Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH2:16][CH:17]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C@H:30]4[CH2:34][CH2:33][NH:32][CH2:31]4)=[CH:25][CH:24]=3)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13]2)=[CH:8][CH:7]=1)(=[NH:5])[NH2:4].Cl.[C:36](=[NH:41])(OCC)[CH3:37].C(N(CC)CC)C.Cl>C(O)C>[ClH:1].[ClH:1].[C:36]([N:32]1[CH2:33][CH2:34][C@H:30]([O:29][C:26]2[CH:27]=[CH:28][C:23]([CH:17]([CH2:16][C:12]3[CH:11]=[CH:10][C:9]4[C:14](=[CH:15][C:6]([C:3](=[NH:4])[NH2:5])=[CH:7][CH:8]=4)[CH:13]=3)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:24][CH:25]=2)[CH2:31]1)(=[NH:41])[CH3:37]
Reactant: CCOC(C)=N
Reactant: CCOC(=O)C(Cc1ccc2ccc(C(=N)N)cc2c1)c1ccc(O[C@H]2CCNC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc2ccc(C(=N)N)cc2c1)c1ccc(O[C@H]2CCN(C(C)=N)C2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 193.4 %

Procedure:
In 1,000 ml of ethanol was dissolved 105.3 g of ethyl (+)-3-(7-amidino-2-naphthyl)-2-[4-[((3S)-3-pyrrolidinyl)oxy]phenyl]propionate dihydrochloride. With stirring at room temperature, the thus prepared solution was mixed with 51.5 g of ethyl acetimidate hydrochloride. With ice cooling and stirring, 89 ml of triethylamine was added dropwise to the above solution while keeping the inner temperature at 3 to 5° C., and the stirring was continued for 2.5 hours while keeping the temperature at 5° C. or below. After distilling off the solvent under a reduced pressure at a low temperature, the resulting reaction solution was adjusted to pH 4-5 with dilute hydrochloric acid, followed by further distillation under a reduced pressure to remove the solvent. The resulting residue was purified by subjecting it to column chromatography using a column packed with a highly porous polymer type synthetic adsorbent (styrene-divinylbenzene polymer: Diaion HP-20) and using a water/acetonitrile mixture as an elution solvent. Thereafter, thus eluted fractions of interest were pooled, mixed with a small amount of dilute hydrochloric acid, and then concentrated to dryness. In this way, 110.1 g of the title compound was obtained in the form of a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=O.[OH-].[Na+].[C:11]([O-:16])(=[O:15])[C:12]([CH3:14])=O.[Na+]>CCO>[S:4]1[C:3]2[C:2](=[N:1][C:12]([C:11]([OH:16])=[O:15])=[CH:14][CH:7]=2)[CH:6]=[CH:5]1
Reactant: CC(=O)C(=O)[O-]
Reactant: Nc1ccsc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2sccc2n1
Temperature: 60 °C
Yield: 71.5 %

Procedure:
To a solution of 3-amino-2-formylthiophene (10 g, 78 mmol) in EtOH (50 mL) was added a mixture of aqueous NaOH (50 mL, 5%) and sodium pyruvate (17.16 g, 156 mmol). The mixture was heated to 60° C. for 2 hr. The mixture was cooled and washed with Et2O: EtOAc 1:1 and then acidified with 1 N HCl to pH 3 at 0° C. The mixture was filtered and the solid was air dried to give 10 g (71%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.Cl[C:16]1[N:21]=[C:20]([Cl:22])[CH:19]=[C:18]([O:23][CH3:24])[N:17]=1>C(OCC)C.CCCCCC>[Cl:22][C:20]1[CH:19]=[C:18]([O:23][CH3:24])[N:17]=[C:16]([C:5]2[S:4][C:3]([C:2]([F:9])([F:8])[F:1])=[CH:7][CH:6]=2)[N:21]=1
Reactant: FC(F)(F)c1cccs1
Reactant: COc1cc(Cl)nc(Cl)n1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1cc(Cl)nc(-c2ccc(C(F)(F)F)s2)n1
Temperature: -40 °C

