Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([Br:9])=[C:7]([C:10](=[O:12])N)[S:6](=[O:13])[N:5]=1)[CH3:2].N([O-])=[O:15].[Na+]>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]1[C:8]([Br:9])=[C:7]([C:10]([OH:15])=[O:12])[S:6](=[O:13])[N:5]=1)[CH3:2]
Reactant: O=N[O-]
Reactant: CCOC1=NS(=O)C(C(N)=O)=C1Br
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCOC1=NS(=O)C(C(=O)O)=C1Br
Reaction time: 0.03 h
Yield: 64.9 %

Procedure:
3-Ethoxy-4-bromo-5-carbamoylisothiazole-1-oxide (267 mg, 1.0 mmol) was dissolved in 2 ml of trifluoroacetic acid and sodium nitrite (138 mg, 2.0 mmol) was added in small portions over a two minute period with stirring. Stirring was continued for two minutes at room temperature and then the solvent was removed in vacuo. The residual gum was stirred in 5 ml of ice water for five minutes. Filtration gave 174 mg (65% yield) of yellow solid; mp 158°-160° C., dec.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1>>[CH3:18][C:16]1[NH:15][N:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:17]=1
Reactant: OB(O)c1cccnc1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(-c3cccnc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-pyridine-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-(1-pyridin-3-yl-isoquinolin-3-yl)-amine. LC-MS m/e 302(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[OH-:13].[Na+].Cl>C(Cl)(Cl)Cl.CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:4]([CH3:9])([CH3:3])[C:5]([OH:8])=[O:13])=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: [OH-]
Reactant: Oc1ccc(Cl)cc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)(Oc1ccc(Cl)cc1C(F)(F)F)C(=O)O
Reaction time: 0.67 h
Yield: 37 %

Procedure:
A three-neck round bottom flask affixed with an overhead stirrer was charged with 4-chloro-2-(trifluoromethyl)phenol (prepared according methods described in U.S. Pat. No. 4,262,152), (5.0 g, 127 mmol, 1.0 eq) and dissolved in chloroform (3.3 mL) and acetone (8.4 mL). NaOH pellets (4.2 g, 104 mmol, 3.75 eq) were added in 2 portions and the mixture was stirred vigorously for 40 min. The resulting slurry was acidified to pH 2 with 3N HCl and extracted with EtOAc. The organic extracts were treated with satd. aq. sodium bicarbonate, and the basic layer was acidified to pH 4 with conc. HCl and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford 2.7 g (37%) of 2-(4-chloro-2-(trifluoromethyl)phenoxy)-2-methylpropanoic acid as a light brown crystalline solid. 1H NMR (400 MHz, CDCl3): δ 7.57 (d, J=2.6 Hz, 1H), 7.40 (dd, J=8.9, 2.6 Hz, 1H), 6.91 (d, J=8.9 Hz, 1H), 1.67 (s, 6H). LCMS (0-99% MeCN/water, 5 min, negative ion), Tret=2.99 min, [M−H]−=281.3 observed.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][CH:4]([C:6]([O:8][CH3:9])=[O:7])[CH2:3]1.[H-].[Na+].F[C:13]1[C:18]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:17][C:16]([F:25])=[CH:15][N:14]=1>CN(C=O)C>[CH3:9][O:8][C:6]([CH:4]1[CH2:5][CH:2]([O:1][C:13]2[C:18]([CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[CH:17][C:16]([F:25])=[CH:15][N:14]=2)[CH2:3]1)=[O:7]
Reactant: COC(=O)C1CC(O)C1
Reactant: Fc1cnc(F)c(C2CCOCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1CC(Oc2ncc(F)cc2C2CCOCC2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 114.9 %

