Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:14]2[C:10](=[CH:11][S:12][C:13]=2[N:15]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.O.NN>C(O)C>[NH2:15][C:13]1[S:12][CH:11]=[C:10]2[CH2:9][C:8]3[C:3]([C:2](=[O:1])[C:14]=12)=[CH:4][CH:5]=[CH:6][CH:7]=3
Reactant: O=C1c2ccccc2Cc2csc(N3C(=O)c4ccccc4C3=O)c21
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1scc2c1C(=O)c1ccccc1C2
Temperature: 25 °C

Procedure:
To a suspension of 2-[4-oxo-9H-naphtho[2,3-c]thiophene-3-yl]-isoindole-1,3-dione (0.45 mmol, Example 32, Part G) in absolute ethanol (5 mL) is added hydrazine hydrate (0.5 mmol). The mixture is heated to reflux for one hour, cooled to room temperature, concentrated in vacuo, and the residue dissolved in methylene chloride. The solution is chilled to 5° C. for one hour, during which time the phthaloyl hydrazide precipitates. The precipitate is removed by filtration, the filtrate concentrated in vacuo, and the residue purified by column chromatography on silica gel, eluting with a 4:1 mixture of petroleum ether and ethyl acetate. Fractions containing the product are collected, evaporated, and the product recrystallized.
Reaction SMILES: O1C2C=CC(CN(C3CCN(CC[N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[C:35]([O:38][CH3:39])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:40])CC3)C(=O)OC(C)(C)C)=CC=2OCC1.[ClH:41].C(OCC)(=O)C>>[ClH:41].[CH3:39][O:38][C:35]1[CH:36]=[C:37]2[C:32]([CH:31]=[CH:30][C:29](=[O:40])[NH:28]2)=[CH:33][CH:34]=1
Reactant: COc1ccc2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc2ccc(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
0.29 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate was added to 10 mL of 4 mol/L hydrogen chloride/ethyl acetate solution, and stirred at room temperature for 22 hours. The solvent was removed under reduced pressure, 2-propanol was added to the residue obtained and the resulting solid was filtered to afford 0.20 g of 1-(2-(4-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxyquinolin-2(1H)one hydrochloride as a pale yellowish white solid.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([CH3:19])[C:15]=2[CH:20]=O)=[CH:10][CH:9]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([CH3:19])[C:15]=2[CH:20]=[CH2:1])=[CH:10][CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1c(C)noc1-c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Potassium tert-butoxide (1.0M in THF, 13.53 mL, 13.53 mmol) was added to a suspension of methyltriphenylphosphonium bromide (4.8 g, 13.53 mmol) in THF (40 mL) at 0° C. 5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (1.8 g, 6.76 mmol) in THF (40 mL) was then added and the reaction stirred at 0° C. for 30 minutes. The reaction was then submitted to standard aqueous workup and purified on silica gel to afford the title compound.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[C:8]([C:11]#[N:12])[C:9]#[N:10])SC)[CH2:3][CH2:2]1.O.[NH2:14][NH2:15]>CCO>[NH2:10][C:9]1[NH:15][N:14]=[C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)[C:8]=1[C:11]#[N:12]
Reactant: CSC(NC1CC1)=C(C#N)C#N
Reactant: NN
Solvent: O
Solvent: CCO
Product: N#Cc1c(NC2CC2)n[nH]c1N
Temperature: 0 °C

Procedure:
2-((cyclopropylamino)(methylthio)methylene)malononitrile in EtOH (100 mL) and added hydrazine hydrate (1 eq), then heated to reflux until complete by TLC (absence of starting material, 18 hrs). Poured into ice water and filtered to obtain 5-amino-3-(cyclopropylamino)-1H-pyrazole-4-carbonitrile as a yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7](Br)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2].[CH:24]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([NH:30][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2]
Reactant: NC1CCCCC1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1Br
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1NC1CCCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 23.7 %

