Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.[F:61][C:62]([F:73])([F:72])C1C=CC(N=C=O)=CC=1>>[CH3:33][CH:32]([CH3:34])[C@H:27]([N:21]1[CH2:20][C:19]2[C:23](=[CH:24][CH:25]=[C:17]([C:14]3[CH:13]=[CH:12][C:11]([NH:10][C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([C:62]([F:73])([F:72])[F:61])=[CH:3][CH:4]=4)=[O:35])=[CH:16][CH:15]=3)[CH:18]=2)[C:22]1=[O:26])[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccc2C1=O
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)cc3)ccc2C1=O

Procedure:
The compound of example 244 was prepared analogous to compound of example 224 by reaction of compound of example 223 with 4-trifluoromethyl phenyl isocyanate. The compound of example 244 was used directly without isolation for the preparation of compound of example 245.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=[O:4].[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH2:22][C:23](O)([OH:25])[CH3:24].CC1C=CC(S(O)(=O)=O)=CC=1.C(O)CCC>C1C=CC=CC=1>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=2[Cl:12])[O:25][CH:23]([CH2:22][CH2:21][C:15]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=2[Cl:13])[CH2:24][O:4]1
Reactant: CC(O)(O)CCc1ccc(Cl)cc1Cl
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCCCO
Product: Clc1ccc(CCC2COC(CBr)(c3ccc(Cl)cc3Cl)O2)c(Cl)c1

Procedure:
A mixture of 13.6 parts of 2-bromo-1-(2,4-dichlorophenyl)-1-ethanone, 14.1 parts of 1-[2-(2,4-dichlorophenyl)ethyl]ethanediol, 3 parts of 4-methylbenzenesulfonic acid, 80 parts of butanol and 180 parts of benzene is stirred and refluxed for 24 hours. The reaction mixture is evaporated and the residue is stirred for 2 hours with 160 parts of methanol. The precipitated product is filtered off, yielding 2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-[2-(2,4-dichlorophenyl)ethyl]-1,3-dioxolane.
Reaction SMILES: C1(N[CH:8]=[N:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)C=CC=CC=1.NC1C=CC=CC=1.C(OCC)(OCC)[O:24][CH2:25][CH3:26]>>[C:10]1([N:9]=[CH:8][O:24][CH2:25][CH3:26])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C(=Nc1ccccc1)Nc1ccccc1
Reactant: CCOC(OCC)OCC
Solvent: Nc1ccccc1
Product: CCOC=Nc1ccccc1

Procedure:
The synthesis is achieved in three steps. The first step is the preparation of N,N′-diphenyl formamidine (by the reaction of aniline with triethyl orthoformate). This intermediate is then further reacted with triethyl orthoformate to produce ethyl N-phenylimidoformate. The final step is the reaction of ethyl phenylimidoformate with 4-aminostyrene to give the product.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]=[O:11])[C:4]=2[O:3][CH2:2]1.[BH4-].[Na+]>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][OH:11])[C:4]=2[O:3][CH2:2]1
Reactant: O=Cc1cccc2c1OCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1cccc2c1OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
Dissolve benzo[1,3]dioxole-4-carbaldehyde (2.0 g, 13.3 mmol) in anhydrous THF (30 mL) and treat with sodium borohydride (0.5 g, 13.3 mmol) at 0° C. Stir the reaction mixture for 30 min at ambient temperature and quench with water (30 mL). Extract the reaction mixture with DCM (3×10 mL), combine the organic extracts and dry over anhydrous Na2SO4. Remove the solvent to obtain the desired intermediate as a colorless oil (1.9 g, 94%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7][CH2:6]1)[CH3:2].[ClH:20].[CH:21](O)=O>C=O.CCOCC>[ClH:20].[ClH:20].[CH2:1]([N:3]([CH2:4][CH:5]1[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:9][CH2:10]1)[CH3:21])[CH3:2]
Reactant: O=CO
Reactant: CCNCC1CCN(CCOc2ccccc2)CC1
Agent: C=O
Agent: Cl
Solvent: CCOCC
Product: CCN(C)CC1CCN(CCOc2ccccc2)CC1