Procedure:
To a solution of methyl 3-hydroxycyclobutanecarboxylate (1.2 g, 9.0 mmol) in DMF (20 mL) was added sodium hydride (60% wt in mineral oil) (1.8 g, 45 mmol) at RT. The mixture was stirred for 1 h and then 2,5-difluoro-3-(tetrahydro-pyran-4-yl)-pyridine (1.8 g, 9.0 mmol) was added. The reaction mixture was heated to 60° C. for 3 h and then quenched with saturated NH4Cl. The solution was diluted with EtOAc and water and extracted with EtOAc (2×10 mL). The organic extracts were combined, washed with brine (10 mL), dried over MgSO4, filtered, and concentrated to get a residue, which was purified by flash column chromatography on silica gel (5% to 30% EtOAc in hexanes) to give the product (3.2 g) as yellow oil.
Reaction SMILES: Br[C:2]1[N:3]=[N:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].CCN(C(C)C)C(C)C.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1>CCO>[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH:38][C:2]2[N:3]=[N:4][C:5]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[CH:6][C:7]=2[C:8]([F:11])([F:10])[F:9])=[CH:35][CH:34]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c(Br)nn2)cc1
Reactant: COc1ccc(CN)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2nnc(-c3ccc(C(F)(F)F)cc3)cc2C(F)(F)F)cc1
Yield: 94.9 %

Procedure:
A mixture of 3-bromo-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridazine (example C.26 step 7) (5.76 g, 16 mmol), DIPEA (3.19 mL, 19 mmol) and 4-methoxybenzylamine (2.4 mL, 19 mmol) in EtOH (25 mL) was refluxed for 18 h under argon atmosphere. Cooled to 23 C, the mixture was poured onto water, the precipitated solid was filtered off, washed with water and dried in air at 60° C. on the heating plate to give the title compound as an off-white solid (6.49 g, 98%). MS (ISP) 428.3 [(M+H)+]; mp 101-103° C.
Reaction SMILES: CC(C)=O.[CH2:5]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:27]=[CH:26][C:25]3[C:24](=[N:28]O)[CH2:23][CH2:22][CH2:21][C:20]=3[N:19]=2)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.[OH-].[K+]>O>[CH2:5]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:27]=[CH:26][C:25]3[C:24](=[N:28][S:36]([C:33]4[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=4)(=[O:38])=[O:37])[CH2:23][CH2:22][CH2:21][C:20]=3[N:19]=2)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ON=C1CCCc2nc(N3CCN(Cc4ccccc4)CC3)ncc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)N=C2CCCc3nc(N4CCN(Cc5ccccc5)CC4)ncc32)cc1

