Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=[C:4]([CH3:17])[N:3]=1.[C:18]1([C:24]2[CH:28]=[C:27]([CH2:29][NH2:30])[O:26][N:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([N:34](C(C)C)CC)(C)C>C(O)CCC>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[N:7]=[C:2]([NH:30][CH2:29][C:27]4[O:26][N:25]=[C:24]([C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:28]=4)[NH:3][C:4]([CH3:17])([NH2:34])[CH:5]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: Cc1cc(Nc2cc(C3CC3)[nH]n2)nc(Cl)n1
Reactant: NCc1cc(-c2ccccc2)no1
Reactant: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC1(N)C=C(Nc2cc(C3CC3)[nH]n2)N=C(NCc2cc(-c3ccccc3)no2)N1
Temperature: 160 °C
Yield: 55.3 %

Procedure:
A mixture of 2-chloro-6-methylpyrimidin-4-yl-(5-cyclopropyl-1H-pyrazol-3-yl)-amine (1.9 g, 7.6 mmol), 3-phenylisoxazol-5-ylmethylamine (1.7 g, 9.9 mmol) and diisopropylethylamine (1.8 mL, 11 mmol) in 1-butanol (30 mL) was heated to 160° C. in a 50 mL sealed tube for 8 h. The hot mixture was filtered to give the desired product (1.7 g, 58%) as a white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33]/[CH:34]=[C:35](\[C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[CH:41][CH:40]=2)/[C:36]([OH:38])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[CH2:49]([O:51][C:52]([C:54]1[S:58][C:57]([NH2:59])=[N:56][CH:55]=1)=[O:53])[CH3:50]>C(Cl)Cl>[CH2:49]([O:51][C:52]([C:54]1[S:58][C:57]([NH:59][C:36](=[O:38])/[C:35](/[C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[CH:41][CH:40]=2)=[CH:34]/[CH2:33][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)=[N:56][CH:55]=1)=[O:53])[CH3:50]
Reactant: CS(=O)(=O)c1ccc(/C(=C\CC2CCCC2)C(=O)O)cc1
Reactant: CCOC(=O)c1cnc(N)s1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1cnc(NC(=O)/C(=C/CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
A solution of triphenylphosphine (787 mg, 3 mmol) in methylene chloride (40 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (534 mg, 3 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with (E)-4-cyclopentyl-2-(4-methanesulfonyl-phenyl)-but-2-enoic acid (prepared in Example 21, 462 mg, 1.5 mmol). The clear solution was stirred for 10 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1 h. The reaction mixture was then treated with 2-aminothiazole-5-carboxylic acid ethyl ester (774 mg, 4.5 mmol), and the resulting suspension was stirred at 25° C. over the weekend. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (70 mL) and a 1N aqueous hydrochloric acid solution (70 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×50 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 3/1 to 1/1 hexanes/ethyl acetate) afforded (E)-2-[4-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-but-2-enoylamino]-thiazole-5-carboxylic acid ethyl ester (250 mg, 36%) as an amorphous white solid: ET-HRMS m/e calcd for C22H26N2O5S2 (M+) 462.1283, found 462.1282.
Reaction SMILES: [C:1]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[N:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([CH2:26][CH2:27][CH3:28])=[CH:24][C:23](C(O)=O)=[N:22]2)=[CH:16][CH:15]=1)(=[O:7])=[O:6])(=[O:3])[CH3:2].CN([CH:35]=[O:36])C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:61][C@H:62]([CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[C@@H:63]([OH:67])[C:64]([OH:66])=[O:65].Cl.CCN(C(C)C)C(C)C>>[C:1]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[N:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([CH2:26][CH2:27][CH3:28])=[CH:24][C:23]([C:35]([NH:61][C@H:62]([CH2:68][C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C@@H:63]([OH:67])[C:64]([OH:66])=[O:65])=[O:36])=[N:22]2)=[CH:16][CH:15]=1)(=[O:7])=[O:6])(=[O:3])[CH3:2]
Reactant: CCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)=O)nc1
Reactant: N[C@H](Cc1ccccc1)[C@@H](O)C(=O)O
Reactant: CN(C)C=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(C(=O)N[C@H](Cc2ccccc2)[C@@H](O)C(=O)O)nn1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)=O)nc1
Temperature: 40 °C
Yield: 91 %

