Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.Cl>C(O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)/C=C/c1ccc(-c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)/C=C/c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6.27 mL of a 1M sodium hydroxide solution is added to a solution of 0.9 g (3.13 mmol) of ethyl (E)-3-(4′-chlorobiphenyl-4-yl)acrylate in 30 mL of ethanol and stirred for 3 hours at ambient temperature. The reaction is stopped by the addition of 6.27 mL of 1N hydrochloric acid and the reaction mixture is stirred for 2 hours. Then the mixture is evaporated down, the residue is combined with water, and the precipitate is filtered off. The precipitate is repeatedly rinsed with water and dried at 80° C. in the vacuum drying chamber. Yield: 0.68 g (67% of theory); C15H11ClO2 (M=258.70); calc.: molecular ion peak (M−H)−: 257/259; found: molecular ion peak (M−H)−: 257/259; Rf value: 0.5 (silica gel, dichloromethane/methanol (90:10)).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]([OH:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:22][C:23]([CH3:27])([CH3:26])[CH2:24]O>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][O:21][CH:8]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(N)CO
Reactant: OC(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(N)COC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
Trifluoroacetic acid (25 ml) was added to a solution of benzhydrol (9.2 g) and 2-amino-2-methylpropanol (4.5 g) in methylene chloride (5 ml) and the mixture was stirred at room temperature for 3 hours and evaporated. The residue was partitioned between water and ethyl acetate and the organic layer was washed with water, dried over magnesium sulphate and evaporated. The residue was triturated with hexane and recrystallised from ethyl acetate to give the title compound as a colourless solid (2.98 g, 16%), m.p. 160°-161°.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][NH2:34])=[CH:29][CH:28]=2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[C:42](OC(=O)C)(=[O:44])[CH3:43]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:42](=[O:44])[CH3:43])=[CH:29][CH:28]=2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1cccc(CN(c2ccc(CN)cc2)C2CCN(C(=O)OCc3ccccc3)CC2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of the above amine (462 mg, 1.02 mmol) in CH2Cl2 (10 mL) were added Et3N (0.45 mL, 3.23 mmol) followed by acetic anhydride (0.20 mL, 2.12 mmol) and the mixture was stirred at room temperature overnight to afford 4-[[4-(acetylamino-methyl)-phenyl]-(3-cyano-benzyl)-amino]-piperidine-1-carboxylic acid benzyl ester as a white solid (463 mg, 91%) following work-up and purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16]([N:20]([C:29](=[O:31])[CH3:30])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][N:20]([C:16]1[N:15]=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=[N:18][CH:17]=1)[C:29](=[O:31])[CH3:30]
Reactant: CC(=O)N(Cc1cccc(Cl)c1)c1cncc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N(Cc1cccc(Cl)c1)c1cncc(N2CCNCC2)n1
Temperature: 25 °C
Yield: 126.3 %

Procedure:
To a solution of 6′-[acetyl-(3-chloro-benzyl)-amino]-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester I-5c (27.1 mg, 0.06 mmol) in methylene chloride (1 mL) was added trifluoroacetic Acid (1 mL). The reaction mixture was stirred at room temperature until the reaction was completed. The reaction mixture was poured into saturated NaHCO3 (20 mL) and extracted with methylene chloride (2×15 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated to dryness to yield the title compound 5-A (26.2 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][N+:7]3[CH2:20][CH2:19][C:18]4[C:13](=[CH:14][C:15]5[O:23][CH2:22][O:21][C:16]=5[CH:17]=4)[C:8]=3[CH:9]=2)[C:4]=1[O:24][CH3:25].[Cl-].[C:27]([Mg]Cl)#[CH:28]>C(OCC)C>[C:27]([CH:6]1[N:7]2[CH2:20][CH2:19][C:18]3[C:13]([C:8]2=[CH:9][C:10]2[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[C:4]([O:24][CH3:25])[C:5]1=2)=[CH:14][C:15]1[O:23][CH2:22][O:21][C:16]=1[CH:17]=3)#[CH:28]
Reactant: COc1ccc2cc3[n+](cc2c1OC)CCc1cc2c(cc1-3)OCO2
Reactant: C#C[Mg]Cl
Agent: [Cl-]
Solvent: CCOCC
Product: C#CC1c2c(ccc(OC)c2OC)C=C2c3cc4c(cc3CCN21)OCO4
Temperature: 0 °C
Reaction time: 16 h
Yield: 20.2 %