Procedure:
Added to a mixture of 30 ml of acetone, 2 g (5.35 mmol, Referential Example 49) of 2-(4-benzylpiperazino)-5,6,7,8-tetrahydro-5-hydroxyiminoquinazoline, and 1.6 g (8.4 mmol) of p-toluenesulfonyl chloride was a solution of 0.7 g (11 mmol) of KOH in 10 ml of water. The resultant mixture was stirred at 20° C. for 4 hours.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][C:6]([C:8]#[N:9])=[CH:5][CH:4]=1.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][N:21]([C:24]2[S:25][C:26]([C:30](O)=[O:31])=[C:27]([CH3:29])[N:28]=2)[C:20](=[O:33])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][N:21]([C:24]2[S:25][C:26]([C:30]([NH:9][CH2:8][C:6]3[O:7][C:3]([C:2]#[N:1])=[CH:4][CH:5]=3)=[O:31])=[C:27]([CH3:29])[N:28]=2)[C:20](=[O:33])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1ccc(CN)o1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1ccc(C#N)o1
Yield: 72 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use 5-(aminomethyl)furan-2-carbonitrile in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 72% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.84 (t, J=5.6 Hz, 1H), 8.61 (d, J=8.1 Hz, 1H), 7.52 (d, J=3.6 Hz, 1H), 7.45-7.30 (m, 5H), 6.55 (d, J=3.6 Hz, 1H), 6.39 (dd, J=8.1, 2.7 Hz, 1H), 6.23 (d, J=2.6 Hz, 1H), 5.16 (s, 2H), 4.44 (d, J=5.6 Hz, 2H), 2.54 (s, 3H); MS (ES+) m/z 447.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]([C@@H:15]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]2[OH:17])[C:4]2[C:9]([C:10]=1[C:11]#[N:12])=[CH:8][C:7]([Cl:13])=[C:6]([Cl:14])[CH:5]=2.[CH3:24][OH:25].O>CO.CN(C=O)C>[Cl:1][C:2]1[N:3]([C@@H:15]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]2[OH:17])[C:4]2[C:9]([C:10]=1[C:11](=[NH:12])[O:25][CH3:24])=[CH:8][C:7]([Cl:13])=[C:6]([Cl:14])[CH:5]=2
Reactant: N#Cc1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Reactant: CO
Solvent: CN(C)C=O
Solvent: O
Product: COC(=N)c1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
2,5,6-Trichloro-3-cyano-1-(β-D-ribofuranosyl)indole (4.4, 107 mg, 0.28 mmol) was dissolved in dry MeOH (10 mL) which was cooled to 0 C in an ice bath. Hydrogen chloride gas was slowly bubbled through the solution for 2 h, then the reaction vessel was tightly capped, and the resulting solution was stirred at room temperature for 24 h. The acidic solution was diluted with Et2O (20 mL) and evaporated to dryness. The residual solid was suspended in 10% aqueous NaHCO3 (100 mL) and extracted with EtOAc (3×100 mL, with vigorous shaking) The combined organic extracts were dried over MgSO4, filtered and evaporated to yield a white solid which was dissolved in DMF (0.5 mL) and subjected to column chromatography (40×350 mm) on C18-reverse phase silica gel with 75% MeOH/H2O. Fractions containing product were pooled and evaporated to yield 64 mg (58%) of 4.34 as a white crystalline solid: mp 248-249 C; Rf 0.6 (20% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 8.55 (s, 1H), 8.43 (s, 1H, D2O exch.), 7.96 (s, 1H), 5.98 (d, 1H), 5.39 (d, 1H, D2O exch.), 5.37 (t, 1H, D2O exch.), 5.24 (d, 1H, D2O exch.), 4.41 (q, 1H), 4.14 (s, 1H), 3.98 (d, 1H), 3.85 (s, 3H), 3.71 (m, 2H). 13C-NMR (125 MHz, DMSO-d6): δ 161.40, 132.01, 128.23, 125.67, 124.82, 124.50, 121.32, 115.19, 106.29, 88.73, 86.08, 71.40, 69.50, 60.99, 52.45. HRMS (EI) m/z calcd. for C15H15Cl3N2O5 408.0047. found 408.0043. Anal calcd for C15H15Cl3N2O5: C, 43.98; H, 3.69; N, 6.84. Found: C, 43.97; H, 3.81; N, 6.75.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=1[O:25][CH3:26])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(Cl)(Cl)Cl>[CH2:1]([NH:8][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:18]([O:25][CH3:26])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: COc1cc(CNCc2ccccc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
To a stirred solution of benzylamine (13.1 mL, 0.12 mol) and 4-benzyloxy-3-methoxybenzaldehyde (24.2 g, 0.1 mol) in 1,2-dichloroethane (50 mL) and chloroform (250 mL) was added sodium triacetoxyborohydride (31.79 g, 0.15 mol). The mixture was stirred at room temperature for 18 hrs, saturated NaHCO3 was added. The organic phase was separated and aqueous phase extracted with chloroform. The combined extracts were washed with brine, dried over MgSO4 and evaporated to afford the crude product. Purification by flash column chromatography afforded the title compound as a pale yellow oil in 76% yield (25.2 g). Rf: 0.17 (petrol:ethyl acetate; 1:1). 1H NMR (270 MHz, CDCl3) δ 3.73 (2H, s), 3.79 (2H, s), 3.89 (3H, s), 5.13 (2H, s), 6.75-6.84 (2H, m), 6.91 (1H, d, J=1.4), 7.23-7.44 (10H, m); HRMS (ESI+) calcd. for C22H24NO2 (M++H) 334.1802, found 334.1787; LC/MS (ES+) tr=1.19 min, m/z 334.5 (M++H);
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[OH:8].CO[CH:11](OC)[N:12]([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[CH:13]([N:12]([CH:11]=[N:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[OH:8])[CH:16]([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: Nc1ccncc1O
Reactant: COC(OC)N(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(C)N(C=Nc1ccncc1O)C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-amino-3-pyridinol (3.0 g), N,N-diisopropylformamide dimethyl acetal (9.54 g) and 15 ml dry toluene was stirred at room temperature for 18 hours and thereafter heated to 60°-70° C. After 90 minutes, the mixture was cooled to room temperature, concentrated in vacuo and chromatographed on silica using 10:90 CH3OH/ethyl acetate as an eluent. The fractions containing the desired product were combined and concentrated to a thick oil, which solidified on refrigeration. This solid (5.3 g) was triturated with hexane three times to provide the product as a white solid, m.p. 77°-79° C.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.[C:19]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>ClCCl>[C:19]1([CH:25]2[CH2:26][CH2:27][N:28]([C:2]([Cl:1])=[O:4])[CH2:29][CH2:30]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: c1ccc(C2CCNCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cl)N1CCC(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 0.68 g (2.26 mmol) triphosgene in 6,8 mL dichloromethane at −80° C. is added 0.52 mL (6.5 mmol) pyridine. Then 1.05 g 4-phenylpiperidine (6.5 mmol) is added over a period of 10 minutes. The reaction mixture is allowed to warm to room temperature and stirred for another 2 hours. 4.5 mL 1N hydrochloric acid is added for hydrolization. The organic phase is separated, washed with saturated sodium bicarbonate solution and dried with sodium sulfate. After evaporation of the solvent the crude product is purified via column chromatography on silica gel using dichloromethane as eluent
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]([CH2:20][CH3:21])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=2)[CH2:4][C@H:3]1[O:22][CH2:23][CH3:24].[Cl:25][C:26]1[N:27]=[C:28]([C:33](O)=[O:34])[NH:29][C:30]=1[CH2:31][CH3:32].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.ClCCl>[Cl:25][C:26]1[N:27]=[C:28]([C:33]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[O:9][C:10]([CH2:20][CH3:21])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=3)[CH2:4][C@H:3]2[O:22][CH2:23][CH3:24])=[O:34])[NH:29][C:30]=1[CH2:31][CH3:32]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](N)[C@H](OCC)C2)oc1CC
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)oc1CC
Yield: 50.4 %

