Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:16])[NH2:15])=[N:6]1.[F:21][CH:22]([C:28](=O)[CH3:29])[C:23](OCC)=[O:24]>>[F:21][C:22]1[C:23]([OH:24])=[N:16][C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=3[F:1])[N:6]=2)=[N:15][C:28]=1[CH3:29]
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12
Reactant: CCOC(=O)C(F)C(C)=O
Product: Cc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(O)c1F

Procedure:
The compound is prepared in analogy to example I, step 6. Starting from 650 mg (2.41 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide (example I, step 5) and ethyl 2-fluoro-3-oxobutanoate, 520 mg (60% of theory) of the product are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].O.[OH-].[Na+]>CO.CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:17][CH:18]=2)=[CH:4][C:3]=1[C:21]([F:22])([F:23])[F:24]
Reactant: CCOC(=O)c1ccc(COc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(COc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 55 °C
Yield: 85.2 %

Procedure:
To a solution of ethyl 4-{[4-chloro-3-(trifluoromethyl)phenoxy]methyl}benzoate (Preparation 17, 350 mg, 0.98 mmol) in methanol (8.0 mL) was added water (2 mL) followed by sodium hydroxide (400 mg, 9.8 mmol). The reaction mixture was heated to 55° C. for 3 hours, then cooled and diluted with EtOAc (50 mL) and 2M HCl (50 mL). The aqueous layer was separated and washed with EtOAc (2×50 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to yield a white solid as the title compound (276 mg, 86%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[CH:13]=[C:14]([CH2:16][NH2:17])[O:15][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[N:29]=[C:28]([CH2:30][O:31][CH3:32])[CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O.CN(C)C=O>[NH2:20][C:21]1[N:29]=[C:28]([CH2:30][O:31][CH3:32])[CH:27]=[CH:26][C:22]=1[C:23]([NH:17][CH2:16][C:14]1[O:15][C:11]2[CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:19]=[CH:18][C:12]=2[CH:13]=1)=[O:24]
Reactant: COCc1ccc(C(=O)O)c(N)n1
Reactant: NCc1cc2ccc(OCc3ccccc3)cc2o1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCc1ccc(C(=O)NCc2cc3ccc(OCc4ccccc4)cc3o2)c(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
To a N,N-dimethylformamide (8 mL) solution of C-(6-benzyloxy-benzofuran-2-yl)-methylamine (400 mg, 1.58 mmol) described in Production Example 1-2-4 were added 2-amino-6-methoxymethyl-nicotinic acid (316 mg, 1.74 mmol) described in Production Example 4-1-5, triethylamine (660 μL, 4.74 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (908 mg, 2.05 mmol) at room temperature, which was stirred at room temperature for 2 hours 30 minutes. To the reaction solution was added water at room temperature followed by extraction with ethyl acetate. After washing the organic layer with water and sat. NaCl, the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under a reduced pressure and purified by silica gel column chromatography (heptane:ethyl acetate=1:2) to obtain the title compound (454 mg, 69%) as a white solid.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[C:5]2[C:10]([N:11]=[C:12]3[C:17]=1[C:16](=[O:18])[CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26]Br)=[CH:21][CH:20]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[CH2:26]([NH:3][C:4]1[C:5]2[C:10]([N:11]=[C:12]3[C:17]=1[C:16](=[O:18])[CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:25][C:22]1[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1
Reactant: BrCCc1ccccc1
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCCc2nc3ccccc3c(NCCc3ccccc3)c21
Yield: 17 %

