Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([OH:9])=[N:5][CH:6]=[N:7][CH:8]=1.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[C:20](=O)[C:21](=[O:25])[C:22]=1[O:23]C>CO>[OH:9][C:4]1[C:3]([NH:2][C:20]2[C:21](=[O:25])[C:22](=[O:23])[C:19]=2[O:18][CH3:17])=[CH:8][N:7]=[CH:6][N:5]=1
Reactant: Nc1cncnc1O
Reactant: COc1c(OC)c(=O)c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1c(Nc2cncnc2O)c(=O)c1=O
Temperature: 50 °C
Yield: 79.4 %

Procedure:
1.00 g (6.78 mmol, 1 eq) of 5-aminopyrimidin 4-ol hydrochloride and 0.95 ml (6.78 mmol, 1 eq) of triethylamine were added to a suspension of 3.86 g (27.16 mmol, 4 eq) of 3,4-dimethoxycyclobut-3-ene-1,2-dione in 20 ml of methanol. The reaction medium was heated at 50° C. for 18 hours. The reaction medium was left at ambient temperature. The precipitate was filtered off and washed with methanol. 1.19 g of product were obtained in the form of a yellow solid. Yield=79%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([Si](C)(C)C)=[CH:27][C:26]=3[F:35])[C:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:36]N1C(=O)CCC1=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([Br:36])=[CH:27][C:26]=3[F:35])[C:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)c1ccc2c(cnn2C(=O)OC(C)(C)C)c1Nc1ccc([Si](C)(C)C)cc1F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc2c(cnn2C(=O)OC(C)(C)C)c1Nc1ccc(Br)cc1F
Yield: 91.8 %

Procedure:
To a solution of 4-(2-fluoro-4-trimethylsilanyl-phenylamino)-indazole-1,5-dicarboxylic acid di-tert-butyl ester (850 mg, 1.7 mmol) in DCM (10 mL) at −15° C. was added N-bromosuccinimide (303 mg, 1.7 mmol) as a solution in DCM (3 mL) dropwise. The reaction mixture was stirred at −15° C. for 1.25 hours before DCM was added and the solution washed (saturated aqueous NaHCO3 then water), dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 0 to 10% ethyl acetate in cyclohexane) to give the title compound as an orange gum (790 mg, 92%). LCMS (method B) RT=5.41 min, [M+CH3CN+Na]+=569/571.
Reaction SMILES: [C:1]([Si:5]([CH3:23])([CH3:22])[O:6][C:7]1[CH:8]=[C:9]([CH:13]2[C:18](=[O:19])[NH:17][C:16](=[O:20])[NH:15][C:14]2=[O:21])[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[Br:24]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([Si:5]([CH3:23])([CH3:22])[O:6][C:7]1[CH:8]=[C:9]([C:13]2([Br:24])[C:14](=[O:21])[NH:15][C:16](=[O:20])[NH:17][C:18]2=[O:19])[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C2C(=O)NC(=O)NC2=O)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C2(Br)C(=O)NC(=O)NC2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
A mixture of 5-[3-(tertbutyldimethylsilyloxy)phenyl]barbituric Acid (680 mg), N-bromosuccinimide (432 mg) and dibenzoyl peroxide (catalytic amount) in 10 ml of carbon tetrachloride are stirred at room temperature for 1 hour. The solvent is evaporated off and the residue is purified by silica gel chromatography (eluent:ethyl acetate/hexane 7:3) to give 550 mg of the product, m.p. 170-172° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][O:29][C:30]2[C:35]([F:36])=[CH:34][CH:33]=[C:32]([F:37])[C:31]=2[Cl:38])=[CH:22][CH:21]=1)[C:4]([N:6]([CH:16]1[CH2:18][CH2:17]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[Cl:15])=[O:5].[CH:39](=O)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH2:39]([NH:1][CH2:2][CH:3]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][O:29][C:30]2[C:35]([F:36])=[CH:34][CH:33]=[C:32]([F:37])[C:31]=2[Cl:38])=[CH:22][CH:21]=1)[C:4]([N:6]([CH:16]1[CH2:17][CH2:18]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[Cl:15])=[O:5])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=Cc1ccccc1
Reactant: NCC(Cc1ccc(CCCOc2c(F)ccc(F)c2Cl)cc1)C(=O)N(Cc1cccc(Cl)c1Cl)C1CC1
Product: O=C(C(CNCc1ccccc1)Cc1ccc(CCCOc2c(F)ccc(F)c2Cl)cc1)N(Cc1cccc(Cl)c1Cl)C1CC1

