Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][C:12]1[CH:16]=[CH:15][NH:14][C:13]=1[CH:17]=O>N1CCCCC1.C(O)C>[CH3:11][C:12]1[CH:16]=[CH:15][NH:14][C:13]=1[CH:17]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: Cc1cc[nH]c1C=O
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc[nH]c1C=C1C(=O)Nc2ccccc21
Temperature: 90 °C
Reaction time: 3 h
Yield: 67.4 %

Procedure:
A reaction mixture of 133.0 mg of oxindole, 130.9 mg of the 3-methylpyrrole-2-carboxaldehyde, and 3 drops of piperidine in 2 mL of ethanol was stirred at 90° C. for 3 h. After cooling, the precipitate was filtered, washed with cold ethanol, and dried to yield 150.9 mg (67%) of the title compound as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([CH2:2][O:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:5]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COc2ccccc2)cc1
Reaction time: 8 h
Yield: 87.7 %

Procedure:
To a stirred mixture of 5.72 g (25.0 mmol, 1.0 eq.) of methyl 4-bromomethylbenzoate (Aldrich) and 3.80 g (27.5 mmol, 1.1 eq.) of K2CO3 in 10 mL of DMF at ambient temperature was added a solution of 2.59 g (27.5 mmol, 1.1 eq.) of phenol in 10 mL of DMF dropwise and the mixture stirred overnight. The reaction mixture was poured into 100 mL of water and extracted with 3×100 mL portions of 25% CH2Cl2 -hexanes. The combined organic phases were extracted with 3×100 mL portions of water, dried (MgSO4), filtered and concentrated in vacuo. The solid residue was recrystallized from ~50 mL of hexanes to give 5.31 g (88%) of the title compound as a white, crystalline solid. 1H NMR (300 MHz, CDCl3) δ8.05 (d, 2H), 7.51 (d, 2H), 7.26-7.33 (m, 2H), 6.95-7.02 (m, 3H), 5.13 (s, 2H), 3.92 (s, 3H). MS (DCl) m/e 260 (M+NH4)+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=[C:29]([N:36]2[CH2:40][CH2:39][C:38](F)(F)[CH2:37]2)C2N=NNC=2N=1)(C)(C)C.Br.BrCCC1C=CN=CC=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH2:15][C:38]3[CH:37]=[CH:29][N:36]=[CH:40][CH:39]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: Br
Agent: BrCCc1ccncc1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CCc3ccncc3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 4-(2-bromoethyl)pyridine hydrobromide and isolated as white solid. MS (m/e): 388.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:6][C:5]([F:8])=[CH:4][CH2:3]1.[H][H]>CO.C(OCC)(=O)C.[C].[Pd]>[NH2:1][C:2]1([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:6][CH:5]([F:8])[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: COC(=O)C1(N)CC=C(F)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C1(N)CCC(F)CC1

Procedure:
Methyl 1-amino-4-fluoro-3-cyclohexenecarboxylate (52 mg) was dissolved in the mixed solvents of methanol (2 mL) and ethyl acetate (2 mL), and 10% palladium-carbon (35 mg) was added and hydrogen gas was introduced for 14 hours. The insoluble matter was filtered and the solvent was removed by distillation under reduced pressure, and a mixture of the desired matter (BB09, 38 mg) was obtained.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16]N)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH2:25][C:26](=O)[CH3:27])[CH:22]=[CH:23][CH:24]=1.S(=O)(=O)(O)O>C(O)C>[CH2:2]([O:9][C:10]1[CH:15]=[C:14]2[C:13](=[CH:12][CH:11]=1)[NH:16][C:26]([CH3:27])=[C:25]2[C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[CH:20]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NNc1ccc(OCc2ccccc2)cc1
Reactant: CC(=O)Cc1cccc(Cl)c1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cc1[nH]c2ccc(OCc3ccccc3)cc2c1-c1cccc(Cl)c1