Procedure:
In a mixture consisting of 300 ml of dichloromethane and 200 ml of 50% NaOH were combined 10.00 g of 9-amino-3,4-dihydroacridin-1(2H)-one, 28 ml (6 eq) of 2-phenethyl bromide, and 3 g (0.2 eq) of tetrabutylammonium hydrogensulfate catalyst. The mixture was mechanically stirred for 4 days, during which 28 ml of 2-phenethyl bromide was added at intervals of 12 hours. After 4 days the layers were separated and the dichloromethane layer was evaporated to an oil, which was extracted into 3N HCl and washed with EtOAc. The HCl solution was then made basic with 10% NaOH. The resulting precipitate was extracted into dichloromethane and the dichloromethane layer was evaporated to an oil containing mostly the starting material and the end product. The purification method was chromatography on silica gel with 20% EtOAc/dichloromethane solvent. The product thus obtained was recrystallized from dichloromethane/hexanes to yield 2.52 g (17%) of a solid, melting point 129°-132° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14]CC)=O.[H-].[Na+].O>C(N)CC>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([NH:5][CH2:4][CH2:3][CH3:2])=[O:14]
Reactant: CCOC(=O)c1cnc2ccccc2c1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCN
Product: CCCNC(=O)c1cnc2ccccc2c1O
Temperature: 50 °C
Reaction time: 16 h
Yield: 95.6 %

Procedure:
A suspension of 2.17 g of ethyl 4-hydroxy-3-quinoline-carboxylate in 20 ml of propylamine in the presence of traces of sodium hydride was refluxed and then was stirred at 50° C. for 16 hours. The mixture was pouredinto water and the suspension was vacuum filtered. The product was washed with water, dried in an oven at 100° C. and was crystallized from methanol to obtain 1.1 g of 4-hydroxy-N-propyl-3-quinoline-carboxamide melting at 210° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl.[C-:13]#[N:14].[Na+].CS(C)=O>O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH2:6][C:13]#[N:14])[CH:8]=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1cccc(C(F)(F)F)c1
Yield: 107.1 %

Procedure:
A mixture of 12.0 g (61.5 mmole) m-trifluoromethylbenzyl chloride, 9.56 g (195 mmole) sodium cyanide and 60 ml dimethylsulfoxide was heated at 50° to 80° C. for four hours and poured into water. The aqueous mixture was extracted with methylene chloride, the extracts dried over sodium sulfate and the solvent evaporated in vacuo to give 12.2 g of yellow oil which was used in the next step.
Reaction SMILES: CN1CCCC1=O.[NH2:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([Cl:16])=[C:11](F)[N:10]=1.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1.C1C=CC=CC=1>CCCCCC>[NH2:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([Cl:16])=[C:11]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[N:10]=1
Reactant: Nc1nc(F)c(Cl)cc1F
Reactant: COc1ccc(CN)cc1
Solvent: CCCCCC
Solvent: CN1CCCC1=O
Solvent: c1ccccc1
Product: COc1ccc(CNc2nc(N)c(F)cc2Cl)cc1
Temperature: 150 °C
Reaction time: 24 h
Yield: 109.9 %

Procedure:
To 2 ml of N-methylpyrrolidone was added 510 mg of 2-amino-5-chloro-3,6-difluoropyridine and 910 mg of p-methoxybenzylamine, and the mixture was stirred at 150° C. for one day, and allowed to cool. After adding a mixed solution of 60 ml benzene and n-hexane (1:1, v/v), the solution was washed twice with 400 ml of distilled water. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 960 mg of the title compound as a brown crude oil.
Reaction SMILES: [C:1](OC1C=CC([N+]([O-])=O)=CC=1)(=[O:3])[CH3:2].[CH3:14][C:15]1([CH3:23])[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][C:16]1=[O:22].C(N(CC)CC)C.CC(C)(O)C#N.C([O-])(=O)C>C(#N)C>[C:1]([CH:17]1[C:16](=[O:22])[C:15]([CH3:23])([CH3:14])[CH2:20][CH2:19][C:18]1=[O:21])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC1(C)CCC(=O)CC1=O
Agent: CC(=O)[O-]
Agent: CC(C)(O)C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)C1C(=O)CCC(C)(C)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 50-mL single neck round bottom flask was charged with 4-nitrophenyl acetate (2.03 g, 11.2 mmol), 4,4-dimethyl-1,3-cyclohexanedione (2.10 g, 15 mmol) and acetonitrile (15 mL). Then triethylamine (2.5 g, 25 mmol) and acetone cyanohydrin (0.14 mL, 1.5 mmol) were added and the mixture was stirred for 2 hours at ambient temperature. NMR analysis of an aliquot showed that 43% of the starting acetate was still unreacted. The mixture was then refluxed for 2 hours after which time NMR analysis of an aliquot showed no starting acetate remaining.
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][C:8]1[N:9]=[C:10]([C:13]([O:15]CC)=[O:14])[S:11][CH:12]=1)(=O)C>CO>[OH:6][CH2:7][C:8]1[N:9]=[C:10]([C:13]([OH:15])=[O:14])[S:11][CH:12]=1
Reactant: CCOC(=O)c1nc(COC(C)=O)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1nc(CO)cs1
Reaction time: 1 h

