Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[Li]CCCC.C1CCCCC1.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>C1COCC1>[CH2:10]([O:9][C:3](=[O:8])[CH2:4][C:5](=[O:6])[CH2:7][CH2:28][C:27]1[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=1)[CH3:11]
Reactant: CCOC(=O)CC(C)=O
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred suspension of NaH (60% suspension in mineral oil, 1.42 g, 36 mmol) in dry THF (50 mL) was added ethyl acetoacetate (4.3 g, 33 mmol) dropwise at 0° C. After 10 min stirring at this temperature, a 2.0 M solution of n-BuLi in cyclohexane (17.7 mL, 35 mmol) was added dropwise under N2. The stirring was continued at 0° C. for 10 min., 4-fluorobenzyl bromide (9.45 g, 50 mmol) was then added dropwise at 0° C. The resultant solution was allowed to warm to rt. After 20 min, the reaction as quenched with 2 N HCl/Et2O (20 mL/40 mL). Layers were separated, the aqueous layer was extracted with ether (3×50 mL). Combined ether solution was washed with H2O (50 mL), brine (50 mL), and dried with Na2SO4. After removal of the solvent under reduced pressure, the resultant oily material was purified by flush column chromatography on silica gel (hexane to 4:1 hexane/EtOAc). The corresponding intermediate 5-(4-Fluoro-phenyl)-3-oxo-pentanoic acid ethyl ester was obtained as a colorless liquid (7.16 g, 92%). 1H NMR (300 MHz, CDCl3) δ1.25 (t, 3H, J=7), 2.80-2.95 (m, 4H), 3.40 (s, 2H), 4.10-4.25 (m, 2H), 6.9-7.0 (m, 2H), 7.1-7.2 (m, 2H). ESMS calcd (C13H15FO3): 238.1; found: 239.1 (M+H)+.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[C:9]([CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12])#[CH:10].C(NCC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[N:6]1[CH:7]=[CH:8][C:3]([C:10]#[C:9][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[OH:12])=[CH:4][CH:5]=1
Reactant: Brc1ccncc1
Reactant: C#CC(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCNCC
Product: OC(C#Cc1ccncc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 8 %

Procedure:
Place 4-bromopyridine hydrochloride (2.33 g, 12 mmol), α-(ethynyl)-benzenemethanol (1.95 g, 14.8 mmol) and diethylamine (25 mL) under nitrogen atmosphere. Add bis(triphenylphosphine)palladium(II) chloride (105 mg) then copper(I) iodide (59 mg). Stir at room temperature for 3 hours. Evaporate the solvent in vacuo, stir the residue in ethyl acetate (50 mL) and filter the solids. Evaporate the solvent in vacuo and purify by silica gel chromatography (4:3 ethyl acetate/hexane) to yield 0.4 g. Recrystallize (hexane/chloroform) to yield 0.2 g of the title compound; mp 93°-96° C.
Reaction SMILES: [C:1]([C:4]1[NH:5][N:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[C:7](=[O:9])[CH:8]=1)(=O)[NH2:2].C(#N)C.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[C:1]([C:4]1[NH:5][N:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[C:7](=[O:9])[CH:8]=1)#[N:2]
Reactant: Cc1ccccc1-n1[nH]c(C(N)=O)cc1=O
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccccc1-n1[nH]c(C#N)cc1=O
Temperature: 0 °C

Procedure:
22.5 g of 3-carbamoyl-1-(2-methylphenyl)-5-pyrazolone and 150 ml of acetonitrile were put into a 300 ml three-necked flask. A mixture solution of 35 ml of phosphorus oxychloride and 100 ml of N,N-dimethylformamide was added dropwise thereto at a temperature of 15° C. or below. After completion of the dropwise addition, the reaction mixture was poured into ice water and the crystals thus deposited were collected by filtration.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:10][C:11]([O:13]CC)=[O:12])[C:6](=[O:9])[C:7]=1[Br:8].[OH-].[Na+].C(OCC)(=O)C>O1CCOCC1>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:10][C:11]([OH:13])=[O:12])[C:6](=[O:9])[C:7]=1[Br:8]
Reactant: CCOC(=O)Cn1ncc(Br)c(Br)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(O)Cn1ncc(Br)c(Br)c1=O
Yield: 96 %

