Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:31][CH3:32])[CH:3]=1.[CH:33](=O)[CH3:34].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:33][CH3:34])[CH2:22][C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:31][CH3:32])[CH:3]=1
Reactant: CC=O
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2cccs2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1cccs1

Procedure:
4-Amino-5-chloro-2-methoxy-N-((1-(5-((2-thienylmethyl)amino)-pentyl)piperidin-4-yl)methyl)benzamide (1.5 g) as starting compound, acetaldehyde (0.23 ml) and sodium cyanoborohydride (0.25 g) were reacted and treated in the same manner as in Example 136 to give 0.96 g of 4-amino-5-chloro-N-((1-(5-(N-ethyl-N-(2-thienylmethyl)amino)pentyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH2:15][CH3:16])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.Cl.[CH2:18]([O:20][CH2:21][CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[NH:32][CH:33]1[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][C:41]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:45][CH2:44][NH:43][CH2:42]2)[CH2:35][CH2:34]1)[CH3:19]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH2:15][CH3:16])[C:11]=1[O:12][CH3:13])[C:6]([N:43]1[CH2:44][CH2:45][C:41]([CH2:40][CH2:39][N:36]2[CH2:37][CH2:38][CH:33]([NH:32][C:24]3[N:23]([CH2:22][CH2:21][O:20][CH2:18][CH3:19])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=3)[CH2:34][CH2:35]2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:42]1)=[O:8]
Reactant: CCOc1cc(C(=O)O)cc(OC)c1OC
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OC)c(OCC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 3,4-dimethoxy-5-ethoxybenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-(2-hydroxyethyl)-3-phenylpyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH:18]([C:20]3[S:24][C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)=[N:22][C:21]=3[CH3:35])[CH3:19])[CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[OH-].[Na+].Cl>C1COCC1.CO>[CH3:35][C:21]1[N:22]=[C:23]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:29][CH:30]=2)[S:24][C:20]=1[CH:18]([O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][N:8]2[CH2:7][C:6]([OH:36])=[O:5])=[CH:12][CH:13]=1)[CH3:19]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)Oc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)Oc1ccc2ccn(CC(=O)O)c2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.7 %

Procedure:
To a solution of [rac]-(6-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester (30 mg, 58 μmol) in THF/methanol 2/1 (4.5 ml) was added a 1 N aqueous NaOH solution (1.5 ml). The reaction mixture was stirred for 14 h at ambient temperature, neutralized with 1 N aqueous HCl solution under ice cooling and concentrated under reduced pressure. The residue was dissolved in 1 N HCl/ice water 1/1 and ethyl acetate, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with ice water/brine 1/1, dried over sodium sulfate and the solvent was evaporated in vacuo to give the title compound (24 mg, 52 μmol, 90%) as light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].BrC[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([CH2:17][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc([N+](=O)[O-])cc3)CC1)O2
Yield: 93.2 %

Procedure:
(E)-3-{4-Oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (337 mg, 1.00 mmol, Intermediate 1, hydrochloride salt) was alkylated using 1-(2-bromo-ethyl)-4-nitro-benzene (460 mg, 2 mmol) as described in Example 56, Step A, giving (E)-3-{1′-[2-(4-nitro-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (420 mg) as a light brown solid.
Reaction SMILES: [F:1][C:2]1[C:11]([CH2:12][C:13]2[N:17]3[N:18]=[C:19]([C:22](=O)[CH3:23])[CH:20]=[CH:21][C:16]3=[N:15][N:14]=2)=[C:10]([F:25])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH2:26][NH:27][C:28]([NH2:30])=[O:29].C(=O)(O)[O-].[Na+]>CO>[F:1][C:2]1[C:11]([CH2:12][C:13]2[N:17]3[N:18]=[C:19](/[C:22](=[N:26]/[NH:27][C:28]([NH2:30])=[O:29])/[CH3:23])[CH:20]=[CH:21][C:16]3=[N:15][N:14]=2)=[C:10]([F:25])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1ccc2nnc(Cc3c(F)cc4ncccc4c3F)n2n1
Reactant: NNC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: C/C(=N\NC(N)=O)c1ccc2nnc(Cc3c(F)cc4ncccc4c3F)n2n1
Temperature: 40 °C
Reaction time: 20 h
Yield: 81.8 %

