Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C([NH:14][C:15]2([PH:20](=[O:22])[OH:21])[CH2:19][CH2:18][CH2:17][CH2:16]2)C2C=CC=CC=2)C=CC=CC=1>Br>[NH2:14][C:15]1([PH:20](=[O:21])[OH:22])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=[PH](O)C1(NC(c2ccccc2)c2ccccc2)CCCC1
Agent: Br
Product: NC1([PH](=O)O)CCCC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 63.9 %

Procedure:
The crude 1-(diphenylmethylamino)cyclopentylphosphinic acid (1.53 g) obtained in the above step (a) was added with 47% aqueous hydrobromic acid (20 ml) and stirred at 100° C. for 2 hours. The reaction product was extracted with water from the residue obtained by removing the solvent from the reaction system under reduced pressure. The aqueous layer was washed with diethyl ether and concentrated. The resulting oil was dissolved in ethanol and added with propylene oxide (3 ml) and ethyl acetate. The precipitated crystals were collected by filtration and dried to give 1-aminocyclopentylphosphinic acid (462 mg, 13%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]([NH2:28])[CH3:27])=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:29](O)(=[O:33])[C:30]#[C:31][CH3:32]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]([NH:28][C:29](=[O:33])[C:30]#[C:31][CH3:32])[CH3:27])=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: C[C@H](N)c1nc(-c2ccc(C(=O)Nc3ccccn3)cc2)c2c(N)nccn12
Reactant: CC#CC(=O)O
Product: CC#CC(=O)N[C@@H](C)c1nc(-c2ccc(C(=O)Nc3ccccn3)cc2)c2c(N)nccn12
Yield: 26.9 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from (S)-4-(8-amino-3-(1-aminoethyl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (intermediate 45) and 2-butynoic acid, to afford the title compound (9.5 mg, 26.9%). Data: UPLC(C) Rt: 1.38 min; m/z 440.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Mg].C(O[CH2:21][C:22]([F:38])=[CH:23][C:24]1([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)[CH2:26][CH2:25]1)(=O)C>O1CCCC1>[F:38][C:22]([CH2:21][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=1)=[CH:23][C:24]1([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:35])([F:36])[F:37])=[CH:29][CH:28]=2)[CH2:26][CH2:25]1
Reactant: Fc1ccc(Br)cc1Oc1ccccc1
Reactant: CC(=O)OCC(F)=CC1(c2ccc(OC(F)(F)F)cc2)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: FC(=CC1(c2ccc(OC(F)(F)F)cc2)CC1)Cc1ccc(F)c(Oc2ccccc2)c1
Yield: 21 %

Procedure:
The method of Example 25 was repeated using a Grignard reagent, prepared from 4-fluoro-3-phenoxyphenyl bromide (0.27 g), tetrahydrofuran (2 ml) and magnesium (21 mg) and 1-(3-acetoxy-2-fluoroprop-1-enyl)-1-(4-trifluoro-methoxyphenyl) cyclopropane (Example 19) (0.1 g). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) and then preparative high performance liquid chromatography (column: C18; solvent: methanol; flow rate: 3 ml/min) to afford 1-(2-fluoro-3-(4-fluoro-3-phenoxy-phenyl)prop-1-enyl)-1-(4-trifluoromethoxy phenyl) cyclopropane (29.4 mg, 21%).
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][CH:5]([NH:8][NH2:9])[CH2:4][CH2:3]1.C(O[CH:13]=[C:14]([C:20]#[N:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C.C([O-])(=O)C.[Na+]>C(O)C>[CH2:18]([O:17][C:15]([C:14]1[CH:13]=[N:9][N:8]([CH:5]2[CH2:6][CH2:7][O:2][CH2:3][CH2:4]2)[C:20]=1[NH2:21])=[O:16])[CH3:19]
Reactant: NNC1CCOCC1
Reactant: CCOC=C(C#N)C(=O)OCC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnn(C2CCOCC2)c1N
Temperature: 82.5 °C
Yield: 92.3 %

Procedure:
(Tetrahydro-pyran-4-yl)-hydrazine hydrochloride (1.975 g, 12.94 mmol), ethyl (ethoxymethylene)-cyanoacetate (1.958 g, 11.57 mmol) and sodium acetate (1.370 g; 16.70 mmol) were combined in ethanol (16 mL). The mixture was heated at 80-85° C. for 17 hours. After cooling to room temperature, the reaction was concentrated and the residue was partitioned between methylene chloride and water. The organic phase was separated and washed with water and then brine. Each aqueous phase was back extracted with methylene chloride. The two organic phases were combined, dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography eluting with 60-100% ethyl acetate/hexanes to give 5-amino-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (2.554 g, 92%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[C:10](=[O:17])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[NH2:11].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[C:13]([O:12][C:10](=[O:17])[NH:11][C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[C:4]([F:9])[CH:3]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Fc1cc(Br)cnc1Cl
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1cnc(Cl)c(F)c1
Temperature: 85 °C
Yield: 85.6 %

