Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:13][C:14]1[CH:23]=[CH:22][C:17]3[O:18][CH2:19][CH2:20][O:21][C:16]=3[CH:15]=1)[C:7]2=[O:12].[CH:24]1([CH2:31][C:32](O)=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.F[P-](F)(F)(F)(F)F.FC(N(C)C)=[N+](C)C.C(N(CC)C(C)C)(C)C.C(Cl)Cl>>[CH:24]1([CH2:31][C:32]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]([CH2:13][C:14]2[CH:23]=[CH:22][C:17]4[O:18][CH2:19][CH2:20][O:21][C:16]=4[CH:15]=2)[C:7]3=[O:12])=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Nc1cccc2c(=O)n(Cc3ccc4c(c3)OCCO4)ccc12
Reactant: O=C(O)CC1CCCCCC1
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC1CCCCCC1)Nc1cccc2c(=O)n(Cc3ccc4c(c3)OCCO4)ccc12

Procedure:
5-Amino-2-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-2H-isoquinolin-1-one (50 mg, 0.0002 mol), 2-cycloheptylacetic acid (63 mg, 0.00041 mol), fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (110 mg, 0.00041 mol) and N,N-diisopropylethylamine (100 mg, 0.0008 mol) were stirred in methylene chloride (3 mL, 0.05 mol) at room temperature for 72 hours. The mixture was purified via flash chromatography (12 g of silica gel, 50% EtOAc/Hexane) to give a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][N:13]([CH3:28])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[C:23]([CH3:24])=[C:22]([CH:25]=O)[NH:21][C:20]=1[CH3:27])=[O:18]>>[CH3:12][N:13]([CH3:28])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[C:23]([CH3:24])=[C:22]([CH:25]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:21][C:20]=1[CH3:27])=[O:18]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN(C)C
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(C)c1C(=O)NCCN(C)C
Yield: 86.9 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (0.17 g, 0.8 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-dimethylaminoethyl)amide (0.2 g, prepared by method C) using method B to give 0.3 g (83%) of the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH:13]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][CH2:13][CH:12]([O:15][CH3:16])[O:11][CH3:10])=[CH:4][CH:3]=1
Reactant: COC(C=O)OC
Reactant: NCc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(CNCc1ccc(F)cc1)OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.9 %

Procedure:
To a solution of 4-fluorobenzylamine (2.00 mL, 17.6 mmol) and dimethoxyacetaldehyde (60% solution in water, 3.00 mL, 19.9 mmol) in tetrahydrofuran (100 mL) was added sodium triacetoxyborohydride (5.90 g, 26.4 mmol) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 5 hours, followed by the addition of saturated sodium bicarbonate (50 mL) and extraction with ethyl acetate (3×100 mL). The combined organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by column chromatography to afford N-(4-fluorobenzyl)-2,2-dimethoxyethanamine (2.70 g, 71%): 1H NMR (300 MHz, CDCl3) δ 7.24-7.19 (m, 2H), 6.97-6.89 (m, 2H), 4.43-4.39 (m, 1H), 3.70 (s, 2H), 3.30 (s, 6H), 2.67 (dd, J=5.4, 1.5 Hz, 2H); MS (ES+) m/z 214.3 (M+1).
Reaction SMILES: C([O:5][C:6]([C:8](NC(=O)OC(C)(C)C)=[CH:9][C:10]1[N:11]=[CH:12][O:13][C:14]=1[C:15]([CH3:18])([CH3:17])[CH3:16])=[O:7])(C)(C)C.Cl.[O:28]1CCOCC1>>[C:15]([C:14]1[O:13][CH:12]=[N:11][C:10]=1[CH:9]=[C:8]([OH:28])[C:6]([OH:5])=[O:7])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NC(=Cc1ncoc1C(C)(C)C)C(=O)OC(C)(C)C
Reactant: C1COCCO1
Agent: Cl
Product: CC(C)(C)c1ocnc1C=C(O)C(=O)O