Procedure:
A solution of 1-[6-(2-acetylsulfamoylphenyl)pyridin-3-ylmethyl]-5-propyl-1H-pyrazole-3-carboxylic acid (100 mg, 226 μmol) in DMF (7.0 mL, 90 mmol) was added to HATU (85.9 mg, 226 μmol). The resulting mixture was stirred for 5 minutes before (2R,3R)-3-amino-2-hydroxy-4-phenylbutyric acid.HCl (52.4 mg, 226 μmol) and DIPEA (315 μL, 1.8 mmol) were added. The resulting solution was heated at 40° C. overnight. The mixture was concentrated, re-dissolved in water/MeCN/TFA and purified using reverse phase liquid chromatography to yield the title compound (48 mg; 91% purity) as a TFA salt. MS m/z: [M+H]+ calcd for C31H33N5O7S, 620.21. found 620.4.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH3:5][NH:6][CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.C(N(CC)CC)C>>[CH3:5][N:6]([CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)[C:1]([Cl:4])=[O:2]
Reactant: O=C(Cl)Cl
Reactant: CNC1CCOCC1
Solvent: CCN(CC)CC
Product: CN(C(=O)Cl)C1CCOCC1

Procedure:
248 g (2.5 mol) of phosgene, 96 g (0.83 mol) of N-methyl-N-(tetrahydro-2H-pyran-4-yl)amine and 84 g (0.83 mol) of triethylamine were reacted by the method of the process described in Intermediate 1.2. Yield 108 g. 1H NMR (250 MHz, in CDCl3): δ=1.60-1.95 (m, 4H), 2.94 and 3.01 (2 s, together 3H), 3.35-3.55 (rm, 2H), 3.95-4.10 (m, 2H), 4.27-4.46 (m, 1H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6].[S-:15][C:16]#[N:17].[NH4+].BrBr>C(O)(=O)C>[NH2:2][C:3]1[CH:13]=[C:12]([Br:14])[C:11]([S:15][C:16]#[N:17])=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1ccc(Br)cc1N
Reactant: N#C[S-]
Agent: BrBr
Agent: Cl
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(SC#N)c(Br)cc1N
Temperature: 25 °C

Procedure:
In a 100 ml three-neck round bottom flask equipped with an internal thermometer and magnetic stirrer, a solution of 3.26 g (0.0116 mol) of ethyl 2-amino-4-bromobenzoate hydrochloride, 2.12 g (0.0279 mol) of ammonium thiocyanate and 30 ml of acetic acid was cooled to 15° C. Bromine (1.86 g, 0.0116 mol) was then added dropwise with stirring. A precipitate formed. When the addition was complete, the solution was allowed to warm to room temperature, and to stir for an hour. The product was filtered, dried under nitrogen, and recrystallized from hexane and ethyl acetate to furnish crystalline ethyl 2-amino-4-bromo-5-thiocyanatobenzoate: yield 2.05 g (59%); m.p. 149°-150° C.; ir(KBr) 3487 cm, 3453, 3375, 3346, 2980, 2146, 1697, 1614 among others; 1H-NMR(CDCl3) 1.4 ppm (triplet, 3H, CH2CH3) , 4.3 (quartet, 2H, CH2CH3), 6.0 (broad singlet), 6.9 1H , aromatic H), 8.1 (singlet, 1H aromatic H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([CH3:16])[CH:15]=1)[CH2:5][S:6][CH2:7][C@@H:8]([CH3:12])[C:9]([OH:11])=[O:10].[OH:17]OS([O-])=O.[K+].[OH2:23]>C(#N)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][S:6]([CH2:7][C@@H:8]([CH3:12])[C:9]([OH:11])=[O:10])(=[O:17])=[O:23])[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: O
Reactant: Cc1cc(Br)cc(CSC[C@@H](C)C(=O)O)c1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cc(Br)cc(CS(=O)(=O)C[C@@H](C)C(=O)O)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 6.48 g (21 mmol) (S)-3(3-bromo-5-methyl-benzylsulfanyl)-2-methyl-propionic acid in 70 ml acetonitrile and 35 ml water is added 65.7 g (107 mmol) oxone®. After stirring for 2.5 hrs at rt the mixture is diluted with EtOAc and water to get a clear solution. The organic layer is washed with brine, dried over magnesium sulfate and the solvent is evaporated. Crystallization from DCM/diethyl ether and a little methanol gives the title compound as white crystals.
Reaction SMILES: C(C1C=CC=CC=1)(=[O:3])C.C[C:11]([C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:16]=[CH:15][C:14]=1[O:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[O:12]>>[F:28][C:27]([F:30])([F:29])[CH2:26][O:25][C:14]1[CH:15]=[CH:16][C:17]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:18][C:13]=1[C:11]([OH:12])=[O:3]
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: CC(=O)c1ccccc1
Product: O=C(O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
replacing the methyl moiety of the acetophenone function of said 2,5-bis(2,2,2-trifluoroethoxy)acetophenone to yield 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid;
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH2:22][CH3:23])[C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([O:18][C:19](=O)[CH3:20])=[CH:12][CH:11]=3)(=O)[CH3:2].[ClH:24].C([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29][Cl:30])C.C[O-].[Na+]>ClC1C=CC=CC=1>[ClH:30].[ClH:24].[CH2:31]([N:27]([CH2:28][CH3:29])[CH2:2][CH2:1][O:4][C:5]1[CH:17]=[CH:16][C:8]2[N:9]([CH2:22][CH3:23])[C:10]3[C:11]([C:7]=2[CH:6]=1)=[CH:12][C:13]([O:18][CH2:19][CH2:20][N:9]([CH2:10][CH3:11])[CH2:8][CH3:7])=[CH:14][CH:15]=3)[CH3:32]
Reactant: CCn1c2ccc(OC(C)=O)cc2c2cc(OC(C)=O)ccc21
Reactant: CCN(CC)CCCl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Clc1ccccc1
Product: CCN(CC)CCOc1ccc2c(c1)c1cc(OCCN(CC)CC)ccc1n2CC

