Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][C:28]([CH3:33])=[CH:29][C:30](O)=[O:31]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[CH:29]=[C:28]([CH3:33])[CH3:27])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: CC(C)=CC(=O)O
Agent: Cl
Product: CC(C)=CC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (84 mg, 82%), MS (ISP) m/z=411.4 [(M+H)+], mp 177° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 3-methyl-but-2-enoic acid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([O:18]C)=O.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1>C(#N)C>[O:18]=[C:16]1[CH2:15][C:10]2[C:9](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][N:20]1[CH:21]1[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]1
Reactant: COC(=O)Cc1ccccc1CCl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(N2Cc3ccccc3CC2=O)CC1
Temperature: 25 °C
Yield: 40 %

Procedure:
Potassium carbonate (1.4 g, 10 mmol) was added to a solution of methyl 2-(2-(chloromethyl)phenyl)acetate (940 mg, 4.7 mmol) in acetonitrile (20 mL). 4-Amino-N-Boc-piperidine (1.13 g, 5.6 mmol) was added to the mixture. Reaction was heated at reflux for 1 hour. Mixture was cooled to room temperature and then filtered over celite. Filtrate was concentrated in vacuo. Residue was treated with toluene (29 mL). Acetic acid (1.5 ml) was added to the mixture. Reaction was heated at reflux for 2 hours. Mixture was concentrated in vacuo. Residue was treated with ethyl acetate (50 mL). Mixture was washed successively with aqueous sodium bicarbonate (2×30 mL), 1N hydrochloric acid (30 mL), and brine (20 mL). Organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. Silica gel chromatography gave the title compound as lightly colored oil in 40% yield. MS m/e (M+H)+=331.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[C:9]([CH2:11][C:12]([O:14][CH3:15])=[O:13])#[N:10].[Cl-].[NH4+]>CCOCC>[NH2:10][C:9]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CC#N
Reactant: Brc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: COC(=O)C=C(N)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.4 %

Procedure:
47 g of bromobenzene in 90 ml of ether were added dropwise to 7.2 g of magnesium in 20 ml of ether under reflux, and the stirred mixture was refluxed for 1 hour. Thereafter, 9.9 g of methyl cyanoacetate were added dropwise while cooling with ice, and stirring was carried out for 1 hour at room temperature, for 5 hours under reflux and again for 15 hours at room temperature. 300 ml of ammonium chloride were carefully added to the reaction mixture and the aqueous phase was extracted twice with ether and the combined organic phases were washed three times with water, dried over sodium sulfate and evaporated down. The residue was distilled under greatly reduced pressure. 13 g of methyl β-amino-cinnamate were obtained (110-112° C., 10.15 mbar).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]([CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[S:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[S:14][C:13]=2[CH:21](O)[C:22]2[CH:27]=[C:26]3[O:28][CH2:29][O:30][C:25]3=[CH:24][C:23]=2[CH3:31])(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[Cl:1][C:2]1[C:3]([N:8]([CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[S:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[S:14][C:13]=2[CH2:21][C:22]2[CH:27]=[C:26]3[O:28][CH2:29][O:30][C:25]3=[CH:24][C:23]=2[CH3:31])(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7]
Reactant: COCCOCN(c1noc(C)c1Cl)S(=O)(=O)c1c(C(O)c2cc3c(cc2C)OCO3)sc2ncccc12
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COCCOCN(c1noc(C)c1Cl)S(=O)(=O)c1c(Cc2cc3c(cc2C)OCO3)sc2ncccc12
Yield: 53.9 %