Procedure:
1-Bromo-6-methoxy-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (100 mg, 0.27 mmol) obtained in Example 18 was dissolved in THF (10 mL), and cyclohexylamine (132.86 mg, 0.15 mL, 1.34 mmol) was added dropwise thereto. The mixture was stirred for 12 hrs at RT, and the solvent was removed under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 25 mg of the titled compound (yield: 24%).
Reaction SMILES: O[C@H:2]([CH3:35])[CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[CH:15]=[C:14]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:13]=2)=[CH:10][CH:11]=1)=[O:6].CS(O)(=O)=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:33][O:32][CH2:31][C@H:30]([CH3:34])[O:29][C:14]1[CH:13]=[C:12]([C:9]2[NH:8][C:7]([C:5]3[O:6][C@@H:2]([CH3:35])[CH2:3][N:4]=3)=[CH:11][CH:10]=2)[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][CH:20]=2)[CH:15]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NC[C@@H](C)O)[nH]2)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.9 %

Procedure:
N-[(2R)-2-Hydroxypropyl]-5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxamide (191 mg, 0.380 mmol) synthesized in Example (31a) was dissolved in tetrahydrofuran (10 mL), and anhydrous methanesulfonic acid (100 mg, 0.574 mmol) and triethylamine (0.16 mL, 1.15 mmol) were added, followed by stirring at room temperature for 18 hours under nitrogen atmosphere. A saturated aqueous sodium hydrogencarbonate solution (10 mL) was added, and the solution was separated with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-70%) to afford the desired product (136 mg, yield 74%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:27]([NH:29][NH2:30])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45](Cl)=[O:46])=[CH:40][CH:39]=1.O>O1CCCC1>[F:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45]([NH:30][NH:29][C:27]([C:10]2[N:11]=[C:12]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:28])=[O:46])=[CH:40][CH:39]=1
Reactant: NNC(=O)c1nc2ccc(CN3CCOCC3)cn2c(=O)c1OCc1ccccc1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Cc1ccc(F)cc1)NNC(=O)c1nc2ccc(CN3CCOCC3)cn2c(=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To a mixture of the product of example 15 (807 mg, 1.97 mmol) and sodium carbonate (418 mg, 3.95 mmol) in tetrahydrofuran (25 ml), 4-fluorophenylacetyl chloride (374 mg, 2.17 mmol) was added drop-wise. The resulting mixture was stirred overnight at room temperature. Then water (25 ml) was added and the mixture was stirred for 1 hour. The resulting solids were collected by filtration, washed with water and PE successively and dried to give the titled product (697 mg, 64.8%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:9][CH3:10].[C:11]([Si:13]([CH3:16])([CH3:15])[CH3:14])#[CH:12]>C(#N)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>[CH3:10][O:9][C:3]1[CH:4]=[C:5]([NH2:8])[CH:6]=[CH:7][C:2]=1[C:12]#[C:11][Si:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: COc1cc(N)ccc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Product: COc1cc(N)ccc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
4-Iodo-3-methoxy-phenylamine (3.17 g, 12.7 mmol) and ethynyl-trimethyl-silane (3.5 mL, 25 mmol) in dry acetonitrile were purged with nitrogen and treated with TEA (17.6 mL, 127 mmol), CuI (123 mg, 0.635 mmol) and Pd(Ph3P)2Cl2 (447 mg, 0.635 mmol). The reaction was stirred at room temperature for 2 h. The volatiles were evaporated, the residue was taken up with EtOAc (200 mL), washed with water (50 mL), dried over sodium sulfate and purified by flash chromatography on silica gel (hexane/EtOAc 55/45) to afford the title compound (1.86 g, 66%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:11]=2[CH:29]=1.[CH:30]1([C:36]2[CH:41]=[CH:40][C:39]([SH:42])=[CH:38][CH:37]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:30]1([C:36]2[CH:37]=[CH:38][C:39]([S:42][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]3[CH:8]=[CH:9][C:10]4[NH:15][C:14](=[O:16])[O:13][C:12]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:11]=4[CH:29]=3)=[CH:40][CH:41]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: Sc1ccc(C2CCCCC2)cc1
Reactant: CCCCCCC1(CCCCCC)OC(=O)Nc2ccc(OCCCCCl)cc21
Product: CCCCCCC1(CCCCCC)OC(=O)Nc2ccc(OCCCCSc3ccc(C4CCCCC4)cc3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-di-n-hexyl-4H-3,1-benzoxazin-2-one [oil, RF value: 0.7; silica gel plate; chloroform/acetone (19:1)] and 4-cyclohexyl-thiophenol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][CH:5]=1.C1COCC1.[CH2:17]([Mg]Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CN1CCCC1=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:6][CH:5]=1
Reactant: CCCCCC[Mg]Br
Reactant: COC(=O)c1ccc(Cl)cc1
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CCCCCCc1ccc(C(=O)OC)cc1
Reaction time: 0.08 h
Yield: 90 %