Procedure:
Ethyl 2-(4,5-dibromo-6-oxopyridazin-1(6H)-yl)acetate (6.01 g, 17.7 mmol) in 1,4-dioxane (60 mL) was stirred with 1 M aqueous sodium hydroxide (53.1 mL, 53.1 mmol) at room temperature for 1 hour. After completion of the reaction, the reaction solution was mixed with ethyl acetate and extracted with 1 M aqueous sodium hydroxide twice. The resulting aqueous layer was acidified to pH 1 with 1 M hydrochloric acid and extracted with ethyl acetate twice. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product (5.30 g, 88% yield).
Reaction SMILES: [N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[CH:12][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:23][O:24][CH2:25]Cl.O>CN(C)C=O.C(OCC)(=O)C>[CH3:23][O:24][CH2:25][N:9]1[C:8]2[CH:11]=[CH:12][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:14][C:7]=2[S:6][C:5]2[N:4]=[CH:3][CH:2]=[N:1][C:10]1=2
Reactant: ClCOCCl
Reactant: CCOC(=O)c1ccc2c(c1)Sc1nccnc1N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)Sc1nccnc1N2COC
Reaction time: 1 h

Procedure:
100 ml of a solution of 7.0 g of ethyl 10H-pyrazino[2,3-b][1,4]benzothiazine-7-carboxylate in N,N-dimethylformamide was ice-cooled in a nitrogen atmosphere and 1.3 g of sodium hydride (60% oily) was added thereto. Then the resulting mixture was brought back to room temperature and stirred for 1 hour. Next, it was ice-cooled again and 2.5 ml of chloromethyl ether was dropped thereinto. After the completion of the reaction, the reaction mixture was distributed into water and ethyl acetate. The organic layer was extracted, washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate/hexane) to thereby give 5.0 g of ethyl 10-(methoxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine-7-carboxylate as pale yellow crystals.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.C(N(CC)CC)C.[CH3:18][CH:19]1[CH2:24][NH:23][CH2:22][CH2:21][NH:20]1.C(OCC)(=O)C>CN(C=O)C>[CH3:18][CH:19]1[NH:20][CH2:21][CH2:22][N:23]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH2:8])[CH2:24]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC1CNCCN1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1CN(c2ccccc2N)CCN1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Fluoronitrobenzene (7.1 g, 50 mmol) was dissolved in DMF (100 mL) containing triethylamine (10 g, 100 mmol) and placed under a nitrogen atmosphere. To the solution was added 2-methyl-piperazine (5.5 g, 55 mmol). The reaction was heated to 80° C. for 16 hours. The reaction was allowed to cool to room temperature before the solvent was reduced to half volume in vacuo. Ethyl acetate (200 mL) and ice-water (250 mL) were added to the solution and the product was extracted with diethyether (2×200 mL). The aqueous phase was saturated with sodium chloride and extracted with ethyl acetate (2×200 mL). The organic phases were combined, washed with saturated brine, dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The product (10.5 g) was dissolved in ethanol (250 mL). Palladium on charcoal catalyst (10% w/w, 2.2 g) was added to the solution and the solution was hydrogenated in a Parr apparatus at 3 bar for 3 hours. The solution was filtered and the solvents evaporated in vacuo to give the aniline product. Yield (8.0 g, 83%)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)/[S:6][C:5]1=[O:20].[C:21](Cl)([O:23][CH2:24][CH:25]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22].CCN(C(C)C)C(C)C.C(OC1C=CC(/C=C2/C(=O)N(CCNC(=O)C)C(=O)S/2)=CC=1)C>>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11](/[CH:10]=[C:7]2/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][C:21](=[O:22])[O:23][CH2:24][CH:25]3[C:37]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:31]4[C:26]3=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:5](=[O:20])[S:6]/2)=[CH:12][CH:13]=1)[CH3:19]
Reactant: CCOc1ccc(/C=C2\SC(=O)N(CCN)C2=O)cc1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: CCOc1ccc(/C=C2\SC(=O)N(CCNC(C)=O)C2=O)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(/C=C2\SC(=O)N(CCNC(=O)OCC3c4ccccc4-c4ccccc43)C2=O)cc1