Procedure:
The title compound was prepared by the method of Example 5(A) using N-(4-chloro-5-methyl-3-isoxazolyl)-N-(methoxyethoxymethyl)-2-[α-hydroxy-2 -methyl-4,5-(methylenedioxy)benzyl]thieno[2,3-b]pyridine-3-sulfonamide (0.11 g, 0.19 mmoles), CH2Cl2 (5 ml), triethyl silane (0.31 ml, 1.9 mmoles) and boron trifluoride etherate (0.12 ml, 0.97 mmoles). Flash chromatography (35% EtOAc/hexanes) provided 58 mg (53%) of the title compound as a tan solid.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[CH2:7]1[CH2:11][O:10][CH2:9][CH2:8]1.CON(C)C(=O)CCC>CC(C)=O.O>[S:4]1[CH:5]=[CH:6][C:2]([C:9](=[O:10])[CH2:8][CH2:7][CH3:11])=[CH:3]1
Reactant: C1CCOC1
Reactant: Brc1ccsc1
Agent: CCCC(=O)N(C)OC
Solvent: O
Solvent: CC(C)=O
Product: CCCC(=O)c1ccsc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
3-Bromothiophene (11 g, 67 mmol) dissolved in hexanes (110 ml) was cooled to −20 C in acetone/water bath, and n-Bu Li (28 ml, 71 mmol, 2.5 N solution in hexanes) was added slowly, over 10 min, then stirred 10 min at −20 C. THF was added (10 ml) over 5 min with rapid stirring. Precipitate formed after about ⅔ of addition. After adding all of the THF, the reaction mixture was stirred 20 min at −20 C, then 20 ml hexanes was added and the reaction mixture was allowed to warm to zero degrees C. N-Methoxy-N-methyl-butyramide (9.29 g, 71 mmol) dissolved in 20 ml hexanes was added via cannula over 5 minutes, and the reaction mixture was stirred at zero degrees C. for 1.5 hours. The reaction mixture was quenched with water, then 1 N HCl (75 ml), extracted twice with ether, washed 1 N HCl, brine, and dried over magnesium sulfate. Solvent was removed under reduced pressure to give an oil, which was chromatographed by flash chromatography (5% EtOAc/hexanes) to give 6.7 g, 64% of 1-Thiophen-3-yl-butan-1-one as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[S:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2].[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([C:32]2[CH:31]=[CH:30][C:29]([N:26]3[CH2:25][CH2:24][O:23][CH2:28][CH2:27]3)=[CH:34][CH:33]=2)[C:9]2[S:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Reactant: CCOC(=O)c1nc(Br)c2sc(-c3ccccc3)nc2c1O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(-c2ccc(N3CCOCC3)cc2)c2sc(-c3ccccc3)nc2c1O
Temperature: 25 °C
Yield: 20.2 %

Procedure:
A mixture of 4-bromo-7-hydroxy-2-phenyl-thiazolo[5,4-c]pyridine-6-carboxylic acid ethyl ester (230 mg, 0.61 mmole), 4-morpholinophenylboronic acid (252 mg, 1.22 mmole), cesium carbonate (596 mg, 1.83 mmole) and tetrakis(triphenylphosphine)-palladium (70 mg, 0.06 mmole) in dioxane (3 ml) was refluxed for 18 h before it was cooled to room temperature, quenched with water and filtered. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a white solid (57 mg). MS: (+) m/z 462.35 (M+H+)
Reaction SMILES: I[C:2]1[C:3]([C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])=[N:4][NH:5][CH:6]=1.I[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17]>[Cu].CN(C=O)C>[F:12][C:7]([F:13])([C:3]1[C:2]([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])=[CH:6][NH:5][N:4]=1)[C:8]([F:11])([F:10])[F:9]
Reactant: FC(F)(F)C(F)(F)I
Reactant: FC(F)(F)C(F)(F)c1n[nH]cc1I
Agent: [Cu]
Solvent: CN(C)C=O
Product: FC(F)(F)C(F)(F)c1c[nH]nc1C(F)(F)C(F)(F)F
Temperature: 122.5 °C
Reaction time: 8 h
Yield: 9.9 %