Procedure:
2.05 g 2-Trifluoromethylthiophene in 20 mL diethylether are treated with 8.2 mL of a 1.6 M solution of n-butyllithium in hexane at -70° C. After 30 minutes the mixture is warmed to -40° C. and added dropwise to a solution of 2,4-dichloro-6-methoxypyrimidine in 20 mL of ether, which is kept at 0° C. The mixture is allowed to reach room temperature, is washed with water and 0.24 g of the product are isolated as an oil after flash chromatography.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CN(C)C=O>[CH3:13][O:12][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[N:1]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:2]=[CH:3]2)=[O:11]
Reactant: CCCCCBr
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCn1ccc2cc(C(=O)OC)ccc21
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Methyl indole-5-carboxylate (0.875 g, 5.0 mmol) was added to a suspension of sodium hydride (60% in oil, 0.22 g, 5.5 mmol) in N,N-dimethylformamide (15 mL) at 0° C. The resultant solution was stirred at room temperature for 30 min. Bromopentane (0.706 mL, 5.69 mmol) was added to the solution, and stirring was continued for 4 hours. The solution was poured into ice water (100 mL), and the product was extracted into dichloromethane. The organic solution was washed several times with water and dried over sodium sulfate. The solvent was evaporated in vacuo, and the residue was purified by flash silica gel chromatography using 5% ethyl acetate in hexane as the eluant, to give the product, 0.975 g (79%), as an oil. MS: m/z 280 (MH+). 1H NMR (CDCl3): 0.87 (t, 3 H), 1.22-1.40 (m, 4 H), 1.77-1.87 (m, 2 H), 3.92 (s, 3 H), 4.11 (t, 2 H), 6.58 (d, 1 H), 7.14 (d, 1 H), 7.32 (d, 1 H), 7.90 (d of d, 1 H) and 8.40 (d, 1 H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](O)=O)=[CH:11][C:10]=1[CH2:18][O:19][CH3:20])[CH3:2].[NH2:21][C:22](=[N:40][OH:41])[C:23]1[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:28])=[C:25]([F:39])[CH:24]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:41][N:40]=[C:22]([C:23]3[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:28])=[C:25]([F:39])[CH:24]=3)[N:21]=2)=[CH:11][C:10]=1[CH2:18][O:19][CH3:20])[CH3:2].[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:41][N:40]=[C:22]([C:23]3[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[C:25]([F:39])[CH:24]=3)[N:21]=2)=[CH:11][C:10]=1[CH2:18][O:19][CH3:20])[CH3:2]
Reactant: CCc1ccccc1-c1ccc(C(=O)O)cc1COC
Reactant: CCOC(=O)CCNC(=O)c1ccc(C(N)=NO)cc1F
Product: CCOC(=O)CCNC(=O)c1ccc(-c2noc(-c3ccc(-c4ccccc4CC)c(COC)c3)n2)cc1F
Product: CCc1ccccc1-c1ccc(-c2nc(-c3ccc(C(=O)NCCC(=O)O)c(F)c3)no2)cc1COC

Procedure:
Ethyl N-(4-{5-[2′-ethyl-2-(methoxymethyl)biphenyl-4-yl]-1,2,4-oxadiazol-3-yl}-2-fluorobenzoyl)-beta-alaninate was prepared following the general procedure 3 starting from Intermediate 7 and Intermediate 6. It was hydrolyzed following the general procedure 9 affording the title compound as a white powder. 1H NMR (DMSO-d6, 300 MHz) δ 12.31 (s, 1H), 8.61-8.55 (m, 1H), 8.33 (d, J=1.8 Hz, 1H), 8.17 (dd, J=7.9, 1.8 Hz, 1H), 8.03 (dd, J=8.0, 1.5 Hz, 1H), 7.95 (dd, J=10.7, 1.5 Hz, 1H), 7.84 (t, J=7.6 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.41 (s, 1H), 7.39 (s, 1H), 7.34-7.26 (m, 1H), 7.12 (d, J=7.5 Hz, 1H), 4.23 (d, J=12.8 Hz, 1H), 4.14 (d, J=12.8 Hz, 1H), 3.49 (m, 2H), 3.25 (s, 3H), 2.53 (t, J=6.8 Hz, 2H), 2.47-2.19 (m, 2H), 0.99 (t, J=7.5 Hz, 3H). LC/MS (Method B): 502.4 (M−H)−, 504.4 (M+H)+. HPLC (Method A) Rt 5.03 min (Purity: 97.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:16]=[N:17][CH:18]=[C:19](F)[CH:20]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:24][NH:25][CH3:26]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:20]=[C:19]([N:25]([CH3:26])[CH3:24])[CH:18]=[N:17][CH:16]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNC
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cncc(F)c1
Agent: Cl
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cncc(N(C)C)c1