Procedure:
A mixture of 15.5 g (0.05 mole) of N-ethyl-3,6-carbazolediol diacetate, 17.2 g (0.1 mole) of 2-diethylaminoethylchloride hydrochloride, 10.8 g (0.2 mole) of sodium methoxide and 400 ml. of chlorobenzene was refluxed for 24 hours. Upon cooling, the reaction mixture was filtered, and the filtrate was washed with several portions of water, dried over anhydrous magnesium sulfate, diluted with ether and acidified with ethereal HCl. The resulting precipitate was separated and recrystallized from methanol-ethyl acetate to give the desired product. M.P. 208°-210°C, λmaxEtOH 232, E1cm1% 853.
Reaction SMILES: C(N1C2N=CN=C(OC3C=CC(NC(NC(=O)CC4C=CC=CC=4)=S)=CC=3F)C=2C=C1)C1C=CC=CC=1.[F:38][C:39]1[CH:40]=[C:41]([NH:55]C(NC(=O)CC2C=CC=CC=2)=S)[CH:42]=[CH:43][C:44]=1[O:45][C:46]1[CH:51]=[CH:50][N:49]=[C:48]2[CH:52]=[CH:53][S:54][C:47]=12.[Cl:68][C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([Cl:75])[C:70]=1[CH2:76][C:77]([N:79]=[C:80]=[S:81])=[O:78]>>[Cl:68][C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([Cl:75])[C:70]=1[CH2:76][C:77]([NH:79][C:80](=[S:81])[NH:55][C:41]1[CH:42]=[CH:43][C:44]([O:45][C:46]2[CH:51]=[CH:50][N:49]=[C:48]3[CH:52]=[CH:53][S:54][C:47]=23)=[C:39]([F:38])[CH:40]=1)=[O:78]
Reactant: O=C(Cc1c(Cl)cccc1Cl)N=C=S
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Agent: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3c2ccn3Cc2ccccc2)c(F)c1
Product: O=C(Cc1c(Cl)cccc1Cl)NC(=S)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Yield: 7 %

Procedure:
Starting from the amine 169 (scheme 33), following the procedures described above for the synthesis of compound 170a (example 133) but replacing 2-phenylacetyl isothiocyanate with 2-(2,6-dichlorophenyl)acetyl isothiocyanate, title compound 192a was obtained in 7% yield. Characterization of 192a is provided in table 18.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.N(C(OCC)=O)=NC(OCC)=O.[N:65]([Sn](CCCC)(CCCC)CCCC)=[N+:66]=[N-:67]>CCOC(C)=O.C1(C)C=CC=CC=1.C1COCC1>[NH:18]1[C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][N:9]=[C:8]3[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:45][CH2:46][N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)[CH:3]=2)=[N:67][N:66]=[N:65]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)c(-c1cccc(O)c1)nn2C1CCCCO1
Reactant: OCCN1CCOCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1cc(OCCN2CCOCC2)cc(-c2n[nH]c3ccc(-c4nnn[nH]4)cc23)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 8.8 %

