252.3 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:18])[N:4](C)[C:5]2[C:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:19]C1C=C2C(=CC=1)NC(=O)C2=O>>[OH:1][C:2]1[C:3](=[O:18])[NH:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:8]([CH3:19])=[CH:7][CH:6]=2
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Reactant: CCOC(=O)c1c(O)c(=O)n(C)c2ccccc12
Product: CCOC(=O)c1c(O)c(=O)[nH]c2ccc(C)cc12

Procedure:
Intermediate 17 was prepared as a white powder following the procedure described for Intermediate 16 by replacing indoline-2,3-dione with 5-methylindoline-2,3-dione. 1H NMR (400 MHz, chloroform-d) δ ppm 11.23 (1 H, br. s.), 9.64 (1 H, br. s.), 7.83 (1 H, s), 7.01-7.56 (2 H, m), 4.58 (2 H, q, J=7.1 Hz), 2.43 (4 H, s), 1.51 (3 H, t, J=7.1 Hz). LC-MS (ESI) m/z 247.9 (M+H), RT=1.76 min (Method B)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11](C(O)=O)[C:12](=[O:15])[NH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1>N1C2C(=CC=CC=2)C=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2c[nH]c(=O)c(C(=O)O)c2)c1
Solvent: c1ccc2ncccc2c1
Product: COc1cccc(-c2ccc(=O)[nH]c2)c1

Procedure:
In the manner described in Example 20, heating 1,2-dihydro-5-(3-methoxyphenyl)-2-oxo-3-pyridinecarboxylic acid in quinoline provides the product of the Example.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][CH:13]=[N:12][CH:11]=2)=[C:6]([O:15][CH3:16])[CH:5]=1)([O-])=O>[Pd].CCO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][CH:13]=[N:12][CH:11]=2)=[C:6]([O:15][CH3:16])[CH:5]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-c1cnco1
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N)ccc1-c1cnco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
In a 2 L hydrogenation flask was placed 1C (130.0 g, 0.6131 mol), Pd/C (10%, 26.2 g) and absolute EtOH (1280 mL). The mixture was hydrogenated at 35–45 psi H2 until the reaction was complete. The mixture was filtered over a pad of celite (20 g) and the cake was washed with EtOH (3×100 mL). The filtrate was concentrated to a volume of 350 mL. Heptane (500 mL) was added to the resulting slurry. After stirring for 2 hours at room temperature, the slurry was filtered. The cake was washed with heptane (3×100 mL) and air-dried to give 80.0 g of 1D. Another 30.2 g of product was recovered from the mother liquor affording a total yield of 95%. 1H NMR (CDCl3) d 7.88 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.41 (s, 1H), 6.41 (dd, J=8.4, 2.1 Hz, 1H), 3.34 (d, J=2.1 Hz, 1H), 3.98 (bs, 2H), 3.94 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[CH2:33]([O:32][C:30]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][N:12]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=[CH:11]1)=[O:31])[CH3:34]
Reactant: COc1ccc(-c2nc[nH]c2-c2ccc(OC)cc2)cc1
Reactant: CCOC(=O)CCCCCCCBr
Product: CCOC(=O)CCCCCCCn1cnc(-c2ccc(OC)cc2)c1-c1ccc(OC)cc1
Yield: 83.6 %

Procedure:
4,5-Bis(4-methoxyphenyl)imidazole (1.8 g) (J. Med. Chem., 1974, 17, 1182-8) and ethyl 8-bromooctanoate (3.2 g) were reacted in a method similar to Example 9. Colnmn chromatography on silica gel eluted with a dichloro-methane:ethanol gradient gave 1-(7-ethoxycarbonyl-heptyl)- 4,5-bis(4-methoxyphenyl)imidazole (2.42 g, 83%) as an oil. Found: C, 72.30; H, 7.72; N, 6.21%; C27H34N20 4 requires: C, 71.97; H, 7.61; N, 6.22%.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[O:13])[NH:5][CH2:4][C:3]1=[O:14].[N+:15]([O-])([O-:17])=[O:16].[K+]>S(=O)(=O)(O)O>[N+:15]([C:11]1[CH:10]=[CH:9][C:8]2[N:2]([CH3:1])[C:3](=[O:14])[CH2:4][NH:5][C:6](=[O:13])[C:7]=2[CH:12]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])[O-]
Reactant: CN1C(=O)CNC(=O)c2ccccc21
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CN1C(=O)CNC(=O)c2cc([N+](=O)[O-])ccc21
Reaction time: 8 h