Procedure:
A degassed mixture of 5-bromo-2-chloro-3-fluoropyridine (22.5 g, 107 mmol), tert-butyl carbamate (13.8 g, 117.5 mmol), tris(dibenzylideneacetone) dipalladium(0) (2.95 g, 3.2 mmol), XantPhos (2.48 g, 4.28 mmol) and cesium carbonate (69.7 g, 214 mmol) in dioxane (340 mL) was heated at 85° C. for 24 hours. The reaction mixture was cooled to ambient temperature and the resultant solid was removed by filtration. The resultant solid was washed with ethyl acetate followed by dichloromethane and the filtrate was combined and concentrated in-vacuo to afford a residue that was purified by flash chromatography (silica: cyclohexane to 25% ethyl acetate/cyclohexane) to afford the title compound as a pale yellow solid (22.6 g, 86%). 1H NMR (300 MHz, CDCl3): 8.04 (dd, J=10.1, 2.4 Hz, 1H), 7.98 (d, J=2.4 Hz, 1H), 6.62 (s, 1H), 1.53 (s, 9H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([Si:15]([CH3:27])([CH3:26])[O:16][C@@H:17]1[CH2:24][CH2:23][CH2:22][C@H:21]([OH:25])[CH2:20][CH2:19][CH2:18]1)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[C:11]([Si:15]([CH3:27])([CH3:26])[O:16][CH:17]1[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[CH2:20][CH2:19][CH2:18]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCC[C@@H](O)CCC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCCC(=O)CCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
A solution of 4.5 g (58 mmol) of dimethyl sulphoxide in 25 mL dichloromethane was added dropwise to a stirred solution of 3.7 g (29 mmol) of oxalyl chloride in 50 mL of dichloromethane at −78° C. The solution was stirred for 30 minutes at −78° C. and then 5.0 g (19.3 mmol) of cis-5-(tert-butyl-dimethyl-silanyloxy)-cyclooctanol (57) in 30 mL of dichloromethane was added dropwise keeping the temperature at −78° C. After stirring for 30 minutes, 9.8 g (97 mmol) of triethylamine was added dropwise and the temperature allowed to warm to −30° C. Further 50 mL of dichloromethane were added and the solution stirred for 1 h at −30° C. With stirring 300 mL of a saturated ammonium chloride solution were added portionwise and then the organic layer was separated. After washing with further ammonium chloride solution, the organic phase was dried over magnesium sulfate, filtered and evaporated to give 5.0 g of the desired product as a yellow oil which was used without purification. Rt=1.96 min (Method C). Detected mass: 257.3 (M+H+).
Reaction SMILES: [F:1][CH:2]([F:28])[CH2:3][CH2:4][C:5]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:27])/[CH:24]=N/O)=[CH:18][CH:17]=1)([CH2:11][CH2:12][CH:13]([F:15])[F:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7].S(=O)(=O)(O)[OH:30]>>[F:14][CH:13]([F:15])[CH2:12][CH2:11][C:5]([C:16]1[CH:17]=[C:18]2[C:19](=[CH:20][CH:21]=1)[NH:22][C:23](=[O:27])[C:24]2=[O:30])([CH2:4][CH2:3][CH:2]([F:1])[F:28])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(CCC(F)F)(CCC(F)F)c1ccc(NC(=O)/C=N/O)cc1
Reactant: O=S(=O)(O)O
Product: CCOC(=O)C(CCC(F)F)(CCC(F)F)c1ccc2c(c1)C(=O)C(=O)N2
Temperature: 50 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
3.0 g of ethyl 2-(3,3-difluoropropyl)-5,5-difluoro-2-[4-[[(2E)-2-hydroxyiminoacetyl]amino]phenyl]pentanoate are added in portions to 20 ml of sulfuric acid (98%) at 50° C., during which the temperature rises to 60° C. When the addition is complete, the mixture is stirred at 50° C. for a further 120 min and subsequently poured into 400 ml of ice-water. The mixture is washed three times with 200 ml of dichloromethane/ethanol (9:1) each time, the combined organic phases are dried over sodium sulfate, filtered off and evaporated to dryness in vacuo. The crude product obtained is employed in the next reaction without further purification. Yield: 1.9 g (66%) of ethyl 2-(3,3-difluoropropyl)-2-(2,3-dioxoindolin-5-yl)-5,5-difluoropentanoate obtained; LC-MS retention time: 2.17 min.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13]C)[CH:8]=2)[N:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:13])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)cc(F)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc2nc(Cl)cc(F)c2c1
Yield: 67.9 %