Procedure:
The same operation as in Example (106d) was performed using butyl cis(±)-2-(4-amino-3-ethoxypiperidin-1-yl)-5-ethyl-1,3-oxazole-4-carboxylate obtained in Example (115b) (0.89 g, 2.63 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (85% content, 0.2 g, 1 mmol), WSC hydrochloride (0.5 g, 2.5 mmol), HOBt (0.2 g, 1.5 mmol), dichloromethane (5 mL) and DMA (3 mL), to obtain 0.25 g of the title compound as a colorless amorphous solid (49%).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[CH2:35]([C@@H:37]1[O:39][CH2:38]1)Cl>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:35][CH:37]2[CH2:38][O:39]2)=[CH:9][CH:10]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: ClC[C@H]1CO1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC2CO2)cc1

Procedure:
Analogously to Method D, 5.60 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 2.05 ml of (R)-(−)-epichlorohydrin are reacted. The title compound is obtained as a colourless oil. Rf=0.12 (1:3 EtOAc-heptane); Rt=5.55.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][N:15]3[C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH:30]=[CH:29][N:28]=[CH:27]4)[N:21]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][N:15]3[C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH:30]=[CH:29][N:28]=[CH:27]4)[N:21]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: c1cn(-c2nccc(N3CCCCC3CCNCc3ccc4c(c3)OCO4)n2)cn1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N(CCC1CCCCN1c1ccnc(-n2ccnc2)n1)Cc1ccc2c(c1)OCO2
Reaction time: 16 h
Yield: 48.2 %