Procedure:
4-Iodo-3-pentafluoroethyl-1H-pyrazole (12.48 g), copper powder (7.63 g), iodopentafluoroethane (29.50 g) and DMF (60 ml) were set in an autoclave and heated and stirred for 8 hours, maintaining the inside temperature of 120-125° C. After cooling to room temperature, the insoluble material was filtered off through Celite and washed with diethyl ether. The filtrate was diluted with water and extracted with diethyl ether. The organic phase was washed with water and dried over sodium sulfate, and concentrated under the reduced pressure. The crude product was distilled under reduced pressure to obtain 3,4-bis-pentafluoroethyl-1H-pyrazole (1.20 g), bp. 110-115° C./20 mbar.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:25][C:26]1[CH:27]=[C:28]([CH:45]=[CH:46][CH:47]=1)[O:29][C:30]1[CH:42]=[CH:41][C:33]2[N:34]=[C:35]([NH:37][C:38](=[O:40])[CH3:39])[S:36][C:32]=2[C:31]=1[C:43]#[N:44]>O1CCCC1.C(OCC)(=O)C>[C:38]([NH:37][C:35]1[S:36][C:32]2[C:31]([C:43]#[N:44])=[C:30]([O:29][C:28]3[CH:27]=[C:26]([NH:25][C:9](=[O:11])[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=4)([CH3:13])[CH3:12])[CH:47]=[CH:46][CH:45]=3)[CH:42]=[CH:41][C:33]=2[N:34]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c(C#N)c2s1
Reactant: CC(C)(C(=O)O)c1cccc(Br)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)C(C)(C)c4cccc(Br)c4)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To a solution of 2-(3-bromophenyl)-2-methylpropionic acid (89 mg, 0.361 mmol) in tetrahydrofuran (1 mL) were added oxalyl chloride (40 μL, 0.466 mmol) and N,N-dimethylformamide (10 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (1 mL). N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (100 mg, 0.308 mmol) produced in Example 12(ii) was added to the solution, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate (12 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (6 mL) and saturated brine (6 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=30/70→80/20), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethanol to give the title compound (136 mg, 81%) as a white powder.
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11](=O)[CH:12]=[N:13][OH:14])=[N:5]1)([CH3:3])[CH3:2].[NH2:16][CH:17]([C:20]#[N:21])[C:18]#[N:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CC(O)C.CCOC(C)=O.O>[NH2:21][C:20]1[C:17]([C:18]#[N:19])=[N:16][C:11]([C:6]2[CH:7]=[CH:8][C:9](=[O:10])[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=2)=[CH:12][N+:13]=1[O-:14]
Reactant: N#CC(N)C#N
Reactant: CC(C)n1nc(C(=O)C=NO)ccc1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)n1nc(-c2c[n+]([O-])c(N)c(C#N)n2)ccc1=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 26.4 %

Procedure:
A mixture of (1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl) (oxo)acetaldehyde oxime (11.16 g), aminomalononitrile (13.6 g) and p-toluenesulfonic acid (10.2 g) in 2-propanol (200 ml) was stirred at 50° C. for 3 hours. Water, aq. NaHCO3 and EtOAc were added to the reaction mixture to give a pale yellow precipitate. The precipitate was collected by filtration to obtain 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinecarbonitrile 4-oxide (3.84 g) as white powder.
Reaction SMILES: [C:1]([O:12][CH:13]([CH3:15])[CH3:14])(=[O:11])[C@H:2]([CH2:4][C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])[OH:3].[CH2:16](Br)[CH:17]=[CH2:18]>C1COCC1>[CH2:18]([C@H:4]([C@H:2]([OH:3])[C:1]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])[CH:17]=[CH2:16]
Reactant: CC(C)OC(=O)C[C@H](O)C(=O)OC(C)C
Reactant: C=CCBr
Solvent: C1CCOC1
Product: C=CC[C@@H](C(=O)OC(C)C)[C@H](O)C(=O)OC(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a cold (−78° C.) solution of diisopropyl (S)-(−)-malate (4.74 mL; 22.9 mmol; 1.0 eq.) in anhydrous THF (8.50 mL) was slowly added under argon lithium bis(trimethylsilyl)amide (48.1 mL; 1.0 M in THF; 48.11 mmol; 2.1 eq.) keeping the temperature below −66° C. After to 45 min of addition, the reaction mixture was stirred at −78° C. for 2 h, then the temperature of the reaction mixture was allowed to reach 11° C. After 1 h at that temperature, the mixture was cooled at −78° C. and allyl bromide (2.9 mL; 34.4 mmol; 1.5 eq.) was added. The solution was stirred overnight allowing the temperature to reach RT. The reaction was then quenched with ice water and an aqueous saturated solution of NH4Cl. The aqueous layer was extracted 3 times with EtOAc and the combined organic layers were washed with a saturated solution of NaCl, dried over MgSO4 and evaporated to obtain an orange oil (5.4 g). Purification by chromatography (SiO2, 10/90 EtOAc/c-hex) gave the title product as a colorless oil (3.05 g, 51.5%). 1H NMR (CDCl3, 300 MHz) δ 5.76-5.59 (m, 1H), 5.07-4.80 (m, 4H), 4.08 (d, J=2.3 Hz, 1H), 3.03 (br s, 1H), 2.80-2.72 (m, 1H), 2.53-2.41 (m, 1H), 2.34-2.21 (m, 1H), 1.14 (d, J=6.4 Hz, 6H), 1.07 (d, J=6.4 Hz, 6H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.[N+](=[CH2:15])=[N-]>CCOCC.C(OCC)(=O)C.CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:15])=[O:11])=[CH:2]1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1c[nH]c2ccccc12
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1c[nH]c2ccccc12