Procedure:
A flame-dried two-necked flask is charged under argon with 4-chlorobenzoic acid methyl ester (0.5 g, 2.93 mmol), FeCl2 (19 mg, 0.15 mmol), THF (7 mL) and N-methylpyrrolidone (NMP, 1 mL). A solution of n-hexylmagnesium bromide (2M in Et2O, 1.9 mL, 3.8 mmol) is added via syringe to the resulting red solution, causing an immediate color change to dark brown and finally to violet. The resulting mixture is stirred for 5 min. Work-up as described above provides 4-hexylbenzoic acid methyl ester as a colorless syrup (90%). The spectroscopic and analytical data are identical to those compiled above.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:4][C:3]=1[C:17](=[O:19])[CH3:18].[C:20](OCC)(=O)[C:21]([O:23]CC)=[O:22].C[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:8][C:7]1[C:2]2[O:1][C:20]([C:21]([OH:23])=[O:22])=[CH:18][C:17](=[O:19])[C:3]=2[CH:4]=[CH:5][C:6]=1[O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(C)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1c(OCc2ccccc2)ccc2c(=O)cc(C(=O)O)oc12
Yield: 95.4 %

Procedure:
A mixture of 1-[2-hydroxy-3-methyl-4-(phenylmethoxy)phenyl]-ethanone (0.098 mol) and ethanedioic acid, diethyl ester (0.11 mol) in toluene (100 ml) was added dropwise to a mixture of sodium methoxide (0.22 mol) in toluene (150 ml). The reaction mixture was stirred and refluxed for 2 hours. The solvent was evaporated. The residue was added to a mixture of acetic acid (150 ml) and hydrochloric acid (50 ml). The reaction mixture was stirred and refluxed for 1 hour. The mixture was poured out onto ice. The resulting precipitate was filtered off and dried (vacuum; 70° C.), yielding 29 g (95.4%) of 8-methyl-4-oxo-7-(phenylmethoxy)-4H-1-benzopyran-2-carboxylic acid (interm. 9).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:7])=[CH:5][CH:6]=1.CO[CH2:10][Cl:11]>C(O)(=O)C>[Cl:11][CH2:10][C:6]1[CH:5]=[C:4]([CH3:7])[S:3][C:2]=1[CH3:1]
Reactant: COCCl
Reactant: Cc1ccc(C)s1
Solvent: CC(=O)O
Product: Cc1cc(CCl)c(C)s1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
36.4 G., 0.325 mol. of 2,5-dimethylthiophene, 24.7 g. (0.307 mol) of freshly distilled chloromethyl methyl ether (b.p. 58°-60° C.) and 87.0 g. of glacial acetic acid were combined in a glass pressure bomb and stirred at room temperature for 5 hours. After 0.5 to 1 hr. an exothermic reaction took place. The reaction mixture was cooled externally in an ice bath so that the reaction temperature did not exceed 35° C. The color of the mixture changed from green to blue. The resulting solution was poured into ice water, stirred for ten minutes and extracted four times with benzene. The combined benzene extracts were washed twice with saturated sodium chloride solution, dried and evaporated. The resulting liquid was quickly distilled and the material which boiled at 90°-125° C./18 mm. was collected. A second distillation yielded the pure product, b.p. 109°-115° C./18 mm.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[CH:23]1[C:24]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:22]=1[O:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CO)C1
Reactant: Oc1ccc2ccccc2c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](COc2ccc3ccccc3c2)C1
Yield: 53.8 %