Procedure:
Compound 2 (6.0 g, 16.3 mmol) was treated with 4N HCl-dioxane (64 ml) for 1 h at room temperature. After the solvent was removed, the residue was extracted with EtOAc, washed with 5% citric acid and saturated NaCl. Then, the organic layer was dried over Na2SO4 and evaporated in vacuo to obtain compound 3. yield 2.6 g (76%); m.p. 150-155° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.59 (s, 1H), 6.55 (s, 1H), 1.36 (s, 1H); m/z 211.0841 (M+) (calcd for C10H13NO4: 211.0844).
Reaction SMILES: O.Cl[C:3]1[C:12]([CH:13]=[O:14])=[C:11]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[C:10]2[CH:9]=[C:8]3[O:23][CH2:24][CH2:25][O:26][C:7]3=[CH:6][C:5]=2[N:4]=1.[I-:27].[Na+].Cl>C(#N)C>[I:27][C:3]1[C:12]([CH:13]=[O:14])=[C:11]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[C:10]2[CH:9]=[C:8]3[O:23][CH2:24][CH2:25][O:26][C:7]3=[CH:6][C:5]=2[N:4]=1
Reactant: [I-]
Reactant: CN1CCN(Cc2c(C=O)c(Cl)nc3cc4c(cc23)OCCO4)CC1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CN1CCN(Cc2c(C=O)c(I)nc3cc4c(cc23)OCCO4)CC1
Temperature: 25 °C

Procedure:
A 4-necked 12-L round-bottom flask is equipped with a mechanical stirrer and water-cooled condenser. Under nitrogen, the flask is charged with 7-chloro-9-(4-methyl-piperazin-1-ylmethyl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-carbaldehyde (120 g, 346 mmol), as prepared above, sodium iodide (1.04 kg, 6.92 mmol), and 3 L of acetonitrile. To the yellow suspension is added concentrated hydrogen chloride (59.7 mL, 726 mmol) over 5 min. The white slurry is refluxed for 15 hr. The solvent is mostly removed by short-path distillation in vacuo. The resultant thick slurry is cooled to ambient temperature and treated with 2.5 L of water and 2.5 L of methylene chloride. The organic layer is separated and the aqueous layer is extracted with methylene chloride (3×2 L). The combined organic layers are washed with brine (2.5 L), dried over anhydrous sodium sulfate, concentrated and dried in vacuo at 30° C. yielding 7-iodo-9-(4-methyl-piperazin-1-ylmethyl)- 2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-carbaldehyde as a yellow solid. This crude product is used for the next step without further purification. Recrystallization from CH2Cl2 -MeOH (1:1) gave an analytical sample as an off-white solid: 198°-200° C. (dec.). 1H NMR (CDCl3, 200 MHz) δ2.30 (s, 3H), 2.43, 2.57 (m, 8H), 3.93 (s, 2H). 4.40(s, 4H), 7.47 (s, 1H), 7.50 (s, 1H), 10.1 (s, 1H). Elemental analysis: Calculated for C18H20IN3O3 : C 47.70, H 4.45, N 9.27. Found: C 47.78, H 4.45, N 9.26.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([NH:13][CH3:14])[CH2:10][CH:9]1[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[C:25]#[N:26])[CH2:19][CH2:18]1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[Cl:40])[CH:35]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CCN(CC)CC>C(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH:11]([N:13]([CH2:35][C:34]2[CH:37]=[CH:38][C:39]([Cl:40])=[C:32]([Cl:31])[CH:33]=2)[CH3:14])[CH2:10][CH:9]1[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[C:25]#[N:26])[CH2:19][CH2:18]1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CNC1CC(C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(Cc1ccc(Cl)c(Cl)c1)C1CC(C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2ccccc2)C1
Reaction time: 8 h
Yield: 4.4 %

Procedure:
To a mixture of 2-[4-(1-benzyl-4-methylamino-pyrrolidine-2-carbonyl)-piperazin-1-yl]-benzonitrile (0.1 mmol) and 3,4-dichloro-benzaldehyde (0.15 mmol) in 2 mL of CH2Cl2 stirring at rt, was added NaBH(OAc)3 (0.15 mmol) and NEt3 (0.3 mmol), and then the resulting mixture was stirred overnight. After purification through preparative HPLC, 2.5 mg of 2-(4-{1-benzyl-4-[(3,4-dichloro-benzyl)-methyl-amino]-pyrrolidine-2-carbonyl}-piperazin-1-yl)-benzonitrile was obtained as colorless oil in 4.8% yield.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].[CH3:14][O:15][CH2:16]Cl>C1COCC1>[CH3:14][O:15][CH2:16][O:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:3])=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1ccc(N)c([N+](=O)[O-])c1
Yield: 59.8 %

