Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[CH:11][C:5](/[CH:6]=[CH:7]/N(C)C)=[C:4]([N+:14]([O-])=O)[CH:3]=1.C[O:18][C:19]([C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1C(Cl)=O)=[O:20]>>[Cl:13][C:12]1[CH:11]=[C:5]2[C:4](=[CH:3][C:2]=1[Cl:1])[NH:14][C:7]([C:22]1[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=1[C:19]([OH:20])=[O:18])=[CH:6]2
Reactant: COC(=O)c1ccccc1C(=O)Cl
Reactant: CN(C)/C=C/c1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Product: O=C(O)c1ccccc1-c1cc2cc(Cl)c(Cl)cc2[nH]1

Procedure:
Starting from trans-4,5-dichloro-2-nitro-β-dimethylaminostyrene and 2-(methoxycarbonyl)benzoyl chloride and following successively the procedures of Descriptions 2, 3 and 4 afforded the title compound as a light brown solid which was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:15]2[CH2:17][O:16]2)[CH2:10][C:11]([O:13]C)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>FC(F)(F)CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH2:17][N:19]([CH3:18])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:16][C:11](=[O:13])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNc1ccccc1
Reactant: COC(=O)CC(c1ccc(Cl)c(Cl)c1)C1CO1
Solvent: OCC(F)(F)F
Product: CN(CC1OC(=O)CC1c1ccc(Cl)c(Cl)c1)c1ccccc1
Temperature: 23 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
Treat a solution of the product of step 2 (368 mg, 1.34 mmol) in 2,2,2 trifluoroethanol (1 mL) with N-methyl aniline (217 μL, 2.01 mmol, 1.5 eq) and stir for 6 h at 23° C. followed by 6 h at 80° C. Cool to 23° C., concentrate in vacuo and purify by silica gel chromatography (column: 3.5×12 cm; eluant: hexane:EtOAc (4:1)) to provide 446 mg (1.3 mmol, 97%) of 4-(3,4-dichlorophenyl)-dihydro-5-[(methylphenylamino)methyl]-2(3H)furanone as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]([N:22]2[CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:31]4[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=4)[CH:28]=3)[C:23]2=[O:37])[CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[Br:38]N1C(=O)CCC1=O>O1CCCC1>[Br:38][C:32]1[CH:33]=[N:34][N:35]([CH3:36])[C:31]=1[C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:37])[N:22]([C@@H:9]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH2:10][N:11]1[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]1=[O:21])[CH2:30]2
Reactant: Cn1nccc1-c1ccc2c(c1)CN([C@@H](Cc1cccc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: Cn1ncc(Br)c1-c1ccc2c(c1)CN([C@@H](Cc1cccc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of 2-{(2S)-3-(3-fluorophenyl)-2-[5-(1-methyl-1H-pyrazol-5-yl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]propyl}-1H-isoindole-1,3(2H)-dione (200.0 mg, 0.4044 mmol) [prepared in Example 1] in tetrahydrofuran (5 mL) was added N-bromosuccinimide (72.0 mg, 0.404 mmol). The solution was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was purified by combi-flash chromatography eluted with EtOAc/hexane (50-100%). The purification afforded 231 mg (99.6% yield) of the desired product as white solid. LC/MS found: 573.0 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=3[OH:16])[N:8]=[C:4]2[CH:3]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:11][C:10]=3[OH:16])[N:8]=[C:4]2[CH:3]=1
Reactant: CCCCCCCCBr
Reactant: Oc1ccc(-n2nc3ccc(Cl)cc3n2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCCCCCCCOc1ccc(-n2nc3ccc(Cl)cc3n2)c(O)c1
Yield: 9.7 %

