Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([C:26]#[N:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)C1C=CC=CC=1.Cl.[H][H]>[C].[Pd].C(O)C>[C:26]([C:13]([C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[N:27]
Reactant: [H][H]
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@@H]1CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: N#CC(c1ccccc1)(c1ccccc1)[C@@H]1CCNC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
A mixed solution obtained by mixing 3.5 g of 79% pure (S)-1-benzyl-3-(1-cyano-1,1-diphenylmethyl)-pyrrolidine with 2.8 ml of ethanol and adding dropwise 0.72 ml of 35% aqueous hydrochloric acid thereto with cooling on an ice-water bath was charged, together with 139 mg of moist 5% palladium-carbon (water content 52% by weight), into an autoclave, hydrogen was introduced thereinto and the autoclave was heated to raise the temperature to 60° C. and the pressure to 203 kPa, and the reaction was allowed to proceed for 3 hours. Hydrogen absorption came to an end in 2.6 hours after the start of hydrogen introduction. After completion of the reaction, the reaction mixture was cooled to room temperature and depressurized. The reaction mixture was taken out, the catalyst was filtered off, the filtrate obtained was concentrated under reduced pressure, toluene and water were added to the thus-obtained oily concentrate, and the pH was adjusted to 13 by adding dropwise 30% aqueous sodium hydroxide with stirring on an ice-water bath. The toluene layer was recovered, the aqueous layer was further extracted with toluene, and the toluene layers were combined, washed with a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and, after filtration, concentrated under reduced pressure and further dried under vacuum to give 2.1 g of (S)-3-(1-cyano-1,1-diphenylmethyl)-pyrrolidine as an oil (yield: 91 mole percent).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[C:8]([NH:11][C:12]1[CH:21]=[CH:20][C:15]([S:16](Cl)(=[O:18])=[O:17])=[CH:14][CH:13]=1)(=[O:10])[CH3:9].O>CC(C)=O>[C:8]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([S:16]([N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])(=[O:18])=[O:17])=[CH:20][CH:21]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCNCCO
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(S(=O)(=O)N(CCO)CCO)cc1
Temperature: 5 °C

Procedure:
Step 1) Diethanolamine (105 parts) was added dropwise over 10 minutes to a stirred mixture of N-acetyl sulphanilyl chloride (93.5 parts), water (400 parts) and acetone (200 parts) while maintaining the temperature at approximately 5° C. The mixture was allowed to warm to room temperature and stirred over night. The resultant 4-acetylamino-N,N-bis-(2-hydroxyethyl)benzenesulphonamide (103 parts) was isolated by filtration, washed with water and dried.
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1.CCN(CC)CC.[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[NH2:1][C:2]1[S:10][C:5]2[CH2:6][N:7]([C:34]([NH:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:35])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1
Reactant: Nc1sc2c(c1C(=O)c1ccc(Br)cc1)CCNC2
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1sc2c(c1C(=O)c1ccc(Br)cc1)CCN(C(=O)Nc1ccccc1)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-amino-3-(4-bromobenzoyl)-4,5,6,7-tetrahydrothieno(2,3-c)pyridine) (1.02 mmol) in dry CH2Cl2 (20 mL), Et3N (1.2 eq) and phenylisocyanate (1.2 eq) were added. The mixture was stirred at room temperature for 4 hours, then was concentrated at reduced pressure and the residue puri fied by flash chromatography (EtOAc/light petroleum 3/7) to afford the desired compound as a solid (mp 89-90 ° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:10]([SH:13])[CH2:11][SH:12]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[S:13][CH2:10][CH2:11][S:12]1
Reactant: SCCS
Reactant: O=Cc1ccccc1Cl
Product: Clc1ccccc1C1SCCS1

Procedure:
Following the general procedure described in Example 1, 55.3 gm (0.393 moles) of 2-chlorobenzaldehyde and 37.21 gm (0.395 moles) of 1,2-ethanedithiol gave, after distillation, 65.65 gm (0.303 moles) of a clear, colorless liquid, b.p. 121°-125° C. (0.03 mm/Hg). Elemental analysis for C9H9ClS2 :
Reaction SMILES: S(C)C.[C:4]([Li])([CH3:7])([CH3:6])[CH3:5].[C:9]([NH:28][C@@H:29]([CH2:32][CH3:33])[CH:30]=[O:31])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH4+].[Cl-]>CCOCC>[CH3:5][C:4]([CH3:7])([CH:30]([OH:31])[C@@H:29]([NH:28][C:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:32][CH3:33])[CH3:6]
Reactant: [Li]C(C)(C)C
Reactant: CC[C@@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CSC
Solvent: CCOCC
Product: CC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(O)C(C)(C)C
Temperature: 25 °C