Procedure:
An amount of 11.7 g (47 m mole) of 4-benzyloxyphenylhydrazine-hydrochloride and 6.39 g (38 m mole) of (3-chlorophenyl)-acetone was dissolved in 35 ml of absolute ethanol, and after addition of 2.7 ml of concentrated sulfuric acid the mixture was refluxed for five hours. After the ethanol was distilled off, the residue was mixed with water and extracted with chloroform. The extracts were dried over sodium sulfate and evaporated. The evaporation residue was purified by chromatography on silicagel by using toluene as solvent.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:23][C:24](=[O:32])[NH:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:16][C:17](=[O:22])[NH:18][CH2:19][C:20]#[CH:21])=[CH:11][CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:23][C:24](=[O:32])[NH:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:16][C:17](=[O:22])[NH:18][CH2:19][C:20]#[CH:21])=[CH:11][CH:10]=1
Reactant: C#CCNC(=O)CC(NC(=O)NCC(=O)OCC)c1ccc(NC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#CCNC(=O)CC(NC(=O)NCC(=O)OCC)c1ccc(N)cc1
Reaction time: 2 h
Yield: 59.7 %

Procedure:
ethyl 2-(3-(1-(4-(tert-butoxycarbonylamino) phenyl)-3-oxo-3-(prop-2-ynylamino)propyl)ureido)acetate (108 mg) was dissolved in 4 ml of DCM and 2 ml of TFA was added then the reaction mixture was let 2 h at room temperature. The mixture was concentrated and the crude was purified on reverse phase (H2O/MeCN) to afford the amine 201 (50 mg, 60%) as a white solid, Rf=0.45 (EtOAc/MeOH 90/10). 1H NMR (200 MHz, DMSO) δ 8.25 (t, J=5.5 Hz, 1H), 6.94 (d, J=8.3 Hz, 2H), 6.56 (d, J=8.5 Hz, 1H), 6.50 (d, J=8.3 Hz, 2H), 6.27 (t, J=6.0 Hz, 1H), 5.05-4.79 (m, 3H), 4.10 (q, J=7.1 Hz, 2H), 3.86-3.71 (m, 4H), 3.14-3.08 (m, 1H), 2.58-2.45 (m, 2H), 1.21 (t, J=7.1 Hz, 3H). HPLC method A tr=5.12 nm (98.1%). ESI-MS m/z: 347.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9]C(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=O.C1COCC1.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=1[C:7]([N:21]([CH2:22][CH3:23])[CH2:19][CH3:20])=[O:9]
Reactant: CCNCC
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.6 %

Procedure:
A solution of 5-Bromoisatoic anhydride (2.00 g, 8.26 mmol) in THF (53.62 mL, 661.1 mmol) was treated with diethylamine (1.28 mL, 12.40 mmol) and allowed to stir overnight at rt. The mixture was concentrated in vacuo and purified using a Teledyne ISCO Combiflash® Rf system [0→4% MeOH in DCM] to afford 326 mg of the title compound (15%). 1H NMR (400 MHz, CD3OD) δ 7.24 (dd, J=2.27, 8.84 Hz, 1H), 7.13 (d, J=2.27 Hz, 1H), 6.71 (d, J=8.59 Hz, 1H), 3.43 (br. s., 4H), 1.18 (br. s., 6H). MS (ESI): m/z 271.41 [M+H]+. UPLC: tR=1.09 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[C:5]([C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1.[I:22]I.S(=O)(=O)(O)O.[N+]([O-])(O)=O>C(O)(=O)C>[I:22][C:3]1[CH:4]=[C:5]([C:19]([OH:21])=[O:20])[C:6](=[O:18])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:17])[F:15])[CH:9]=2)[C:2]=1[CH3:1]
Reactant: II
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: Cc1c(I)cc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Yield: 85.7 %