Procedure:
A mixture of 1-[3-(5,7-difluoro-quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-ethanone (38 mg, 0.112 mmol), semicarbazide (37.5 mg, 0.336 mmol) and sodium bicarbonate (40 mg, 0.67 mmol) in methanol (3 mL) was stirred at 40° C. for 20 h. LC/MS showed the reaction was complete, and the suspension was filtered. The filtrate cake was washed successively with cold water and methanol, and then dried to afford 36.3 mg (82% yield) of the title compound as white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.85 (s, 1H), 8.99 (dd, 1H), 8.49 (d, 1H), 8.35 (d, 1H), 8.18 (d, 1H), 7.73 (d, 1H), 7.62 (dd, 1H), 6.82 (s br, 2H), 4.75 (s, 2H), 2.19 (s, 3H). LCMS (method A): [MH]+=397, tR=4.43 min.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[NH:25][NH2:26]>CN(C=O)C>[C:29]([O:28][C:24]([NH:25][NH:26][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)NN
Reactant: BrCc1ccc(-c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NNCc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
4-(Bromomethyl)biphenyl (2.0 g, 8.1 mmol, 1.0 eq.) and DIPEA (1.4 mL, 1.0 eq.) were dissolved in DMF (40.0 mL). t-Butyl carbazate (2.1 g, 16.2 mmol, 2.0 eq.) was added and the mixture was stirred at room temperature overnight. The mixture was partially concentrated, and the residue was partitioned between EtOAc and a saturated aqueous NaHCO3 solution. The EtOAc layer was then dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (0-60% EtOAc/hexanes with 0.5% DIPEA) to yield compound 1, N′-biphenyl-4-ylmethyl-hydrazinecarboxylic acid t-butyl ester (1.7 g).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[C:8]3[C:13]([C:14]([CH2:15][CH2:16][NH2:17])=[C:6]2[CH2:5][CH2:4][CH2:3]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.C(N(C(C)C)CC)(C)C.[CH3:27][N:28]([CH3:38])[C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>>[CH3:27][N:28]([CH3:38])[C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:17][CH2:16][CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]3[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][C:6]=23)=[O:34])=[CH:31][CH:30]=1
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Reactant: NCCc1c2n(c3ccccc13)C(=O)CCC2
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1ccc(C(=O)NCCc2c3n(c4ccccc24)C(=O)CCC3)cc1

Procedure:
E10 was prepared analogously to E9 from 7 g D4 of EP-0167901, 11.2 ml diisopropylethylamine and 4.5 g 4-dimethylaminobenzoic acid chloride.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([OH:10])=O)[CH:2]=1.[NH2:21][CH2:22][C:23]#[N:24].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O.C(OCC)(=O)C>[C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([NH:24][CH2:23][C:22]#[N:21])=[O:10])[CH:2]=1
Reactant: N#CCN
Reactant: CC(C)CC(C(=O)O)c1cccc(-c2ccccc2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CC(C(=O)NCC#N)c1cccc(-c2ccccc2)c1
Reaction time: 4 h
Yield: 97.8 %

Procedure:
A solution comprised of 2-biphenyl-3-yl-4-methylpentanoic acid (0.251 mg, 0.91 mmol), prepared as in Example 3, in DMF (5 mL) was treated with aminoacetonitrile (180 mg, 2 mmol), PyBOP (520 mg 1 mmol) and triethylamine (500 μL, 3 mmol). The mixture was stirred for 4 hours and then diluted with water (50 mL) and ethyl acetate (20 mL). The organic layer was separated, washed with 1 M saturated sodium bicarbonate solution, 1 M hydrochloric acid solution, water and brine, dried (MgSO4) and concentrated. The residue was recrystallized from 30% ethyl acetate in hexane to provide 2-biphenyl-3-yl-N-cyanomethyl-4-methylpentanamide (300 mg, 0.89 mmol). 1H NMR (DMSO-d6): 1.01 (d, 6H), 1.81-1.85 (m, 3H), 3.73 (dd, 1H), 4.35 (m, 2H), 7.12 (d, 1H), 7.24-7.37 (m, 8H) 8.31 (s, 1H). LCMS: 307.3 (M+H+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])=[O:15].Cl[Si:25]([CH3:28])([CH3:27])[CH3:26]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[C:14]([O:15][Si:25]([CH3:28])([CH3:27])[CH3:26])=[CH2:13]
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: C=C(O[Si](C)(C)C)c1ccc(Cl)cc1Cl
Reaction time: 0.17 h