Procedure:
To a suspension of sodium hydride (60%, 2.70 g (67.5 mmol)) in THF (100.0 ml), under cooling with ice and with stirring, 4-amino-3-nitrophenol (10.0 g (64.9 mmol)) was added. To the resulting mixture, after 10 minutes' stirring under cooling with ice, chloromethyl methyl ether (5.50 g (68.3 mmol)) was added dropwise and the mixture was stirred at 5° C. for one hour and at room temperature for one hour, and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and saturated aqueous solution of sodium bicarbonate successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Then the residue was subjected to silica gel column chromatography with chloroform-ethanol (100:1) as eluent to give 7.69 g (60%) of 4-methoxymethoxy-2-nitroaniline as red oil.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:3]([CH2:2][NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16])([O:5][CH3:6])=[O:4]
Reactant: NCCCN1CCCC1=O
Reactant: COC(=O)CBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNCCCN1CCCC1=O
Reaction time: 12 h

Procedure:
Methyl bromoacetate (1.35 mL, 14.3 mmol) was added dropwise to a solution of 3-aminopropyl-2-pyrrolidinone (2.0 mL, 14.3 mmol) and diisopropylethylamine (2.7 mL) in CH2Cl2. The reaction was stirred for 12 hours and was then concentrated in vacuo, and carried forward without further purification.
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].Br[C:8]1[S:9][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:11][CH:12]=1>[Pd]>[CH3:1][C:2]([OH:6])([CH3:3])[C:4]#[C:5][C:8]1[S:9][C:10]([C:13]#[C:14][C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)=[CH:11][CH:12]=1
Reactant: C#CC(C)(C)O
Reactant: Brc1ccc(C#Cc2ccncc2)s1
Agent: [Pd]
Product: CC(C)(O)C#Cc1ccc(C#Cc2ccncc2)s1

Procedure:
The 2-ethynyl-5-(4-pyridyl)ethynyl thiophene is synthesized by the reaction sequence shown below. In the first step, bromination of 1-(2-thienyl)-2-(4-pyridyl)ethene followed by base-catalyzed dehydrohalogenation gives 2-bromo-5-{2-(4-pyridyl)ethynyl}thiophene (I): ##STR5## In the second step, the palladium catalyzed addition of 2-methyl-3-butyn-2-ol to compound I gives 2-{3-methyl-3-hydroxybutynyl}-5-{2-(4-pyridyl)ethynyl}thiophene (II): ##STR6## The term "Ph" in the palladium catalyst formula means "phenyl". In the third step, removal of the protecting group using KOH in methanol gives the acetylene-terminated thermoset monomer 2-ethynyl-5-(4-pyridyl)ethynyl thiophene (III): ##STR7##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][C@H:16]1[C@@H:20]([CH3:21])[CH2:19][N:18]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:17]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:15][C@H:16]3[C@@H:20]([CH3:21])[CH2:19][N:18]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[CH2:17]3)=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Intermediate 2 (1000 mg, 3.64 mmol), (+/−)-(cis)-benzyl 3-amino-4-methylpyrrolidine-1-carboxylate (Intermediate 5, 1024 mg, 4.37 mmol) and DIPEA (1.27 mL, 7.29 mmol) in DMA (4.0 mL) was heated at 90° C. for 5 h then was allowed to cool to rt and stir overnight. The reaction mixture was added to crushed ice, stirred for 30 min, and the resulting solid that had precipitated was collected by vacuum filtration and was rinsed with water and dried to afford the title compound as a cream colored solid. HPLC (method B) retention time=3.67 min. LCMS (m+1)=472/474 (1:1).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].C(=O)([O-])[O-].[Ca+2].[CH2:10]([O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl.O>[CH2:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]([N:22]=[C:1]=[S:2])=[CH:23][CH:24]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: O
Product: S=C=Nc1ccc(OCc2ccccc2)cc1
Temperature: 15 °C
Reaction time: 4 h