Procedure:
Alternatively, to THF (3 mL) was added N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl)piperidine-2-ethanamine (8 mg, 0.03 mmol), Hünig's base (8 mg, 0.06 mmol), and methanesulfonyl chloride (4.5 mg, 0.04 mmol). After stirring for 16 hours, the solvent was removed in vacuo and the residue was chromatographed (CH2Cl2/MeOH. 19/1) to give 7 mg (51%) of N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]-N-(methylsulfonyl)piperidine-2-ethanamine (the compound of formula (Iff)); 1H NMR (CDCl3) δ 8.10 (s, 1), 7.78 (d, 1), 7.13 (s, 1), 6.82 (s, 1), 6.72 (s, 2), 6.30 (d, 1), 5.94 (s, 2), 4.23 (m, 3), 3.20 (m, 2), 2.80 (s, 3), 1.14 (m); MS: 485.7 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[C:16](Cl)=[N:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:26]>Cl>[CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([C:15]2[C:16](=[O:26])[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1(c2cc3ccccc3nc2Cl)CCN(Cc2ccccc2)CC1
Reactant: O
Agent: Cl
Product: O=c1[nH]c2ccccc2cc1C1=CCN(Cc2ccccc2)CC1

Procedure:
3-(1-Benzyl-4-hydroxypiperidin-4-yl)-2-chloroquinoline (11.0 g, 31.1 mmol) was refluxed in 6 N hydrochloric acid for 8 h. The solution was cooled and water (100 mL) added. The precipitated solid was collected and dried to give the title compound, 7.9 g. MS 317 (M+1). 1H NMR (500 MHz, CD3OD) δ 7.97 (s, 1H), 7.70 (d, J=7 Hz, 1H), 7.60 (m, 2H), 7.55 (m, 4H), 7.35 (d, J=9 Hz, 1H), 7.27 (t, J=8 Hz, 1H), 6.50 (m, 1H), 4.49 (ABq, J=13 Hz, Δv=16 Hz, 2H), 3.92 (m, 2H), 3.76 (dt, J=12.4 Hz, 1H), 3.40 (m, 1H), 2.96 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:11]1[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:11]2[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)[CH:2]=1
Reactant: Nc1cnc(Br)cn1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cnc(-c2cccnc2)cn1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
Pyridin-3-ylboronic acid (307 mg, 2.50 mmol), 5-bromopyrazin-2-amine (391 mg, 2.25 mmol) and dichlorobis(triphenylphosphine)-palladium(II) (88 mg, 0.13 mmol) were added to degassed dioxane (12 mL) and the mixture was stirred for 30 min. Then sodium carbonate (795 mg, 7.50 mmol) and degassed water (8 mL) were added and the reaction was heated in a closed reaction vial at 100° C. for 8 h. The reaction was allowed to stand at ambient temperature over the weekend. It was diluted into ethyl acetate (100 mL) and extracted with brine (3×25 mL). The organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (0 to 5% methanol/ethyl acetate) to afford 5-(pyridin-3-yl)pyrazin-2-amine (235 mg, 1.37 mmol, 54.6% yield). 1H NMR (400 MHz, Acetone) δ ppm 9.13 (1H, d, J=1.51 Hz), 8.54 (1H, d, J=1.26 Hz), 8.50 (1H, dd, J=4.78, 1.51 Hz), 8.22-8.28 (1H, m), 8.07 (1H, d, J=1.26 Hz), 7.39 (1H, ddd, J=7.87, 4.72, 0.76 Hz), 6.05 (2H, br. s.). MS (LC/MS) R.T.=0.58; [M+H]+=173.20.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([CH:29]=[CH:30][CH:31]=2)[O:10][C:11]2[CH:12]=[CH:13][C:14]([N+:26]([O-])=O)=[C:15]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:16]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CO>[Pd].C1(C)C=CC=CC=1>[NH2:26][C:14]1[CH:13]=[CH:12][C:11]([O:10][C:9]2[CH:29]=[CH:30][CH:31]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[CH:8]=2)=[CH:16][C:15]=1[N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(N3CCOCC3)c2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: Cc1ccccc1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(N3CCOCC3)c2)ccc1N
Yield: 96.8 %