Procedure:
To a stirred suspension of CuBr.SMe2 (1.37 g, 2.2 eq, 6.66 mmol) in Et2O (100 mL) under an argon atmosphere at −78° C., was added tert-butyl lithium (1.5 M in pentane, 8.0 mL, 4 eq, 12.0 mmol) dropwise and the solution allowed to warm to room temperature. The mixture was recooled to −55° C., to which was added a solution of (S)-2-(trityl-amino)-butyraldehyde (1 g, 1 eq, 3.03 mmol) in Et2O (25 mL) dropwise with stirring, and stirred at this temperature for 3 h. To the reaction mixture was added a saturated aqueous solution of NH4Cl (100 mL) and allowed to warm to room temperature over 16 h. The reaction mixture was extracted with Et2O (2×200 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel column chromatography, eluted with hexane: Et2O (100:0→90:10) to afford the title compound as a light yellow oil. Yield: 0.47 g (40%). (53% de 3R,4S: 47% de 3S,4S). 1H-NMR (d6-DMSO, 250 MHz): δ 0.37 & 0.87 (2×t, 3H, J=7.46 Hz, —NHCH (CH2CH3)CH(C(CH3)3)OH), 0.58 & 0.71 (2×s, 9H, —NHCH(CH2CH3)CH(C(CH3)OH), 1.38-1.52 (m, 2H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 2.00 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 2.28 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 2.95 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 4.24 & 4.79 (2×d, 1H, J=5.21 & 6.16 Hz, —NHCH(CH2CH3)CH(C(CH3)3)OH), 7.15-7.53 (m, 15H, 3×Ph).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])[CH3:2].[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([N+:24]([O-:26])=[O:25])=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([N+:24]([O-:26])=[O:25])=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:19]=1)=[O:7])[CH3:2]
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: CCOc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccccc1C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
2-ethoxy--benzoyl chloride was condensed with 5-Amino-2-nitrobenzotrifluoride in dichloromethane in presence of triethylamine as acid scavenger to yield 2-Ethoxy-N-(4-nitro-3-trifluromethyl-phenyl)-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH:22]([CH2:23][C:24]4[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=4)[O:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:21][CH2:20][NH:19]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35](Cl)(=[O:37])[CH3:36].[OH-].[Na+]>C1COCC1.O>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH:22]([CH2:23][C:24]4[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=4)[O:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:21][CH2:20][N:19]3[C:35](=[O:37])[CH3:36])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)COc1cccc(CC2CCNC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1CCC(Cc2cccc(OCC(=O)O)c2)C1c1nc(-c2ccccc2)c(-c2ccccc2)o1

Procedure:
To a solution of [3-[[2-(4,5-diphenyloxazol-2-yl)pyrrolidin-3-yl]methyl]phenoxy]acetic acid (140 mg) in a mixture of THF (10 ml) and water (10 ml) was added acetyl chloride (1.0 ml) dropwise at 0° C. keeping pH 8-9 with 1N NaOH solution. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, 1N-HCl and brine. The dried solvent was evaporated in vacuo and the residue was purified by trituration with hexane to afford [3-[[2-(4,5-diphenyloxazol-2-yl)-1-acetylpyrrolidin-3-yl]methyl]phenoxy]acetic acid (150 mg).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([NH:12]C(=O)C)=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[F:29])[CH3:2].Cl>CO>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([NH2:12])=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[F:29])[CH3:2]
Reactant: CCn1c(Cn2ccnc2-c2cc(F)ccc2F)nc2cc(NC(C)=O)ccc21
Agent: Cl
Solvent: CO
Product: CCn1c(Cn2ccnc2-c2cc(F)ccc2F)nc2cc(N)ccc21

Procedure:
Crude N-{1-Ethyl-2-{[2-(2,5-difluorophenyl)-1H-imidazol-1-yl]methyl}-1H-benzimidazol-5-yl}acetamide is treated with 10% aqueous HCl (20 mL) in methanol (10 mL) at reflux for 1.5 h. After cooling, the methanol is removed in vacuo, and the aqueous layer washed with ethyl acetate. The aqueous layer is adjusted to pH 10 with 3 N NaOH, then extracted with ethyl acetate (3×), and the combined organic extracts washed with water (2×) then saturated aqueous sodium chloride, dried (MgSO4), and concentrated to give 1-Ethyl-2-{[2-(2,5-difluorophenyl)-1H-imidazol-1-yl]methyl}-5-amino-1H-benzimidazole. LCMS MH+ 354.4.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11](O)[CH3:12])=[C:9]2[C:4]([C:5]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:6][CH:7]=[CH:8]2)=[N:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:10]([CH:11]=[CH2:12])=[C:9]2[C:4]([C:5]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:6][CH:7]=[CH:8]2)=[N:3]1
Reactant: Cc1cc(C)c(-c2cccc3c(C(C)O)n(C)nc23)c(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=Cc1c2cccc(-c3c(C)cc(C)cc3C)c2nn1C
Yield: 54.7 %