Procedure:
Indole-3-carboxylic acid (757 mg, 4.7 mmol, 1.0 eq.) was partially dissolved in a mixture of ether, ethyl acetate and methanol. While stirring, a solution of diazomethane in ether was added until a yellow color persisted. The solvent was removed in vacuo and the remaining white solid was passed through a silica gel column, eluting with dichloromethane to give the title A compound (819 mg), m.p. 147°-149° C.
Reaction SMILES: [N+](C1C=CC(/C(=C\C2C=CC(O)=C(OC)C=2)/C([O-])=O)=CC=1)([O-])=O.C(O)C(N)(CO)CO.Cl.[N+:33]([C:36]1[CH:41]=[CH:40][C:39]([O-:42])=[CH:38][CH:37]=1)([O-:35])=[O:34]>CS(C)=O.C([O-])(=O)C.[Na+]>[CH:37]1[C:36]([N+:33]([O-:35])=[O:34])=[CH:41][CH:40]=[C:39]([OH:42])[CH:38]=1
Reactant: O=[N+]([O-])c1ccc([O-])cc1
Agent: CC(=O)[O-]
Agent: COc1cc(/C=C(/C(=O)[O-])c2ccc([N+](=O)[O-])cc2)ccc1O
Agent: Cl
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(O)cc1
Reaction time: 0.17 h

Procedure:
A p-nitrophenylferulate stock solution was made by dissolving p-nitrophenylferulate in dimethylsulfoxide (DMSO) to constitute a 0.1 M solution. Before assay, a sample of the stock solution was diluted 100-fold in 50 mM sodium acetate pH 5.0 to make a 1 mM solution. A 100 μl volume of 1 mM p-nitrophenylferulate was mixed with each dilution of the enzyme to give a 200 □l total volume, and then incubated at 25° C. for 10 minutes. Substrate alone, enzyme alone, and buffer alone were run as controls. p-Nitrophenol standard solutions of 0.25, 0.2, 0.1, 0.05, and 0.02 mM were prepared by diluting a 10 mM stock solution in 50 mM sodium acetate pH 5.0. At 10 minutes, 50 μl of 1.0 M Tris-HCl pH 8.0 buffer was added to each well (including samples, substrate control, enzyme control, reagent control, and standards), mixed, and the absorbance at 405 nm and 540 nm immediately measured on a SPECTRAMAX™ 340 PC plate reader (Molecular Devices, Sunnyvale, Calif., USA). The absorbance at 405 nm was corrected for the background absorbance at 540 nm from the insoluble substrate material. The activity measured was 14 Units per mg of protein. One unit of feruloyl esterase activity was defined as the amount of enzyme capable of releasing 1 μmole of p-nitrophenolate anion per minute at pH 5, 25° C.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]([O:21][CH3:22])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44])(OCC)=O.CCOCC>O.C(#N)C>[C:35]1(=[O:44])[N:1]([CH:2]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:9]([O:21][CH3:22])[CH:8]=2)[CH2:3][C:4]([OH:6])=[O:5])[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: COc1cc(C(N)CC(=O)O)ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CC#N
Product: COc1cc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)ccc1OCc1ccccc1
Reaction time: 1 h
Yield: 75.6 %