Procedure:
To acetic acid (263.7 L, 6.8 rel vol) was charged 6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylic acid (38.6 kg, 1 mol eq, limiting reagent), iodine (17.4 kg, 0.53 mol eq) and concentrated sulfuric acid (3.7 L, 0.1 rel vol). The temperature was adjusted to 50° C.-55° C. and 90% nitric acid (4.1 kg, 0.6 mol eq) charged over 15 minutes. The reaction was stirred until deemed to be complete as judged by HPLC analysis. The reaction was cooled, stirred and the product collected by filtration. The solid was washed twice with water (2×77.0 L, 2×2 rel vol) and acetone (2×38.6 kg, 2×1 rel vol). The solid was dried under vacuum to constant weight to yield the title compound (47.0 kg, 111.0 mol, 85.7%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:14]([CH3:16])=O)[C:12]=2[OH:13])=[CH:4][CH:3]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][C:25]([C:27]2[S:28][C:29]([C:32]([NH:34][NH2:35])=[O:33])=[CH:30][CH:31]=2)=[O:26])[CH:18]=1>CS(C)=O>[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][C:25]([C:27]2[S:28][C:29]([C:32]([NH:34][N:35]=[C:14]([C:11]3[C:12]([OH:13])=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=4)[S:9][CH:10]=3)[CH3:16])=[O:33])=[CH:30][CH:31]=2)=[O:26])[CH:18]=1
Reactant: NNC(=O)c1ccc(C(=O)NCc2cccnc2)s1
Reactant: CC(=O)c1csc(-c2ccc(Br)cc2)c1O
Solvent: CS(C)=O
Product: CC(=NNC(=O)c1ccc(C(=O)NCc2cccnc2)s1)c1csc(-c2ccc(Br)cc2)c1O
Temperature: 110 °C
Yield: 81 %

Procedure:
2-(4-Bromophenyl)-3-hydroxy-4-methylcarbonylthiophene (50.5 mg, 0.17 mmol) (synthesized in accordance with WO2004/108683) and 5-hydrazinocarbonylthiophene-2-carboxylic acid 3-picolylamide prepared in Reference Synthetic Example 11 were dissolved in dimethylsulfoxide (4.0 mL) and heated at 110° C. for 24 hours. The solvent was evaporated, and the residue was washed with methanol and water to give the desired product (yield 81%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.N1C=CC=CC=1.[Cl:14][CH2:15][C:16](Cl)=[O:17]>C(Cl)(Cl)Cl>[Cl:14][CH2:15][C:16]([NH:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1)=[O:17]
Reactant: Cc1cc(N)no1
Reactant: O=C(Cl)CCl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1cc(NC(=O)CCl)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
To 800 ml of chloroform is added 118 grams (1.12 moles) of 3-amino-5-methylisoxazole followed by 118 grams (1.5 moles) of pyridine. To this solution is added 147 grams (1.3 moles) of chloroacetylchloride with the addition temperature maintained at 0°-10° C. The reaction is then stirred at room temperature for 1 hour, filtered and dried in a vaccum desiccator to give 116 grams (56%) of 3-(chloroacetamido)-5-methylisoxazole, mp 192°-195° C. This material is slightly irritating to the skin and due caution should be exercised.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:2]1.[C:12]1([C:18](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>CN(C=O)C>[C:12]1([C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:1]2[CH:5]=[N:4][C:3]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:2]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)Cc1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.3 %