Procedure:
A solution of 1-[2-methyl-7-(2,4,6-trimethyl-phenyl)-2H-indazol-3-yl]-ethanol (0.263 g, 0.893 mmol) and 4-toluenesulfonic acid hydrate (0.217 g, 1.14 mmol) in 10 mL of toluene was stirred at 103° C. for 16 h then allowed to cool. The yellow-orange solution was sequentially washed with 10 mL of a 10% aqueous NaOH solution and 10 mL of a saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated to an orange oil. Column chromatography (20% EtOAc/hexanes) afforded 2-methyl-7-(2,4,6-trimethyl-phenyl)-3-vinyl-2H-indazole (15: Ra=Rb=H, Ar=2,4,6-trimethylphenyl; 0.135 g; 55%; m.p. 84.9-95.4) as a pale yellow solid.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[C:8]3[C:13]([C:14]([CH2:15][CH2:16][NH:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22]Cl)=[C:6]2[CH2:5][CH2:4][CH2:3]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[CH:25]([N:28](C(C)C)[CH2:29]C)(C)C.Cl.CNC.O>CN(C=O)C>[CH3:25][N:28]([CH3:29])[CH2:22][CH2:21][CH2:20][CH2:19][C:18]([NH:17][CH2:16][CH2:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]2[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][C:6]=12)=[O:24]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(CCCCCl)NCCc1c2n(c3ccccc13)C(=O)CCC2
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCCCC(=O)NCCc1c2n(c3ccccc13)C(=O)CCC2
Reaction time: 48 h

Procedure:
15 g 6-Oxo-10-[2-(5-chlorovaleryl)aminoethyl]-6,7,8,9tetrahydropyrido[1,2-a]indole (D 3 of EP-0213696), 14.6 ml diisopropylethylamine, 1 g KI and 3.5 g dimethylamine hydrochloride were dissolved in 100 ml DMF and stirred for 48 hours at room-temperature. After further stirring for 7 hours at 40° C. the reaction mixture was dissolved with water and extracted with ethyl acetate. After acid-base separation the product was crystallised from diisopropylether.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH2:38]([O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[C:47]1[N:52]=[CH:51][N:50]=[C:49]([NH2:53])[CH:48]=1)[CH3:39]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:53][C:49]2[CH:48]=[C:47]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[O:40][CH2:38][CH3:39])[N:52]=[CH:51][N:50]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1ccccc1-c1cc(N)ncn1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOc1ccccc1-c1cc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)ncn1
Reaction time: 0.12 h
Yield: 39.8 %

Procedure:
To a stirred solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (V), (1.27 g, 5.54 mmol) in dry dichloromethane, HOBt (1.27 g, 9.30 mmol) and EDCI (1.78 g, 9.30 mmol) were added at 0° C. and the reaction mixture was stirred for 5-10 minutes. Then 6-(2-ethoxy-phenyl)-pyrimidin-4-ylamine (III) (1.00 g, 4.65 mmol) was added and the reaction mixture was heated to reflux under an atmosphere of nitrogen for 48 hours. The reaction mixture was diluted with dichloromethane and washed with 1N HCl, aqueous sodium bicarbonate, water and brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the crude product was purified by column chromatography to obtain 4-[6-(2-ethoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester (IV) (0.79 g, 40%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][N:4]([NH:7][C:8](=[O:19])[C@@H:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH3:10])[C:3]=1[C:20]([O:22]C)=O.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][NH2:32]>>[Br:1][C:2]1[CH:6]=[CH:5][N:4]([NH:7][C:8](=[O:19])[C@@H:9]([NH:11][C:12](=[O:13])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH3:10])[C:3]=1[C:20](=[O:22])[NH:32][CH2:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[Cl:24]
Reactant: COC(=O)c1c(Br)ccn1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: NCc1ccccc1Cl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1ccc(Br)c1C(=O)NCc1ccccc1Cl
Yield: 64.8 %