Procedure:
The procedure is the same as for Example 1 (Stage 1.2) starting from 2.00 g (9.94 mmol) of tert-butyl (R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (commercial), 2.00 g (13.91 mmol) of naphth-2-ol, 3.90 g (14.91 mmol) of triphenylphosphine and 3.01 g (14.91 mmol) of diisopropyl azodicarboxylate. 1.75 g of product are obtained in the form of an oil after purification on a column of silica gel, elution being carried out with dichloromethane.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:24](O)=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:27][NH2:28]>C1COCC1.ClCCl>[CH3:27][NH:28][C:24](=[O:25])[C@H:19]([CH2:20][CH:21]([CH3:22])[CH3:23])[NH:18][C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:17]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)[C@H](CC(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
A solution of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-leucine, acid chloride (3.5 g, 10 mmol) in 50 mL of THF was charged with solution of methylamine (0.62 g, 20 mmol) in 50 mL of dichloromethane, at room temperature. The reaction mixture was stirred for 30 min. The solvents were removed and the residue was dissolved in 100 mL of ethyl acetate. The solution was washed with aqueous solution of 10% potassium carbonate, water, brine, dried over magnesium sulfate and evaporated. Recrystallization of the product from ethyl acetate/hexane mixture afforded 1.67g (46.6%) of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-leucine methylamide, mp 173°-174° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.[CH3:16][S:17]SC>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([S:17][CH3:16])[S:10][C:3]=12
Reactant: Clc1ccnc2ccsc12
Reactant: CSSC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1cc2nccc(Cl)c2s1
Reaction time: 0.17 h
Yield: 94.3 %

Procedure:
To a solution of 2 (200 mg, 1.18 mmol) in dry THF (11 ml) at −78° C. was added n-BuLi (0.57 mL, 2.5M solution on hexane, 1.41 mmol) and the resultant brown precipitate was stirred for 10 minutes. Methyl disulfide (0.16 ml, 1.77 mmol) was added slowly, the mixture was stirred at −78° C. for 3 hours and partitioned between DCM and water. Organic phase was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford title compound 229 (0.240 g, 94% yield, crude) as a yellow solid. MS (m/z): 216.1 (100%), 218.1 (39%) (M+1).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@@H:7]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:6][CH2:5]2.C(N(CC)CC)C.[CH3:28][C:29]1([CH3:36])[C:33]([CH3:35])([CH3:34])[O:32][BH:31][O:30]1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:28][C:29]1([CH3:36])[C:33]([CH3:35])([CH3:34])[O:32][B:31]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[O:8][C@@H:7]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:6][CH2:5]3)[O:30]1
Reactant: CC1(C)OBOC1(C)C
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CCc2cc(I)ccc2O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2ccc3c(c2)CC[C@H](CO[Si](C)(C)C(C)(C)C)O3)OC1(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
Argon was bubbled through a solution of tert-butyl(dimethyl)silyl [(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl ether (Example 59, 11.1 mmol, 1.0 eq.) in dioxane (45 mL) for 10 minutes before Pd(dppf)Cl2 (0.306 mmol, 0.03 eq.), triethylamine (33.4 mmol, 3.0 eq.), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (17.8 mmol, 1.6 eq.) were added. The resulting reaction mixture was stirred at 80° C. overnight. The resulting reaction mixture was filtered through a Celite pad. The filtrate was concentrated and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, hexanes:EtOAc=10:1). The product was obtained as a pale brown waxy solid in 94% yield. MH+=405.3, retention time (LC-MS) =4.79 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8](S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][CH:18]2[C:27]3[N:26]=[CH:25][CH:24]=[C:23]([O:28][CH3:29])[C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:12][CH:11]=1.C1(S)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][NH:17][CH:18]2[C:27]3[N:26]=[CH:25][CH:24]=[C:23]([O:28][CH3:29])[C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:15]=1
Reactant: COc1ccnc2c1CCCC2NCc1ccc(CN(Cc2ccccn2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CC#N
Product: COc1ccnc2c1CCCC2NCc1ccc(CNCc2ccccn2)cc1
Yield: 81.3 %