Procedure:
Ethyl (1H-1,2,4-triazol-3-yl)acetate (2.83 g) was dissolved in DMF (40 ml). To the solution were added triphenyl methyl chloride (5.08 g) and triethylamine (2.55 ml). The mixture was stirred for 3 hours at 25° C. The reaction mixture was added to ice-water (150 ml), which was subjected to extraction with ethyl ether (100 ml). The organic layer was washed twice with water (150 ml), which was dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The concentrate was purified by means of a column chromatography (carrier: silica gel, 150 g, developing solvent: ethyl acetate-hexane, 1:1) to afford the title compound (2.56 g) as a crystalline product, m.p.117-119° C.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[C:7]([OH:16])=[C:8]([O:14][CH3:15])[CH:9]=[C:10]([CH:13]=1)[CH:11]=[O:12])([O-:5])=[O:4].[CH2:17](I)[CH2:18][CH3:19].O>CN(C)C=O>[CH3:15][O:14][C:8]1[CH:9]=[C:10]([CH:13]=[C:6]([N+:3]([O-:5])=[O:4])[C:7]=1[O:16][CH2:17][CH2:18][CH3:19])[CH:11]=[O:12]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1c(OC)cc(C=O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of sodium hydride (6.09 g, 152.3 mmole) in 20 mL of dry dimethylformamide (DMF) was cooled to 0° C. and then 5-nitrovanillin (25 g, 126.8 mmole) in 41 mL of DMF was added dropwise. After 30 minutes, propyl iodide (25.87 g, 152.0 mmole) was added dropwise at 0° C. When the addition was completed, the reaction was maintained at room temperature for 2 hours and then stirred overnight at 70° C. Water was added, and-the solution extracted with ethyl ether, washed with 10% NaOH, dried over MgSO4, filtered and then evaporated in vacuo to an oil (19 g, 62.7%).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[C:3]=1[C:18]([OH:20])=O.Cl.C(N=C=NCCCN(C)C)C.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:38]=[CH:39][CH:40]=1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:15])[F:16])=[CH:9][CH:8]=2)[C:3]=1[C:18]([N:44]1[CH2:43][CH2:42][N:41]([C:37]2[CH:38]=[CH:39][CH:40]=[C:35]([O:34][CH3:33])[CH:36]=2)[CH2:46][CH2:45]1)=[O:20]
Reactant: Nc1onc(-c2ccc(OC(F)(F)F)cc2)c1C(=O)O
Reactant: COc1cccc(N2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1cccc(N2CCN(C(=O)c3c(-c4ccc(OC(F)(F)F)cc4)noc3N)CC2)c1
Yield: 69 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(4-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (588 mg, 1.27 mmol, 69%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[CH:3]=1.[BrH:14]>>[Br:14][C:4]1[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=1
Reactant: Br
Reactant: Cc1cc([N+](=O)[O-])cc(C(=O)O)n1
Product: Cc1cc(Br)cc(C(=O)O)n1
Temperature: 25 °C

Procedure:
A solution of 3.6 g (19.6 mmol) of 6-Methyl-4-nitro-pyridine-2-carboxylic acid in 40 ml of 48% hydrobromic acid was heated at 100° C. overnight and then allowed to cool to room temperature. The solution was then evaporated to dryness in vaccuo. The crude material (10.5 g) containing inorganic salts was directly used in the next step.
Reaction SMILES: S(=O)(=O)(O)O.Cl.[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][CH2:13][NH:14][CH:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[C:16](N)=[O:17].Cl.[CH3:27][OH:28]>>[ClH:25].[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][CH2:13][NH:14][CH:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[C:16]([O:28][CH3:27])=[O:17]
Reactant: CO
Reactant: NC(=O)C(NCCc1cccs1)c1ccccc1Cl
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)C(NCCc1cccs1)c1ccccc1Cl