Procedure:
A solution of 4-(ethylaminomethyl)-1-(2-phenoxyethyl)piperidine (3.0 g) in 98% formic acid (2.2 ml) and 37% aqueous formaldehyde (2.06 ml) was heated on a steam bath for 5 hours. Work up as described in Example 10 gave an oil which was dissolved in ether and treated with ethereal hydrogen chloride solution to give a solid which was collected by filtration and recrystallised from absolute ethanol to give 4-(N-ethyl-N-methylaminomethyl)-1-(2-phenoxyethyl)piperidine dihydrochloride, m.p. 248°-250° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10]C)=[O:9])[C:5]([CH3:12])=[CH:4][CH:3]=1.[OH-].[K+:14]>C(O)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O-:10])=[O:9])[C:5]([CH3:12])=[CH:4][CH:3]=1.[K+:14]
Reactant: COC(=O)c1nc(Cl)ccc1C
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1ccc(Cl)nc1C(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
Methyl 6-chloro-3-methyl-pyridine-2-carboxylate (50 g, 269.4 mmoles) is added to a solution of potassium hydroxide (18.7 g, 282.9 mmoles) in isopropyl alcohol (2000 mL). The mixture is stirred at ambient temperature for 1 hour. Hexanes (500 mL) are added, and the solid is filtered, washed with hexanes, and dried under reduced pressure at 45° C. for 4 hours to give the title compound (52 g, 92%). Mass spectrum (m/z): 172.0 (M+1). 1H NMR (300 MHz, D2O): 7.62 (d, J=8.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 2.23 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:3]=1[CH2:4][CH:5]([CH2:9]C)[C:6]([OH:8])=[O:7]>O>[CH3:16][O:15][C:12]1[CH:11]=[C:3]([CH2:4][CH:5]([CH3:9])[C:6]([OH:8])=[O:7])[CH:2]=[CH:14][CH:13]=1
Reactant: CCC(Cc1cc(OC)ccc1Br)C(=O)O
Solvent: O
Product: COc1cccc(CC(C)C(=O)O)c1
Temperature: 100 °C
Yield: 86 %

Procedure:
A mixture of the butyric acid (4c, 51.6 g) and polyphosphoric acid (511 g) was heated at 100° C. for 2.5 hours. The mixture was poured into water (1 L) and extracted with AcOEt. The combined extracts were washed with water, 5% sodium bicarbonate solution and brine, dried over MgSO4 and filtered. After removing the solvent under reduced pressure, the residue was chromatographed on silica gel eluting with hexane:AcOEt (4:1 to 1:2) to give the titled compound (30.0 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28](=[O:52])[CH:29]([C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][CH:38]=1)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:26]>>[CH2:25]([O:27][C:28](=[O:52])[CH:29]([C:37]1[CH:42]=[CH:41][C:40]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:39][CH:38]=1)[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH3:26]
Reactant: CCOC(=O)C(Cc1ccccc1)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CCCc1ccccc1
Product: CCOC(=O)C(Cc1ccccc1)c1ccc(-c2ccc(-c3onc(C)c3C(O)CCCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-butan-1-ol and 3-phenyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:5]=[C:6]([CH3:23])[C:7]=1[C:8]1[C:9](=[O:22])[CH:10]([CH:15](O)[CH:16]2[CH2:20][CH2:19][O:18][CH2:17]2)[CH2:11][C:12]=1[O:13]C.Cl>CC(C)=O>[CH3:23][C:6]1[CH:5]=[C:4]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:3]=[C:2]([CH3:1])[C:7]=1[CH:8]1[C:9](=[O:22])[C:10](=[CH:15][CH:16]2[CH2:20][CH2:19][O:18][CH2:17]2)[CH2:11][C:12]1=[O:13]
Reactant: COC1=C(c2c(C)cc(-c3ccccc3)cc2C)C(=O)C(C(O)C2CCOC2)C1
Agent: Cl
Solvent: CC(C)=O
Product: Cc1cc(-c2ccccc2)cc(C)c1C1C(=O)CC(=CC2CCOC2)C1=O
Temperature: 130 °C
Yield: 28.7 %