Procedure:
The title compound, MS: m/e=337.3 (M+), was prepared in accordance with the general method of example 27 from 3-[4-(3-chloro-phenylethynyl)-2-methyl-imidazol-1-yl]-5-fluoro-pyridine and dimethylamine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:21]1[CH2:30][C@H:29]([O:31][CH2:32][CH2:33][CH2:34][OH:35])[CH2:28][C@H:22]1[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20].[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[C:40]([O:48][C:49]([F:52])([F:51])[F:50])[CH:39]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:44]([C:41]1[CH:42]=[CH:43][C:38]([O:37][CH3:36])=[CH:39][C:40]=1[O:48][C:49]([F:50])([F:51])[F:52])(=[O:46])=[O:45])[C:6](=[O:11])[C:5]2([N:21]1[CH2:30][C@H:29]([O:31][CH2:32][CH2:33][CH2:34][OH:35])[CH2:28][C@H:22]1[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20]
Reactant: COc1ccc(C)cc1C1(N2C[C@H](OCCCO)C[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C)ccc3OC)(N3C[C@H](OCCCO)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 29.8 %

Procedure:
With 870 mg of the compound obtained in Step 139-4 and 603 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 390 mg of the title compound (amorphous) was obtained by a similar procedure to Example 2.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[NH2:14][C:15]1[C:24]([Br:25])=[CH:23][C:22](I)=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18].C([O-])([O-])=O.[K+].[K+].O1CCOCC1>O>[NH2:14][C:15]1[C:24]([Br:25])=[CH:23][C:22]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=2)=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1cc(I)cc(Br)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)cc(Br)c1N
Temperature: 70 °C
Yield: 174 %

Procedure:
N-Bromosuccinimide (13.5 g, 76.0 mmol) was added in portions over 1.5 h to a stirred solution of methyl 2-amino-5-iodobenzoate (20 g, 72 mmol) in CHCl3 (320 mL) at RT. This was stirred overnight and then silica gel chromatography (step gradient elution with hexane containing 10 to 30% DCM) afforded impure methyl 2-amino-3-bromo-5-iodobenzoate (21 g) as a white solid that was used as such. A flask containing a mixture of 3- (trifluoromethyl)phenylboronic acid (3.73 g, 19 6 mmol), methyl 2-amino-3-bromo-5-iodobenzoate (7.0 g, 16 mmol), K2CO3 (6.85 g, 49 6 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1.4 g, 1 7 mmol), dioxane (140 mL), and water (28 mL) was degassed and flushed with N2 twice and then heated at 70° C. for 3 h. It was cooled to RT, diluted with EtOAc, washed with water (2×), brine, and then dried over Na2SO4. Removal of the solvents followed by silica gel chromatography (step gradient elution with DCM containing 0 to 7% MeOH) afforded impure methyl 4-amino-5-bromo-3′-(trifluoromethyl)biphenyl-3-carboxylate (6.2 g, 10.44 mmol, 63.2% yield) as a white solid that was used as such. A mixture of 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (303 mg, 1.00 mmol), methyl 4-amino-5-bromo-3′-(trifluoromethyl)biphenyl-3-carboxylate (250 mg, 0.668 mmol), tetrakistriphenylphosphine palladium(0) (77 mg, 0.067 mmol), K2CO3 (369 mg, 2.67 mmol) in a microwave vial was flushed with nitrogen and DMF (2.7 mL) was added. The vial was sealed and heated at 100° C. overnight. The reaction was partitioned between EtOAc and water. The organic phase was washed with brine, dried over sodium sulfate, and the solvent removed. Silica gel chromatography (step gradient elution with hexane containing 0, to 20% EtOAc) afforded methyl 4′-amino-4″-(4-methylpiperidin-1-yl)-3-trifluoromethyl-[1,1′:3′,1″-terphenyl]-5′-carboxylate (150 mg, 0.532 mmol, 80% yield). MS (ESI) m/z 470.20 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 8.16 (1H, d, J=2.14 Hz), 7.81 (1H, s), 7.73-7.78 (1H, m), 7.49-7.56 (3H, m), 7.37 (2H, d, J=8.55 Hz), 7.05 (2H, d, J=8.55 Hz), 6.15 (2H, br, s.), 3.95 (3H, s), 3.26-3.38 (4H, m), 2.60-2.69 (4H, m), 2.39 (3H, s).
Reaction SMILES: C([Si]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=1[Cl:21])(C)C)(C)(C)C.O.O.Cl[Sn]Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>CCO>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][OH:8])=[C:13]([Cl:21])[CH:14]=1
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc([N+](=O)[O-])cc1Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(OCCO)c(Cl)c1
Reaction time: 4 h
Yield: 3.4 %