Procedure:
A mixture of 6.5 g of 5-chloro-2-(2,4-dihydroxyphenyl)-2H-benzotriazole, 7.1 g of 1-bromooctane, 5.2 g of anhydrous potassium carbonate and 100 mL of acetone is refluxed for 24 hours. To the resulting mixture, about 100 mL of water and ethyl acetate are added, and petroleum eg of crude product is isolated. Column chromatography using petroleum ether yields 0.9 g of the title compound whose structure is confirmed by Hnmr and mass spectrometry.
Reaction SMILES: [OH-].[Na+].[N+:3]([N:6]=[C:7]1[NH:11][CH2:10][CH2:9][N:8]1[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([S:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])=[N:17][CH:18]=1)([O-:5])=[O:4]>O.C(O)C>[N+:3]([N:6]=[C:7]1[NH:11][CH2:10][CH2:9][N:8]1[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([S:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[N:17][CH:18]=1)([O-:5])=[O:4]
Reactant: CCOC(=O)CCSc1ccc(CN2CCNC2=N[N+](=O)[O-])cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCSc1ccc(CN2CCNC2=N[N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
0.44 g (11 mmol) of sodium hydroxide dissolved in 30 ml water was added to a suspension containing 1.3 g (3.7 mmol) of ethyl 3-[5-(2-nitroiminoimidazolidin-1-ylmethyl)-2-pyridylthio]propionate (4) in 40 ml of ethanol and stirred at room temperature for 1 hour. The ethanol was distilled away under reduced pressure, and 20 ml of water and 30 ml of ether were added to the residues which were then partitioned, and the aqueous layer was adjusted to pH 5 with dilute hydrochloric acid and extracted twice with 70 ml of ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residues were purified by silica gel chromatography (ethyl acetate: methanol=1:1) to give 0.6 g of (5) (yield 50%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(OC(=O)C)(=O)C.[Br:12][C:13]1[C:17]([Br:18])=[CH:16][S:15][CH:14]=1>C(O)(=O)C>[Br:12][C:13]1[C:17]([Br:18])=[CH:16][S:15][C:14]=1[N+:1]([O-:4])=[O:2]
Reactant: Brc1cscc1Br
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1scc(Br)c1Br
Reaction time: 0.17 h

Procedure:
41.4 ml of fuming nitric acid was slowly added to 500 ml of acetic acid under ice-cooling, followed by stirring for 10 minutes, and a solution of 78 ml of acetic acid anhydride containing 50 g of 3,4-dibromothiophene was slowly added, followed by stirring at room temperature for 18 hours. Ice was added to the reaction solution, and the resulting crystals were collected by filtration, and washed with water and diethyl ether/n-hexane=1/5 successively, to give 40.2 g of the title compound.
Reaction SMILES: FC1C=CC([C:8]2[N:12](O)[C:11]3[CH:14]=[C:15](C(N4C=CN=C4)C4C=CC=CC=4)[CH:16]=[CH:17][C:10]=3[N:9]=2)=CC=1.[OH-].[Na+].CO>O>[NH:9]1[C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[N:12]=[CH:8]1
Reactant: On1c(-c2ccc(F)cc2)nc2ccc(C(c3ccccc3)n3ccnc3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: c1ccc2[nH]cnc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2.7 parts of 2-(4-fluorophenyl)-6-[(1H-imidazol-1-yl)-phenylmethyl]-1H-benzimidazol-1-ol, 7 parts of a sodium hydroxide solution in water 1N and 20 parts of methanol was stirred for 15 minutes at room temperature. After evaporation, the residue was taken up in methylbenzene and the solvent was evaporated (this proces was repeated twice). The residue was dissolved in 22.5 parts of N,N-dimethylformamide and a solution of 0.89 parts of (chloromethyl)benzene in a small amount of N,N-dimethylformamide was added dropwise. Upon complete addition, stirring was continued for 1 hour at room temperature. After standing overnight at room temperature, the solvent was evaporated. Water was added to the residue and the product was extracted with dichloromethane. The extract was dried, filtered and concentrated. The concentrate was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 17.5 parts of 2-propanol. The product was filtered off, washed with 2,2'-oxybispropane and 2-propanol and dried, yielding 2.1 parts (63.5%) of 2-(4-fluorophenyl)-6-[(1H-imidazol-1-yl)phenylmethyl]-1-phenylmethoxy)-1H-benzimidazole; mp. 177.6° C. (compound 241).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OS(O)(=O)=O.[C:14]([CH2:16][C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:15].[Na]>O.C(Cl)(Cl)Cl.CCO>[CH2:21]([O:20][C:18]([C:17]1[CH:16]=[C:14]([NH2:15])[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)C(=O)CC#N
Reactant: NNc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CCO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(N)n(-c2ccccc2)n1
Temperature: 135 °C
Yield: 79.9 %

