Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH:20]=O)[CH:18]=3)[S:13][C:6]=12.CC(O)=O.[CH3:33][NH:34][CH2:35][CH2:36][OH:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][N:34]([CH3:33])[CH2:35][CH2:36][OH:37])[CH:18]=3)[S:13][C:6]=12
Reactant: CNCCO
Reactant: O=CCn1cc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(CCO)CCn1cc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cn1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of 146 (810 mg, 2.033 mmol) in DCM (40 mL) was added HOAc (0.233 mL, 4.07 mmol) and 2-(methylamino)ethanol (305 mg, 4.07 mmol), and the reaction mixture was stirred at RT for an hour. Sodium triacetoxyborohydride (1.293 g, 6.10 mmol) was added and the mixture was stirred at RT overnight. The mixture was then diluted with saturated NaHCO3 solution then solid NaHCO3 was added to neutralize the acid. The DCM layer was collected, dried over anhydrous Na2SO4, filtered and concentrated to afford title compound 147 (930 mg, 100% yield) that was used directly in the next step with no additional purification. MS (m/z)=458.50 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:24])[CH2:11][CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34].[NH4+].[Cl-]>C(Cl)Cl>[CH3:32][S:33]([O:14][CH:13]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH2:12][CH2:11][CH:10]([O:24][S:33]([CH3:32])(=[O:35])=[O:34])[C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(C(O)CCC(O)c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
To a solution of the product from Example 1B (0.80 g, 2.407 mmol) in dry CH2Cl2 (25 ml) at 0° C. was added triethylamine (1.007 ml, 7.22 mmol), followed by dropwise addition of methanesulfonyl chloride (0.469 ml, 6.02 mmol). The resulting mixture was stirred at 0° C. for 30 min, during which time the starting material slowly went into solution. After stirring an additional 1 h at 0° C., a precipitate began to form. Saturated aq NH4Cl (4 ml) was added, and stirring was continued at room temperature for 20 min. The mixture was washed with water (2×10 ml), and the organic layer was treated with hexanes (10 ml) to give an orange solid that was collected by filtration to give the title compound (0.75 gm, 64% yield).
Reaction SMILES: S(Cl)(Cl)=O.[F:5][CH:6]([F:10])[C:7](O)=[O:8].[NH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[F:5][CH:6]([F:10])[C:7]([NH:11][C:12](=[O:13])[O:14][CH2:15][CH3:16])=[O:8]
Reactant: CCOC(N)=O
Reactant: O=C(O)C(F)F
Solvent: O=S(Cl)Cl
Product: CCOC(=O)NC(=O)C(F)F
Temperature: 25 °C

Procedure:
During a 30 minute period 65.4 g (0.55 mole) of thionyl chloride was added to 50.0 g (0.52 mole) of difluoroacetic acid while stirring. Gas evolved during the addition was returned to the reaction mixture by condensation on a dry ice condenser. After complete addition, the mixture was stirred at room temperature for approximately two hours. Urethane, 46.4 g (0.52 mole), was added and, after complete addition, the reaction mixture was heated at 60°-70° C. for three hours. The mixture was cooled to room temperature and stirred for approximately 18 hours. The mixture was heated at about 75° C. for two hours, then cooled. The mixture was evaporated under reduced pressure to leave an oily residue. This residue crystallized upon standing. The crystallized residue was washed with petroleum ether and filtered to yield 68.4 g of ethyl difluoroacetylcarbamate (mp 55°-57° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][OH:17])=[CH:11][C:10]=2[F:18])[CH:5]=[N:6][CH:7]=1.Cl[C:20]1[CH:21]=[C:22]2[N:29]([CH3:30])[C:28]([CH3:32])([CH3:31])[CH2:27][N:23]2[C:24](=[O:26])[N:25]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[C:10]([F:18])=[CH:11][C:12]([CH2:16][O:17][C:20]3[CH:21]=[C:22]4[N:29]([CH3:30])[C:28]([CH3:32])([CH3:31])[CH2:27][N:23]4[C:24](=[O:26])[N:25]=3)=[CH:13][C:14]=2[F:15])[CH:5]=[N:6][CH:7]=1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1cc(F)c(Oc2cncc(Cl)c2)c(F)c1
Product: CN1c2cc(OCc3cc(F)c(Oc4cncc(Cl)c4)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (4-((5-chloropyridin-3-yl)oxy)-3,5-difluorophenyl)methanol and 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([CH:19]([CH3:30])[CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:31](Cl)(=[O:35])[CH:32]([CH3:34])[CH3:33].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([CH:19]([CH3:30])[CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]([C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Cl
Reactant: CC(CCNC(=O)OC(C)(C)C)C1(c2ccccc2)NN=C(c2cccc(F)c2)S1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)N1N=C(c2cccc(F)c2)SC1(c1ccccc1)C(C)CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 3-(5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)butylcarbamate (50 mg, 116 mmol) in anhydrous DCM (5 mL) was added isobutyryl chloride (16 pt, 151 mmol) followed by triethylamine (21 μL, 151 mmol). After stirring at room temperature for 16 hours the mixture was partitioned between sat. NaHCO3 (20 mL) and DCM (20 mL). The aqueous layer was extracted with DCM (10 mL) and the combined organic phases were washed with brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was chromatographed (19:1, hexanes/ethyl acetate) to afford two diastereomeric pairs, diastereomer pair A (more polar, 13.1 mg) and diastereomer pair B (less polar, 11 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[CH:11][C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2/[C:14](/[NH:17]O)=[N:15]\[H])=[N:2]1.[C:23]([O:27][CH3:28])(=[O:26])[C:24]#[CH:25].O>CO>[CH3:28][O:27][C:23]([C:24]1[NH:15][C:14]([C:13]2[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=2/[CH:11]=[CH:10]/[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[N:17][CH:25]=1)=[O:26]
Reactant: [H]/N=C(/NO)c1ccccc1C=Cc1n[nH]c2ccccc12
Reactant: C#CC(=O)OC
Solvent: O
Solvent: CO
Product: COC(=O)c1cnc(-c2ccccc2/C=C/c2n[nH]c3ccccc23)[nH]1
Yield: 4.5 %