Procedure:
A mixture of tert-butyl-(2-(2-chloro-4-nitrophenoxy)ethoxy)dimethylsilane (475 mg, 1.4 mmol) and SnCl2.2H2O (1.07 g, 5.7 mmol) in EtOH (40 mL) was heated to reflux and stirred for 4 hr. After allowing to cool, the mixture was poured into EtOAc (50 mL) and saturated NaHCO3 (50 mL), then filtered through celite. The filtrate was partitioned and the aqueous layer extracted with EtOAc (2×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum to leave a crude residue. The residue was dry-loaded on to silica gel and purified by column chromatography on silica gel using EtOAc/heptane (2:8 to 1:0) as eluent to give the product (9 mg, 3% yield).
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5]1.[CH2:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][NH:22]1.[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35]>C(O)(C)C.C(O)C>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([CH:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:20][N:22]4[CH2:23][CH2:24][C:25]5[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:21]4)[CH2:5][CH2:6]3)=[N:11][O:12][C:13]=2[CH:18]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Fc1ccc2c(C3CCN(CC4CO4)CC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CC(C)O
Product: OC(CN1CCC(c2noc3cc(F)ccc23)CC1)CN1CCc2ccccc2C1

Procedure:
A mixture of N-[3-(2,3-epoxy)propyl]-4-(6-fluoro-1,2-benzisoxaz-3-yl)piperidine (3.56 g, 12.9 mmol) and 1,2,3,4-tetrahydroisoquinoline (2.06 g, 15.4 mmol) in isopropyl alcohol (150 ml) was heated at reflux for 4 hours. At the end of the reaction, the solvent was removed. The residual oil was purified by flash chromatography over a silica gel column (SiO2, 45 g, eluted with 1% CH3OH: 99% methylene chloride). The product thus purified as a light oil, weighed 4.15 g. The oil was treated with a solution of fumaric acid (1.98 gm, 17 mmol) in ethanol. The white crystals so obtained were recrystallized in a large volume of hot ethanol (~150 ml). The recrystallized crystals weighed 2.75 g, m.p. 179-181° C.
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:7][C@@H:6]([O:8][CH2:9][O:10][CH3:11])[CH2:5][N:4]1[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.C(N(CC)CC)C.CS([Cl:33])(=O)=O>ClCCl>[Cl:33][C@H:3]1[CH2:7][C@@H:6]([O:8][CH2:9][O:10][CH3:11])[CH2:5][N:4]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: COCO[C@@H]1C[C@H](CO)N(CCc2ccc(OC)cc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCO[C@@H]1C[C@H](Cl)CN(CCc2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 76 %