Procedure:
The title compound was prepared from (S)-Methyl 3-bromo-1-(2-(tert-butoxycarbonylamino)propanamido)-1H-pyrrole-2-carboxylate (310 mg, 0.8 mmol) and (2-chlorophenyl)methanamine (385 μL, 3.2 mmol) following the experimental procedure described in Preparation 44a. 259 mg (65% yield) of the desired compound were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:14]=1[NH2:15]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:15][C:14]1[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:13]=1[Cl:12])=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Product: O=C(Nc1cc(C(F)(F)F)ccc1Cl)c1cc(Br)ccc1O
Yield: 34.2 %

Procedure:
Using 5-bromosalicylic acid and 2-chloro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 1(1) gave the title compound.
Reaction SMILES: [CH:1]1[C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=[C:3]([OH:12])[CH:2]=1.S(=O)(=O)(O)O.[CH3:18]O>>[OH:12][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[CH:8][C:9]([O:11][CH3:18])=[O:10])=[CH:1][CH:2]=1
Reactant: CO
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)C=Cc1ccc(O)cc1

Procedure:
51.2 g (312 mmol) of p-coumaric acid were dissolved in 330 ml of methanol and treated with 10 ml of concentrated sulphuric acid. The solution was heated under reflux for 2 hours. Subsequently the majority of the methanol (about 200 ml) was distilled off and the residue remaining behind was poured into 1.3 l of ice-water. The separated ester was filtered off under suction and washed in succession with cold water, with a small amount of cold NaHCO3 solution and again with cold water. Drying at 50° C. in a water-jet vacuum gave 51.1 g of methyl 3-(4-hydroxyphenyl)-acrylate in the form of a light brownish coloured powder.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[C@H:11]([N:15]2[CH2:18][C:17]4([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[CH2:16]2)[CH2:10][CH2:9]3)[N:3]=[CH:4][CH:5]=1.[CH3:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][C:32](O)=[O:33])=[N:29][CH:30]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C>CN(C)C=O.CN(C1C=CN=CC=1)C>[CH3:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][C:32]([N:21]2[CH2:22][CH2:23][C:17]3([CH2:16][N:15]([CH:11]4[C:12]5[C:8](=[CH:7][C:6]([N:2]6[N:3]=[CH:4][CH:5]=[N:1]6)=[CH:14][CH:13]=5)[CH2:9][CH2:10]4)[CH2:18]3)[CH2:19][CH2:20]2)=[O:33])=[N:29][CH:30]=1
Reactant: Cc1ccc(CC(=O)O)nc1
Reactant: c1cnn(-c2ccc3c(c2)CC[C@H]3N2CC3(CCNCC3)C2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(CC(=O)N2CCC3(CC2)CN(C2CCc4cc(-n5nccn5)ccc42)C3)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of 2-((R)-5-[1,2,3]triazol-2-yl-indan-1-yl)-2,7-diaza-spiro[3.5]nonane (6-1c, 200 mg, 0.65 mmol) in 3 mL of dimethylformamide was added (5-methyl-pyridin-2-yl)-acetic acid (SM-1ab, 98 mg, 0.65 mmol), triethylamine (131 mg, 1.29 mmol), EDCI (130 mg, 0.68 mmol) and a catalytic amount of DMAP. The mixture was stirred at room temperature overnight. The reaction mixture was quenched by the addition of 10 mL of saturated NaHCO3 and diluted with 50 mL of dichloromethane. The organic layer was washed with saturated brine, dried over Na2SO4 and concentrated. The crude product was purified on Analogix (Analogix Inc., Burlington, Wis.) 4 g silica column (0-20% MeOH in ethyl acetate (1% triethyl amine)) to provide the title compound (207 mg, 72.4%) as a brown gum. MS (ES+) 443.4 (M+H)+. 1H NMR (CD3OD) δ 1.58-1.79 (m, 4H), 1.94-2.16 (m, 2H), 2.20-2.31 (m, 2H), 2.31 (s, 3H), 2.78-2.98 (m, 1H), 3.09-3.16 (m, 1H), 3.17-3.32 (m, 2H), 3.38-3.57 (m, 4H), 3.88 (s, 2H), 3.99-4.20 (m, 1H), 7.21 (d, 1H), 7.39-7.51 (m, 2H), 7.80 (d, 2H), 7.89-7.94 (m, 1H), 7.97 (s, 1H), 8.24-8.38 (m, 1H). [α]D20=+47.2 deg (c=9.4 mg/mL, methanol).
Reaction SMILES: [C:1]1([P:7]([CH2:15][CH:16]=O)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:19][OH:20].[OH-].[Na+].Cl>C(O)C.O>[C:1]1([P:7]([CH2:15]/[CH:16]=[N:19]\[OH:20])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=CCP(=O)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=P(C/C=N\O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a suspension of (diphenyl-phosphinoyl)-acetaldehyde example 1d (2.4 g, 9.0 mmol) and hydroxylamine hydrochloride (0.68 g, 10.0 mmol) in ethanol (50 mL) and water (100 mL) was added at 0° C. an aqueous solution of sodium hydroxide (50%, 5 mL) added dropwise within a 10 min period. After stirring at room temperature overnight, the resulting mixture was acidified with HCl (4 N). The mixture was then extracted with dichloromethane and the combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated to afford the title compound (3.75 g, 98%) which was obtained as a light yellow solid. MS m/e (EI): 260.0 [M].
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[C:11]([N+:26]([O-])=O)[CH:10]=2)=[CH:4][CH:3]=1.C(O)(=O)C>O1CCCC1>[NH2:26][C:11]1[CH:10]=[C:9]([NH:8][CH2:7][C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:14]=[CH:13][C:12]=1[NH:15][C:16](=[O:25])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1
Reactant: O=C(Cc1ccc(F)cc1)Nc1ccc(NCc2ccc(Cl)s2)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Nc1cc(NCc2ccc(Cl)s2)ccc1NC(=O)Cc1ccc(F)cc1
Reaction time: 0.08 h
Yield: 94.2 %