Procedure:
(E)-2-[2-(1H-indazol-3-yl)vinyl]-N-hydroxybenzamidine (0.30 g, 0.83 mmol) obtained in Step 1 of Example 175 was dissolved in methanol (8.0 mL) and after heating methyl propiolate (0.21 mL, 2.5 mmol) under reflux for 5 hours, water was added to stop the reaction. The mixture was extracted with ethyl acetate and the organic layer was concentrated. The residue was purified by preparative thin-layer chromatography (chloroform/acetone=4/1) to obtain Compound 195 (13 mg, 5%).
Reaction SMILES: Cl[C:2]1[C:3]([NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:4][C:5]([C:8]2[C:13]([Cl:14])=[CH:12][N:11]=[C:10]([F:15])[CH:9]=2)=[CH:6][N:7]=1.[CH3:24]B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>COCCOC>[Cl:14][C:13]1[C:8]([C:5]2[N:4]=[C:3]([NH:16][CH2:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:2]([CH3:24])=[N:7][CH:6]=2)=[CH:9][C:10]([F:15])=[N:11][CH:12]=1
Reactant: Fc1cc(-c2cnc(Cl)c(NCC3CCOCC3)n2)c(Cl)cn1
Reactant: CB(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1ncc(-c2cc(F)ncc2Cl)nc1NCC1CCOCC1
Temperature: 105 °C
Reaction time: 0.33 h
Yield: 191.6 %

Procedure:
3-chloro-6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (0.0275 g, 0.077 mmol), methylboronic acid (0.014 g, 0.231 mmol), and sodium carbonate (0.100 ml, 0.200 mmol, 2M aq solution) were dissolved in DME (1.0 ml). The solution was then degassed by sparging with argon for 5 min. It was then treated with PdCl2(dppf).CH2Cl2 adduct (0.013 g, 0.015 mmol). The reaction mixture was then heated in the microwave at 105° C. for 20 min. More of the above reagents in the same amounts were added to the reaction mixture and heating in the microwave was continued at 115° C. for 20 min. The reaction mixture was allowed to cool to ambient temperature. It was then filtered through a pad of Celite. The filtrate was concentrated in vacuo to yield 0.0497 g of a mixture of 6-(5-chloro-2-fluoropyridin-4-yl)-3-methyl-N-((tetrahydro-2H-pyran-4-yl)pyrazine-2-amine and 6-(2-fluoro-5-methylpyridin-4-yl)-3-methyl-N-((tetrahydro-2H-pyran-4-yl_methyl)pyrazine-2-amine.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:20]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21]1>>[NH:20]1[CH:24]=[CH:23][C:22]([CH2:25][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:21]1
Reactant: O=Cc1cc[nH]c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cc[nH]c4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1H-pyrrole-3-carbaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(1H-pyrrol-3-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:12][C:13]1([C:21]([OH:23])=O)[CH2:16][CH:15]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:14]1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:24]([C:26]1[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=1)[NH2:25].CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:1]([O:8][N:9]([CH2:12][C:13]1([C:21]([NH:25][NH:24][C:26]2[N:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=[CH:28][N:27]=2)=[O:23])[CH2:14][CH:15]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:16]1)[CH:10]=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1nccc(C(F)(F)F)n1
Reactant: CCCCC1CC(CN(C=O)OCc2ccccc2)(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCCCC1CC(CN(C=O)OCc2ccccc2)(C(=O)NNc2nccc(C(F)(F)F)n2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.1 %