Procedure:
To a solution of 4.50 g (20.2 mmol) of (2R,4R)-(+)-2-(hydroxymethyl)-4-(methoxymethoxy)-1-(4-methoxyphenethyl)pyrrolidine and 2.40 ml of triethylamine (23.8 mmol) in dichloromethane (35 ml) was added 2.62 ml (22.9 mmol) of methanesulfonylchloride and the mixture was stirred at room temperature for 4.5 hours. The mixture was diluted with dichloromethane and the solution was washed with saturated aqueous sodium carbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silicagel column chromatography (ethyl acetate:n-hexane=1:2) to give 4.82 g (87.2%) of (3S,5R)-(+)-3-chloro-5-(methoxymethoxy)-1-(4-methoxyphenethyl)piperidine as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[C:17]([OH:22])[CH:18]=[CH:19][CH:20]=3)[C:15](=[O:23])[N:14]2[CH3:24])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:25]=[C:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[C:17]([OH:22])[CH:18]=[CH:19][CH:20]=3)[C:15](=[O:23])[N:14]2[CH3:24])[CH2:10][CH2:11][N:35]2[CH2:36][CH2:37][CH:32]([N:27]3[CH2:28][CH2:29][CH2:30][CH2:31][C:26]3=[O:25])[CH2:33][CH2:34]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1C(=O)c2c(O)cccc2C1C(CC=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C1CCCCN1C1CCNCC1
Product: CN1C(=O)c2c(O)cccc2C1C(CCN1CCC(N2CCCCC2=O)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 156.7 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(4-hydroxy-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.31 g) was coupled to 4-(2-oxopiperidino)piperidine (0.156 g) by a method similar to that described in Example 8. The reaction product was purified by chromatography and converted to the corresponding hydrochloride salt as described in the Example 8 to afford the title compound (0.378 g); mp 230-240° C.; MS: m/z=530(M+1); NMR(CD3SOCD3): 1.69 (m,5), 3.36 (s,3), 3.6 (m,3), 4.55 (broad,1), 4.76 (d,1, J=3), 6.81 (m,2), 7.04 (d,1 J=1.7), 7.37 (m,3). Analysis for C28H33Cl2N3O3.1.2 HCl.1.0 H2O: Calculated: C, 56.73; H, 6.16, N, 7.09; Found: C, 56.71; H, 5.91; N, 7.06.
Reaction SMILES: [CH3:1][I:2].[CH3:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:11]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[N:12][S:13][N:14]=2)[CH2:6][CH2:5]1>CC(C)=O>[I-:2].[CH3:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]2[C:11]([C:15]3[CH:16]=[N+:17]([CH3:1])[CH:18]=[CH:19][CH:20]=3)=[N:12][S:13][N:14]=2)[CH2:8][CH2:9]1
Reactant: CI
Reactant: CC1CCN(c2nsnc2-c2cccnc2)CC1
Solvent: CC(C)=O
Product: CC1CCN(c2nsnc2-c2ccc[n+](C)c2)CC1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (0.5 ml, 8 mmol) and 3-(4-(4-methylpiperidino)-1,2,5-thiadiazol-3-yl) pyridine (0.8 g, 3.1 mmol) in acetone (5 ml) was stirred at room temperature for 18 h. The title compound precipitated from the solution and was collected by filtration to yield 1.14 g (92%).
Reaction SMILES: [C:1]([C:4]1[C:25]([OH:26])=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][CH2:7][CH:8]([OH:21])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[O-:27][CH2:28][CH3:29].[Na+].[Na].C([OH:34])C>C(OCC)(=O)C(OCC)=O.CCOCC>[C:28]([C:29]1[O:26][C:25]2[C:4]([C:1](=[O:3])[CH:2]=1)=[C:5]([O:6][CH2:7][CH:8]([OH:21])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:18])([CH3:19])[CH3:20])=[CH:13][CH:12]=1)[CH:22]=[CH:23][CH:24]=2)([OH:34])=[O:27]
Reactant: CCO
Reactant: CC[O-]
Reactant: CC(=O)c1c(O)cccc1OCC(O)COc1ccc(C(C)(C)C)cc1
Agent: [Na+]
Agent: [Na]
Solvent: CCOC(=O)C(=O)OCC
Solvent: CCOCC
Product: CC(C)(C)c1ccc(OCC(O)COc2cccc3oc(C(=O)O)cc(=O)c23)cc1