Procedure:
The title compound 26e was prepared from compound 76 (101 mg, 0.25 mmol), Fmoc chloride (71 mg, 0.28 mmol) and DIPEA (131 μL, 0.75 mmol) in a manner similar to that described for 25a in 96.4% (124 mg) yield as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:27][C:28]1[CH:29]=[C:30]([CH:49]=[CH:50][C:51]=1[F:52])[O:31][C:32]1[CH:46]=[CH:45][C:35]2[N:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[S:38][C:34]=2[C:33]=1[C:47]#[N:48]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:27][C:28]1[CH:29]=[C:30]([O:31][C:32]2[CH:46]=[CH:45][C:35]3[N:36]=[C:37]([NH:39][C:40]([CH:42]4[CH2:44][CH2:43]4)=[O:41])[S:38][C:34]=3[C:33]=2[C:47]#[N:48])[CH:49]=[CH:50][C:51]=1[F:52])=[O:6]
Reactant: N#Cc1c(Oc2ccc(F)c(N)c2)ccc2nc(NC(=O)C3CC3)sc12
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3C#N)ccc2F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
To a solution of 2-chloro-3-(1-cyano-1-methylethyl)benzoic acid (108 mg, 0.482 mmol) in tetrahydrofuran (1.5 mL) were added oxalyl chloride (52 μL, 0.601 mmol) and N,N-dimethylformamide (10 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (1.5 mL). N-[6-(3-Amino-4-fluorophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (150 mg, 0.407 mmol) produced in Example 30(vi) was added to the solution, and the mixture was stirred at room temperature for 10 min. The reaction mixture was diluted with ethyl acetate (10 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (116 mg, 50%) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:30]=[CH:31][CH:32]=1)[CH2:7][NH:8][CH2:9][CH2:10][N:11]1[CH:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:29])[CH:17]=2)[CH2:12]1)([O-:3])=[O:2].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH2:38]([O:37][C:35](=[O:36])[CH2:34][N:8]([CH2:7][C:6]1[CH:30]=[CH:31][CH:32]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH2:9][CH2:10][N:11]1[CH:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:29])[CH:17]=2)[CH2:12]1)[CH3:39]
Reactant: O=[N+]([O-])c1cccc(CNCCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CN(CCN1Cc2ccc(F)cc2CC1Cc1ccc(F)cc1)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
106 mg of N-(3-nitrobenzyl)-2-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethanamine obtained in Example 123-b), 40 mg of ethyl bromoacetate, and 33 mg of potassium carbonate were dissolved in 1 mL of acetonitrile, followed by stirring at room temperature for 3 hours. After completion of the reaction, water was added to the reaction liquid, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue obtained was purified using PLC (chloroform:methanol=20:1) to obtain 97 mg (yield 76%) of a title compound as a pale yellow oily substance.
Reaction SMILES: C(OC([N:8]1[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][N:11]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([O:34][CH3:35])[CH:28]=2)[N:21]([CH2:36][C:37](=[O:42])[NH:38][CH:39]([CH3:41])[CH3:40])[C:20]3=[O:43])[CH2:10][CH:9]1[CH3:44])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C:22]2[N:21]([CH2:36][C:37]([NH:38][CH:39]([CH3:41])[CH3:40])=[O:42])[C:20](=[O:43])[C:19]3[C:24](=[CH:25][CH:26]=[C:17]([N:11]4[CH2:12][C:13]([CH3:16])([CH3:15])[CH2:14][NH:8][CH:9]([CH3:44])[CH2:10]4)[CH:18]=3)[N:23]=2)=[CH:28][C:29]=1[O:34][CH3:35]
Reactant: COc1cc(-c2nc3ccc(N4CC(C)N(C(=O)OC(C)(C)C)CC(C)(C)C4)cc3c(=O)n2CC(=O)NC(C)C)ccc1F
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2nc3ccc(N4CC(C)NCC(C)(C)C4)cc3c(=O)n2CC(=O)NC(C)C)ccc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-[2-(4-Fluoro-3-methoxyphenyl)-3-(isopropylcarbamoylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl]-2,6,6-trimethylperhydro-1,4-diazepine-1-carboxylic acid tert-butyl ester (120 mg, 0.197 mmol) was dissolved in DCM (6 mL) and TFA (3 mL) added. The reaction was stirred at room temperature for 4 h. Product mixture was poured directly onto an SCX cartridge and product eluted with 2N NH3/MeOH. Solvent was evaporated under reduced pressure to afford a red solid. Product was diluted with MeOH (20 mL) and heated at reflux temperature with activated carbon. The mixture was filtered through a celite pad, solvent evaporated under reduced pressure and the resultant product recrystallised from ethanol:heptane. This afforded 2-[2-(4-fluoro-3-methoxyphenyl)-4-oxo-6-(3,6,6-trimethylperhydro-1,4-diazepin-1-yl)-4H-quinazolin-3-yl]-N-isopropylacetamide (EXAMPLE 8a) (74 mg, 0.145 mmol, 74%). Data for 2-[2-(4-fluoro-3-methoxyphenyl)-4-oxo-6-(3,6,6-trimethylperhydro-1,4-diazepin-1-yl)-4H-quinazolin-3-yl]-N-isopropylacetamide (EXAMPLE 8a): MS (ESI) m/z: 510 ([M+H]+).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:4]=1)#[CH:2].I[C:35]1[CH:36]=[N:37][CH:38]=[CH:39][C:40]=1[OH:41].C(N(CC)CC)C.C(OCC)(=O)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[N+:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([C:15]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[N:4]=[C:3]2[C:1]1[O:41][C:40]2[CH:39]=[CH:38][N:37]=[CH:36][C:35]=2[CH:2]=1)([O-:14])=[O:13]
Reactant: Oc1ccncc1I
Reactant: C#Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc([N+](=O)[O-])cc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(c1)c(-c1cc3cnccc3o1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 80 %

