Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1)[CH:5]=O.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].C(O)(=O)C.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1)[CH:5]=[C:24]1[S:20][C:21](=[O:26])[NH:22][C:23]1=[O:25]
Reactant: O=C1CSC(=O)N1
Reactant: Cc1cc(C=O)ccc1Oc1ccc([N+](=O)[O-])cn1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: Cc1cc(C=C2SC(=O)NC2=O)ccc1Oc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C

Procedure:
To a solution of 3-methyl-4-(5-nitropyridin-2-yloxy)benzaldehyde (600 mg, 2.32 mmol) in toluene (35 mL) were added 2,4-thiazolidinedione (270 mg, 2.31 mmol) and piperidine acetate (135 mg, 0.93 mmol). The resulting solution was attached to a Dean Stark, and stirred under reflux for 1.5 hours. After being left to cool for 17 hours at room temperature, the precipitated yellow powder was filtered, to thereby yield 600 mg of the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[Cl:7][C:8]([Cl:20])([Cl:19])[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)O.O>C(Cl)Cl>[CH3:18][O:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:9]([Cl:2])[C:8]([Cl:20])([Cl:19])[Cl:7])[CH:12]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COc1cccc(C(O)C(Cl)(Cl)Cl)c1
Solvent: O
Solvent: ClCCl
Product: COc1cccc(C(Cl)C(Cl)(Cl)Cl)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a suspension of 2.4 g (11.0 mmol) of phosphorous pentachloride in 7.0 mL of CH2Cl2 was added a solution of 2.28 g (9.0 mmol) of the product of Step A in 5.0 mL of CH2Cl2. The reaction mixture became homogenous while it was stiffed at room temperature for 3 h. The reaction mixture was then cooled to 0° C. with an external ice-water bath and ice and water were added. The reaction mixture was allowed to warm to room temperature while stirring for 1 h, and was then extracted with CH2Cl2. The organic layers were combined, dried (Na2SO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 5-20% EtOAc-hexane. Evaporation of the purified fractions afforded the title compound as a colorless oil.
Reaction SMILES: C(O[N:6]([CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([S:34][C:35]4[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=4)=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)[CH:15]=1)=[O:12])[C:7](C)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:42][O:41][C:38]1[CH:39]=[CH:40][C:35]([S:34][C:31]2[CH:30]=[CH:29][C:28]([CH2:27][N:24]3[CH2:25][CH2:26][CH:21]([C:16]4[CH:15]=[C:14]([NH:13][C:11](=[O:12])[CH2:10][NH:6][CH3:7])[CH:19]=[CH:18][C:17]=4[CH3:20])[CH2:22][CH2:23]3)=[CH:33][CH:32]=2)=[CH:36][CH:37]=1
Reactant: COc1ccc(Sc2ccc(CN3CCC(c4cc(NC(=O)CN(OC(C)(C)C)C(C)=O)ccc4C)CC3)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCC(=O)Nc1ccc(C)c(C2CCN(Cc3ccc(Sc4ccc(OC)cc4)cc3)CC2)c1
Reaction time: 0.17 h
Yield: 99.2 %

Procedure:
2-[(tert-butoxy)-N-methylcarbonylamino]-N-[3-(1-{[4-(4-methoxyphenylthio)phenyl]methyl} (4-piperidyl))-4-methylphenyl]acetamide was dissolved in CH2Cl2 (1.00 mL) and trifluoroacetic acid (0.160 mL) was added to the stirred solution. Stirring was continued for 10 min then the reaction mixture was concentrated in vacuo to give a gum. The crude product was dissolved in saturated NaHCO3 solution (10 mL to pH 10) and extracted with CH2Cl2 (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give N-[3-(1-{[4-(4-methoxyphenylthio)phenyl]methyl}(4-piperidyl))-4-methylphenyl]2-(methylamino)acetamide (68.6 mg, 99.2% yield) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13](=[O:16])[CH2:14]Br)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[C-:19]#[N:20].[K+]>O.CO.C1COCC1.O>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13](=[O:16])[CH2:14][C:19]#[N:20])[CH:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: [C-]#N
Reactant: COc1ccc(Cn2cc(C(=O)CBr)cn2)cc1
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(C(=O)CC#N)cn2)cc1
Yield: 96.9 %