Procedure:
A mixture solution of 2-chloro-4-fluoro-6-methoxyquinoline (see U.S. 61/391,225 for synthesis) (280 mg, 1.32 mmol) and BBr3 (0.3 mL, 3.2 mmol, 2.64 g/mL) in DCM (5 mL) was stirred at 20° C. for 12 hours. Aqueous workup with DCM extraction gave the crude product, which was purified by silica gel column (PE/EtOAc=50/1) to give product (177 mg, yield 69%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:22][CH3:23])[C:10](=[O:21])[N:11]([CH3:20])[C:12]=2[C:16]([O:18]C)=[O:17])[C:7]1=[O:24].[Li+].[OH-].Cl>C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:22][CH3:23])[C:10](=[O:21])[N:11]([CH3:20])[C:12]=2[C:16]([OH:18])=[O:17])[C:7]1=[O:24]
Reactant: COC(=O)c1c2c(c(OC)c(=O)n1C)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1c2c(c(C(=O)O)n(C)c1=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 50 °C

Procedure:
To a solution of methyl 6-(3-chloro-4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate (14.3 g, 35 mmol) in THF (1501 mL) and MeOH (150 mL) was added LiOH (2.74 g, 114 mmol) dissolved in 114 mL water and the reaction was heated to 50° C. for 45 minutes. HPLC showed completion. The reaction was neutralized with 1N HCl and cooled to room temperature. THF was removed in vacuo, and the resulting slurry was partitioned between CHCl3 and 5% aqueous HCl. The aqueous was washed with additional CHCl3. The combined organics were dried over sodium sulfate, filtered, and concentrated to dryness to afford the desired product as a pale yellow foam. The material was crystallized from ethyl acetate to give a light yellow solid.
Reaction SMILES: [OH-].[K+:2].[NH2:3][CH:4]([C:9]([OH:11])=[O:10])[CH2:5][C:6]([OH:8])=[O:7].C(O)C>O>[NH2:3][CH:4]([C:9]([O-:11])=[O:10])[CH2:5][C:6]([O-:8])=[O:7].[K+:2].[K+:2]
Reactant: NC(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC(CC(=O)[O-])C(=O)[O-]

Procedure:
Potassium hydroxide 11.3 g was added to a suspension of 13.3 g DL-aspartic acid in a mixed solvent of 60 ml ethyl alcohol and 60 ml water to form a solution of dipotassium DL-aspartate. To the ice-cooled resultant solution a solution of lauric acid-sulfuric acid mixed acid anhydride and 10 ml of 10 N potassium hydroxide was added dropwise simultaneously with stirring. While the pH was controlled to 12 stirring at room temperature was then continued for 1 hour. The reaction mixture was treated in the similar manner as in Example 3 to obtain 14.3 g crude crystals of N-lauroyl-DL-aspartic acid.
Reaction SMILES: [NH2:1][C:2](=[S:19])[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4]1.Br[CH2:21][C:22]([C:24]1[CH2:28][CH:27]([C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=2[F:36])[O:26][N:25]=1)=O.C([O-])(=O)C.[Na+]>CO>[F:36][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([F:35])[C:29]=1[CH:27]1[O:26][N:25]=[C:24]([C:22]2[N:1]=[C:2]([CH:3]3[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4]3)[S:19][CH:21]=2)[CH2:28]1
Reactant: O=C(CBr)C1=NOC(c2c(F)cccc2F)C1
Reactant: CCOC(=O)N1CCC(C(N)=S)CN1C(=O)OCC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)N1CCC(c2nc(C3=NOC(c4c(F)cccc4F)C3)cs2)CN1C(=O)OCC
Temperature: 35 °C
Reaction time: 1 h