Procedure:
A reaction mixture containing 3-ethynyl-5-nitro-1-trityl-1H-indazole (215 mg, 0.5 mmol), 3-iodo-pyridin-4-ol (132 mg, 0.6 mmol), copper (I) iodide (4.5 mg, 0.025 mmol), PdCl2(PPh3)2 and triethylamine (120 mg, 1.2 mmol) in DMF (3 mL) was heated at 100° C. overnight under argon. After the completion of reaction (shown by TLC), ethyl acetate (50 mL) was added and the reaction mixture was added to water. The organic layer was collected, washed with water, brine and concentrated under vacuum. After purification using silica (7% methanol in dichloromethane), the desired product was obtained (210 mg, 0.4 mmol) in 80% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([C:22]([OH:24])=O)=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)OCC(C)C.C([N:35](CC)CC)C.N>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([C:22](=[O:24])[NH2:35])=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NCCOc1noc2ccc(F)c(C(=O)O)c12
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1noc2ccc(F)c(C(N)=O)c12
Temperature: 5 °C
Yield: 77.6 %

Procedure:
To a solution of 3-(2-(N-t-butoxycarbonylamino)ethoxy)-4-carboxy-5-fluoro-1,2-benzisoxazole (0.31 g) in tetrahydrofuran (20 ml) was added isobutyl chlorocarbonate (0.14 g) and triethylamine (0.11 g) with stirring at 5° C., and the mixture was then stirred for 15 minutes. Ammonia-saturated tetrahydrofuran solution (saturated at room temperature, 5 ml) was added to the reaction mixture and stirred for 15 minutes. The reaction mixture was poured into ice water (40 ml), extracted with diethylether (twice each with 40 ml) and the combined extracts were dried over anhydrous magnesium sulphate and filtered. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography with cyclohexane/ethyl acetate (4/1) as an eluent, to give title compound (0.24 g, 78% yield) as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=O.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:50][C@@H:51]([CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=1[C:71]([F:74])([F:73])[F:72])[CH2:52][N:53]1[C:61](=[O:62])[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:54]1=[O:63]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1)[C:5]([NH:50][C@@H:51]([CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=1[C:71]([F:74])([F:72])[F:73])[CH2:52][N:53]1[C:61](=[O:62])[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:54]1=[O:63])=[O:7]
Reactant: Cn1nccc1-c1ccc(C(=O)O)cc1Br
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1ccc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1Br
Reaction time: 16 h
Yield: 78.1 %