Procedure:
According to Scheme 5 Step 1: A solution of 1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-bromoethanone (9.70 mmol, 3.00 g) and potassium cyanide (14.6 mmol, 948 mg) in 120 mL of water/MeOH/THF (1:1:1) was stirred for 30 minutes at room temperature. The reaction mixture was diluted with water (150 mL) and the aqueous phase was extracted with DCM. The organic phase was dried over MgSO4, was filtered and was concentrated to yield 3-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-3-oxopropanenitrile (9.40 mmol, 2.40 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[NH:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:17]([C:21](O)=[O:22])[CH:18]([CH3:20])[CH3:19].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(Cl)CCl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:21](=[O:22])[C@H:17]([NH:16][C:24](=[O:25])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:18]([CH3:20])[CH3:19])[CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1(C)CNCCC1c1ccc(Cl)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(4-chlorophenyl)-3,3-dimethylpiperidine, isomer A (1.1 g, 4.92 mmol), Boc-D-Val-OH (1.068 g, 4.92 mmol), HOBT (1.656 g, 10.82 mmol), and triethylamine (3.43 mL, 24.58 mmol) in methylene chloride (20 mL) was treated with EDC (2.073 g, 10.82 mmol), and the reaction was allowed to stir overnight at room temperature. The mixture was concentrated in-vacuo, and the residue was taken up in ethyl acetate. The organic phase was washed 3× with 1M NaOH, 3× with 1M HCl, and once with brine, dried over sodium sulfate, and concentrated in-vacuo to yield the title compound (2.25 g). MS (ESI+)=423.5, (M+H)+.
Reaction SMILES: O.[C:2]([OH:5])(=[O:4])[CH3:3].CC1O[N:10]=[C:9]([C:12]2[CH:13]=[C:14]([CH:36]=[CH:37][CH:38]=2)[O:15][CH:16]([CH2:33][CH2:34][CH3:35])[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:30][CH2:29][CH2:28][S:27]3(=[O:32])=[O:31])=[CH:22][CH:21]=2)=[O:18])[N:8]=1>CO>[C:9]([C:12]1[CH:13]=[C:14]([CH:36]=[CH:37][CH:38]=1)[O:15][CH:16]([CH2:33][CH2:34][CH3:35])[C:17]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:30][CH2:29][CH2:28][S:27]2(=[O:31])=[O:32])=[CH:24][CH:25]=1)=[O:18])(=[NH:8])[NH2:10].[C:2]([O-:5])(=[O:4])[CH3:3]
Reactant: CC(=O)O
Reactant: CCCC(Oc1cccc(-c2noc(C)n2)c1)C(=O)Nc1ccc(N2CCCS2(=O)=O)cc1
Solvent: O
Solvent: CO
Product: CC(=O)[O-]
Product: CCCC(Oc1cccc(C(=N)N)c1)C(=O)Nc1ccc(N2CCCS2(=O)=O)cc1

Procedure:
1.5 g of water-moist Raney nickel, 0.5 ml of glacial acetic acid and 0.5 ml of water are added to a solution of 200 mg (0.425 mmol) of 2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]-N-[4-(1,1-dioxoisothiazolidin-2-yl)phenyl]-valeramide in 10 ml of methanol, and the mixture is hydrogenated. The reaction mixture is filtered, and the filtrate is evaporated, giving 2-(3-amidinophenoxy)-N-[4-(1,1-dioxoisothiazolidin-2-yl)phenyl]valeramide, acetate (“AA”) as a colourless solid; ESI 431.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:11][N:12]=[C:13]=[S:14]>C(O)(C)C>[C:1]([NH:9][NH:10][C:13](=[S:14])[NH:12][CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: CN=C=S
Reactant: NNC(=O)c1ccncc1
Solvent: CC(C)O
Product: CNC(=S)NNC(=O)c1ccncc1
Temperature: 70 °C
Yield: 93 %