Procedure:
To a suspension of berberine hydrochloride (500 mg, 1.3 mmol) in anhydrous diethyl ether (50 mL) at 0° C. was added ethynylmagnesium chloride solution (1.1 M in tetrahydrofuran, 24 mL, 26 mmol) dropwise. After stirring at 0° C. for 16 h, the reaction was quenched by adding saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with diethyl ether (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from diethyl ether to afford 8-ethynyl-9,10-dimethoxy-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (95 mg, 20%). LC/MS m/e calcd for C22H19NO4 (M+H)+: 362.40, observed: 362.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.78-2.88 (m, 2 H) 3.17 (d, J=2.27 Hz, 1 H) 3.21-3.30 (m, 2 H) 3.81 (d, J=4.80 Hz, 6 H) 5.45 (d, J=2.02 Hz, 1 H) 6.02 (d, J=5.81 Hz, 2 H) 6.18 (s, 1 H) 6.76-6.83 (m, 2 H) 6.93 (d, J=8.59 Hz, 1 H) 7.32 (s, 1 H).
Reaction SMILES: Cl[C:2]([C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5]1)=[O:3].[Br:12][C:13]1[CH:20]=[CH:19][C:16]([NH:17][CH3:18])=[CH:15][CH:14]=1.C(N(CC)CC)C>>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([N:17]([CH3:18])[C:2]([C:4]2([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5]2)=[O:3])=[CH:15][CH:14]=1
Reactant: CCOC(=O)C1(C(=O)Cl)CC1
Reactant: CNc1ccc(Br)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C(=O)N(C)c2ccc(Br)cc2)CC1
Yield: 50 %

Procedure:
Ethyl 1-chlorocarbonylcyclopropanecarboxylate (3.11 grams, 0.02 mole), prepared in Example XVIII, 4-bromo-N-methylaniline (3.00 grams, 0.02 mole) and triethylamine (1.63 grams, 0.02 mole) were reacted in a manner similar to that described in Example III to give 3.79 grams (0.01 mole) of ethyl 1-[N-(4-bromophenyl)-N-methylaminocarbonyl]cyclopropanecarboxylate isolated as a colorless oil. Elemental analysis of the product indicated the following:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.CC1C=CC(S(O[CH2:21][C@@H:22]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH3:23])(=O)=O)=CC=1.O>CN(C=O)C>[CH3:23][C@H:22]([NH:24][C:25](=[O:26])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH2:21][O:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](C)NC(=O)OC(C)(C)C)cc1
Reactant: Oc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](COc1ccncc1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 20.7 %

Procedure:
To a suspension of sodium hydride (oil, 60%, 1.61 g) in DMF (50 mL) was added 4-hydroxypyridine (3.83 g) under ice-cooling. The reaction mixture was stirred for 30 min under ice-cooling, and (2S)-2-[(tert-butoxycarbonyl)amino]propyl 4-methylbenzenesulfonate (13.3 g) was added thereto in small portions under ice-cooling. The reaction mixture was stirred for 2 hr under ice-cooling, and at 60° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.10 g).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][N:28]=2)[CH2:22]1>>[CH3:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:29][N:28]=2)[CH2:22]1
Reactant: COC1CCCN(c2ccc(N)cn2)C1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: COC1CCCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)C1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (3-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 3-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-ylamine. LCMS calcd for C22H21F3N4O3 (m/e) 446, obsd 447 (M+H).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[C:14](OC)=[S:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C(O)(=[O:22])C>O1CCCC1.CN(C)C=O>[OH:22][C:8]1[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:14]=2[S:15][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)O
Reactant: COC(=S)c1ccncc1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Oc1c(-c2ccccc2)sc2cnccc12
Temperature: 60 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
A solution of 4.8 g (19 mmol) of methyl 3-phenylmethylthiopyridine-4-carboxylate in 10 mL of tetrahydrofuran was added to a slurry of 2.40 g (60 mmol) of 60% sodium hydride in 10 mL of N,N-dimethylformamide and the resulting mixture was stirred at 60° C. for 3 hours. The solution was poured onto ice water and acidified with glacial acetic acid. The filtrate was collected to afford 1.6 g (38%) of white solid.
Reaction SMILES: CS(O[C@@H:6]1[C@@H:11]([CH3:12])[CH2:10][N:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[NH:19]C(OC(C)(C)C)=O)[CH2:8][C@H:7]1[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])(=O)=O.[NH:35]1[CH:39]=[N:38][CH:37]=[N:36]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[NH2:19][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[N:9]1[CH2:10][C@H:11]([CH3:12])[C@H:6]([N:35]2[CH:39]=[N:38][CH:37]=[N:36]2)[C@H:7]([NH:27][C:28](=[O:29])[O:30][C:31]([CH3:32])([CH3:33])[CH3:34])[CH2:8]1
Reactant: c1nc[nH]n1
Reactant: C[C@H]1CN(c2ccncc2NC(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1cncn1
Yield: 8 %