Procedure:
To a stirred solution of 3-amino-3-(4-benzyloxy-3-methoxyphenyl)propionic acid (1.505 g, 5.00 mmol) and sodium carbonate (0.572 g, 5.40 mmol) in a mixture of 75 mL of water and 175 mL of acetonitrile (mixture was warmed gently to dissolve solid) was added N-carbethoxyphthalimide (1.096 g, 5.00 mmol). The mixture was stirred for 1 hour, then partially concentrated in vacuo to remove the acetonitrile. A small amount of solid formed which was removed by filtration. The pH of the solution was adjusted to 1 with 4N Hydrochloric acid, a gum formed. To the stirred mixture was added 1 mL of ether and the mixture was then stirred overnight. The resulting slurry was filtered and the solid dried to afford 1.63 g (75%) of 3-phthalimido-3-(4-benzyloxy-3-methoxyphenyl)-propionic acid as a white powder, 1H NMR (DMSO-d6) δ12.43 (br s, 1H, COOH), 8.0-7.8 (m, 4H, Ar), 7.60-7.25 (m, 5H), 7.15-6.85 (m, 3H, Ar), 5.25 (dd, 1H, J=9, 6.6 Hz), 5.05 (s, 2H, OCH2), 3.76 (s, 3H, OMe), 3.52 (dd, 1H, J=9, 16.5 Hz), 2.29 (dd, 1 H, J=6.6, 16.5 Hz); 13C NMR (DMSO-d6) δ171.7, 167.6, 148.9, 147.3, 137.0, 134.6, 131.7, 131.0, 128.3, 127.7, 127.6, 123.1, 119.1, 113.3, 111.3, 69.8, 55.5, 50.1, 36.0. Anal. Calcd for C25H21N1O6. Theory: C, 69.66; H, 4.91; N, 3.25. Found: C, 69.50; H, 4.85; N, 3.22.
Reaction SMILES: [CH2:1]1C2[C:7]3[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9][C:8]=3[C:21]3[CH:22]=[CH:23][CH:24]=[C:4]([C:5]=32)[O:3][CH2:2]1.[BH3-]C#[N:27].[Na+].Cl.[OH-].[Na+]>C(O)(C(F)(F)F)=O>[CH2:1]1[N:27]2[C:5]3[C:21]([CH:8]4[CH2:9][CH2:10][NH:11][CH2:12][CH2:13][CH:7]42)=[CH:22][CH:23]=[CH:24][C:4]=3[O:3][CH2:2]1
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)N1CCC2=C(CC1)C1CCOc3cccc2c31
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: c1cc2c3c(c1)C1CCNCCC1N3CCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 112.4 %