Procedure:
Prepared according to the procedure described in Example 17 but using instead 3-amino-2-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]benzyl}-N-cyclopropyl-N-(2,3-dichlorobenzyl)propanamide (Example 15) and benzaldehyde. The title compound was obtained as a colorless oil. MS (ESI+): 670.8.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH:5]1[C:18](=[O:19])[CH2:17][CH:16]2[N:7]([CH2:8][CH2:9][C:10]3[C:15]2=[CH:14][C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=3)[CH2:6]1)C.[BH4-].[Na+].[CH2:26]([OH:28])C>>[OH:19][CH:18]1[CH2:17][CH:16]2[N:7]([CH2:8][CH2:9][C:10]3[CH:11]=[C:12]([O:22][CH3:23])[C:13]([O:20][CH3:21])=[CH:14][C:15]=32)[CH2:6][CH:5]1[CH2:4][CH:2]([O:28][CH3:26])[CH3:1]
Reactant: CCO
Reactant: COc1cc2c(cc1OC)C1CC(=O)C(CC(C)C)CN1CC2
Agent: [BH4-]
Agent: [Na+]
Product: COc1cc2c(cc1OC)C1CC(O)C(CC(C)OC)CN1CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
Tetrabenazine (Formula 1; 9.01 mg, 0.0284 mmol) was dissolved in 1 mL of ethanol, the solution was cooled to 0° C., and then NaBH4 (3.22 mg, 0.0851 mmol) was slowly added thereto. The temperature was heated to normal temperature and then the mixture was stirred for 1 hr. The mixture was distilled under reduced pressure, water (3 mL) and CH2Cl2 (3 mL) were added thereto to extract an organic layer, and the organic layer collected was washed with a saturated K2CO3 aqueous solution. Anhydrous magnesium sulfate was used to dry the organic layer, filtration under reduced pressure and evaporation under reduced pressure were performed, and then column chromatography was used to obtain 7.30 mg (yield 80%) of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([O:15][C:16]2[CH:17]=[CH:18][C:19]3[N:20]([N:22]=[C:23]([NH:25][C:26]([CH:28]4[CH2:30][CH2:29]4)=[O:27])[N:24]=3)[CH:21]=2)[CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH:9]=1)[O:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([N:22]=[C:23]([NH:25][C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[N:24]=2)[CH:21]=1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1Oc1ccc2nc(NC(=O)C3CC3)nn2c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)nn2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
A mixture of tert-butyl[3-({2-[(cyclopropylcarbonyl)amino][1,2,4]triazolo[1,5-a]pyridin-6-yl}oxy)-4-methylphenyl]carbamate (1.50 g, 3.54 mmol) and trifluoroacetic acid (5 mL) was stirred at 0° C. for 30 min. The solvent was evaporated under reduced pressure, the residue was dissolved in water, and the solution was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, the residue was collected by filtration and washed with ethyl acetate and hexane to give the title compound (1.04 g, 91%) as a white solid.
Reaction SMILES: [O-]Cl.[Na+].[C:4]([C:7]1[S:11][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:9][CH:8]=1)(=[O:6])C.[O-:17]S(S([O-])=O)=O.[Na+].[Na+]>>[C:4]([C:7]1[S:11][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:9][CH:8]=1)([OH:6])=[O:17]
Reactant: CC(=O)c1ccc(-c2cccs2)s1
Reactant: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [O-]Cl
Product: O=C(O)c1ccc(-c2cccs2)s1
Reaction time: 2 h

Procedure:
35 ml of NaOCl solution was heated to 55° C. and 5acetyl-2,2'-bithiophene was then added and stirred at 60°-70° C. for 2 hours. Then the reaction solution was cooled by ice bath and aqueous Na2S2O4 solution was added for removing the residual NaOCl. The reaction mixture was acidified by HCl(aq) and filtered to obtain golden product. The product was further recrystallized with 95% ethanol. The melting point of the product was 183-184%.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1)=O.C([BH3-])#N.[Na+].O>CO>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][C@H:13]2[CH2:14][CH2:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@H]1CC[C@H](C=O)CC1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H](CN[C@@H]2C[C@H]2c2ccccc2)CC1
Reaction time: 1 h