Procedure:
A mixture of 3-(3-hydroxyphenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (400 mg, 1.25 mmol), triphenylphosphine (Ph3P, 1.31 g, 5.00 mmol, 4.00 equiv.), 4.00 mL THF, 4-(2-hydroxyethyl)morpholine (656 mg, 5.00 mmol, 4.00 equiv.), and diethyl azodicarboxylate (DEAD, 871 mg, 5.00 mmol, 4.00 equiv.) were stirred at room temperature for 3 days. The reaction was diluted with EtOAc and washed with 2×6.0 N aq. HCl. The combined aqueous layers were extracted with 2×EtOAc. The acidic aqueous layer was allowed to stand at room temperature for 5 h, and then added to enough 6.0 N aq. NaOH such that the final pH>12.0. The aqueous layer was extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and concentrated. Purification by silica gel chromatography using 0-5% MeOH in EtOAc as eluent afforded an oil. A mixture of the oil (1.25 mmol), azidotributyltin (Bu3SnN3, 2.35 g, 7.08 mmol, 5.66 equiv.), and 13.5 mL toluene was refluxed for 17.5 h and concentrated to an oil. To the oil was added 6.5 mL of dioxane and 6.5 mL of 6.0 N aq. HCl. The mixture was stirred at room temperature for 4 h and then added to 25 mL of 6.0 N aq. NaOH. The mixture was extracted with 3× hexanes, and 3×Et2O. The aqueous layer was filtered to remove particulates. The pH was adjusted with 6.0 N aq. HCl to give maximum visual turbidity (approximately pH 5.0-5.5) and the mixture was extracted with 2×EtOAc. The combined organics were dried (Na2SO4), filtered, and concentrated. Purification by silica gel chromatography using 0-20% MeOH in EtOAc as eluents afforded the title compound (43.1 mg, 8.82% yield): 1H NMR (DMSO-d6) δ 13.54 (s, 1H), 8.72 (s, 1H), 8.10 (d, 1H), 7.77 (d, 1H), 7.61 (d, 1H), 7.52-7.45 (m, 2H), 7.06 (d, 1H), 4.23 (t, 2H), 3.65-3.56 (m, 4H), 2.82 (t, 2H), 2.52-2.45 (m, 4H); ES-MS (m/z) 392 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:15])=[CH:4][C:5]([Cl:14])=[C:6]([CH:8]2[S:13][CH2:12][CH2:11][CH2:10][S:9]2)[CH:7]=1.[N:16]([O-])=O.[Na+].O.O.[Sn](Cl)Cl.[CH:25](=O)[CH3:26]>Cl.O>[Cl:14][C:5]1[C:6]([CH:8]2[S:13][CH2:12][CH2:11][CH2:10][S:9]2)=[CH:7][C:2]([NH:1][N:16]=[CH:25][CH3:26])=[C:3]([F:15])[CH:4]=1
Reactant: O=N[O-]
Reactant: Nc1cc(C2SCCCS2)c(Cl)cc1F
Reactant: CC=O
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CC=NNc1cc(C2SCCCS2)c(Cl)cc1F
Temperature: -5 °C
Reaction time: 0.75 h

Procedure:
To a stirred, cold (-5° C.) mixture of 10.0 g (0.0379 mole) of 2-(5-amino-2-chloro-4-fluorophenyl)-1,3-dithiane in 100 mL of concentrated hydrochloric acid is added dropwise a solution of 2.55 g (0.0379 mole) of sodium nitrite in 20 mL of water. This mixture is stirred at -5° C. for approximately 45 minutes. A solution of 17.1 g (0.0758 mole) of tin (II) chloride dihydrate in 30 mL of concentrated hydrochloric acid is added dropwise. This mixture is allowed to stir for one hour. A solution of 5.16 g (0.117 mole) of acetaldehyde in 200 mL of water is added slowly. The resultant mixture is stirred for one hour during which a precipitate forms. This solid is collected by filtration and is washed with water and dried to yield acetaldehyde 4-chloro-2-fluoro-5-(1,3-dithian-2-yl)phenylhydrazone.
Reaction SMILES: [CH:1]1[C:5]2=[C:6]([OH:15])[C:7]3[CH:14]=[CH:13][C:11](=[O:12])[O:10][C:8]=3[CH:9]=[C:4]2[O:3][CH:2]=1.[O:16]([CH2:23][CH2:24][CH2:25]Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[O:16]([CH2:23][CH2:24][CH2:25][O:15][C:6]1[C:7]2[CH:14]=[CH:13][C:11](=[O:12])[O:10][C:8]=2[CH:9]=[C:4]2[O:3][CH:2]=[CH:1][C:5]=12)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCCCOc1ccccc1
Reactant: O=c1ccc2c(O)c3ccoc3cc2o1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=c1ccc2c(OCCCOc3ccccc3)c3ccoc3cc2o1
Reaction time: 0.29 h