Procedure:
A mixture of 1,2-diethyl 4-(aminothioxomethyl)tetrahydro-1,2-pyridazinedicarboxylate (i.e. the product of Step F) (2.58 g, 0.0089 mol) and 2-bromo-1-(4,5-dihydro-5-(2,6-difluorophenyl)-3-isoxazolyl)ethanone (i.e the product of Step C) (2.63 g, 0.0086 mol) in methanol (20 mL) were carefully heated to 35° C. No exotherm was observed and the temperature was raised to between 45 to 50° C. and held at this temperature for 1 h. The reaction mixture was neutralised with aqueous sodium acetate (0.73 g in about 20 mL water). The reaction mixture was extracted with diethyl ether (3×), dried magnesium sulfate, filtered, and concentrated under reduced pressure to provide the title compound (4.18 g), which was used without purification.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][CH:12]([O:14]C(=O)C)[CH:11]=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.[OH-].[Li+].O>C1COCC1.CO.O>[Si:1]([O:8][C@@H:9]1[CH2:13][C@H:12]([OH:14])[CH:11]=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)OC1C=CC(O[Si](C)(C)C(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1C=C[C@@H](O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
Dissolve (-)-acetic acid 4-tert-butyldimethylsilyloxy-cyclopent-2-enyl ester (2.3 mmol, prepared in example 10) in THF/methanol/water (2.7/0.9/0.9 mL). Add lithium hydroxide monohydrate (2.5 mmol) with stirring. After stirring for about 3 hours at room temperature, dilute the reaction with water (10 mL) and extract with tert-butyl methyl ether. Combine the organic phases, dry over anhydrous magnesium sulfate, filter and concentrate under vacuum. Purify the residue by flash chromatography (silica gel, 20% ethyl acetate/hexane) to provide the title compound (452 mg, 92% yield) [α]20D =+21.8°, (c=1.02, chloroform).
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:34]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:19]1([C:9]2[C:10]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:28][C:29]4[CH:30]=[N:31][CH:32]=[C:33]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)[CH:34]=4)=[CH:26][CH:25]=3)[N:8]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1cncc(-c2ccccc2)c1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3cncc(-c4ccccc4)c3)cc2)nc1-c1ccccc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 81.4 %

Procedure:
A mixture of ethyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazol-4-yl]propionate (840 mg), 3-chloromethyl-5-phenylpyridine (550 mg), potassium carbonate (500 mg) and N,N-dimethylformamide (10 ml) was stirred at 80° C. for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-phenyl-1-[4-(5-phenyl-3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (1010 mg, yield: 81%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:18][C@H:19]([OH:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[O:27]1[CH:32]=[CH:31][CH2:30][CH2:29][CH2:28]1>ClCCl.C(OCC)(=O)C.O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]([CH2:18][C@@H:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[O:26][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][O:27]2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Br)cc1)C[C@H](O)c1ccccc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCc1ccc(Br)cc1)C[C@H](OC1CCCCO1)c1ccccc1
Reaction time: 5 h
Yield: 107 %

Procedure:
To a solution of tert-butyl [2-(4-bromophenyl)ethyl]-[(2R)-2-hydroxy-2-phenylethyl]carbamate (3.20 g) in dichloromethane (40 ml) were added 3,4-dihydro-2H-pyran (1.28 g) and pyridinium p-toluenesulfonate (191 mg) at room temperature and the mixture was stirred at the same temperature for 5 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give tert-butyl [2-(4-bromophenyl)ethyl][(2R)-2-phenyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]carbamate (4.11 g).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].Cl[C:6]1[N:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>CO>[CH3:1][O:2][C:6]1[N:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(Cl)nc1Cl
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)c1ccc(Cl)nc1OC

Procedure:
A sodium methoxide solution prepared from 3.46 g (0.15 mole) of sodium and 150 ml of absolute methanol is added dropwise at 40° C in the course of 1 hour to a solution of 312 g (0.15 mole) of methyl 2,6-dichloronicotinate in 100 ml of methanol. The reaction mixture is refluxed for 3 hours and the solvent is then evaporated in vacuo. The dry residue is triturated with methylene chloride, the undissolved constituents are filtered off and the filtrate is evaporated in vacuo to dryness. The crystallised residue is recrystallised from petroleum ether to yield pure methyl 2-methoxy-6-chloronicotinate with a melting point of 68°-69° C.
Reaction SMILES: O.[NH2:2][NH2:3].Br[CH2:5][CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH3:9]>C(O)C>[C:8]([O:7][CH2:6][CH2:5][NH:2][NH2:3])([CH3:11])([CH3:10])[CH3:9]
Reactant: NN
Reactant: CC(C)(C)OCCBr
Solvent: CCO
Solvent: O
Product: CC(C)(C)OCCNN
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 61 %