Procedure:
To a solution of trans-2-phenylcyclopropanamine (80 mg, 0.601 mmol) in methanol (10 mL) was added trans-methyl 4-formylcyclohexanecarboxylate (102 mg, 0.601 mmol) and the reaction was heated to reflux for 2 minutes. After cooling back to the room temperature, sodium cyanoborohydride (75 mg, 1.201 mmol) was added to the reaction mixture and was stirred for 1 hour. Water (20 mL) was added. The reaction was concentrated and 20 mL of ethyl acetate was added. The layers were separated. The organic layer was washed with water, brine, and dried over MgSO4, filtered and evaporated. The resulting oil was purified on preparatory HPLC (10 to 60% AcCN:water with 0.1% formic acid as modifier). 0.5 mL of 6 M HCl was added into each fraction and the product was evaporated. trans-Methyl 4-(((trans-2-phenylcyclopropyl)amino)methyl)cyclohexanecarboxylate (95 mg, 0.250 mmol, 41.7% yield) was isolated as white solid. 1H NMR (400 MHz, METHANOL-d4) δ 7.29-7.38 (m, 2H), 7.22-7.29 (m, 1H), 7.11-7.22 (m, 2H), 3.68 (s, 3H), 3.09 (d, J=7.07 Hz, 2H), 2.99 (dt, J=4.11, 7.45 Hz, 1H), 2.49 (ddd, J=3.79, 6.57, 10.36 Hz, 1H), 2.35 (tt, J=3.63, 12.28 Hz, 1H), 2.07 (dd, J=3.54, 13.39 Hz, 2H), 1.93 (dd, J=3.28, 13.14 Hz, 2H), 1.66-1.83 (m, J=3.57, 3.57, 7.70, 7.70, 15.36 Hz, 1H), 1.50-1.58 (m, 1H), 1.36-1.50 (m, 3H), 1.15 (qd, J=3.54, 12.72 Hz, 2H); LC-MS Rt=0.83 min; MS (ESI): 288.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]4([C:28]([O:30][CH3:31])=[O:29])[CH2:27][CH2:26][CH2:25]4)[CH2:14][C:13](=O)[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:43]>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]4([C:28]([O:30][CH3:31])=[O:29])[CH2:27][CH2:26][CH2:25]4)[CH2:14][C:13](=[S:43])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)C1(Oc2ccc(Cl)cc2C2CC(=O)NC(c3cc(F)ccc3C)C23C(=O)Nc2cc(Cl)ccc23)CCC1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C1(Oc2ccc(Cl)cc2C2CC(=S)NC(c3cc(F)ccc3C)C23C(=O)Nc2cc(Cl)ccc23)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
A mixture of racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-cyclobutoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (30 mg, 0.05 mmol) and P2S5 (44 mg, 0.2 mmol) in THF (1 mL) was stirred at room temperature overnight, and then diluted with toluene (10 mL). The mixture was concentrated in vacuo and the residue was washed with DCM twice. The DCM solution was collected and purified by flash chromatography to give the title compound as white solid (12 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7]2)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[CH2:22]([O:29][C:30](Cl)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:30]([O:29][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:31])[CH2:7]2)([O-:3])=[O:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc2c(c1)CNC2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1Cc2ccc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-nitroisoindoline (1.16 g, 7.79 mmol) in CH2Cl2 (100 mL), was added diisopropylethylamine (2.7 mL, 15.6 mmol) followed by benzylchloroformate (1.2 mL, 8.56 mmol). The mixture was stirred at room temperature under N2 for 1 h. The reaction mixture was diluted with CH2Cl2 and washed with 1N HCl. The organic layer was dried (Na2SO4), filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica gel to provide benzyl 5-nitro-1,3-dihydro-2H-isoindole-2-carboxylate. LCMS calc.=321.1; found=320.8 (M+Na)+. 1H NMR (500 MHz, CDCl3): δ 8.22-8.14 (m, 2H); 7.49-7.37 (m, 6H); 5.27 (s, 2H); 4.89 (s, 2H); 4.87 (s, 2H).
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[NH:25][C:26](=[O:30])[N:27]([CH3:29])[CH3:28].[OH-].[Na+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[NH:25][C:26](=[O:30])[N:27]([CH3:28])[CH3:29])[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: CN(C)C(=O)Nc1ccc(Cl)cc1CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)C(=O)Nc1ccc(Cl)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Yield: 10.3 %