Procedure:
To a stirred red solution of N-{4-[(5-chlorothiophen-2-ylmethyl)amino]-2-nitrophenyl}-2-(4-fluorophenyl)acetamide (320 mg, 0.762 mmol) in tetrahydrofuran (25 ml) and acetic acid (8 mL) zinc powder (particle size <10 micron, 10 g) was periodically added by portions during 30 minutes. The solution turned colorless after 5 minutes. The obtained colorless suspension was filtered via plug of SiO2 (10 g) with ethyl acetate as an eluent and the obtained solution was evaporated in vacuo. The obtained solid was dissolved in a mixture of ethyl acetate/acetone/trifluoroacetic (3 mL/3 mL/0.2 mL), treated with saturated aq. NaHCO3 (50 mL) and heptane (30 mL) and the product was separated by filtration to furnish 280 mg of a pale grey solid. Yield 94.2%. LC/MS (m/z) 390.4 ([M+H]+); RT=2.26 (UV, ELSD) 99%, 100%. 1H NMR (DMSO-d6): 3.56 (s, 2H); 4.28 (d, 2H); 4.57 (s, 2H, NH2); 5.87 (dd, 1H); 5.98 (m, 2H, NH and arom. H); 6.74 (d, 1H); 6.86 (d, 1H); 6.93 (d, 1H); 7.13 (t, 2H); 7.35 (dd, 2H); 9.10 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[CH2:4][C@@H:5]1[CH2:10][C@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][N:6]1C(OC)=O.Br>>[F:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[CH2:4][C@@H:5]1[CH2:10][C@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][NH:6]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@H]1Cc1cc(F)ccc1F
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@H](Cc3cc(F)ccc3F)C2)o[nH]1
Temperature: 25 °C
Reaction time: 22 h
Yield: 69.9 %

Procedure:
(2S,4R)-Methyl 2-(2,5-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (499 mg, 1.42 mmol) (from example 124, step 3) was dissolved in hydrogen bromide (33% in acetic acid, 10 mL, 57.10 mmol) and the mixture stirred at room temperature for 22 h. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx III, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2S,4R)-2-(2,5-difluorobenzyl)piperidin-4-yl)isoxazol-3(2H)-one (292 mg, 70%). 1H NMR (600 MHz, cd3od) δ 1.49 (q, 1H), 1.71 (dq, 1H), 2.00-2.08 (m, 2H), 2.83-2.91 (m, 2H), 2.93-3.00 (m, 2H), 3.25-3.31 (m, 1H), 3.33-3.37 (m, 1H), 5.50 (s, 1H), 6.99-7.12 (m, 3H). HRMS Calculated for [C15H16F2N2O2+H]+: 295.1258. Found: 295.1254
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[CH:13]=[CH:14]/[CH2:15][OH:16])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]>[O-2].[O-2].[Mn+4]>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8](/[CH:11]=[CH:12]/[CH:13]=[CH:14]/[CH:15]=[O:16])=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(/C=C/C=C/CO)cc1
Agent: [Mn+4]
Agent: [O-2]
Product: CC(C)Oc1ccc(/C=C/C=C/C=O)cc1

Procedure:
In substantially the same manner as in Reference Example 14, (E,E)-5-(4-isopropoxyphenyl)-2,4-pentadien-1-ol was oxidized with manganese dioxide to give (E,E)-5-(4-isopropoxyphenyl)-2,4-pentadien-1-al as an oily substance.