Procedure:
Diisopropylamine (16.2 g) was dissolved in tetrahydrofuran (133 ml), and 1.6N n-butyl lithium (100 ml) was dropwise added thereto under ice-cooling. The reaction mixture was stirred at the same temperature for 10 min, and a solution of 2,4-dichoroacetophenone (25.2 g) in tetrahydrofuran (133 ml) was dropwise added under cooling in a dry ice-acetone bath. Hexamethylphosphoramide (26.7 ml) was added little by little. The mixture was stirred at the same temperature for 5 min, and chlorotrimethylsilane (20.3 ml) was dropwise added, which was followed by stirring at room temperature for 30 min. The reaction mixture was partitioned between ice-cooled n-hexane and ice-cooled water. The organic layer was washed twice with ice-cooling water and then once with saturated brine, dried over sodium sulfate and concentrated under reduced pressure to dryness to give a crude product (37.5 g) of the objective compound as a pale-yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)=[CH:9][CH:8]=1)C.[OH-].[Li+]>O1CCCC1.C(O)C>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][CH:14]([O:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]([OH:26])=[O:3])=[CH:12][CH:11]=2)[CH2:15]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CCOC(=O)COc1ccc(OC2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OCC(=O)O)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a solution of 4-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)phenoxyacetic acid ethyl ester (2.5 g) in a mixture of tetrahydrofuran (5 ml) and ethanol (5 ml) was added 1N aqueous lithium hydroxide solution (7.5 ml) with ice-cooling, and the mixture was stirred at room temperature for 30 min. After completion of the reaction, the solvent was evaporated and to the obtained residue were added ice water and 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dried under reduced pressure to give the title compound(2.30 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].Br[C:13]1[CH:14]=[CH:15][C:16]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[C:17]([CH:20]=1)[C:18]#[N:19]>C1(C)C(C)=CC=CC=1.CS(C)=O.[Pd]>[C:18]([C:17]1[CH:20]=[C:13]([C:4]2[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=2)[CH:14]=[CH:15][C:16]=1[O:21][CH2:22][CH:23]([CH3:25])[CH3:24])#[N:19]
Reactant: CC(C)COc1ccc(Br)cc1C#N
Reactant: CCOC(=O)c1scnc1C
Agent: [Pd]
Solvent: Cc1ccccc1C
Solvent: CS(C)=O
Product: CCOC(=O)c1sc(-c2ccc(OCC(C)C)c(C#N)c2)nc1C
Temperature: 140 °C
Reaction time: 24 h