Procedure:
To a mixture of (1-[(benzyloxy-formyl-amino)-methyl)]-3-butyl-cyclobutanecarboxylic acid (0.10 g, 0.31 mmol), 2-hydrazino-4-(trifluoromethyl)pyrimidine (0.067 g, 0.37 mmol), NMM (0.095 g, 0.93 mmol) and HOAt (0.05 g, 0.37 mmol) in DMF (3 mL) at room temperature was added 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (0.072 g, 0.37 mmol). After stirring at room temperature 18 h, the reaction mixture was then purified by preparative, reverse-phase HPLC to afford the title compound as a white solid (0.07 g, 47%). MH+480.
Reaction SMILES: [F: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.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:22][C:23]1[N:28]=[CH:27][C:26]2[C:29](=O)[O:30][CH2:31][C:25]=2[C:24]=1[Cl:33].Cl>C1COCC1>[Cl:22][C:23]1[N:28]=[CH:27][C:26]2[C:29](=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[O:30][CH2:31][C:25]=2[C:24]=1[Cl:33]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: O=C1OCc2c1cnc(Cl)c2Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2ccc(F)cc2C1=C1OCc2c1cnc(Cl)c2Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 67.6 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (1.44 g, 9.54 mmol.) in THF (10 mL) is cooled to 0° C. under an argon atmosphere and treated with a solution of lithium bis(trimethylsilyl)amide (19 mL of a 1 M solution in THF, 19.0 mmol) dropwise. The resulting solution is stirred at 0° C. for 10 min and warmed room temperature. A solution of 6,7-dichloro-1H-furo[3,4-c]pyridin-3-one (1.28 g, 6.27 mmol) in THF (9 mL) is added dropwise to the reaction mixture. The resulting solution is stirred at room temperature for 4 h and the reaction mixture is then poured into aqueous 10% HCl solution (200 mL). The resulting mixture is heated to 90° C. for 2 h and stirred at room temperature for 36 h. The precipitate which formed is collected by filtration, washed with small volumes of ethyl acetate (10×3 mL) and dried under vacuum to give the title compound as a yellow solid (1.43 g, 68%).
Reaction SMILES: [CH2:1]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Br:18]N1C(=O)CCC1=O>CN(C=O)C>[Br:18][C:15]1[S:14][C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:17][CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCCCCCCCc1cccs1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCc1ccc(Br)s1
Temperature: 0 °C
Yield: 89.9 %

Procedure:
2-Dodecylthiophene (100 g, 396 mmol, 1 eq) prepared above was placed in a three-necked flask equipped with a dropping funnel and a reflux tube. The atmosphere in the flask was replaced by Ar, 400 ml of dehydrated N,N-dimethylfolmamid (hereinafter referred to as “DMF”) was added thereto, and the mixture was stirred. The reaction solution was cooled to 0° C., and N-bromosuccinimide (84.5 g, 475 mmol, 1.2 eq) dissolved in 120 ml of dehydrated DMF in a separate vessel was added dropwise to the reaction solution. After the completion of the dropwise addition, the mixture was stirred for one hr, was brought to room temperature, and was stirred for 6 hr. The solvent was removed by evaporation, and the residue was extracted with diethyl ether, followed by washing with water until pH=7. The extract was dehydrated over Na2SO4, and the solvent was removed by evaporation, and the residue was purified by chromatography on silica gel to give an objective substance 2-bromo-5-dodecylthiophene (about 118 g yield about 90%) as a light yellow liquid. An NMR spectrum of the compound thus obtained was measured at room temperature with an NMR spectrometer (model JNM-LA400W, manufactured by Japan Electric Optical Laboratory). 1H-NMR (CDCl3, TMS/ppm): 0.88 (t, 3H, J=6.83 Hz), 1.26 (m, 18H), 1.62 (m, 2H), 2.73 (t, 2H, J=7.32 Hz), 6,53 (d, 2H, J=4.39 Hz), 6.84 (d, 2H, J=3.90 Hz).
Reaction SMILES: [OH-].[Na+].[ClH:3].[O:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]([CH2:14][CH2:15][NH:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[CH2:5]1.O>CO>[ClH:3].[O:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]([CH2:14][CH2:15][NH:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:5]1
Reactant: COC(=O)CCNCCC1COc2ccccc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCNCCC1COc2ccccc2C1
Reaction time: 0.08 h
Yield: 87.5 %