Procedure:
2M NaOH (4.58 mL, 9.16 mmol) was added to a solution of ethyl 4-(acetoxymethyl)thiazole-2-carboxylate (0.7 g, 3.05 mmol) in MeOH (3 mL) and stirred for 1 h. Acidified with 2M HCl, purified by reverse phase HPLC with aqTFA/MeOH as eluent and freeze dried to afford the sub-title compound as a white solid. Yield: 0.510 g
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([NH:8][S:9]([C:12]1[CH:23]=[CH:22][C:15]2[N:16]=[C:17]([S:19][CH2:20][CH3:21])[S:18][C:14]=2[CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].C([O-])([O-])=O.[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(OC(=O)C)C>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([N:8]([S:9]([C:12]1[CH:23]=[CH:22][C:15]2[N:16]=[C:17]([S:19][CH2:20][CH3:21])[S:18][C:14]=2[CH:13]=1)(=[O:11])=[O:10])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:5]([CH3:7])[CH3:6]
Reactant: BrCc1ccccc1
Reactant: CCSc1nc2ccc(S(=O)(=O)N[C@@H](C(=O)OC)C(C)C)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1nc2ccc(S(=O)(=O)N(Cc3ccccc3)[C@@H](C(=O)OC)C(C)C)cc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2R)-3-methyl-2-[(2-ethylthiobenzthiazol-6-sulfonyl)amino]butanoic acid methylester (0.16 g, 0.376 mmol) prepared in a similar manner as in Example 14 was dissolved in DMF (1 mL). K2CO3 (150 mg, 3 equi.) and benzylbromide (0.056 mL, 1.3 equi.) were added at RT. After stirring the reaction solution for 1 hour at RT, ethylacetate (5 mL) and H2O were added to afford the phase separation, when starting material was exhausted. The separated organic phase was washed with H2O for several times, dried over MgSO4 and distilled under reduced pressure to prepare the titled compound, (2R)-3-methyl-2-[(ethylthio-6-benzthiazolsulfonyl)benzylamino]butanoic acid methylester (180 mg, 100%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S-:11].[K+].[CH:13](OC)=O>>[CH3:13][S:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: [S-]c1ccc2ccccc2c1
Reactant: COC=O
Agent: [K+]
Product: CSc1ccc2ccccc2c1
Temperature: 25 °C
Yield: 89.2 %

Procedure:
A mixture of 30 g of potassium naphthalene-2-thiolate and 120 g of methyl formate was introduced into a 0.3 liter stirred autoclave at room temperature and heated at 150° C. for 15 hours, during which the pressure (partial pressure of CO+partial pressure of the reaction mixture) reached 210 bar. The mixture was worked up by a procedure similar to that described in Example 1 to give 23.5 g (89% of theory) of naphth-2-yl methyl thioether. ##STR3##
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:17]=[N:18]O.C([O-])=O.[NH4+]>CO.[Zn]>[F:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:17][NH2:18]
Reactant: ON=Cc1ccc2c(ncn2C2CCCCO2)c1F
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: NCc1ccc2c(ncn2C2CCCCO2)c1F
Temperature: 75 °C
Yield: 47.4 %