Procedure:
A solution of 1-(2-acetyl-3-hydroxyphenoxy)-2-hydroxy-3-p-t-butylphenoxypropane (14.4 g) in diethyl oxalate (15 ml) was added to a suspension of sodium ethoxide, prepared from sodium (3.0 g) and ethanol (30 ml), in ether (200 ml). The mixture was heated under reflux for 1.5 hours, and the brown-coloured residue was poured onto ice (100 g). After acidification with a solution of acetic acid (12 ml) in water (80 ml), the ether layer was separated, and the aqueous solution extracted with ether (3 × 25 ml). The solvent was then removed from the combined ethereal layer and ethereal extracts. The residue was dissolved in a mixture of acetic acid (80 ml) and hydrochloric acid (30 ml) and heated under reflux for 1 hour. On pouring into water (1 L) 1-(2-carboxychromon-5-yloxy)-3-p-t-butylphenoxypropane, 10.7 g, was obtained as a beige gum.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([S:12][C@H:13]1[N:16]([CH:17]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])O)[C:15](=[O:32])[C@@H:14]1[C@H:33]([O:35][C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)=[O:37])[CH3:34])=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.S(Cl)([Cl:57])=O>O1CCCC1>[Si:1]([O:8][CH2:9][C:10]([S:12][C@H:13]1[N:16]([CH:17]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[Cl:57])[C:15](=[O:32])[C@@H:14]1[C@H:33]([O:35][C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)=[O:37])[CH3:34])=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N(C(O)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1SC(=O)CO[Si](C)(C)C(C)(C)C
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N(C(Cl)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1SC(=O)CO[Si](C)(C)C(C)(C)C

Procedure:
A solution of 0.27 g of 4(R)-t-butyldimethylsilyloxyacetylthio-3(S)-[1(R)-p-nitrobenzyloxycarbonyloxyethyl]-1-(1-p-nitrobenzyloxycarbonyl-1-hydroxymethyl)-azetidin-2-one in 3 ml of anhydrous tetrahydrofuran was cooled at 0° C. 0.045 ml of pyridine and 0.03 ml of thionyl chloride were added. After 10 minutes the mixture was filtered.
Reaction SMILES: CS[CH:3]1[CH:8]([C:9]#[N:10])[C:7](=[O:11])[NH:6][C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)=[N:4]1.[O:18]1[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[O:22][CH2:21][CH2:20][CH2:19]1>>[CH2:24]1[C:23]2([O:18][CH2:19][CH2:20][CH2:21][O:22]2)[CH2:28][CH2:27][N:26]([C:3]2[N:4]=[C:5]([CH2:12][C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[NH:6][C:7](=[O:11])[C:8]=2[C:9]#[N:10])[CH2:25]1
Reactant: CSC1N=C(Cc2ccsc2)NC(=O)C1C#N
Reactant: C1COC2(CCNCC2)OC1
Product: N#Cc1c(N2CCC3(CC2)OCCCO3)nc(Cc2ccsc2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-4,6-dihydropyrimidine-5-carbonitrile are reacted with 597 mg (3.80 mmol) of 1,5-dioxa-9-azaspiro[5.5]undecane to give 86 mg (61% of theory) of the title compound.
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:24])[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[C:16](=O)[CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH2:25].[O:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[C:3]1([CH3:24])[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[C:16](=[CH:28][C:27]([O:26][CH2:30][CH3:29])=[O:25])[CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: C1CCOC1
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)N2CCCC(=O)c3ccccc32)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C=C1CCCN(S(=O)(=O)c2ccc(C)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 60% NaH (33.8 g) in tetrahydrofuran (2 liters) is added dropwise triethylphosphonoacetate (189 ml) under ice-cooling, and the mixture is stirred at room temperature for 1.5 hour. To the mixture is added 1-(p-toluenesulfonyl)-5-oxo-2,3,4,5-tetrahydro-1H-benzazepine (150 g) in portions at room temperature, and the mixture is stirred at 50° C. for 8 hours. To the reaction solution is added water, and the mixture is extracted three time with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crystals are collected by filtration, washed with n-hexane, and dried to give 1-(p-toluenesulfonyl)-5-ethoxycarbonylmethylidene-2,3,4,5-tetrahydro-1H-benzazepine (170.4 g).