Procedure:
By using 5.0 g of t-butyl N-{5-[3-(morpholin-4-yl)phenoxy]-2-nitrophenyl}-N-methylcarbamate, 0.5 g of 10% palladium on carbon and a mixed solvent of 30 ml of methanol and 70 ml of toluene, reaction and purification were carried out in a similar manner to that described in Reference Example 7, whereby 4.5 g of the title compound were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:16]([CH3:17])[C:15](=[O:18])[N:14]2[C@@H:19]([CH2:22][C:23]([OH:25])=O)[CH2:20][O:21][CH:13]2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:27]1[C:29]2([CH2:34][CH2:33][NH:32][CH2:31][C@H:30]2[OH:35])[CH2:28]1.CN1CCOCC1>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[C@@H:16]([CH3:17])[C:15](=[O:18])[N:14]2[C@@H:19]([CH2:22][C:23]([N:32]3[CH2:33][CH2:34][C:29]4([CH2:27][CH2:28]4)[C@H:30]([OH:35])[CH2:31]3)=[O:25])[CH2:20][O:21][CH:13]2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1C(=O)N2C(CN1C(=O)OCc1ccccc1)OC[C@@H]2CC(=O)O
Reactant: O[C@@H]1CNCCC12CC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@H]1C(=O)N2C(CN1C(=O)OCc1ccccc1)OC[C@@H]2CC(=O)N1CCC2(CC2)[C@H](O)C1
Yield: 96.5 %

Procedure:
-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (138 mg, 0.36 mmol) was added to a solution of (3S,6S)-3-carboxymethyl-6-methyl-5-oxo-hexahydro-oxazolo[3,2-a]pyrazine-7-carboxylic acid benzyl ester (84 mg, 0.24 mmol), (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (39 mg, 0.24 mmol) and 4-methylmorpholine (73 mg, 0.73 mmol) in DMF(1 mL), then after 16 h the reaction mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; DCM→DCM/MeOH/25% aq. ammonia solution 90:10:0.25) afforded the title compound (106 mg, 96%). Colourless gum, MS: 458.5 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[O:8][C:7](=[O:9])[CH:6]=[CH:5]1)[CH3:2].[Br:10]Br>C(Cl)(Cl)(Cl)Cl>[Br:10][C:5]1[CH:4]([O:3][CH2:1][CH3:2])[O:8][C:7](=[O:9])[CH:6]=1
Reactant: BrBr
Reactant: CCOC1C=CC(=O)O1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC1OC(=O)C=C1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
This procedure may be carried out in a manner similar to that described by C. Escobar, et al., Ann. Quim. (1971), 67, 43-57.). To a solution of 5-ethoxy-5H-furan-2-one (II, R1=Et) (10.0 g, 78.0 mmol) in carbon tetrachloride (50 mL) at 0° C. is added over 0.5 h a solution of bromine (4.05 mL, 78.2 mmol) in carbon tetrachloride (25 mL). The reaction is stirred 1 h at 0° C., then 2 h at room temperature. The solvents are removed under reduced pressure and the residue was short-path distilled at pump vacuum (about 0.5 mm). The fraction collected at 100° C.-120° C. provided 4-bromo-5-ethoxy-5H-furan-2-one (13.2 g, 82% yield) as a yellow oil. 1H-NMR (500 MHz, CDCl3) δ 6.24 (s, 1H), 5.63 (s, 1H), 3.71 (m, 1H), 3.63 (m, 1H), 1.14 (t, J=7.1 Hz, 3H) ppm.