Procedure:
Phenyl hydrazine (2.94 ml, 0.03 moles) was dissolved in water (50 ml) in a 500 ml beaker. Concentrated H2SO4 (1.63 ml, 0.03 mole) was added drop-wise using a pipette while cooling with ice water bath. This phenyl hydrazine solution was then added to a stirred solution of sodium ethyl cyanopyruvate (5.37 g, 0.03 mole) in 70 ml of chloroform in a 500 ml round bottom flask at room temperature. Stirring was maintained for about 24 hrs and the reaction was monitored by LCMS. After the completion of reaction, the organic layer was separated and the aqueous layer was extracted with CHCl3 (2×150 ml). The combined organic layer was then washed with saturated NaHCO3 (1×100 ml), dried over sodium sulfate. Removal of solvent provided a viscous oil which was mainly non-cyclized hydrazone. The crude product was dissolved in minimum amount of dry EtOH (15 ml) and the mixture was heated in sealed tube at 120-150° C. for overnight. After the completion of reaction, ethanol was evaporated in vacuo to give crude product, which was purified by column chromatography eluting with Hexanes/Ethyl Acetate=9/1 to 1/1 to give 5.54 g of 5-Amino-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester (yield: 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)(O)[CH3:10].[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1)[CH3:10]
Reactant: COC(=O)c1ccc(C(C)(O)c2cc(Cl)ccc2Cl)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(C(C)c2cc(Cl)ccc2Cl)cc1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
To the intermediate from Step A (75 mg, 0.23 mmol) in a screw cap tube was added DCM (2 mL), Et3SiH (0.4 mL) and TFA (0.4 mL). The closed tube was then heated at 75° C. for 1.5 hours. The solution was cooled and concentrated. To the residue, which is a mixture of the title compound and methyl 4-[1-(2,5-dichlorophenyl)vinyl]benzoate (1/1), was added DCM (4 mL) and PtO2 (15 mg). The solution was stirred under a hydrogen atmosphere (balloon) for 3 hours. The hydrogen was purged and the solution filtered. The residue was purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound LCMS1 4.19 min. (M+H)=309
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]([C:14]1[CH:15]=[C:16]([CH:33]=[C:34]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:35]=1[OH:36])[C:17]([O:19][C:20]1[C:28]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)=[O:18])([CH3:13])([CH3:12])[CH3:11]>>[CH2:1]([NH:9][C:24](=[O:25])[C:23]1[CH:27]=[C:28]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:20]([O:19][C:17](=[O:18])[C:16]2[CH:15]=[C:14]([C:10]([CH3:12])([CH3:11])[CH3:13])[C:35]([OH:36])=[C:34]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:33]=2)=[CH:21][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN
Reactant: CC(C)(C)c1cc(C(=O)Cl)ccc1OC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Product: CCCCCCCCNC(=O)c1ccc(OC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C(C)(C)C)c1

Procedure:
Following the procedure of Example 8, n-octylamine is reacted with 4-(3,5-di-t-butyl-4-hydroxybenzoyloxy)-5-t-butylbenzoyl chloride to yield N-n-octyl-4-(3,5-di-t-butyl-4-hydroxybenzoyloxy)-5-t-butylbenzamide.
Reaction SMILES: [CH:1]([C@H:4]1[C:9]([O:10][CH3:11])=[N:8][CH:7]([CH3:12])[C:6]([O:13][CH3:14])=[N:5]1)([CH3:3])[CH3:2].C([Li])CCC.I[CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]2[O:30][C:29]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[N:28][C:27]=2[CH:36]=1.[Cl-].[NH4+]>C1COCC1.CCCCCC.CCOC(C)=O>[CH:1]([C@H:4]1[C:9]([O:10][CH3:11])=[N:8][C@@:7]([CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]3[O:30][C:29]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[N:28][C:27]=3[CH:36]=2)([CH3:12])[C:6]([O:13][CH3:14])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CCCCCc1nc2cc(CCI)ccc2o1
Reactant: COC1=N[C@@H](C(C)C)C(OC)=NC1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCc1nc2cc(CC[C@@]3(C)N=C(OC)[C@H](C(C)C)N=C3OC)ccc2o1
Temperature: -65 °C
Reaction time: 1.5 h