Procedure:
A mixture of 2-(3,5-Dimethylbiphenyl-4-yl)-5-[hydroxyl-(tetrahydrofuran-3-yl)-methyl]-3-methoxy-cyclopent-2-enone (1.1 g, 2.8 mmol), acetone (21 ml) and 2N hydrochloric acid (10 ml) is heated under microwave conditions at 130° C. for 40 minutes. The organic solvent is evaporated under vacuo, diluted with water (100 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts are combined, washed with water and brine, dried over anhydrous sodium sulphate, filtered and the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel to give 2-(3,5-dimethylbiphenyl-4-yl)-4-[1-(tetrahydrofuran-3-yl)methylidene]-cyclopentane-1,3-dione (0.29 g).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[N:24]=[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]3[CH:23]=[CH:22][C:17]4[O:18][CH2:19][CH2:20][O:21][C:16]=4[CH:15]=3)[N:8]2[N:7]=1)=[O:4].C(N(CC)CC)C.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>ClCCl>[O:18]1[C:17]2[CH:22]=[CH:23][C:14]([C:13]3[N:8]4[N:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:36]5[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]5)[N:24]=[C:9]4[CH:10]=[CH:11][CH:12]=3)=[CH:15][C:16]=2[O:21][CH2:20][CH2:19]1
Reactant: CN1CCNCC1
Reactant: O=C(CCl)Nc1nc2cccc(-c3ccc4c(c3)OCCO4)n2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(CC(=O)Nc2nc3cccc(-c4ccc5c(c4)OCCO5)n3n2)CC1
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-N-[5-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-acetamide (0.1 g, 0.29 mmol) in dichloromethane (2 mL), triethylamine (0.061 mL, 0.43 mmol) and N-methylpiperazine (0.036 mL, 0.32 mmol) were added successively and the mixture was stirred overnight. The solvent was removed under reduced pressure and the crude then purified by prep LCMS. LCMS Method: 2, RT=2.19 min, MI=409 [M+1], NMR 1H (DMSO): 2.29 (s, 3H), 2.48-2.50 (m, 4H), 2.53-2.58 (m, 4H), 3.25 (brs, 2H), 4.33 (brs, 4H), 7.03 (d, 1H), 7.25 (dd, 1H), 7.47 (dd, 1H), 7.62-7.71 (m, 3H).
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:38]([C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:47](=[O:67])[O:48][CH2:49][C:50]2([C:56](=[O:66])[NH:57][CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=3[Cl:65])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)=[CH:42][CH:41]=1)[CH3:39].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:38]([C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:47](=[O:67])[O:48][CH2:49][C:50]2([C:56](=[O:66])[NH:57][CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=3[Cl:65])[CH2:55][CH2:54][N:53]([C:3](=[O:5])[CH2:2][NH:1][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:52][CH2:51]2)=[CH:42][CH:41]=1)[CH3:39]
Reactant: CCc1ccc(NC(=O)OCC2(C(=O)NCc3ccccc3Cl)CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1ccc(NC(=O)OCC2(C(=O)NCc3ccccc3Cl)CCN(C(=O)CNC(=O)OC(C)(C)C)CC2)cc1
Reaction time: 3 h
Yield: 83.2 %

Procedure:
To a solution of Boc-Gly-OH (54 mg, 0.31 mmol, 1.2 equiv.) in DMF (1 mL) were added HATU (120 mg, 0.31 mmol, 1.2 equiv.), followed by addition of (4-(2-chlorobenzylcarbamoyl)piperidin-4-yl)methyl 4-ethylphenylcarbamate hydrochloride (120 mg, 0.26 mmol, 1 equiv.) and DIEA (89 μL, 0.51 mmol, 2 equiv.) at rt The reaction mixture was stirred for 3 h and purified on RP-HPLC using a mixture of acetonitrile and H2O to give (1-(2-(tert-butoxycarbonyl)aminoacetyl)-4-(2-chlorobenzylcarbamoyl)piperidin-4-yl)methyl 4-ethylphenylcarbamate (127 mg, 84%). LRMS (M-Boc+H+) m/z 487.1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[CH:7]/[C:8](=[O:16])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[H][H]>[Pd].C(#N)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8](=[O:16])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CCC(=O)/C=C/c1ccco1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC#N
Product: CCOC(=O)CCC(=O)CCc1ccco1