Procedure:
Thiophosgene (12.63 g) was added at 0° C. to a stirred suspension of calcium carbonate (11.05 g) in a mixture of dichloromethane (100 ml) and water (100 ml). A solution of p-benzyloxyaniline (16.5 g) in dichloromethane (100 ml) was added dropwise at 0° C. over 30 minutes. The mixture was stirred for four hours at 15° C. The organic layer was separated, dried and the solvent removed by evaporation to give a residue which was extracted into boiling hexane to give 4-benzyloxyphenylisothiocyanate (m.p. 69° C.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[C:29]([N:8]([CH2:9][C:10]1([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH2:11][CH2:12]1)[C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(C(=O)OC(C)(C)C)C1(CNc2ccc(Cl)nc2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)C1(CN(C(=O)c2ccccc2)c2ccc(Cl)nc2)CC1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
10.17 g of the compound obtained in Step 1 of Example 9 are dissolved in 200 ml of tetrahydrofuran, 4.88 ml of triethylamine are added, cooling to 5° C. is carried out and, over a period of 30 minutes, 5.05 g of benzoyl chloride are poured in. Stirring is carried out for one hour at 5° C. and then for one hour at ambient temperature, and subsequently refluxing is carried out for 2 hours. Concentration to dryness is carried out and the residue is taken up in dichloromethane and washed with 50% aqueous potassium carbonate solution. The organic phase is dried over sodium sulphate and concentrated, and chromatography of the residue on silica gel (dichloromethane/tetrahydrofuran: 96/4) allows 13.9 g of expected product to be obtained.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:33])[CH2:30][CH:31]=[CH2:32])[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:42])C=1.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:33])[CH2:30][CH:31]3[CH2:32][O:42]3)[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCC(=O)N1CCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCN(C(=O)CC2CO2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-(3-Butenoyl)-piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (27) (1.00 g; 2.24 mmol) and m-chloroperbenzoic acid (Aldrich Chemical Company; 71% by assay; 0.65 g; 2.91 mmol) are combined in 10 mL of methylene chloride and refluxed for 24 hours. The solution is stirred at ambient temperature for 72 hours, diluted with methylene chloride (50 mL) and shaken with 10% aqueous Na2SO3 (50 mL). The methylene chloride layer is separated and washed successively with saturated aqueous NaHCO3 solution and brine. The organic layer is dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel using a gradient elution (80%→90% ethyl acetate in hexanes, then 50%→60% acetone in hexanes) affording 28 as a solid. CIMS (NH3CI): 463 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[OH:17].Cl[CH2:19][CH2:20][CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[O:17][CH2:19][CH2:20][CH2:21][CH2:22][OH:23]
Reactant: OCCCCCl
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reaction time: 18 h
Yield: 28.4 %

Procedure:
A solution of 33.9 grams (0.126 mole) of 2,6-dichloro-4-phenylmethoxyphenol (known compound), 16.4 grams (0.151 mole) of 4-chlorobutan-1-ol and 20.9 grams (0.151 mole) of potassium carbonate in 300 mL of DMF was warmed to 80° C. where it stirred during an 18 hour period. After this time the reaction mixture was concentrated under reduced pressure to a residue. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with water and then with an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using a mixture of 1:1 ethyl acetate and hexane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 12.2 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][NH:7]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[O:47]=[C:48]([NH:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:65])([F:64])[F:63])[CH:57]=1)[CH2:49][CH2:50][C:51](O)=[O:52]>C1COCC1>[O:52]=[C:51]([N:7]1[CH2:8][CH2:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]1[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:50][CH2:49][C:48]([NH:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:63])([F:64])[F:65])[CH:57]=1)=[O:47]
Reactant: c1csc(C2NCCc3ccccc32)c1
Reactant: O=C(O)CCC(=O)NCc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCC(=O)N1CCc2ccccc2C1c1cccs1)NCc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
236 mg (1.1 mmol) of 1-(thiophen-2-yl)-1,2,3,4-tetrahydroisoquinoline, 380 mg (1.0 mmol) of HATU and 263 μl (1.9 mmol) of NEt3 were added in succession to a solution of 275 mg (1.0 mmol) of 4-oxo-4-(3-(trifluoromethyl)benzylamino)butyric acid (intermediate VVV01) in THF (8 ml) and the mixture was then stirred for 24 h at RT. Then it was diluted with EE (30 ml) and washed twice with a 4M aqueous NH4Cl solution and with a 1M aqueous NaHCO3 solution. The organic phase was dried over MgSO4, filtered and concentrated to small volume under vacuum. Column chromatography (EE) of the residue produced 410 mg (0.87 mmol, 87%) of 4-oxo-4-(1-thien-2-yl-3,4-dihydroisoquinolin-2(1H)-yl)-N-(3-(trifluoromethyl)benzyl)butyric acid amide. MS: m/z 473.1 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]([N:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=1)[C:26]([CH:23]1[CH2:25][CH2:24]1)=[O:27])=[O:10]
Reactant: O=C(Nc1cccc(I)c1)c1ccco1
Reactant: O=C(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccco1)N(C(=O)C1CC1)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.2 %