Procedure:
To a gently heated (35° C.) and mechanically stirred suspension of isonicotinohydrazide (435 g) in isopropyl alcohol (6.0 L) was added (methylimino)(thioxo)methane (230 g) in several small portions. After complete addition, the reaction mixture was heated (70° C.) for 6 h with an additional addition of isopropyl alcohol (600 ml) after 30 min. After cooling (ice-bath) the reaction mixture to 17° C., the obtained precipitate was filtered off and washed with isopropyl alcohol (1.0 L). This solid was then air-dried over night to provide 615 g of the title compound as a white powder.
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[N:13]2[C@@H:18]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=3)[C:19](=[O:34])[N:20]([CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[C@@H:21]([CH3:22])[CH:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:43](OC(=O)C)(=[O:45])[CH3:44]>N1C=CC=CC=1.C(OCC)(=O)C>[C:43]([O:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][C@@H:18]2[N:13]3[C:14](=[O:17])[CH2:15][CH2:16][N:11]([C:9](=[O:10])[NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:12]3[C@H:21]([CH3:22])[N:20]([CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[C:19]2=[O:34])=[CH:37][CH:38]=1)(=[O:45])[CH3:44]
Reactant: C[C@H]1C2N(C(=O)NCc3ccccc3)CCC(=O)N2[C@@H](Cc2ccc(O)cc2)C(=O)N1Cc1cccc2ccccc12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc(C[C@H]2C(=O)N(Cc3cccc4ccccc34)[C@@H](C)C3N(C(=O)NCc4ccccc4)CCC(=O)N32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.3 %

Procedure:
To a solution of (6S,9S)—N-benzyl-6-(4-hydroxybenzyl)-9-methyl-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidine-1-carboxamide 60 mg (0.106 mmol) in pyridine (1 ml), acetic anhydride 1 ml (10.579 mmol) was added and the mixture was stirred at room temperature for 24 hr. The reaction mixture was diluted with ethyl acetate (10 ml) and washed with 10% citric acid (10 ml) 3 times and brine (10 ml). The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by Büchi silica gel column chromatography (chloroform:methanol=99:1 to 98:2) to obtain title compound 39.3 mg (61%).
Reaction SMILES: O=[C:2]1[N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:9][CH2:8][C:3]21[CH2:7][CH:6]=[CH:5][CH2:4]2.[OH-:19].[Na+].OO>C1COCC1>[OH:19][CH:5]1[CH2:6][CH2:7][C:3]2([CH2:8][CH2:9][CH2:10][N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:2]2)[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCCC2(CC=CC2)C1=O
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC2(CCC(O)C2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.4 %

Procedure:
To a solution of tert-butyl 6-oxo-7-azaspiro[4.5]dec-2-ene-7-carboxylate (0.61 g, 2.44 mmol) in anhydrous THF (5 mL) was added borane-methyl sulfide complex (10.0 M, 2.45 mL, 24.5 mmol) at 0° C. After stirring for 10 min, the reaction mixture was warmed to rt and stirred overnight, then cooled down to 0° C. and a mixture of NaOH aqueous solution (3 M, 3 mL, 9 mmol) and H2O2 (30% in water, 3 mL) was added. After stirring for 5 min, the reaction mixture was heated to reflux for 5 h, then cooled down to rt and concentrated in vacuo. The residue was dissolved in water (10 mL), and extracted with EtOAc (15 mL×3). The combined organic phases were washed with brine (50 mL), and dried over anhydrous Na2SO4, then concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/5) to give the title compound as colorless oil (252 mg, 41%).
Reaction SMILES: [C:1]([O:5][K])([CH3:4])([CH3:3])C.N1C=CC=CC=1.I[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1O.[N+:21]([C:24]1C=C([N+]([O-])=O)C2OC3C=CC=CC=3[C:26]=2[CH:25]=1)([O-:23])=[O:22]>C(COC)OC.[Cu]I>[N+:21]([C:24]1[C:4]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[O:5][C:1]=2[CH:3]=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: Oc1ccccc1I
Reactant: CC(C)(C)O[K]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c2oc3ccccc3c2c1
Agent: [Cu]I
Solvent: c1ccncc1
Solvent: COCCOC
Product: O=[N+]([O-])c1cccc2oc3ccccc3c12
Reaction time: 0.17 h
Yield: 101.6 %