Procedure:
In a round bottom flask was placed 1.334 g (6.000 mmol) of (E)-ethyl 6-(furan-2-yl)-4-oxohex-5-enoate. 6 mL of acetonitrile was added and stirring was begun. To this was added 0.064 g Pd/C (en) and hydrogen was added using a balloon (˜1 atm). The reaction mixture was stirred for 48 h and the mixture was then purified by flash column chromatography using 15% ether/hexane, v/v. Purification gave rise to 0.4817 g (73%) of the saturated system 1H (CDCl3) δ 1.25 (t, J=7 Hz, 3H), 2.6 (m, 2H), 2.8 (m, 2H), 2.9 (m, 2H), 3.0 (m, 2H), 4.16 (q, J=7 Hz), 6.0 (1H), 6.3 (1H), 7.3 (1H).
Reaction SMILES: [Cl:1][CH:2]=[C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[O:4][Si](C(C)C)(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(#N)C>[Cl:1][CH2:2][C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)=[O:4]
Reactant: CC(C)[Si](OC(=CCl)c1ccccn1)(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: O=C(CCl)c1ccccn1
Yield: 84.6 %

Procedure:
Crude 2-{2-chloro-1-[(triisopropylsilyl)oxy]ethenyl}pyridine (117.3 g, 0.376 mol) is placed in a 4 L plastic bottle and is dissolved in acetonitrile (0.4 L). To the stirring solution is added 48% aqueous HF (170 mL, 0.45 mL/mmol) and the progress of the reaction is monitored by reverse phase analytical HPLC. After. Ca. 2 hours the reaction is judged to be complete, and the pH of the solution is carefully adjusted to ca. 8 with saturated aq. NaHCO3. The mixture is poured into a separatory funnel containing CH2Cl2 (1.5 L). The organic phase is removed and the aq. layer is extracted with CH2Cl2 (2×1.0 L). The combined organic layers are dried (Na2SO4), and concentration in vacuo affords the title compound (49.5 g, 85%) as a tan solid (after cooling). The crude material is judged to be quite pure by 1H-NMR and HPLC and is used as is in the Noyori asymmetric reduction.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]2[O:22][C:21]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:20]=3[O:19][CH2:18]2)[CH2:12][CH2:11]1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>ClCCl>[Cl:27][C:24]1[CH:25]=[CH:26][C:20]2[O:19][CH2:18][C@H:17]([CH2:16][N:13]3[CH2:14][CH2:15][CH:10]([CH2:9][NH:8][S:35]([C:32]4[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=4)(=[O:37])=[O:36])[CH2:11][CH2:12]3)[O:22][C:21]=2[CH:23]=1
Reactant: NCC1CCN(C[C@H]2COc3ccc(Cl)cc3O2)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NCC1CCN(C[C@H]2COc3ccc(Cl)cc3O2)CC1)c1ccc(F)cc1
Reaction time: 3 h
Yield: 59.3 %

Procedure:
Triethylamine (0.62 ml) was added to a solution of (S)-4-(aminomethyl)-1-(7-chloro-1,4-benzodioxan-2-ylmethyl)piperidine (0.44 g) and 4-fluorobenzenesulphonyl chloride (0.65 g) in dichloromethane (22 ml) under nitrogen and stirred for 3 hours. The reaction was left to stand for 14 hours then diluted with dichloromethane (100 ml), washed with water (100 ml) and brine (100 ml), dried over anhydrous magnesium sulphate and concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with a 19:1 mixture of dichloromethane and methanol gave a yellow oil which on trituration with diethyl ether yielded (S)-(-)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-4-fluorobenzene-sulphonamide as a yellow solid (0.4 g); m.p. 127-129° C., [α]D22 -41.3° (c=0.72, MeOH).
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:21][CH:20]=3)=[CH:18][C:13]=2[CH:12]=[C:11]([C:33]([O:35]C)=[O:34])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:23][CH:24]=3)=[CH:18][C:13]=2[CH:12]=[C:11]([C:33]([OH:35])=[O:34])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccccc2)cc1
Temperature: 50 °C
Yield: 98.8 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 1-benzyl-7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.49 g). To the solution was added 1N sodium hydroxide solution (10 ml), and the mixture was heated at 50° C. overnight and concentrated, then neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 1-benzyl-7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.47 g) as yellow crystals.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1([CH3:14])[NH:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8][S:7]1)=[O:5].C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>>[CH3:1][CH2:2][O:3][C:4]([C:6]1([CH3:14])[N:10]([C:22](=[O:24])[CH3:23])[CH:9]([C:11]([OH:13])=[O:12])[CH2:8][S:7]1)=[O:5]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C1(C)NC(C(=O)O)CS1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C)SCC(C(=O)O)N1C(C)=O