Procedure:
A solution of (3R,4R,5S)-3-(tert-butoxycarbonylamino)-1-(3-(tert-butoxycarbonylamino)pyridin-4-yl)-5-methylpiperidin-4-yl methanesulfonate (1.0 equiv.), 1H-1,2,4-triazole (3.0 equiv.) and Cs2CO3 (3.0 equiv.) in DMF (0.17 M) was stirred at 90° C. for 3 hrs. The mixture was diluted with DMF, filtered and purified by RP HPLC, followed by free basing by partitioning between an equal volume of EtOAc and Na2CO3, separating, washing with NaCl(sat.), drying over MgSO4, filtering, concentrating to yield tert-butyl (3R,4S,5S)-1-(3-aminopyridin-4-yl)-5-methyl-4-(1H-1,2,4-triazol-1-yl)piperidin-3-ylcarbamate in 8% yield. LC/MS (m/z)=374.3 (MH+), Rt=0.53 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:18][C:19]1[NH:23][N:22]=[C:21]([C:24]([OH:26])=[O:25])[CH:20]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:23]3[N:22]=[C:21]([C:24]([OH:26])=[O:25])[CH:20]=[C:19]3[N:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1cc(C(=O)O)n[nH]1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)c(Cl)c1
Solvent: CC(=O)O
Product: O=C(O)c1cc2nc(-c3ccc(Cl)c(Cl)c3)cc(C(F)(F)F)n2n1
Yield: 90.9 %

Procedure:
1-(3,4-Dichloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (1.00 g, 3.51 mmol) and 5-amino-1H-pyrazole-3-carboxylic acid (0.446 g, 3.51 mmoL) in acetic acid (100 mL) was heated at reflux for 48 hours. The reaction concentrated under reduced pressure and the crude product was purified by column chromatography on silica gel to give 5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (1.20 g, 90%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[N+:9]([O-])=O.[H][H]>CO.[Ni]>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[NH2:9]
Reactant: CNc1ccncc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CNc1ccncc1N
Yield: 83.8 %

Procedure:
2.3 g methyl-(3-nitropyridin-4-yl)-amine are hydrogenated in 50 ml of methanol for and with 0.8 g Raney nickel for 2.5 h at 50° C. and 50 psi hydrogen pressure. The catalyst is filtered off and the filtrate is evaporated to dryness. The product is purified by chromatography (Alox, dichloromethane/methanol from 99/1 to 19/1). 1.55 g product are obtained as a solid.
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][OH:10].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].[I-].[K+]>O.CN(C)C=O>[OH:10][CH2:9][C:2]1[O:3][CH:4]=[C:5]([O:8][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])[C:6](=[O:7])[CH:1]=1
Reactant: O=c1cc(CO)occ1O
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1coc(CO)cc1=O
Temperature: 90 °C
Reaction time: 10 h

Procedure:
A mixture of 56.8 g (0.4 mole) kojic acid, 55,3 g (0.4 mole) potassium carbonate, 133.3 g (0.4 mole) 1-octadecyl bromide, 1 g potassium iodide and 450 mL anhydrous dimethylformamide is stirred for 10 hours at 90° C.. After cooling, the mixture is mixed with 1.5 L of water, the precipitate formed is filtered off, well stirred up once with ethyl acetate, filtered off and recrystallized from propan-2-ol with the addition of active charcoal. There is obtained a colorless product: m.p. 71°-73° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][S:9][C@@H:8]([CH2:11][SH:12])[CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:20]([S:12][CH2:11][C@H:8]1[CH2:7][C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:10][S:9]1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)[C@@H]1CS[C@@H](CS)C1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CS[C@@H](CSC(=O)c2ccccc2)C1
Reaction time: 0.17 h
Yield: 86 %