Procedure:
700 mg (3.5 mmol) of 5-hydroxypsoralen and 750 mg (3.5 mmol) of 3-phenoxypropyl bromide were refluxed in 30 ml of 2-butanone in the presence of an excess of anhydrous potassium carbonate (3.0 g) and catalytic amounts of potassium iodide for 36 hours. The progress of the reaction was monitored by thin layer chromatography. After 36 hours the reaction mixture was concentrated under reduced pressure. The oily residue was cooled and diluted with water. The aqueous solution was then acidified with concentrated hydrochloric acid to pH 1. The slurry was stirred for 15-20 min and extracted with 3×30 ml of dichloromethane. The dichloromethane layer was extracted with 25 ml of 1% sodium hydroxide to separate the un-reacted 5-hydroxypsoralen. The dichloromethane layer was washed with 30 ml of 2% hydrochloric acid, dried over anhydrous sodium sulfate and concentrated. The resulting oily residue was dissolved in methanol, treated with charcoal and re-crystallized from a methanol-ethyl acetate (10:90) mixture.
Reaction SMILES: C(OC([N:8]1[CH2:29][CH2:28][N:11]2[C:12](=[O:27])[C:13]3[C:18]([CH:10]2[CH2:9]1)=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O)(C)(C)C.Cl>>[CH2:20]([O:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[C:12](=[O:27])[N:11]1[CH2:28][CH2:29][NH:8][CH2:9][CH:10]12)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(OCc4ccccc4)cccc3C2C1
Agent: Cl
Product: O=C1c2c(OCc3ccccc3)cccc2C2CNCCN12
Reaction time: 0.08 h

Procedure:
To N-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-7-benzyloxy-pyrazino[2,1-a]isoindol-6(2H)-one (31 mg, 0.08 mmol) was added concentrated aqueous hydrogen chloride (1 mL). After 5 min, the solution was concentrated, treated with saturated aqueous ammonium chloride, and reconcentrated. The resulting mixture was purified via radial chromatography (8% methanol in dichloromethane containing 2% ammonium hydroxide) to give (±)-1,3,4,10b-tetrahydro-7-benzyloxy-pyrazino[2,1-a]isoindol-6(2H)-one. This material was treated with aqueous hydrogen chloride (1N), concentrated, diluted with water, and lyopholized to give the desired product as an off-white solid (19 mg, 72%). MS (ESI) 295.3 (M−Cl).
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([Br:15])[CH:7]=1.[CH3:16]O>>[CH3:16][O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:6]([F:5])=[CH:7][C:8]=1[Br:15]
Reactant: CO
Reactant: O=C(O)c1ccc(F)cc1Br
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(F)cc1Br
Yield: 37 %