Procedure:
Tert-butyl 1,7,8,10,11,11b-hexahydropyrano[4′,3′,2′:3,4]indeno[1,2-d]azepine-9(2H)-carboxylate (407 mg, 1.24 mmol) was dissolved in TFA (10 mL). This solution was cooled to 0° C., and NaCNBH3 (234 mg, 3.72 mmol) was added in small portions. The reaction was stirred at 0° C. for 1 hr. Conc. HCl (5 mL) was added to the reaction flask, and then the mixture was refluxed at 50° C. for 30 min. The reaction was re-cooled to 0° C., and ice chips were added. The solution was basified with 50% NaOH until a pH=14. The reaction was extracted with CHCl3 (3×20 mL). The combined organic layers were washed with brine, dried, and concentrated to afford the title compound (321 mg, 100%) as an amorphous solid. 1H NMR (CDCl3, 300 MHz) δ6.57-6.67 (3H, m), 4.39-4.43 (2H, m), 3.61-3.69 (1H, m), 3.45 (1H, dt, J=3.3 Hz, 9.2 Hz), 3.00-3.24 (3H, m), 2.69-2.89 (3H, m), 2.02-2.16 (2H, m), 1.83-1.97 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:42][Si](C)(C)C(C)(C)C(C)C)[C:6]2[CH2:19][S:18][CH2:17][C@@H:16]([C:20]3[O:24][N:23]=[C:22]([CH3:25])[N:21]=3)[NH:15][C:14](=[S:26])[CH2:13][CH2:12][C@@H:11]([CH2:27][O:28][C:29](=[O:38])[C:30]3[CH:35]=[CH:34][C:33]([CH2:36][NH2:37])=[CH:32][CH:31]=3)[CH2:10][O:9][C:8](=[O:39])[C:7]=2[C:40]=1[CH3:41].[F-].[NH4+].[ClH:54]>CO.C(OCC)C>[ClH:54].[OH:42][C:5]1[C:6]2[CH2:19][S:18][CH2:17][C@@H:16]([C:20]3[O:24][N:23]=[C:22]([CH3:25])[N:21]=3)[NH:15][C:14](=[S:26])[CH2:13][CH2:12][C@@H:11]([CH2:27][O:28][C:29](=[O:38])[C:30]3[CH:31]=[CH:32][C:33]([CH2:36][NH2:37])=[CH:34][CH:35]=3)[CH2:10][O:9][C:8](=[O:39])[C:7]=2[C:40]([CH3:41])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C(C)C)c2c(c1C)C(=O)OC[C@H](COC(=O)c1ccc(CN)cc1)CCC(=S)N[C@H](c1nc(C)no1)CSC2
Agent: Cl
Agent: [F-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CO
Product: COc1cc(O)c2c(c1C)C(=O)OC[C@H](COC(=O)c1ccc(CN)cc1)CCC(=S)N[C@H](c1nc(C)no1)CSC2

Procedure:
4-Aminomethyl-benzoic acid (4R,9S)-14-methoxy-13-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-16-[dimethyl -(1,1,2-trimethyl-propyl)-silanyloxy]-12-oxo-6-thioxo-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-9-ylmethyl ester was treated with ammonium fluoride in methanol in an analogous manner to the procedure described in Example 1, and the resulting product was treated in methanol with a 3N solution of hydrochloric acid in diethyl ether to yield 4-aminomethyl-benzoic acid (4R,9S)-16-hydroxy-14-methoxy-13-methyl-4-(3-methyl -1,2,4-oxadiazol-5-yl)-12-oxo-6-thioxo-1,3, 4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-9-ylmethyl ester hydrochloride as white solid.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH:4]=[N:3][CH:2]=1.[N+:12]([CH:15]=[C:16](SC)SC)([O-:14])=[O:13].CS>C(O)C>[N:1]1[CH:6]=[C:5]([CH2:7][N:8]2[CH2:9][CH2:10][NH:11][C:16]2=[CH:15][N+:12]([O-:14])=[O:13])[CH:4]=[N:3][CH:2]=1
Reactant: NCCNCc1cncnc1
Reactant: CSC(=C[N+](=O)[O-])SC
Agent: CS
Solvent: CCO
Product: O=[N+]([O-])C=C1NCCN1Cc1cncnc1
Temperature: 25 °C
Yield: 63.7 %

Procedure:
A mixture of N-(5-pyrimidinylmethyl)ethylenediamine (15.2 g), 1-nitro-2,2-bis(methylthio)ethylene (14.9 g) and ethanol (100 g) was refluxed with stirring until the generation of methylmercaptan ceased (for about 3 hours). The reaction mixture was cooled to room temperature, and the resultant crystals were collected by filtration. The crystals were washed with ethanol, and dried to give 1-(5-pyrimidinylmethyl)-2-(nitromethylene)imidazolidine (12.7 g) as pale yellow crystals. This product decomposes at 236° C.