Procedure:
To a test tube-type reaction vessel (60 mL) were added ethyl 4-methylthiazole-5-carboxylate (2.14 g, 12.5 mmol), 5-bromo-2-isobutoxybenzonitrile (2.54 g, 10.0 mmol) obtained in the Reference Example 1, and a solvent (7.6 mL), a palladium compound (0.025 mmol), a ligand (0.10 mmol), a base (21.0 mmol), carboxylic acid (0.10 mmol), an additive (0.10 mmol), and a reducing agent (0.10 mmol) listed in the Table 10. Thereafter, the reaction vessel was filled with nitrogen gas and sealed air-tight and the mixed solution was heated to 140° C. and stirred for 24 hours. After the completion of the reaction, a portion of the reaction solution was diluted with xylene and DMSO and the resulting solution was analyzed by HPLC measurement. The total HPLC area % of the compound A to D and TM was adjusted to 100%, the calculated yield of the subject material was computed from each HPLC area %. Calculation of the calculated yield from the HPLC area % of subject material was carried out by applying corresponding numbers in the following calculation formula. Yield (%) of TM=total amount of TM (mol)/[{total amount of A (mol)+total amount of C (mol)×2+total amount of TM (mol)}]×100 Total amount of each compound (mol)=HPLC area value (mAU) of each compound/HPLC area value (mAU/mol) per mol of each compound
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[CH2:9][CH2:8][S:7][CH:6]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])=[S:4].Cl.Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH:25]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O>[CH3:1][NH:2][C:3]([N:5]1[CH2:9][CH2:8][S:7][CH:6]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH2:19][CH2:20][N:21]1[CH2:22][CH:23]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[CH2:25][CH2:26]1)=[S:4]
Reactant: Fc1cccc(C2=CCN(CCCl)CC2)c1
Reactant: CNC(=S)N1CCSC1c1ccccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CNC(=S)N1CCSC1c1ccccc1OCCN1CC=C(c2cccc(F)c2)CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
A mixture of 1.27 g of N-methyl-2-(2-hydroxyphenyl)thiazolidine-3-carbothioamide, 1.38 g of 1-(2-chloroethyl)-4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride, 1.50 g of potassium carbonate, 0.75 g sodium iodide and 25 ml of dimethylformamide is stirred at 90° C. for 8 hours. 0.7 g of 1-(2-chloroethyl)-4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride is added to the reaction mixture, and the mixture is further stirred at the same temperature for 15 hours. The mixture is evaporated under reduced pressure to remove the solvent. Water is added to the residue, and the aqueous solution is extracted with ethyl acetate. The extract is washed with water, dried and then evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent, chloroform:ethanol=45:1), whereby 0.39 g of N-methyl-2-{2-[2-(4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)ethyloxy]phenyl}thiazolidine-3-carbothioamide is obtained.
Reaction SMILES: [CH:1]([CH:3]1[CH2:9][CH:8]2[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]([CH2:6][CH2:7]2)[CH2:4]1)=[O:2].[O-:16][Mn](=O)(=O)=O.[K+]>CC(O)(C)C>[CH2:14]([O:13][C:11]([N:10]1[CH:8]2[CH2:7][CH2:6][CH:5]1[CH2:4][CH:3]([C:1]([OH:16])=[O:2])[CH2:9]2)=[O:12])[CH3:15]
Reactant: CCOC(=O)N1C2CCC1CC(C=O)C2
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)N1C2CCC1CC(C(=O)O)C2
Reaction time: 0.17 h

Procedure:
A solution of ethyl 3-formyl-8-azabicyclo[3.2.1]octane-8-carboxylate (1-3) (1.84 g, 8.71 mmol) in t-BuOH (50.0 mL) was diluted with an aqueous 5% NaH2PO4 solution (35.3 mL, 14.8 mmol, 0.42 N in water). With vigorous stirring, an aqueous 1.0 M KMnO4 solution (52.3 mL, 52.3 mmol) was added at room temperature. The mixture was stirred for 10 minutes and quenched with a saturated aqueous solution of Na2SO3. The resulting pH of the mixture was adjusted to 3 with cold (0° C.) dilute HCl to dissolve the colloidal MnO2. The mixture was then extracted with EtOAc and the combined organic layers were washed with brine, dried over anhydrous MgSO4, concentrated to give (1-4) as white solid.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12]([CH3:14])=O.C[OH:16]>[Pd]>[CH3:1][CH:2]1[CH:3]([CH2:10][CH2:11][CH2:12][CH3:14])[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][C:7]1=[O:16]
Reactant: CC(=O)/C=C/C1=C(C)CCCC1(C)C
Reactant: CO
Agent: [Pd]
Product: CCCCC1C(C)C(=O)CCC1(C)C