Procedure:
In a flame dried 3-neck flask, CuI (10.3 g, 54.3 mmol) and tBuOK (6.7 g, 60 mmol) were stirred in 120 mL dimethoxyethane for 1 h. To the stirred solution was added 280 mL pyridine and the solution turn purplish. In a separate flask 2-iodophenol (24.1 g, 109 mmol) and tBuOK (12.9 g, 115 mmol) were dissolved in 60 mL dimethoxyethane and transferred to the reaction flask. Solid 2,4-dinitrodibenzofuran (16 g, 95 mmol) was then immediately added to the reaction flask and stirred for 10 minutes. Reaction mixture was then refluxed for 2.5 h. After completion, reaction mixture was cooled and carefully quenched with 8M H2SO4. Dark color solution was filtered thru a Celite and the filtrate was partitioned between ethylacetate and water. Aqueous layer was extracted twice with ethylacetate. Combined organic layer was washed with sodium sulfite solution followed by Na2CO3 solution and dried over anhydrous Na2SO4. Organic solvent was removed under vacuum. Crude product was purified by flash chromatography over silica gel with 20% DCM/Hexanes. Target compound (13 g, 64% yield) was isolated as yellow solid upon evaporation of organic solvent under vacuum.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[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.[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36]>>[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[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])(=[O:37])=[O:36]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Product: O=C(N[C@@H](CCCCNS(=O)(=O)c1ccccc1Br)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 61 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with 2-bromobenzenesulfonyl chloride under the conditions used in example 2 giving 61% of the title compound.
Reaction SMILES: [OH:1][CH:2]([CH3:22])[CH:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]1[CH3:21])[CH3:4].[H-].[Na+].I[CH3:26]>C1COCC1.C(OCC)(=O)C>[CH3:26][O:1][CH:2]([CH3:22])[CH:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]1[CH3:21])[CH3:4]
Reactant: CI
Reactant: Cc1c(C(=O)OC(C)(C)C)c2ccccc2n1C(C)C(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(C)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2ccccc21
Reaction time: 0.33 h

Procedure:
To a suspension of tert-butyl 1-(3-hydroxybutan-2-yl)-2-methyl-1H-indole-3-carboxylate (500 mg, 1.65 mmol) in THF (8 mL) was added sodium hydride (330 mg, 8.25 mmol) at 30° C. under N2. The reaction was stirred for 20 min. Then iodomethane (0.4 mL) was added and the reaction was stirred at 60° C. for 3 hrs. Then the mixture was diluted with ethyl acetate, washed with water and saturated aqueous NaHCO3. The crude product was purified by column chromatography on silica gel eluted with petroleum ether:ethyl acetate=80:1 to afford the title compound as a yellow solid which was used directly (400 mg, 76.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O)[CH2:6]Cl.[Na+].[CH3:15][S:16]([O-:18])=[O:17].O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][S:16]([CH3:15])(=[O:18])=[O:17])[CH:8]=[CH:9][C:10]=1[NH2:11]
Reactant: CS(=O)[O-]
Reactant: COc1cc(CCl)ccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc(CS(C)(=O)=O)ccc1N
Temperature: 80 °C
Yield: 83.4 %