Procedure:
N-(2-pyridinylmethyl)-N-(2-nitrobenzenesulfonyl)-N′-(4-methoxy-5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (0.269 g, 0.50 mmol) was treated with thiophenol (0.35 mL, 3.41 mmol) and K2CO3 (0.757 g, 5.48 mmol) in CH3CN (10 mL). Purification of the crude material by radial chromatography on silica gel (2 mm plate, 20:1:1 CH2Cl2-CH3OH NH4OH) provided 0.158 g (82%) of the title compound as a yellow oil. 1H NMR (CDCl3) □1.61-1.80 (m, 2H), 1.98-2.17 (m, 2H), 2.56-2.70 (m, 2H), 3.79-3.83 (m, 6H), 3.88-3.98 (m, 4H), 6.60 (d, 1H, J=5.7 Hz), 7.15 (dd, 1H, J=5.1, 6.9 Hz), 7.23-7.41 (m, 5H) 7.63 (ddd, 1H, J=7.8, 7.8, 1.8 Hz), 8.30 (d, 1H, J=5.7 Hz); 8.55 (d, 1H, J=3.9 Hz);
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3=[N:13][N:14]=[C:15]([C:16]4[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=4)[N:10]3[N:9]=2)=[CH:4][C:3]=1[N+:28]([O-])=O.[Sn](Cl)Cl.[OH-].[Na+]>CO.O>[NH2:28][C:3]1[CH:4]=[C:5]([C:8]2[S:12][C:11]3=[N:13][N:14]=[C:15]([C:16]4[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=4)[N:10]3[N:9]=2)[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: COc1cc(-c2nnc3sc(-c4ccc(C)c([N+](=O)[O-])c4)nn23)cc(OC)c1OC
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(-c2nnc3sc(-c4ccc(C)c(N)c4)nn23)cc(OC)c1OC
Yield: 27.7 %

Procedure:
A mixture of 6-(4-methyl-3-nitrophenyl)-3-(3,4,5-trimethoxyphenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (256 mg, 0.6 mmol) and tin(II) chloride (675 mg, 3 mmol) in methanol (25 mL) was refluxed under argon for 6 h. It was then diluted with water (30 mL) and neutralized with 2N aqueous sodium hydroxide to pH=12, and extracted with ethyl acetate (3×20 mL). The extracts were dried, concentrated and the residue was purified by column chromatography (EtOAc as eluent) to give 66 mg (28%) of the title compound as solid. 1H NMR (CDCl3): 7.71 (s, 2H), 7.23 (m, 2H), 7.17 (s, 1H), 4.00 (s, 6H), 3.94 (s, 3H), 2.26 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].Br[C:28]1[N:29]=[C:30]([N:38]2[CH2:43][CH2:42][N:41]([CH2:44][CH3:45])[CH2:40][CH2:39]2)[C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.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>[CH2:44]([N:41]1[CH2:40][CH2:39][N:38]([C:30]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:37]=[C:28]([C:11]3[CH:10]=[CH:9][C:8]([CH2:7][CH:2]([C:3]([O:5][CH3:6])=[O:4])[CH3:1])=[CH:13][CH:12]=3)[N:29]=2)[CH2:43][CH2:42]1)[CH3:45]
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(CC(C)C(=O)OC)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCN1CCN(c2nc(-c3ccc(CC(C)C(=O)OC)cc3)cc3ccccc23)CC1
Yield: 88.6 %

Procedure:
Methyl 2-methyl-3-(4-tributylstannylphenyl)propionate (2.69 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (1.16 g) were heated under reflux overnight in the presence of tetrakistriphenylphosphinepalladium(0) (0.17 g) in xylene in nitrogen atmosphere. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid. The aqueous layer was washed with ethyl acetate, adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, and then extracted with ethyl acetate. The extract was washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (toluene/acetone system), to give obtain 1-(4-ethylpiperazin-1-yl)-3-[4-(2-methoxycarbonylpropyl)phenyl]isoquinoline (1.34 g) in pale yellow viscous oil.