Procedure:
To a solution of 150 (5.8 g, 0.022 mol) in MeOH (100 mL) was added zinc dust (2.9 g, 0.044 mol) and ammonium formate (2.8 g, 0.044 mol). The resulting mixture was heated to 75° C. for 2 h. The mixture was filtered through a Celite® pad. The filtrate was concentrated and the crude product was purified by SiO2 chromatography eluting with 5% MeOH/DCM to afford 2.6 g (47%) of (4-fluoro-1-tetrahydropyran-2-yl-benzimidazol-5-yl)methanamine (152) as a yellow solid: 1H-NMR (400 MHz, RT, CDCl3): δ 1.66-1.80 (m, 3H), 1.92-1.96 (m, 1H), 2.06-2.14 (m, 2H), 3.68-3.74 (m, 1H), 4.23-4.26 (m, 1H), 4.40 (br, 2H), 5.49-5.52 (dd, 1H), 6.94-6.99 (dd, 1H), 7.18-7.23 (t, 1H), and 7.37-7.39 (d, 1H); MS (ESI) m/z=250.2 [M+1]+.
Reaction SMILES: [O:1]=[C:2]([CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3]P(OC)(=O)OC.[NH:17]1[CH:21]=[CH:20][N:19]=[C:18]1[CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.C1CCN2C(=NCCC2)CC1>C(COC)OC>[CH2:12]([O:11][CH2:10][C:2](=[O:1])/[CH:3]=[CH:27]/[C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C:18]2[NH:19][CH:20]=[CH:21][N:17]=2)=[CH:30][CH:29]=1)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCOCC(=O)CP(=O)(OC)OC
Reactant: O=Cc1ccc(Cc2ncc[nH]2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CCCCCOCC(=O)/C=C/c1ccc(Cc2ncc[nH]2)cc1

Procedure:
2 g (7.93 mmol) of dimethyl 2-oxo-3-pentyloxypropanephosphonate, 1.7 g (9.13 mmol) of 4-(1-imidazolylmethyl)benzaldehyde and 1.33 g (8.74 mmol) of DBU were stirred in 150 ml of dimethoxyethane at room temperature for 31 h. The mixture was filtered through silica gel and the solvent was removed from the filtrate in vacuo. Chromatography on silica gel (chloroform/methanol/25% aqueous NH3 =20/1/0.2) produced 1.5 g (4.80 mmol, 60%) as a yellowish oil which solidified in the refrigerator, melting point 35°-36° C.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]([CH3:15])=[CH2:14])[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].[Pt].CCO>[C:1]1([C:7]2[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(C)c1ccnc(-c2ccccc2)c1
Agent: [Pd]
Agent: [Pt]
Solvent: CCO
Product: CC(C)c1ccnc(-c2ccccc2)c1
Reaction time: 2 h
Yield: 73.4 %

Procedure:
2-Phenyl-4-(prop-1-en-2-yl)pyridine (13.5 g, 69.1 mmol) was added to a hydrogenator bottle containing EtOH (150 mL). The reaction mixture was degassed by bubbling with nitrogen for 10 min. Pd/C (0.736 g, 6.9 mmol) and Pt/C (0.674 g, 3.5 mmol) was added to the reaction mixture. The reaction mixture was placed on the Parr hydrogenator for 2 h. The reaction mixture was filtered on a tightly packed Celite® bed and washed with dichloromethane. The solvent was removed on a rotary evaporator and GC/MS confirmed complete conversion. The crude product was adsorbed on Celite® for column chromatography. The crude product was chromatographed on silica gel with 10% EtOAc in hexane to yield 10 g (75%) of 2-phenyl-4-isopropylpyridine (HPLC purity: 99.8%). The product was confirmed by GC/MS.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]#[N:12])=[CH:2]1.N#N>CCO>[CH2:13]([CH:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH2:11][NH2:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#CC(=Cc1ccccc1)c1c[nH]c2ccccc12
Agent: N#N
Solvent: CCO
Product: NCC(Cc1ccccc1)c1c[nH]c2ccccc12