Procedure:
(Step 5) 2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.5 g) and 3-[2-(aminomethyl)-4-chlorophenyl]-1,1-dimethylurea hydrochloride obtained in Step 4 (1.12 g) were stirred in ethanol (5 ml) overnight at 90° C. The reaction mixture was poured into 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in ethanol, 4N hydrogen chloride-ethyl acetate solution (1 ml) was added, and the mixture was crystallized from ethanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized to give the title compound (46 mg).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH:15]=[C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31][CH3:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][CH3:24])[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:36]CCl>C(O)C>[ClH:36].[CH2:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][CH3:32])=[CH:15][O:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1)[CH3:24]
Reactant: ClCCl
Reactant: CCOC(=O)[C@@H]1CCCN(CCOC=C(c2ccccc2CC)c2ccccc2CC)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1ccccc1C(=COCCN1CCC[C@@H](C(=O)O)C1)c1ccccc1CC
Temperature: 25 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
(R)-1-[2-[[2,2-bis(2-Ethylphenyl)ethenyl]oxy]ethyl]-3-piperidine carboxylic acid ethyl ester (1.20 g, 0.00275 mol) (prepared as described in Method D) was dissolved in ethanol (10 ml) and 12 N sodium hydroxide solution (0.7 ml) was introduced. After stirring the solution at room temperature for 5 h, 37% hydrochloric acid solution was added until the pH was measured as ca. 1. Dichloromethane (250 ml) was introduced, and the mixture was dried (Na2SO4), filtered and evaporated to a residue, which was co-evaporated with acetone. Recrystallization from acetone provided the title compound (0.85 g, 70%) as a white solid, m.p. 205°-206°.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([N+:20]([O-])=O)[CH:11]=2)[CH2:6][CH2:5]1>CO.[Pd]>[F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[C:12]([CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=2)[NH2:20])[CH2:6][CH2:5]1
Reactant: O=[N+]([O-])c1cc(N2CCN(CCF)CC2)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(N2CCN(CCF)CC2)cc(C(F)(F)F)c1
Yield: 0.1 %

Procedure:
Stir the mixture of 1-(2-fluoroethyl)-4-(3-nitro-5-(trifluoromethyl)phenyl)piperazine (120 mg, 0.50 mol) and Pd/C (10%, 30 mg) in methanol (5 mL) under hydrogen atmosphere for 2 hrs at room temperature. Filter and concentrate the filtrate under reduced pressure to afford the white solid as the target compound (90 mg, 84%).
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])([CH3:32])[C:29](O)=[O:30]>>[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:29](=[O:30])[C:28]([CH3:33])([CH3:32])[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)(C)C(=O)O
Agent: Cl
Product: CC(C)(C)C(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (89 mg, 87%), MS (ISP) m/z=413.5 [(M+H)+], mp 192° 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 dihydro chloride (intermediate B) (100 mg, 0.25 mmol) and 2,2-dimethyl-propionic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:14][C:5]2[NH:6][C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:8][C:4]=2[CH2:3]1.[H-].[Na+].Br[CH2:19][C:20]#[N:21].O>CN(C=O)C.C(OCC)(=O)C>[C:20]([CH2:19][N:6]1[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:8][C:4]2[CH2:3][C:2]([CH3:1])([CH3:15])[CH2:14][C:5]1=2)#[N:21]
Reactant: CCOC(=O)c1cc2c([nH]1)CC(C)(C)C2
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2c(n1CC#N)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.7 %

Procedure:
A 250-mL single neck round bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with 107b (6.2 g, 30 mmol) in DMF (57 mL). To the solution was added NaH (80% dispersion in mineral oil, 1.26 g, 42.1 mmol). The resulting mixture was stirred at rt for 90 min. After that time, bromoacetonitrile (2.94 mL, 42 mmol) was added. The mixture was stirred for 14 h. After that time, water (100 mL) and ethyl acetate (200 mL) were added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography to afford a 95% yield (7 g) of 107c.
Reaction SMILES: [CH2:1]([C:6]1[C:7]([F:13])=[C:8]([F:12])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[I:14]I.O>C(OCC)C>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([I:14])=[C:8]([F:12])[C:7]=1[F:13])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: II
Reactant: CCCCCc1cccc(F)c1F
Solvent: O
Solvent: CCOCC
Product: CCCCCc1ccc(I)c(F)c1F
Temperature: -70 °C