Procedure:
1-Methyl-3,4-dihydro-1H-benzo[e][1,4]diazapine-2,5-dione (3.4 g, 17.9 mmol) was dissolved in concentrated sulfuric acid (30 ml) and to this was added potassium nitrate (1.95 g, 19.3 mmol) at 0° C. The mixture was stirred overnight, dumped onto ice, and the solids filtered off (3.62 g, 86%), m.p. 274-276° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClC(Cl)C>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[N:5]=[C:4]([NH:18][CH:19]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:3]=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][C:30]=3[O:34][CH3:35])[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Reactant: COc1cccc(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: COc1ccc(-c2nc(Nc3ccc(OC)c(Cl)c3)nc(NC3CCCCCC3)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A mixture of compound 133 (0.5 grams), 1,3-dimethoxybenzene (0.18 g) and AlCl3 (0.2 grams) in dichloroethane (10 mL) was stirred under nitrogen atmosphere at room temperature for 30 min. It was then heated at 80° C. for 3 hours with stirring. The reaction mixture was poured into ice-cold water (50 mL), extracted with chloroform (3×30 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The residue thus obtained was purified by column chromatography using petroleum ether-ethyl acetate to afford the expected product (yield 64%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]([NH:32][C:33](=[O:35])[CH3:34])([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=O)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH2:10][O:11][C:12](=[O:14])[CH3:13])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>C([SiH](CC)CC)C>[C:1]([O:4][CH2:5][CH2:6][C:7]([NH:32][C:33](=[O:35])[CH3:34])([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH2:10][O:11][C:12](=[O:14])[CH3:13])(=[O:3])[CH3:2]
Reactant: CCCCCCCC(=O)c1ccc(CCC(CCCOC(C)=O)(CCOC(C)=O)NC(C)=O)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCCc1ccc(CCC(CCCOC(C)=O)(CCOC(C)=O)NC(C)=O)cc1
Temperature: 0 °C
Yield: 64.3 %

Procedure:
To a solution of 3-acetamido-6-acetoxy-3-[2-(4-octanoylphenyl)ethyl]hexyl acetate (720 mg) in triiluoroacetic acid (15 ml), triethylsilane (0.53 ml) was added at room temperature. After stirring for an hour, the reaction solution was poured into ice-water and potassium carbonate was carefully added to the mixture to neutralize. The mixture was extracted with ethyl acetate and the extract was washed with water and a saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled away and the residue obtained was purified by silica gel chromatography (eluent; hexane-ethyl acetate=1:1) to give the subject compound (450 mg) as a colorless oily substance.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH:15]([O:20][C:21]3[CH:26]=[CH:25][C:24](CCC(OCC)=O)=[CH:23][CH:22]=3)[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-:36].[Na+]>C1COCC1.CO>[F:34][C:2]([F:1])([F:35])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]([CH:15]([O:20][C:21]3[CH:26]=[CH:25][C:24]([CH:13]([CH3:12])[C:15]([OH:20])=[O:36])=[CH:23][CH:22]=3)[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCCCC(Oc1ccc(CCC(=O)OCC)cc1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCC(Oc1ccc(C(C)C(=O)O)cc1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1

Procedure:
To a stirred solution of ethyl 3-{4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoate (92 mg, 0.19 mmol) in THF (3 mL) and methanol (3 mL) was added, drop-wise, aqueous NaOH (2M, 3 mL). After 17 hours the mixture was concentrated under vacuum and the solid residue acidified with aqueous HCl (2M, 3.5 mL), diluted with water (10 mL) and extracted with DCM (2×10 mL). The combined organic layer was washed with brine (20 mL), dried (MgSO4) and concentrated under vacuum. The acid was loaded onto a PE-AX isolute SPE cartridge (pre-conditioned with 1 column volume of methanol) in 9 mL of methanol and a few drops of Et3N. The cartridge was washed with 3 column volumes of methanol followed by 10% aqueous HCl (2M) in methanol (2×5 mL) and 20% aqueous HCl (2M) in methanol (2×5 mL), yielding the title compound (38 mg).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:29]=1)[C:18]1[CH:17]=[C:16](Br)[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([O:20][C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[C:23]#[N:24])=[CH:9][CH:10]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1.C1COCC1.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:29]=1)[C:18]1[CH:17]=[C:16]([C:32]3[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=3)[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([O:20][C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[C:23]#[N:24])=[CH:9][CH:10]=1
Reactant: N#Cc1ccccc1Oc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(Br)ccc1O2
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1ccccc1Oc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2
Temperature: 100 °C

Procedure:
A vial was charged with (R)-2-(2-amino-2′-bromo-5H-spiro[oxazole-4,9′-xanthene]-7′-yloxy)benzonitrile (75 mg, 0.167 mmol), pyridin-3-ylboronic acid (51.4 mg, 0.418 mmol), tetrakis(triphenylphosphine)palladium(0) (9.67 mg, 8.37 μmol), THF (837 μL), and potassium carbonate (418 μL, 0.837 mmol) (as a 2.0 M aq. solution). The vial was sealed and heated to 100° C. in a shaker overnight. The mixture was diluted with EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc (2×). The combined organic extracts were evaporated, and the residue was chromatographed on a 25-g SNAP column, eluting with 0-80% of a 90:10:1 mix of DCM/MeOH/NH4OH in DCM to give (S)-2-(2-amino-2′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yloxy)benzonitrile as a pale-yellow solid.