Procedure:
To a solution of 3-methoxy-4-nitrobenzyl chloride (2.76 g, 13.7 mmol) in 20 mL of absolute ethanol was added methanesulphinic acid sodium salt (1.0 g, 27.4 mmol). The reaction was heated to 80° C. for 16 h. The reaction was cooled to room temperature and poured into water and the aqueous layer was extracted with ethyl acetate. Combined organics were dried over anhydrous MgSO4, filtered, concentrated onto silica gel and purified by flash chromatography with ethyl acetate/hexanes as the eluent. The fractions containing the desired product were concentrated to dryness, then redisolved in absolute ethanol and 10% Palladium on carbon (500 mg) was added and the reaction was placed on the Fischer-Porter hydrogenation apparatus and treated with 50 psi of H2 gas overnight to afford 2-(methyloxy)-4-[(methylsulfonyl) methyl]aniline (2.46 g, 83%). 1H NMR (400 MHz, CDCl3) δ ppm 6.80 (d, J=1.7 Hz, 1H), 6.68 (d, J=8.0, 1.6 Hz, 1H), 6.57 (d, J=8.1, 1H), 4.82 (s, 2H), 4.21 (s, 2H), 3.72 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([C@H:4]([NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:5]([O:7]C1C=CC([N+]([O-])=O)=CC=1)=O)[CH3:3].[NH2:28][C@H:29]([C:33]([NH:35][C@H:36]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:38]([CH3:40])[CH3:39])=[O:34])[C@@H:30]([CH3:32])[OH:31].N[C@H](C(N[C@@H](C(OC(C)(C)C)=O)CC(C)C)=O)[C@@H](C)O>CN(C=O)C>[NH:17]([C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[C@H:4]([C:5]([NH:28][C@H:29]([C:33]([NH:35][C@H:36]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:38]([CH3:39])[CH3:40])=[O:34])[C@@H:30]([CH3:32])[OH:31])=[O:7])[CH:2]([CH3:1])[CH3:3]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)[C@@H](C)O)C(=O)OC(C)(C)C
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: CC(C)C[C@@H](NC(=O)[C@@H](N)[C@@H](C)O)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)[C@@H](C)O)C(=O)OC(C)(C)C
Yield: 72 %

Procedure:
Coupling of 7.85 g Z-Val-ONp with 5.53 g H-Thr-Leu-OtBu in 160 ml DMF in the way described in C (2) provides Z-Val-Thr-Leu-OtBu in 72% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=[O:28])[CH2:12][CH2:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22]COC)=[C:16]([O:26][CH3:27])[CH:15]=2)=[C:5]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:4]=1[CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38].Cl.CO>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=[O:28])[CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([O:26][CH3:27])[C:17]([OH:22])=[C:18]([O:20][CH3:21])[CH:19]=2)=[C:5]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:4]=1[CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38]
Reactant: COCOc1c(OC)cc(CCC(=O)c2c(OC)cc(OC)c(CCC(C)C)c2OCC(=O)OC)cc1OC
Agent: Cl
Solvent: CO
Product: COC(=O)COc1c(CCC(C)C)c(OC)cc(OC)c1C(=O)CCc1cc(OC)c(O)c(OC)c1
Yield: 73.8 %

Procedure:
Then, 2.8 g of 1-(4,6-dimethoxy-2-methoxycarbonylmethoxy- 3-isopentylphenyl)-3-(3,5-dimethoxy-4-methoxymethoxyphenyl)-1-propanone was dissolved in 4 ml of methanol, and 4 ml of hydrochloric acid/methanol was added to the solution and the mixture was heated and refluxed for 10 minutes After the reaction, the solvent was removed from the reaction mixture by distillation, and the obtained solid was dissolved in a small amount of ethyl acetate and crystallized from diethyl ether/hexane to obtain 1.9 g (yield=75%) of 1-(4,6-dimethoxy-2-methoxycarbonylmethoxy-3-isopentylphenyl)-3-(4-hydroxy-3,5-dimethoxyphenyl)-1-propanone in the form of a cotton-like crystal.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]([CH3:18])[C:16](=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[C:4]([CH3:20])[CH:3]=1.O[CH:22]1[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]1.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>C1COCC1.C(OCC)(=O)C.O>[CH3:18][N:17]1[C:16](=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([O:1][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:3][C:4]=1[CH3:20]
Reactant: Cc1cc(O)ccc1-c1nc2ccccc2c(=O)n1C
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OC2CCNCC2)ccc1-c1nc2ccccc2c(=O)n1C
Temperature: 0 °C
Yield: 93.4 %