Procedure:
β-Benzyltryptamine was prepared by the addition of 2-1H-indol-3-yl-3-phenylacrylonitrile (500 mg, 2.04 mmol) and EtOH (25 mL) to a N2 purged 100 mL flask. To the solution was added approximately 2 g of Raney-Ni slurry. To the reaction solution, dropwise with stirring, was added hydrazine monohydrate (2.5 mL). The reaction solution was allowed to stir at 65° C. for 4 hours. The slurry was filtered through a pad of Celite to remove excess Raney-Ni. The filtrate was concentrated under reduced pressure, and the crude product was used without further purification; MS (ESI): 251 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1([CH2:14][CH2:15][CH3:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH2:9]1.Cl.[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[C:23]2[CH2:30][CH2:31][CH2:32][C@@H:33]1[CH2:38][CH2:37][NH:36][CH2:35][C@@H:34]1[C:39]([OH:41])=[O:40].O>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[C:23]2[CH2:30][CH2:31][CH2:32][C@@H:33]1[CH2:38][CH2:37][N:36]([CH2:16][CH2:15][CH2:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:35][C@@H:34]1[C:39]([O:41][CH2:16][CH2:15][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:40]
Reactant: CCCC1(Br)C=CC=CC1
Reactant: COc1ccc2nccc(CCC[C@@H]3CCNC[C@@H]3C(=O)O)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2nccc(CCC[C@@H]3CCN(CCCc4ccccc4)C[C@@H]3C(=O)OCCCc3ccccc3)c2c1
Reaction time: 17 h

Procedure:
1.75 g of potassium carbonate and then 1.15 cm3 of 1-bromophenylpropane were added with stirring, at a temperature in the region of 25° C., to a solution of 0.91 g of (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylic acid hydrochloride in 20 cm3 of anhydrous dimethylformamide. The suspension was brought to a temperature in the region of 60° C. for 17 hours. After cooling, the mixture was poured onto 200 cm3 of water and extracted with 3 times 30 cm3 of ether. The combined ethereal extracts were washed with 2 times 20 cm3 of water. The ethereal solution was extracted with 20 cm3 of normal aqueous hydrochloric acid and twice with 20 cm3 of water. The combined aqueous extracts were rendered alkaline by addition of solid sodium hydrogencarbonate. After extracting with 3 times 20 cm3 of ether and washing the ethereal extracts with 3 times 20 cm3 of water, drying was carried out over magnesium sulfate in the presence of 0.1 g of animal charcoal. After filtering through paper and then concentrating under reduced pressure (5 kPa) at a temperature in the region of 30° C, 0.84 g of 3-phenylpropyl (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-(3-phenylpropyl)piperidine-3-carboxylate was obtained in the form of an oil with a light brown color.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:13][C:14](=[O:55])[CH2:15][NH:16][C:17]([C:19]1[C:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:23]([CH3:33])[N:22]=[C:21]([CH2:34][CH:35]2[CH2:40][CH2:39][N:38]([C:41]3[CH:46]=[CH:45][C:44]([C:47]4[CH:52]=[CH:51][C:50]([CH2:53][OH:54])=[CH:49][CH:48]=4)=[CH:43][CH:42]=3)[CH2:37][CH2:36]2)[N:20]=1)=[O:18])[CH3:12].C(N(CC)CC)C>ClCCl.O>[CH2:11]([O:13][C:14](=[O:55])[CH2:15][NH:16][C:17]([C:19]1[C:24]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[C:23]([CH3:33])[N:22]=[C:21]([CH2:34][CH:35]2[CH2:40][CH2:39][N:38]([C:41]3[CH:42]=[CH:43][C:44]([C:47]4[CH:48]=[CH:49][C:50]([CH:53]=[O:54])=[CH:51][CH:52]=4)=[CH:45][CH:46]=3)[CH2:37][CH2:36]2)[N:20]=1)=[O:18])[CH3:12]
Reactant: CCOC(=O)CNC(=O)c1nc(CC2CCN(c3ccc(-c4ccc(CO)cc4)cc3)CC2)nc(C)c1OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)c1nc(CC2CCN(c3ccc(-c4ccc(C=O)cc4)cc3)CC2)nc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.5 %