Procedure:
Under an argon atmosphere, a −70° C. solution of (S)-2-Isopropyl-3,6-dimethoxy-5-methyl-2,5-dihydro-pyrazine (652.5 μl, 3.291 mmol) in dry THF (7 ml) was treated with a solution of n-butyl lithium in n-hexane (2.1 ml of a 1.6M solution, 3.29 mmol). After stirring for 10 minutes a solution of 5-(2-iodo-ethyl)-2-pentyl-benzoxazole (753 mg, 2.19 mmol) in dry THF (5 ml) was added and the reaction mixture was stirred for 90 minutes at −65° C. followed by 2 hours at 0-5° C. The reaction was distributed between AcOEt and saturated aqueous ammonium chloride. The organic layer dried over MgSO4 and concentrated in vacuum. Silica-gel flash chromatography (pentane/diethyl ether 4/1) provided the crude 5-[2-((2R,5S)-5-Isopropyl-3,6-dimethoxy-2-methyl-2,5-dihydro-pyrazin-2-yl)-ethyl]-2-pentyl-benzoxazole. The crude product was dissolved in acetonitrile (21 ml) and treated with water (21 ml) and trifluoroacetic acid (450 μl) and stirred for 3 days at RT. The solvents were removed in vacuum and the title compound was obtained after reversed phase chromatography (Waters, C-18, eluent: gradient of water/acetonitrile containing 0.1% trifluoroacetic acid) as an amorphous solid. 1H-NMR (CDCl3) δ: 8.50 (s; 1H), 6.98 (s; 1H); 8.86/6.83 (2 broad singlets; 2H), 3.71 (s; 3H), 2.75-2.35 (m; 4H), 2.20 (broad s; 2H), 1.70 (broad s; 2H), 1.61 (s; 3H), 1.40-1.20 (m; 4H), 0.90 (m; 3H).
Reaction SMILES: ClCCl.Cl.[NH2:5][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7]O.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(N(CC)CC)C>[C:14]1([C:13]([NH:5][C:6](=[CH2:7])[C:9]([O:11][CH3:12])=[O:10])=[O:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(NC(=O)c1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To dichloromethane (400 mL) were added methyl serinate hydrochloride (45.0 g) and triethylamine (132 mL), and benzoyl chloride (77.0 mL) was added dropwise. After stirring at room temperature overnight, the reaction system was washed twice with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (300 mL), and 2,3,4,6,7,8,9,10-octahydroprimido[1,2-a]azepine(52.0 g) was added. The mixture was stirred at room temperature for 4 hr, and the reaction system was washed twice with water and saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give a crude product (67.0 g) of the title compound as a brown oil.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[CH2:11]([C@H:18]1[CH2:22][NH:21][C@H:20]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)=[O:24])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[N:2]1([CH2:7][C:8]([N:21]2[CH2:22][C@H:18]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:19][C@H:20]2[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)=[O:24])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(O)Cn1cncn1
Reactant: O=C(Nc1ccc(Oc2ccc(Cl)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(Cl)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)Cn1cncn1
Yield: 37 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-chlorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 79, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-benzyl-N-(4-(4-chlorophenoxy)phenyl)pyrrolidine-2-carboxamide (187 mg, 37%). 1H-NMR (400 MHz, CDCl3): σ 9.04 (s, 1H), 8.24 (s, 1H), 7.99 (s, 1H), 7.43 (d, 2H), 7.31 (d, 2H), 7.27-7.18 (m, 4H), 6.93 (d, 2H), 6.88 (d, 2H), 5.03 (d, 1H), 4.95 (d, 1H), 4.81 (d, 1H), 3.63 (dd, 1H), 3.25 (dd, 1H), 3.05-2.90 (m, 3H), 2.70-2.63 (m, 2H). MS (EI) for C28H26ClN5O3. found 515.9 (MH+).
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][CH:10]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19](Cl)(=[O:21])[CH3:20]>>[C:19]([C:4]1[CH:3]=[CH:2][C:1]([CH:7]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([CH3:17])([CH3:16])[CH3:18])=[CH:13][CH:14]=2)[CH3:8])=[CH:6][CH:5]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: CC(c1ccccc1)c1ccc(C(C)(C)C)cc1
Product: CC(=O)c1ccc(C(C)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
In like manner as in Preparation Example 1, 200 g of this 1-phenyl-1-(4'-tert-butylphenyl)ethane was reacted with acetyl chloride to obtain 1-(4-acetylphenyl)-1-(4'-tert-butylphenyl)ethane. Also in like manner as in Preparation Example 1, this compound was converted into an alcohol by using sodium borohydride, and the product was then dehydrated with potassium hydrogensulfate to obtain 1-(4-tert-butylphenyl)-1-(4'-vinylphenyl)ethane in a yield of 69.2% (b.p. 171° C./10 mmHg, 130° C./2 mmHg).
Reaction SMILES: C[C:2]([P:8]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])=[O:9])([CH3:7])[CH2:3][C:4](=O)[CH3:5].[P:16]([O-:23])([O:20]CC)[O:17][CH2:18][CH3:19].[Na].[C:25](O)(=O)C>C1(C)C=CC=CC=1.[Na]>[O:20]=[P:16]1([O:17][CH2:18][CH3:19])[C:4]([CH3:5])([CH3:25])[CH2:3][C:2]([CH3:7])([P:8]([O:10][CH2:11][CH3:12])([O:13][CH2:14][CH3:15])=[O:9])[O:23]1
Reactant: CC(=O)O
Reactant: CCOP(=O)(OCC)C(C)(C)CC(C)=O
Reactant: CCOP([O-])OCC
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCOP1(=O)OC(C)(P(=O)(OCC)OCC)CC1(C)C
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
10 ml of a mixture of 70.8 g of 4-methyl-4-(diethylphosphono)-pentan-2-one (prepared from mesityl oxide and diethyl phosphite) and 82.8 g of diethyl phosphite were dissolved in 100 ml of toluene, and the solution was heated to 80° C. A catalytic amount of sodium was added and a vigorous exothermic reaction commenced. The reaction temperature was held between 80° C. and 90° C. by alternately adding the previously prepared mixture and small pieces of sodium. Altogether 1.65 g of sodium was used as catalyst. The reaction took 20 minutes. The reaction mixture was subsequently stirred at 80°-90° C. for 30 minutes with heating, then cooled and neutralized with 4.5 g of glacial acetic acid. This reaction mixture was distilled to yield 2-oxo-2-ethoxy-3,3,5-trimethyl-5-diethylphosphono-1,2-oxaphospholane with a boiling point of 156°-161° C./1.1 mm. This substance is identical to the oxaphospholane manufactured according to Example 4.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[F:25][C:26]1[C:27]([N:35]2[N:39]=[CH:38][CH:37]=[N:36]2)=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([OH:31])=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:29]([C:28]1[CH:32]=[CH:33][CH:34]=[C:26]([F:25])[C:27]=1[N:35]1[N:39]=[CH:38][CH:37]=[N:36]1)=[O:31]
Reactant: O=C(O)c1cccc(F)c1-n1nccn1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-n2nccn2)[C@@H]1CN