Procedure:
2-(4-Hydroxy-2-methylphenyl)-3-methyl-4(3H)-quinazolinone (200 mg, 0.751 mmol), tert-butyl 4-hydroxytetrahydro-1(2H)-pyridinecarboxylate (227 mg, 1.12 mmol) and triphenyl phosphine (295 mg, 1.12 mmol) were dissolved in THF (2.0 mL), and with stirring at 0° C., diisopropyl azodicarboxylate (228 mg, 1.12 mmol) was added thereto and stirred for 24 hours. The reaction solution was diluted with ethyl acetate, poured into saturated saline water, extracted with ethyl acetate, and the organic layer was dried with magnesium sulfate. The solvent was evaporated off, and the resulting residue was dissolved in chloroform (3 mL), trifluoroacetic acid (2 mL) was added thereto, and stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate, washed with aqueous 1 N sodium hydroxide solution and saturated saline water, and the organic layer was dried with magnesium sulfate. The solvent was evaporated off, and the residue was purified through silica gel column chromatography (chloroform/methanol=1/1) to obtain the intended compound (245 mg, 93%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:7]Br)=[N:4][S:5][CH:6]=1.[NH2:9][CH2:10][CH2:11][SH:12]>>[BrH:1].[Br:1][C:2]1[C:3]([CH2:7][S:12][CH2:11][CH2:10][NH2:9])=[N:4][S:5][CH:6]=1
Reactant: NCCS
Reactant: BrCc1nscc1Br
Product: Br
Product: NCCSCc1nscc1Br

Procedure:
The reaction of 4-bromo-3-(bromomethyl)isothiazole (8.5 g) with cysteamine (from cysteamine hydrochloride (3.76 g)) was performed under conditions similar to those described in Example 72. From the reaction there was obtained 4-bromo-3-[(2-aminoethyl)thiomethyl]isothiazole hydrobromide, which, following recrystallisation from ethanol-ether and acetonitrile, gave needles (4.05 g), m.p. 111°-112°. The amine base (2.73 g) was isolated by basification with sodium hydroxide and extraction with chloroform.
Reaction SMILES: [C:1]1([C:7]([O:20]C(=O)C(F)(F)C(F)(F)C(F)(F)F)([CH3:19])[CH2:8][C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>ClC(F)(Cl)C(F)(F)Cl>[C:1]1([C:7]([OH:20])([CH3:19])[CH2:8][C:9]([F:17])([F:18])[C:10]([F:15])([F:16])[C:11]([F:13])([F:14])[F:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(CC(F)(F)C(F)(F)C(F)(F)F)(OC(=O)C(F)(F)C(F)(F)C(F)(F)F)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: FC(F)(Cl)C(F)(Cl)Cl
Product: CC(O)(CC(F)(F)C(F)(F)C(F)(F)F)c1ccccc1
Yield: 98 %

Procedure:
In 100 ml of 1,1,2-trichlorotrifluoroethane solution containing 5.00 g (0.01 mol) of 2-phenyl-2-heptafluorobutyryloxy-1-heptafluoropropyl propane ##STR19## 200 ml of an aqueous 10% sodium hydroxide solution added thereto was stirred. An organic layer was separated from the resultant mixture and was dried with magnesium sulfate. By analyzing the reaction product, i.e. the organic layer, by gas chromatography, IR, and NMR, the reaction was foundn to have produced 2-phenyl-2-hydroxy-1-heptafluoropropyl propane ##STR20## in a yield of 98%.