Procedure:
Oxalyl chloride (0.31 g, 2.5 mmol) was dissolved in dichloromethane (5 mL), and a solution of dimethyl sulfoxide (0.18 g, 2.3 mmol) in dichloromethane (4 mL) was added dropwise at −78° C., followed by stirring at the same temperature for 15 minutes. To the reaction solution was added dropwise a solution of ethyl({[5-(benzyloxy)-2-{(1-[4′-(hydroxymethyl)biphenyl-4-yl]piperidin-4-yl}methyl)-6-methylpyrimidin-4-yl]carbonyl}amino)acetate (1.0 g, 1.6 mmol) obtained in Example 1-(11) in dichloromethane (26 mL), followed by stirring at the same temperature for 25 minutes, and subsequently triethylamine (1.1 mL, 8.2 mmol) was added dropwise, and the temperature was raised to room temperature over 1.5 hours. Water was added to the reaction solution, followed by extraction with dichloromethane, and subsequently the extract was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Biotage Ltd., elution solvent: dichloromethane/ethyl acetate) to afford the title compound (0.85 g, 1.4 mmol) as a yellow solid (yield 85%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](Br)([CH3:15])[CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1>C1C=C(Cl)C(Cl)=CC=1.Cl[Cu]>[Cl:1][C:2]1[C:3]([C:9](=[CH2:15])[CH2:10][C:11]([Cl:12])([Cl:14])[Cl:13])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: CC(Br)(CC(Cl)(Cl)Cl)c1nc(Cl)ccc1Cl
Agent: Cl[Cu]
Solvent: Clc1ccccc1Cl
Product: C=C(CC(Cl)(Cl)Cl)c1nc(Cl)ccc1Cl
Yield: 37.8 %

Procedure:
A slurry of 15 g (0.039 mole) of 3,6-dichloro-2-(1-bromo-3,3,3-trichloro-1-methylpropyl)pyridine and 5 g of finely divided CuCl in O-dichlorobenzene was washed at reflux for two hours. The mixture was cooled, filtered and the filtrate concentrated in vacuo. Recrystallization from pentane yielded 4.5 g (38%) of product, m.p. 71°-74° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].[Br:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25](Br)[N:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2>CN1CCCC1=O.O>[Br:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([NH:1][C@H:2]3[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]3)[N:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: Brc1cc2cccnc2c(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(Br)cc3cccnc23)C1
Temperature: 135 °C
Reaction time: 0.08 h
Yield: 95.3 %

Procedure:
To (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (0.776 g, 4.17 mmol) in N-methyl-2-pyrrolidinone (12 mL) at 0° C. was added NaH (0.139 g, 3.47 mmol). The mixture was stirred for 5 minutes. Next, 6,8-dibromo-1,7-naphthyridine (1 g, 3.47 mmol) was added and the reaction mixture was stirred at RT for 5 minutes and then heated at 135° C. for 30 minutes in a microwave reactor. The reaction mixture was diluted with water and extracted with EtOAc (2×). The organic layers were combined, dried over Na2SO4, and concentrated. The crude product was purified using silica column chromatography eluting with a gradient of 0-75% EtOAc in hexane over a 45 minute period to give the title compound as a yellow solid (1.3 g, 95%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[F:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(OC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 835.7 %

Procedure:
2 g (7 mmol) of 4-(4-fluoro-phenoxy)-piperidine 1-carboxylic acid tert-butyl ester was solvated in dichloromethane (12 mL) and trifluoroacetic acid was added at 0° C. (6.17 mL, 54 mmol). The mixture was stirred at room temperature overnight. NaHCO3 was slowly added until pH 9 and the mixture extracted 3 times with dichloromethane and ethyl acetate. The solvent was evaporated to yield 1.81 g (58.5 mmol, 85%) of a white solid that was used without purification on the next steps. MS (m/e): 196.3 (M+H+).