Procedure:
3-Pentyl-1,2-difluorobenzene is metalated according to 1a) or 1b). A solution of 0.1 mol of iodine in 100 ml of diethyl ether is added slowly at -70° C. The mixture is subsequently stirred for a further hour at -70° C. and warmed to 0° C., and water is added to the solution. After washing with sodium hydrogen sulfite solution and dilute sodium hydroxide solution the mixture is worked up as customary.
Reaction SMILES: [NH2:1][NH2:2].C1(C)C=CC(S([O:12][CH2:13][C@H:14]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:15](OC)=O)(=O)=O)=CC=1>C(Cl)Cl>[C:23]([O:22][C:20]([NH:19][CH:14]1[CH2:15][NH:2][NH:1][C:13]1=[O:12])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: COC(=O)[C@H](COS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Reactant: NN
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CNNC1=O
Temperature: 25 °C
Yield: 47.7 %

Procedure:
Under a nitrogen atmosphere, dry methylene chloride (50 ml) was cooled in an ice bath and anhydrous hydrazine (97%, 11.0 g, 333 mmole) was added. The ice bath was removed and the solution was stirred until it warmed to room temperature. At this time a solution of methyl 3-(p-toluenesulfonyloxy)-2-(S)-(t-butoxycarbonylamino)propionate (20.0 g, 53.6 mmole) in dry methylene chloride (50 ml) was gradually added. The reaction solution was stirred under nitrogen at room temperature for 5 hours. The solution was then concentrated under reduced pressure and the concentrate was taken up in saturated aqueous sodium bicarbonate solution. The aqueous solution was continuously extracted for 14 hours with methylene chloride (700 ml). The methylene chloride solution was dried over sodium sulfate, filtered and concentrated under reduced pressure to yield approximately 5.15 g, 48% of 4-(R,S)-(t-butoxycarbonylamino)-3-oxo-1,2-diazolidine: n.m.r. (CDCl3, 90 MHz): δ7.04 (m, 1), 5.12 (m, 1), 4,28 (m, 1, C-4 proton), 3.94 (m, 1, C-5 proton), 3.20 (m, 1, C-5 proton), 1.45 (s, 9, t-butyl protons); i.r. (CHCl3): 3430, 3250, 3019, 2983, 1702, 1545, 1503, 1370, 1297, 1241, 1215, 1165 cm-1 ; f.d.m.s.: M+ =201;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9](Cl)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[NH2:13][C@@H:14]1[CH2:29][N:17]2[CH2:18][CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][C@@H:16]2[CH2:15]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([NH:13][C@@H:14]2[CH2:29][N:17]3[CH2:18][CH2:19][N:20]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:21][C@@H:16]3[CH2:15]2)(=[O:11])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@@H](N)C[C@H]2C1
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN2C[C@@H](NS(=O)(=O)Cc3ccc(Cl)cc3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4-chlorophenyl)methanesulfonyl chloride (1.125 g, 5 mmol) in dichloromethane (10 mL) was added (7S,8aS)-tert-butyl 7-aminohexahydro-pyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (1.400 g, 5.80 mmol) followed by triethylamine (0.758 g, 7.5 mmol). The mixture was stirred at room temperature overnight, and then concentrated. The residue was purified by chromatography on silica gel (ethyl acetate) to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.25 (m, 1H), 1.39 (s, 9 H), 1.80 (m, 1 H), 1.95 (m, 1 H), 2.07-2.23 (m, 2 H), 2.89 (m, 3 H), 2.75-3.98 (m, 3 H), 4.32 (s, 2H), 7.43 (m, 5H). MS (ESI) m/z 431 (M+H)+.
Reaction SMILES: Br[CH2:2][CH3:3].[CH3:4][C:5]1([CH3:18])[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][NH:7][CH2:6]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH2:2]([N:7]1[CH2:6][C:5]([CH3:18])([CH3:4])[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8]1)[CH3:3]
Reactant: CC1(C)CNCc2cc([N+](=O)[O-])ccc21
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1Cc2cc([N+](=O)[O-])ccc2C(C)(C)C1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Bromoethane (0.75 g, 6.88 mmol) was added to a solution of 4,4-dimethyl-7-nitro-1,2,3,4-tetrahydroisoquinoline (1.4 g, 6.79 mmol) and K2CO3 (2 g, 14.47 mmol) in N,N-dimethylformamide (80 mL). The mixture was stirred at 50° C. for 4 hours. The solvent was removed under vacuum to give a residue which was purified by silica gel column chromatography eluting with 10% ethyl acetate/heptane to provide the title compound.