Procedure:
21 ml (42 mmol) of 2N sodium hydroxide solution are added at room temperature while stirring to a solution of 2.99 g (10 mmol) of N-[2-(chroman-3-yl)ethyl]-N-(2-methoxycarbonylethyl)-amine hydrochloride in 60 ml of methanol. After 5 minutes, 40 ml of water are added to the reaction mixture which is then stirred for 30 minutes at 50°-60°. After cooling, the mixture is concentrated by evaporation in vacuo. The residue is dissolved in 30 ml of water, and then 10 ml of hydrochloric acid (36% strength) are added and the whole is cooled in an ice bath. The crystals formed are filtered off with suction. 2.5 g (87.5%) of N-[2-(chroman-3-yl)ethyl]-N-(2-carboxyethyl)-amine hydrochloride are obtained (m.p. 186°-188°).
Reaction SMILES: C([O:8][C:9]1[C:10]2[CH2:11][N:12]([CH2:32][C:33]([OH:35])=[O:34])[CH2:13][CH2:14][N:15]([CH2:28][C:29]([OH:31])=[O:30])[CH2:16][CH2:17][N:18]([CH2:24][C:25]([OH:27])=[O:26])[CH2:19][C:20]([N:23]=2)=[CH:21][CH:22]=1)C1C=CC=CC=1>Cl>[C:29]([CH2:28][N:15]1[CH2:14][CH2:13][N:12]([CH2:32][C:33]([OH:35])=[O:34])[CH2:11][C:10]2=[N:23][C:20](=[CH:21][CH:22]=[C:9]2[OH:8])[CH2:19][N:18]([CH2:24][C:25]([OH:27])=[O:26])[CH2:17][CH2:16]1)([OH:31])=[O:30]
Reactant: O=C(O)CN1CCN(CC(=O)O)Cc2ccc(OCc3ccccc3)c(n2)CN(CC(=O)O)CC1
Agent: Cl
Product: O=C(O)CN1CCN(CC(=O)O)Cc2ccc(O)c(n2)CN(CC(=O)O)CC1

Procedure:
8 g (0.0170 mol) of (12-benzyloxy-6,9-bis(carboxymethyl)-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(14),11(15),12-trien-3-yl)acetic acid are added to 100 ml of 10N HCl. The mixture is left to react overnight at 40° C. It is concentrated. The product is crystallized from acetone. w=6 g.
Reaction SMILES: [OH:1][C@H:2]1[C@:7](O)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1>C(O)C.[Ni]>[OH:1][C@H:2]1[C@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@](O)(c2ccccc2)[C@H](O)C1
Agent: [Ni]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2ccccc2)[C@H](O)C1
Yield: 92.6 %

Procedure:
To a solution of tert-butyl (3R,4R)-3,4-dihydroxy-4-phenylpiperidine-1-carboxylate (120 g) in ethanol (4.3 L) was added Raney nickel (240 g), and the mixture was refluxed for 48 hours with bubbling of hydrogen gas. The reaction solution was cooled, and filtered on celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give the title compound (105.1 g, 99.4% ee).
Reaction SMILES: [NH2:1][C@@H:2]([CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)[C:3]([OH:5])=[O:4].C(=O)(O)[O-].[Na+].Cl[C:18]([O:20][CH3:21])=[O:19].Cl>>[CH3:21][O:20][C:18]([NH:1][C@@H:2]([CH:6]1[CH2:7][CH2:8][O:9][CH2:10][CH2:11]1)[C:3]([OH:5])=[O:4])=[O:19]
Reactant: COC(=O)Cl
Reactant: N[C@H](C(=O)O)C1CCOCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)N[C@H](C(=O)O)C1CCOCC1
Reaction time: 1 h
Yield: 99.7 %

Procedure:
A solution of (S)-amino-(tetrahydro-pyran-4-yl)-acetic acid (1 g, 6.28 mmol) in saturated aqueous sodium bicarbonate solution (12.32 mL, 125.6 mmol) was stirred until all solids were dissolved. Methyl chloroformate (0.97 mL, 12.56 mmol) was added dropwise, the reaction mixture was stirred for 1 h, and 1N HCl was added to adjust pH to 1. The reaction mixture was extracted with ethyl acetate (3×15 mL) and the organic extracts were dried over sodium sulfate, filtered, concentrated and dried overnight under vacuum to give the title intermediate (1.36 g, 99% yield) as a white, sticky solid. (m/z): [M+H]+ calcd for C9H15NO5 218.10 found 218.3.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][N:6]=[C:7]([O:9][CH2:10][CH3:11])[CH3:8].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C1CCN2C(=NCCC2)CC1.[Cl-].[NH4+]>ClCCl>[N:12]1([CH2:2][CH2:3][CH2:4][O:5][N:6]=[C:7]([O:9][CH2:10][CH3:11])[CH3:8])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCOC(C)=NOCCCBr
Reactant: C1CCNCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCOC(C)=NOCCCN1CCCCC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 32 %