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) 318 (M+H).
Reaction SMILES: [CH2:1](O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[N:10]12[CH2:17][CH2:16][CH:13]([CH2:14][CH2:15]1)[C@@H:12]([OH:18])[CH2:11]2.C([O:26][C:27]([N:29]1[CH2:38][CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C@@H:30]1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=O)C1C=CC=CC=1>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:1]([CH:11]1[CH:12]([O:18][C:27]([N:29]2[CH2:38][CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]2[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:26])[CH:13]2[CH2:16][CH2:17][N:10]1[CH2:15][CH2:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCc2ccccc2[C@@H]1c1ccccc1
Reactant: OCc1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: [Na]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(OC1C2CCN(CC2)C1Cc1ccccc1)N1CCc2ccccc2C1c1ccccc1
Yield: 173.5 %

Procedure:
In a mixture of sodium benzyl alkoxide prepared from 0.19 g of benzyl alcohol and 0.04 g of metallic sodium with 15 ml of toluene and 0.75 ml of DMF, 1.33 g of (R)-quinuclidin-3-ol was allowed to react with 3.00 g of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester for 8 hours while evaporating the solvents, thereby obtaining 1.38 g of 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid 2-benzylquinuclidin-3-yl ester (to be referred to as “compound F” hereinafter).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH:13]=[C:12]2[CH:26]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:28]1[CH2:32][C:31](=[O:33])[NH:30][C:29]1=[O:34].N1CCCCC1>CCO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH:13]=[C:12]2[CH:26]=[C:32]1[S:28][C:29](=[O:34])[NH:30][C:31]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1cn(-c2ccc(Cl)c(Cl)c2)c2ccc(OCc3ccccc3)cc12
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2cn(-c3ccc(Cl)c(Cl)c3)c3ccc(OCc4ccccc4)cc23)S1

Procedure:
A solution of 5-benzyloxy-N-(3,4-dichlorophenyl)-indole-3-carbaldehyde (1 eq.), 2,4-thiazolidinedione (1.5 eq.) and piperidine (1.5 eq.) in EtOH was heated to 70° C. for 18 hrs. Volatiles were removed under reduced pressure and the residue was taken up in EtOAc. Addition of ether precipitated the product, which showed the appropriate mass ion and was greater than 60% pure by HPLC (uv readout at 254 nm): isocratic 35:65 H2O/CH3CN. Pure material was obtained by column chromatography on silica gel; (5:3) EtOAc/hexanes. Purity by HPLC was 85%; m\e 510 (M+1); 44% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].O.[NH2:13][NH2:14]>CC(O)C>[FH:1].[NH:13]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11])[NH2:14]
Reactant: NN
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Solvent: O
Solvent: CC(C)O
Product: Cc1cc([N+](=O)[O-])ccc1NN
Product: F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4.6 g of 1-fluoro-2-methyl-4-nitrobenzene and 3 ml of hydrazine hydrate in 45 ml of 2-propanol is heated to reflux for 2 hours. 3 ml of hydrazine hydrate are added, refluxing is continued for 2 hours and the mixture is left overnight with stirring at RT. The precipitate formed is drained. 3.53 g of the expected product are obtained, m.p.=182° C.