Procedure:
To a solution of 3-bromo-4-(1-methyl-1H-pyrazol-5-yl)benzoic acid (100 mg, 0.36 mmol), PyBrOP (277 mg, 0.59 mmol) and diisopropylethyl amine (0.11 mL, 0.59 mmol) in DCM (6 mL) at 25° C. was added 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (161 mg, 0.36 mmol) [prepared according to Preparation 3]. After 16 h, the solution was concentrated and purified via column chromatography (silica, hexanes/EtOAc, 2:1) affording the title compound (172 mg, 78%) as a white solid: LC-MS (ES) m/z=612 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[N:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.O1CCCC1.[CH2:26]([Mg]Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Cl-].[NH4+]>O>[CH2:26]([C:8]1([NH:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: COc1ccc(CN=C2CCC3(CC2)OCCO3)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CNC2(Cc3ccccc3)CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
In a heated flask a 0.6 M solution of (1,4-dioxaspiro[4,5]dec-8-ylidene)-(4-methoxybenzyl)amine in tetrahydrofuran (17 ml, 10 mmol) was added slowly dropwise under argon and with ice cooling to a 2 M solution of benzyl magnesium chloride in tetrahydrofuran (10 ml, 20 mmol). The mixture was stirred for 20 h at room temperature and then added dropwise to 20% ammonium chloride solution (20 ml) with iced water cooling. The organic phase was separated off and the aqueous phase was extracted with diethyl ether (3×20 ml). The combined organic phases were washed with 2 N sodium hydroxide solution (20 ml) and water (20 ml), dried with sodium sulfate and concentrated to small volume under vacuum. The crude product (3.7 g) was purified by flash chromatography (370 g, 22×7.5 cm) with ethyl acetate/cyclohexane (1:2) with 1% triethylamine. Yield: 1.27 g (34%), yellowish oil.
Reaction SMILES: II.[Mg].[I-].[Mg+2].[I-].C[O:8][C:9]1[C:17]2[CH:18]=[CH:19][C:20]([O:22][C:16]=2[CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][O:13]2)=[O:21]>CCOCC>[CH:11]1[C:10]2=[C:9]([OH:8])[C:17]3[CH:18]=[CH:19][C:20](=[O:21])[O:22][C:16]=3[CH:15]=[C:14]2[O:13][CH:12]=1
Reactant: COc1c2ccoc2cc2oc(=O)ccc12
Agent: II
Agent: [I-]
Agent: [Mg+2]
Solvent: CCOCC
Product: O=c1ccc2c(O)c3ccoc3cc2o1
Reaction time: 1.5 h

Procedure:
A solution of iodine (1.0 g, 4 mmol) and magnesium (0.2 g, 8 mmol) was stirred in anhydrous ether (30 ml) under reflux until colourless to prepare magnesium iodide. Bergapten (1.0 g, 4.5 mmol) was suspended in anhydrous ether and added to the solution. After heating the mixture to reflux for 45 min, the solvent was removed under reduced pressure. The residue was dried at 120° C. for 30 min, kept at 160-165° C. for 90 min, and decomposed with 25% sulfuric acid. The crude product was filtered, washed with a solution of thiosulfate, dried, and used for the synthesis of the 5-phenylalkoxy- and 5-cyclohexylalkoxypsoralens without further purification.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[CH:16][C:17]2[C:18](=[O:32])[N:19]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=[CH:21][C:22]=2[C:23]=1[OH:24])=[O:13])(C)(C)C.[F:34][C:35]([F:40])([F:39])C(O)=O>C(Cl)Cl>[F:34][C:35]([F:40])([F:39])[C:6]([NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[CH:16][C:17]2[C:18](=[O:32])[N:19]([CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:20]=[CH:21][C:22]=2[C:23]=1[OH:24])=[O:13])=[O:5]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Solvent: ClCCl
Product: O=C(NCCCNC(=O)C(F)(F)F)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
{3-[(7-Benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carbonyl)-amino]-propyl}-carbamic acid tert-butyl ester (27 mg, 0.060 mmol) was dissolved in CH2Cl2 (2 mL). Trifluoroacetic acid (1 mL) was added, and the mixture was stirred at r.t. for 1 h. Solvent and excess TFA were removed in vacuo. To the residue were added THF (3 mL), triethylamine (0.050 mL), and ethyl trifluoroacetate (2 mL), and the resulting mixture was refluxed for 16 h. After cooling to r.t., mixture was concentrated to dryness. 0.1 M HCl and EtOAc were added, and the aqueous layer was extracted with additional EtOAc. The organic layers were combined, dried over MgSO4, and concentrated. The crude product was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to give 16.4 mg of the title compound as a pale yellow solid. MS: (+) m/z 449.23 (M+1).