Procedure:
21.5 ml (0.4 mol) of 100% sulfuric acid is dissolved, under cooling in 100 ml of methanol, the solution is heated under reflux for ½ hour, then cooled to room temperature and to it 33.1 g (0.1 mol) of [2-(2-thienyl)ethylarnino](2-chlorophenyl)acetamide hydrochloride, prepared as described in Example 5., is added and the mixture is heated under reflux conditions for 10 hours. Methanol is then distilled off in vacuo and to the residue 150 ml of 1,2-dichloroethane and 150 ml of water are added, shaken well, and the two phases are separated. The aqueous layer is extracted with 2×30 ml of 1,2-dichloroethane, the combined organic layers are washed with 80 ml of 5% sodium hydroxide solution, then with 100 ml of water, dried over anhydrous sodium sulfate and evaporated in vacuo. Weight of the residue: 28.5 g. The oily product, which is the base of formula (VIII), is dissolved in 50 ml of isopropyl acetate, 7.3 ml (0.087 mol) of concentrated hydrochloric acid solution is added to it, and the mixture is stirred at room temperature for 1 hour. The precipitating product is filtered off, washed with 2×10 ml of isopropyl acetate and dried. Weight: 28.4 g (82%) mp.: 177-178° C. (lit. 175° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[C@@H:7]([CH3:9])[NH2:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[N:20]([CH:23]([CH2:29][CH2:30]Br)[C:24](OCC)=[O:25])=[N+:21]=[N-:22].[I-].[Na+]>C(#N)C>[N:20]([CH:23]1[CH2:29][CH2:30][N:8]([C@H:7]([CH3:9])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:10])[C:24]1=[O:25])=[N+:21]=[N-:22]
Reactant: CCOC(=O)C(CCBr)N=[N+]=[N-]
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](C(=O)OC(C)(C)C)N1CCC(N=[N+]=[N-])C1=O
Temperature: 60 °C
Yield: 18.9 %

Procedure:
To a solution of D-alanine tert-butylester (1.28 g) and N,N-diisopropylethylamine (1.22 ml) in acetonitrile (15 ml), was added a solution of ethyl 2-azido-4-bromobutanoate (1 g) and sodium iodide (0.02 g) in acetonitrile (5 ml). The mixture was heated at 60° C. for 60 h and then concentrated under reduced pressure to give a brown oil. This oil was partitioned between DCM and water. The separated organic layer was washed further with water and dried (over magnesium sulphate), and concentrated under reduced pressure. The residual brown oil was purified using Biotage™ chromatography (silica, eluting with cyclohexane:ethyl acetate 3:1) to give the title compound (0.204 g) as a mixture of two diastereoisomers.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][C@H:5](O)[C:6]([O:8][CH3:9])=[O:7].Cl.O1CCOCC1.S(Cl)([Cl:20])=O>N1C=CC=CC=1>[ClH:20].[NH2:2][CH2:3][CH2:4][C@@H:5]([Cl:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)[C@@H](O)CCN
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cl)CCN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To methyl (S)-4-amino-2-hydroxybutyrate hydrochloride (170.1 mg; 133.5 mg when calculated as methyl (S)-4-amino-2-hydroxybutyrate) was added 3 ml of 4 N-HCl/dioxane, followed by further addition of 189.1 mg of thionyl chloride. The mixture was stirred at room temperature for 1 hour. Thereafter, 2.5 mg of pyridine was added, and the mixture was further stirred at 50° C. for 6 hours. After confirmation of disappearance of the starting material by TLC, the solvent was distilled off under reduced pressure to give methyl (R)-4-amino-2-chlorobutyrate hydrochloride. To this were added 10 ml of chloroform and 5 ml of a saturated aqueous solution of sodium hydrogen carbonate, and the aqueous layer was further extracted six times with chloroform. The organic layer was dried over sodium sulfate and the solvent was distilled off to give 120.7 mg of (R)-3-chloro-2-pyrrolidinone (yield quantitative, optical purity 93.9% ee). The optical purity was determined by high performance liquid chromatography using a chiral column (Chiralcel OB-H (Daicel)).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([Cl:12])[CH:4]=1.[CH3:13]O>C(OCC)C>[Br:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:13])=[O:8])=[C:5]([Cl:12])[CH:4]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Br)cc1Cl
Agent: Cl
Solvent: CCOCC
Product: COC(=O)c1ccc(Br)cc1Cl
Yield: 94 %