Procedure:
L-Cysteine hydrochloride monohydrate (100 g, 569 mmol) was dissolved in water (200 ml), and the pH of the solution was adjusted to 5.03 with 6N aqueous sodium hydroxide. The reaction mixture was heated to 40° C., ethyl pyruvate (76 ml, 684 mmol) was gradually added thereto, and the mixture was stirred at 40° C. for 3.5 hr to give 2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (the ratio of trans form:cis form of the resultant product in the reaction mixture was confirmed by the area ratio of an HPLC chart to find about 55:45). After completion of the reaction, the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. To the obtained ethyl acetate solution was added triethylamine (159 ml, 1141 mmol) under argon, and acetyl chloride (61 ml, 858 mmol) was slowly added dropwise thereto. The reaction mixture was heated under reflux for 4 hr to give N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (the ratio of trans form:cis form of the resultant product in the reaction mixture was confirmed by the area ratio of an HPLC chart to find about 95:5). After completion of the reaction, water (300 ml) was added thereto, and the pH of the mixture was adjusted to 1.0 with HCl. The aqueous layer was separated, and the organic layer was washed with water (300 ml), washed with saturated brine, and dried over anhydrous magnesium sulfate. The obtained ethyl acetate solution was concentrated until a weight of 500 g, to the residue was added heptane to allow recrystallization of the residue, and the crystals were washed with heptane/ethyl acetate=2/1, and dried at 50° C. under reduced pressure to give the trans form (mixture of (2R,4S)-form, (2S,4R)-form) of N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester as crystals (81 g, yield 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.[CH2:13]([N:15]([CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH:19]([NH2:21])[CH3:20])[CH3:14]>>[CH3:14][CH2:13][N:15]([CH2:16][CH2:17][CH2:18][CH:19]([NH:21][C:6]1[CH:7]=[CH:8][N:9]=[C:10]2[CH:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=12)[CH3:20])[CH2:22][CH3:23]
Reactant: CCN(CC)CCCC(C)N
Reactant: O=C1CCNc2cc(Cl)ccc21
Product: CCN(CC)CCCC(C)Nc1ccnc2cc(Cl)ccc12
Yield: 98.05 %

Procedure:
17.904 millimols, i.e. a yield of 98.05% relative to the 7-chloro-1,2,3,4-tetrahydroquinolin-4-one converted, and a yield of 96.86% relative to the 1-diethylamino-4-amino-pentane converted, and
Reaction SMILES: [Pd:1].C([O:6][C:7](=[O:9])[CH3:8])CCC>>[C:7]([O-:9])(=[O:6])[CH3:8].[Pd+2:1].[C:7]([O-:9])(=[O:6])[CH3:8]
Reactant: CCCCOC(C)=O
Reactant: [Pd]
Product: CC(=O)[O-]
Product: [Pd+2]