Procedure:
3.19 g of furan-2-carboxylic acid (3-iodo-phenyl)-amide (Example 13bf)) are dissolved in 25 ml of methylene chloride with 2.78 ml of triethylamine and 100 mg of 4-dimethylaminopyridine. 1.60 g of cyclopropanecarbonyl chloride are added thereto and the mixture is stirred at room temperature for 5 hrs. The mixture is concentrated, poured into water and extracted three times with ethyl acetate. Chromatography on silica gel with ethyl acetate/hexane 3:7 gives 1.56 g of cyclopropanecarboxylic acid (furan-2-carbonyl)-(3-iodo-phenyl)-amide as a colourless solid. Yield: 58%. Mass spectrum: peaks inter alia at m/e: 381 (20%), 353 (28%), 313 (86%), 95 (75%), 69 (100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](=O)[CH2:6]Br)[CH3:2].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][N:12]=1>C(#N)C>[CH2:1]([O:3][C:4]([C:5]1[N:10]=[C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][N:12]2[CH:6]=1)=[O:9])[CH3:2]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1ccc(I)cn1
Solvent: CC#N
Product: CCOC(=O)c1cn2cc(I)ccc2n1
Yield: 55.7 %

Procedure:
Add 3-bromo-2-oxo-propionic acid ethyl ester (1.75 g, 9.09 mmol) to a solution of 2-amino-5-iodo pyridine (Tetrahedron 2002, 58, 2885-2890; 1.0 g, 4.54 mmol) in acetonitrile (100 ml). Reflux for 12 h, concentrate to ˜30 ml, and dilute with saturated aqueous sodium bicarbonate. Extract into dichloromethane, combine organic extracts, dry over anhydrous magnesium sulfate, and concentrate. Titurate the residue in diethyl ether and filter to give 0.8 g (56%) of the subtitled compound as an off-white solid. TOF MS ES+ exact mass calculated for C10H91N2O2 (p+1): m/z=316.9787; Found: 316.9784. 1H NMR (400 MHz, DMSO-d6) δ 8.97 (m, 1H), 8.46 (s, 1H), 7.57-7.49 (m, 2H), 4.32 (q, T 7.0 Hz, 2 Hz), 1.33 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][S:2][CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][C:4]1=[O:16].[Cl:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:17][C:3]1([S:2][CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][C:4]1=[O:16]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CSC1C(=O)Nc2ccc(C(F)(F)F)cc21
Solvent: ClC(Cl)(Cl)Cl
Product: CSC1(Cl)C(=O)Nc2ccc(C(F)(F)F)cc21

Procedure:
A solution of 3-methylthio-5-trifluoromethyloxindole (1.40 g, 0.0057 mol) and N-chlorosuccinimide (800 mg, 0.006 mol) in 100 ml of carbon tetrachloride was stirred at room temperature for 1 hour. The precipitated succinimide was removed by filtration, and the filtrate was evaporated to give 3-chloro-3-methylthio-5-trifluoromethyl oxindole as a yellow solid which was dissolved in 30 ml of tetrahydrofuran and added to a vigorously stirred slurry of red mercuric oxide (1.30 g, 5.8 mmol) and boron trifluoride etherate (860 mg, 5.8 mmol) in 100 ml of 20 percent aqueous tetrahydrofuran. The resulting mixture was stirred for 2 hours at room temperature, filtered through a pad of Celite and the filtrate was extracted with four 100-ml portions of methylene chloride. The methylene chloride extracts were dried over anhydrous magnesium sulfate, filtered, and evaporated to give a residue which was chromatographed on silica gel. Elution with methylene chloride gave 5-trifluoromethylisatin as yellow needles (860 mg, 73%), mp 191°-193° (recrystallized from benzene); ir (KBr) 3200 (NH), 1750 (C=O), 1710 cm-1 (C=O); nmr (DMSO-d6), τ-1.20 (b s, 1H, NH), 2.15 (d, 1H, H6), 2.30 (s, 1H, H4), 2.90 (d, 1H, J6,7 =8 Hz, H7); mass spectrum m/e obs. 215.0196 (calc. 215.0194).