Procedure:
The mixture of compounds obtained according to example 1 starting from β-ionone is dissolved in methanol and hydrogenated at atmospheric pressure and room temperture using 5% Palladium on charcoal as a catalyst.
Reaction SMILES: C(OP([CH2:9][S:10]([CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)(=[O:12])=[O:11])(OCC)=O)C.[H-].[Na+].[N:29]1[CH:30]=[C:31]2[N:40]3[C:35](=[CH:36][CH:37]=[CH:38][C:39]=13)[S:34][C:33]([CH:41]=O)=[CH:32]2>C1(C)C=CC=CC=1.CN(C)C=O.O>[C:23]([O:22][C:20]([N:17]1[CH2:16][CH2:15][CH:14]([CH2:13][S:10](/[CH:9]=[CH:41]/[C:33]2[S:34][C:35]3[N:40]4[C:31](=[CH:30][N:29]=[C:39]4[CH:38]=[CH:37][CH:36]=3)[CH:32]=2)(=[O:11])=[O:12])[CH2:19][CH2:18]1)=[O:21])([CH3:24])([CH3:25])[CH3:26]
Reactant: O=CC1=Cc2cnc3cccc(n23)S1
Reactant: CCOP(=O)(CS(=O)(=O)CC1CCN(C(=O)OC(C)(C)C)CC1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CS(=O)(=O)/C=C/C2=Cc3cnc4cccc(n34)S2)CC1
Reaction time: 1 h

Procedure:
To a solution of 2.01 g (4.87 mM) of tert-butyl 4-(diethoxyphosphorylmethanesulfonylmethyl)piperidine-1-carboxylate in 30 ml of toluene was added 0.18 g (4.43 mM) of a 60% suspension of sodium hydride in liquid paraffin at room temperature, and the mixture was stirred at the prevailing temperature for 1 hour. This reaction mixture was added to a solution of the above crude 5-thia-1,8b-diazaacenaphthylene-4-carbaldehyde in N,N-dimethylformamide (10 ml)-toluene (30 ml) at room temperature and the mixture was stirred at the prevailing temperature for 0.5 hour. This reaction mixture was poured in water and extracted with 3 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate˜ethyl acetate/methanol=9/1) to provide crude (E)-4-[2-[1-(tert-butoxycarbonyl)piperidin-4-ylmethane-sulfonyl]viny]-5-thia-1,8b-diazaacenaphthylene. This crude product was not purified but used as it was in the next reaction.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-]CC.[Na+].[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[CH2:17]>>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:16][CH2:17][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: C=Cc1ccccn1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(CCc1ccccn1)C(=O)OCC

Procedure:
Diethyl β-(2-pyridyl)-ethylmalonate was prepared in the manner described by V. Boekelheide and S. Rothchild, JACS, 71, 879 (1949). Briefly, diethyl malonate (375 g, 2.35 moles) was added to a solution of sodium ethoxide (23 g of sodium in 225 mL of absolute alcohol). To the boiling mixture, freshly distilled 2-vinylpyridine (106 g, 1.0 mole) in 175 mL of absolute alcohol was added slowly. After the mixture had boiled under reflux for two hours, the alcohol was removed by distillation and the residue was acidified with dilute hydrochloric acid. The unreacted malonic ester was extracted with ether, the aqueous phase was made basic with dilute sodium hydroxide, and the basic organic layer was extracted with ether. After the ethereal solution had been dried over Drierite, the ether and recovered 2-vinylpyridine (boiling point 58° C. at 16 mm) were removed in vacuo.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.O1CCOCC1.[CH:13]1([NH:16][C:17](=O)[C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([CH3:27])[CH:19]=2)[CH2:15][CH2:14]1.[N-:29]=[N+:30]=[N-:31].[Na+]>O.C1(C)C=CC=CC=1>[CH:13]1([N:16]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([CH3:27])[CH:19]=3)=[N:31][N:30]=[N:29]2)[CH2:15][CH2:14]1
Reactant: Cc1cc(C(=O)NC2CC2)ccc1[N+](=O)[O-]
Reactant: [N-]=[N+]=[N-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(-c2nnnn2C2CC2)ccc1[N+](=O)[O-]
Reaction time: 5 h
Yield: 71 %

Procedure:
6.3 g (30 mmol) of phosphorus pentachloride was added to a mixture of 40 ml of toluene and 4 ml of dioxane containing 4.7 g (21 mmol) of N-cyclopropyl-3-methyl-4-nitrobenzamide and the mixture was heated to reflux for three hours. The reaction mixture was concentrated under reduced pressure, then dissolved in 30 ml of DMF and slowly added dropwise to a DMF solution containing 2.8 g (43 mmol) of sodium azide. The reaction mixture was stirred for five hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was filtered and washed with ether to obtain 3.7 g of the desired compound.