Procedure:
A 500 mg (2.23 mmol) portion of ethyl N-(3-bromopropoxy)acetoimidate was dissolved in 6 ml of dichloromethane, and the solution was mixed with 0.22 ml (2.23 mmol) of piperidine and 0.33 ml (2.23 mmol) of 1,8-diazabicyclo[5.4,0]-7-undecene and stirred at room temperature for 36 hours. The reaction solution was mixed with a saturated ammonium chloride aqueous solution and extracted with chloroform. The chloroform layer was washed with saturated brine and dried with anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform/methanol=10/1) to obtain 166 mg (yield, 32%) of ethyl N-(3-piperidinopropoxy)acetoimidate.
Reaction SMILES: [I-].[NH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N+:9]([CH3:14])=[C:10]2[CH3:13])=[CH:5][CH:4]=1.[CH3:15][Mg]Cl.O>C1COCC1>[NH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH3:14])[C:10]2([CH3:15])[CH3:13])=[CH:5][CH:4]=1
Reactant: CC1=[N+](C)CCc2ccc(N)cc21
Reactant: C[Mg]Cl
Agent: [I-]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCc2ccc(N)cc2C1(C)C
Temperature: -78 °C
Reaction time: 18 h
Yield: 8 %

Procedure:
7-Amino-1,2-dimethyl-3,4-dihydroisoquinolinium iodide (1.44 g, 4.8 mmol) was suspended in THF (200 ml), cooled to −78° C. and treated with methyl magnesium chloride (10 ml of a 3M solution in THF) added as a single portion. The reaction was allowed to reach room temperature over 18 h and poured into water (200 ml). The organic solvent was removed in vacuo and the resultant oily residue extracted into dichloromethane (3×50 ml). Evaporation in vacuo and chromatography through silica gel eluting with (0.5% 0.88 NH3: 4.5% CH3OH: 95% CH2Cl2) yielded the title compound as a yellow oil (0.07 g, 8%). For ease of handling the product was converted into a monohydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8](/[CH:15]=[CH:16]/[C:17](=O)[C:18]([F:21])([F:20])[F:19])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:15]=[CH:16][C:17]([C:18]([F:21])([F:20])[F:19])=[C:9]2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN(/C=C/C(=O)C(F)(F)F)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1c(C(F)(F)F)ccn1-c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
To a solution of (E)-ethyl 2-((4-chlorophenyl)(4,4,4-trifluoro-3-oxobut-1-en-1-yl)amino)acetate (0.95 g, 2.83 mmol) in EtOAc (20 mL) was added DBU (0.85 mL, 5.66 mmol) and the resulting mixture heated in a sealed tube for 90 min at 120° C. The resulting mixture was cooled to room temperature, diluted with EtOAc (80 mL) and washed with 5% KHSO4 (2×80 mL) and brine (80 mL). The organic layer was concentrated and the residue purified by elution from a 25-g silica cartridge with 0-20% EtOAc/heptane to yield ethyl 1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=O>>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:25][C:24]1[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=1[Cl:22]
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: O=Cc1ccccc1Cl
Product: O=C(C=Cc1ccccc1Cl)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
The title compound was prepared from a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (100 mg, 0.317 mmol) and 2-chlorobenzaldehyde (36 ul, 0.317 mmol) similar to Example 6. The residue was purified with hexane:ethylacetate (5:1, 4:1) to yield a light yellow solid (13.5 mg, 9.7%). 1H NMR (CDCl3): 8.10 (d, J=15.6 Hz, 1H), 7.73 (dd, J=2.3, 7.1 Hz, 1H), 7.43 (d, J=9.3 Hz, 1H), 7.41 (d, J=15.9 Hz, 1H), 7.33 (t, J=2.1 Hz, 1H), 7.32 (s, 1H), 7.3 (d, J=3.0 Hz, 1H), 7.14 (dd, J=3.2 Hz, 9.2, 1H), 6.96 (d, J=9.0 Hz, 1H), 4.45-4.34 (m, 4H).