Procedure:
Hydrochloric acid (gas) was bubbled through a solution of 10 g (42.5 mmol) of 4-bromo-2-chloro benzoic acid in 100 ml of methanol until reflux occurred. The resulting reaction mixture was allowed to react overnight. When the reaction was substantially complete, as indicated by TLC, the reaction mixture was concentrated in vacuo to provide a residue. This residue was redissolved in diethyl ether and washed sequentially with water (twice) and a saturated sodium chloride solution, dried over sodium sulfate, filtered and then concentrated in vacuo to provide 10 g of a light tan oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](=O)[CH3:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[OH:19][CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1)[CH2:21][NH2:22].O>C1C=CC=CC=1>[Cl:29][C:25]1[CH:24]=[C:23]([CH:20]([CH2:21][NH:22][CH:16]([CH3:17])[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[CH:10][CH:11]=2)[OH:19])[CH:28]=[CH:27][CH:26]=1
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: CC(=O)Cc1ccc(OCc2ccncc2)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(Cc1ccc(OCc2ccncc2)cc1)NCC(O)c1cccc(Cl)c1
Reaction time: 1 h

Procedure:
A mixture of 1-[4-(4-pyridylmethyloxy)phenyl)propan-2-one (2.5 g) and 2-hydroxy-2-(3-chlorophenyl)ethanamine (1.78 g) in benzene (100 ml) was boiled under reflux with azeotropic removal of water until the reaction was complete. The solvent was evaporated, the residue dissolved in methanol (150 ml), cooled in an ice bath and treated with sodium borohydride (1.0 g). After stirring for 1 hour the methanol was evaporated, the residue partitioned between ethyl acetate and water, the washed organic phase dried and evaporated to give an oil which was chromatographed on Kieselgel 60. Elution with 4% methanol in chloroform gave 3-chloro-α-[[[2-[4-[4-pyridylmethyloxy)phenyl]-1-methylethyl]amino]methyl]benzenemethanol m.p. 85°-110° C. (ethylacetate-ether) as a 45:55 mixture of diastereoisomers.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:11][N:12]1[C:17]([CH3:19])([CH3:18])[CH2:16][CH:15]([O:20][CH2:21][CH:22]2[O:24][CH2:23]2)[CH2:14][C:13]1([CH3:26])[CH3:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH:27][CH:28]1[CH2:33][C:32]([CH3:35])([CH3:34])[N:31]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:30]([CH3:46])([CH3:45])[CH2:29]1>O1CCOCC1.C(OCC)C>[CH2:37]([O:36][N:31]1[C:32]([CH3:34])([CH3:35])[CH2:33][CH:28]([O:27][CH2:23][CH:22]([OH:24])[CH2:21][O:20][CH:15]2[CH2:14][C:13]([CH3:25])([CH3:26])[N:12]([O:11][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:17]([CH3:18])([CH3:19])[CH2:16]2)[CH2:29][C:30]1([CH3:45])[CH3:46])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCCCON1C(C)(C)CC(OCC2CO2)CC1(C)C
Reactant: CCCCCCCCON1C(C)(C)CC(O)CC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCCCCCCCON1C(C)(C)CC(OCC(O)COC2CC(C)(C)N(OCCCCCCCC)C(C)(C)C2)CC1(C)C
Yield: 45.7 %

Procedure:
Sodium hydride (0.7 g. 5.9 mmol) is added to a solution of 17.0 g (59.5 mmol) of 1-(1-octyloxy--2,2,6,6-tetramethylpiperidin-4-yloxy)-2,3-epoxypropane (prepared in Example 11) in 75 ml of dioxane. The reaction mixture is heated at reflux for 10 minutes and then cooled to 60° C., whereupon a solution of 10.0 g (29.3 mmol) of 4-hydroxy-1-octyloxy-2,2,6,6-tetramethylpiperidine (prepared in Example 5) in 25 ml of dioxane is rapidly added. The reaction mixture is heated at reflux for 4 hours, treated with an additional 0.6 g of sodium hydride, and heated at reflux for 7 hours. The reaction mixture is diluted with diethyl ether (500 ml), and the organic solution is washed with 1N hydrochloric acid (2×100 ml) and saturated sodium bicarbonate solution, dried over magnesium sulfate, and concentrated to an oil. Purification by flash chromatography on silica gel (9:1 heptane: ethyl acetate) affords 8.4 g (46% yield) of the title compound, a colorless oil.