Procedure:
To a solution of hydrazine monohydrate (36.0 mL, 0.750 mol) in ethanol (70 mL) at 0° C. in an ice-water bath was added 2-(2-bromoethoxy)-2-methylpropane (12.1 mL, 0.075 mol) drop-wise over 20 minutes. The reaction was then allowed to warm to room temperature and stir for 5 minutes and then heated to 40° C. in a preheated oil bath for 4 hours. The reaction was then cooled to room temperature and concentrated to remove the ethanol. To the flask was added water (20 mL) and the aqueous layer was extracted with diethyl ether (2×100 mL). The organic layers were combined and dried over anhydrous Na2SO4, filtered and concentrated to provide (2-tert-butoxyethyl)-hydrazine as a colorless oil (6.05 g, 61%).
Reaction SMILES: Cl.CO.[CH2:4]([C:6]([N+:27]#[C-])([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)[CH2:7][CH2:8][S:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=1)[CH3:5]>>[CH2:4]([C:6]([NH2:27])([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)[CH2:7][CH2:8][S:9][C:10]1[CH:11]=[C:12]([O:20][CH3:21])[C:13]([O:18][CH3:19])=[C:14]([O:16][CH3:17])[CH:15]=1)[CH3:5]
Reactant: [C-]#[N+]C(CC)(CCSc1cc(OC)c(OC)c(OC)c1)c1cccs1
Agent: Cl
Solvent: CO
Product: CCC(N)(CCSc1cc(OC)c(OC)c(OC)c1)c1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
15% Hydrogen chloride/methanol solution (12 ml) is added to 1-ethyl-3-(3,4,5-trimethoxyphenylthio)-1-(2-thienyl)propyl isocyanide (2.3 g) under ice-cooling and the mixture is stirred at room temperature for 3 hours. The mixture is concentrated under reduced pressure to remove solvent and the residue is adjusted to pH 10 with an aqueous potassium carbonate solution. The aqueous mixture is extracted with ethyl acetate and the extract is washed with an aqueous saturated sodium chloride solution, dried and then concentrated to remove solvent. The residue is purified by silica gel column chromatography (solvent, n-hexane:ethyl acetate=4:1), whereby 1-ethyl-3-(3,4,5-trimethoxyphenylthio)-1-(2-thienyl)propylamine (1.9 g) is obtained as colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:17]=[CH:16][O:15][N:14]=2)[CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[CH3:18]S(O)(=O)=O>CO>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:17]=[CH:16][O:15][N:14]=2)[CH2:9][C:10]([O:12][CH3:18])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)CC(c1ccc(O)cc1)c1ccon1
Reactant: CS(=O)(=O)O
Solvent: CO
Product: COC(=O)CC(c1ccc(O)cc1)c1ccon1
Temperature: 0 °C
Yield: 44 %

Procedure:
To a 100 mL RB flask fitted with magnetic stirrer was charged 20 mL of methanol. To the stirred solvent added 3-(4-hydroxyphenyl)-3-(1,2-oxazol-3-yl) propanoic acid (1.48 g, 6.34 mmol) and cooled to 0° C., added 1 mL of methanesulfonic acid. The resulting mixture was stirred at reflux temperature for 2 h. After completion of the reaction (reaction monitored by TLC), the solvent was removed under reduced pressure and the crude mass was dissolved in ethyl acetate (25 mL). The organic layer was washed with water (50 mL), saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as pale yellow color oil (0.69 g, Yield: 44%): MS (ESI, 120 eV): m/z=248.9 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 8.20 (s, 1H), 7.01-7.04 (d, 2H), 6.66-6.69 (d, 2H), 6.00 (d, 1H), 5.56 (bro s, 1H), 4.46-4.51 (t, 1H), 3.56 (s, 3H), 3.17-3.25 (q, 1H), 2.83-2.91 (q, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[C:4]2[CH:14]=[C:15]([C:17]([OH:19])=O)[S:16][C:3]1=2.O=S(Cl)Cl.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[C:4]2[CH:14]=[C:15]([C:17]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:19])[S:16][C:3]1=2
Reactant: C1COCCN1
Reactant: Cn1c2ccc([N+](=O)[O-])cc2c2cc(C(=O)O)sc21
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cn1c2ccc([N+](=O)[O-])cc2c2cc(C(=O)N3CCOCC3)sc21
Reaction time: 1 h

Procedure:
280 mg of (68) was added to 25 ml of THF, 0.5 ml of SOCl2 was added, and the reaction left with stirring for 1 hour. 1 ml of morpholine was added in portions, and stirring continued. The precipitated morpholine hydrochloride was filtered off, and the solvent evaporated. The residue was purified by column chromatography on silica gel, using MeOH in CH2Cl2, 1+9 as the eluent. MeOH was added to the pooled fractions to precipitate the product, giving after filtration and drying 50 mg of (69). M.p. 250°-2° C.