Procedure:
A thin film of organic palladium compound was formed on the substrate 1 that carries thereon the device electrodes 4 and 5 by applying an organic palladium solution prepared by dissolving an organic palladium compound formed from palladium acetate and amine into butylacetate to the substrate 1. Then, the substrate 1 was baked at 300° C. for 10 minutes in the atmosphere within an oven to decompose and oxide the organic palladium on the substrate 1 until a film 7 of PdO was formed there.
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[C:15]([CH3:20])[N:14]=1>COCCOC>[BrH:1].[Br:19][C:16]1[CH:17]=[CH:18][C:13]2[N:14]([CH2:2][C:3]([C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6])([OH:11])[N:12]=2)[C:15]=1[CH3:20]
Reactant: Cc1nc(N)ccc1Br
Reactant: O=C(CBr)C(F)(F)C(F)(F)F
Solvent: COCCOC
Product: Br
Product: CC1=C(Br)C=CC2=NC(O)(C(F)(F)C(F)(F)F)CN21
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
A mixture of 2.4 g of 1-bromo-3,3,4,4,4-pentafluorobutan-2-one and 5 ml of DME was added to a mixture of 1.87 g of 2-amino-5-bromo-6-methylpyridine and 10 ml of DME, and the mixture was stirred at room temperature for 3 hours. The precipitated solid was filtered, and washed with 10 ml of DME to obtain 3.95 g of 6-bromo-5-methyl-2-pentafluoroethyl-2,3-dihydroimidazo[1,2-a]pyridin-2-ol hydrobromide.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][Cl:6].[C:8]1([CH:14]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:16]3([CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[O:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[ClH:6].[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][C:14]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:16]2([CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[O:15]1
Reactant: CN(C)CCCCl
Reactant: c1ccc(C2OC3(CCOCC3)c3ccccc32)cc1
Product: CN(C)CCCC1(c2ccccc2)OC2(CCOCC2)c2ccccc21
Product: Cl

Procedure:
By following the manipulative procedure described above in Example 1c, 3-dimethylaminopropyl chloride is reacted with 1,2',3,3',5',6'-hexahydro-3-phenylspiro(isobenzofuran-1,4'-pyran). The hydrochloride salt of the product is recrystallized from an acetone-ethyl ether mixture to give 3-(3-dimethylaminopropyl)-1,2',3,3',5',6'-hexahydro-3-phenylspiro[isobenzofuran-1,4'-pyran] hydrochloride, m.p. 234.5° - 235.5°C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:26])[N:14]([C:19]4[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:9][CH2:8][C:6]=2[N:7]=1.CCN(CC)CC.[CH3:34][C:35]1[CH:39]=[CH:38][O:37][C:36]=1[C:40](Cl)=[O:41]>C1COCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:26])[N:14]([C:19]4[CH:20]=[CH:21][C:22]([NH:25][C:40]([C:36]5[O:37][CH:38]=[CH:39][C:35]=5[CH3:34])=[O:41])=[CH:23][CH:24]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Cc1ccn(-c2ccc(N)cc2)c(=O)c1N1CCc2nc(N)ncc2C1
Reactant: Cc1ccoc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccoc1C(=O)Nc1ccc(-n2ccc(C)c(N3CCc4nc(N)ncc4C3)c2=O)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
A solution of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-1-(4-aminophenyl)-4-methylpyridin-2(1H)-one (25 mg, 0.075 mmol) was dissolved in THF (2 mL) and NEt3 (3 mL) and then treated with 3-methylfuran-2-carbonyl chloride (13 mg, 0.090 mmol). The reaction was heated to 40° C. and allowed to stir for 3 h. The reaction was cooled and then extracted with EtOAc (3×˜10 mL) and water (˜10 mL). The combined organic layers were then washed with ˜20 mL of NaHCO3(aq). The organic layers were then dried over anhydrous Na2SO4 (s), filtered and the concentrated in vacuo. The crude mixture was purified over silica (EtOAc/Hexanes gradient). Following concentration of the appropriate fractions the title compound was isolated as a grey solid (25 mg, 76%). 1H NMR (DMSO) δ: 9.52 (s, 1H), 7.92 (s, 1H), 7.80(m, 1H), 7.42-7.52 (m, 2H), 7.41 (m, 1H), 7.24-7.32 (m, 2H), 6.66 (m, 1H), 6.28 (s, 2H), 6.14 (m, 1H), 4.01 (br. s, H), 3.24 (s, 2H), 2.67 (t, J=5.3 Hz, 2H), 2.35 (s, 3H), 2.20 (s, 3H).