Procedure:
To a solution of thionyl chloride (2.6 mL, 35.7 mmol) in methanol (500 mL) at 0° C. is added 4-fluoro-2-bromo benzoic acid (5.18 g, 23.6 mmol). The mixture is heated to reflux for 19 h. The mixture is concentrated and purified via flash chromatography on silica (120 g) using a gradient of 0 to 80% ethyl acetate in heptane to provide the title compound (2.06 g, 37%) as an oil. MS m/z 233.0 (M+1)
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[F:12][C:13]1[CH:14]=[C:15]([C:20](=[O:22])[CH3:21])[CH:16]=[CH:17][C:18]=1[F:19]>C1COCC1>[F:12][C:13]1[CH:14]=[C:15]([C:20]2([CH3:8])[CH2:21][O:22]2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: CC(=O)c1ccc(F)c(F)c1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC1(c2ccc(F)c(F)c2)CO1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(3,4-difluorophenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH2:12][CH3:13])=[O:10].CN(C1C=CC=CN=1)C.[CH2:23]([NH:27][C:28]1[N:36]=[C:35]2[C:31]([N:32]=[C:33]([OH:46])[N:34]2[CH2:37][C:38]2[CH:39]=[N:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)=[C:30]([NH2:47])[N:29]=1)[CH2:24][CH2:25][CH3:26]>C(Cl)Cl.O>[CH2:23]([NH:27][C:28]1[N:36]=[C:35]2[C:31]([N:32]=[C:33]([O:46][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:34]2[CH2:37][C:38]2[CH:39]=[N:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)=[C:30]([NH2:47])[N:29]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCNc1nc(N)c2nc(O)n(Cc3ccc(OC)nc3)c2n1
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCNc1nc(N)c2nc(OC(=O)OCC)n(Cc3ccc(OC)nc3)c2n1
Yield: 70.6 %

Procedure:
Triethylamine (100 μL, 0.75 mmol), ethyl chloroformate (67 μL, 0.70 mmol), and dimethylaminopyridine (20 mg, 0.17 mmol) were added to a solution (15 ml) of the compound (200 mg, 0.58 mmol) obtained in Example 19 in methylene chloride in that order, and the resultant was allowed to react at room temperature for 15 hours. Water was added to the reaction solution to extract an organic layer. The organic layer was washed with an aqueous solution of 5% citric acid and 10% saline solution and dried over anhydrous sodium sulfate. The solvent was then removed by distillation. Hexane was added to the residue, and the solid was precipitated, followed by collection by filtration. Thus, 170 mg of the title compound was obtained as a white powdery solid (yield: 71%).
Reaction SMILES: [NH2:1][C@H:2]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)[C:3]([OH:5])=[O:4].C(N(CC)CC)C.[CH2:22]([O:29][C:30](ON1C(=O)CCC1=O)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCOCC1.O>[CH2:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH:6]1[C@@H:2]([NH:1][C:30]([O:29][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:31])[C:3]([OH:5])=[O:4]
Reactant: N[C@@H](C(=O)O)C1Cc2ccccc2C1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(N[C@@H](C(=O)O)C1Cc2ccccc2C1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 94.1 %

Procedure:
(2R)-amino(2,3-dihydro-1H-inden-2-yl)ethanoic acid (1.91 g, 10 mmol) was suspended in dioxane (10 ml) and water (10 ml). To this was added triethylamine (1.7 ml) and N-(benzyloxycarbonyloxy)-succinimide (2.54 g) and the reaction mixture was stirred rapidly at room temperature for 2 days. The reaction mixture was poured into water (50 ml) and extracted with chloroform (100 ml). The organic phase was washed with 1N hydrochloric acid (50 ml) and water (50 ml). This was dried over magnesium sulphate and the solvent removed in vacuo to give the title compound (3.06 g, 94%):
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH2:13]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][C:17]=1[O:25][CH3:26])[CH3:14].C(OC1C=CC(C(O)=O)=CC=1OC)C>N1C=CC=CC=1>[CH2:13]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:10]([OH:12])[CH2:11][CH:2]2[CH3:1])=[O:21])=[CH:18][C:17]=1[O:25][CH3:26])[CH3:14]
Reactant: CC1CC(O)c2ccccc2N1
Reactant: CCOc1ccc(C(=O)Cl)cc1OC
Agent: CCOc1ccc(C(=O)O)cc1OC
Solvent: c1ccncc1
Product: CCOc1ccc(C(=O)N2c3ccccc3C(O)CC2C)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
2-Methyl-1,2,3,4-tetrahydro-4-quinolinol (7.1 g, 43.5 mmol) synthesized in the published manner was dissolved in pyridine (50 ml), followed by addition of 4-ethoxy-3-methoxybenzoyl chloride prepared from 4-ethoxy-3-methoxybenzoic acid (9.2 g, 46.4 mmol). After stirring at room temperature for 16 hours, the reaction mixture was concentrated and extracted by addition of ethyl acetate and water. After the organic layer was dried and concentrated, the residue was applied to silica gel column chromatography (developing solvent: ethyl acetate/hexane=1/1) and the resulting eluate was recrystallized from ethyl acetate-hexane to give the titled compound (4.4 g, yield: 30%) as a white crystal.