Procedure:
To a stirred solution of trans-4-ethoxycarbonyl-2-mercaptomethyltetrahydrothiophene (compound No. 15-1, 60 mg) and triethylamine (42 μl) in methylene chloride (2 ml), benzoyl chloride (43 mg) dissolved in methylene chloride (1 ml) was added under ice-cooling. The mixture was stirred for 10 minutes and concentrated in vacuo. 0.1N hydrochloric acid was added to the residue and extracted with diethylether. The organic layer was washed with aqueous sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 77 mg (86%) of the titled compound (compound No. 23-1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:21](=[O:37])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][O:14][C:12]1[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]2[NH:20][C:21](=[O:37])[CH2:22][C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccccn3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccccn3)c1)=N2

Procedure:
The title compound was prepared from {5-methoxy-2-[3-oxo-3-(3-pyridin-2-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M38) (208 mg, 0.39 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (140 mg).
Reaction SMILES: [NH2:1][CH:2]([CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:3].N([C:16]1[NH:17][CH2:18][CH2:19][N:20]=1)[N+]([O-])=O.C1(C)C(C)=CC=CC=1>CC(C)=O>[NH:20]1[CH2:19][CH2:18][N:17]=[C:16]1[NH:1][CH:2]([CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:3]
Reactant: O=[N+]([O-])NC1=NCCN1
Reactant: CC(N)C(O)c1ccccc1
Solvent: Cc1ccccc1C
Solvent: CC(C)=O
Product: CC(NC1=NCCN1)C(O)c1ccccc1
Reaction time: 0.5 h

Procedure:
A mixture pf 6.5 parts of α-(1-aminoethyl)benzyl alcohol (also known as morephedrine), 5.2 parts of 2-(nitramino)-2-imidazoline and 8 parts of xylene is stirred for 30 minutes while heating at 160°-170°C. The reaction mixture is cooled and diluted with acetone. The latter is removed in vacuo, yielding α-[1-(2-imidazolin-2-ylamino)-ethyl]benzyl alcohol as an oily residue.
Reaction SMILES: [Mg].[CH3:2][CH2:3][O:4][C:5]([C@H:7]1[CH2:11][CH2:10][C:9](=[O:12])[N:8]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:6].O.Br[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29]>O1CCCC1>[C:16]([O:15][C:13]([NH:8][C@H:7]([CH2:11][CH2:10][C:9]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29])=[O:12])[C:5]([O:4][CH2:3][CH3:2])=[O:6])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: Fc1ccc(Br)c(F)c1
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](CCC(=O)c1ccc(F)cc1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of magnesium (736 mg) in tetrahydrofuran (20 mL), 1-bromo-2,4-difluorobenzene (3.42 mL) was added dropwise at 45° C. over five minutes, and the reaction solution was stirred at room temperature for one hour. This solution was added dropwise to a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (6.0 g) in tetrahydrofuran (50 mL) at −40° C. over 20 minutes, and the reaction solution was stirred at −40° C. to 0° C. for one hour. Water was added to the solution in small portions at 0° C., followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 7.5 g of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:4]([O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.C(Cl)(=O)C([Cl:33])=O>C1(C)C=CC=CC=1.CN(C=O)C>[CH3:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:4]([O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([Cl:33])=[O:20])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc2c(Oc3ccc(C(=O)O)cc3)c(-c3ccccc3)c(C)cc2c1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc2c(Oc3ccc(C(=O)Cl)cc3)c(-c3ccccc3)c(C)cc2c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}benzoic acid (16) (0.149 g, 0.388 mmol) in toluene (3 mL) was added oxalyl chloride (0.06 mL, 0.087 g, 0.687 mmol, 1.8 eq) followed by DMF (1 drop). The reaction mixture was stirred at RT under N2 for 45 min. The reaction mixture was concentrated to give crude 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}benzoyl chloride as a yellow oil. Isonipecotic acid (0.051 g, 0.39 mmol), triethylamine (0.12 mL, 0.087 g, 0.86 mmol) and H2O (2 mL) were combined and the solution was cooled in an ice-water bath under N2. To the cold isonipecotic acid solution was slowly added dropwise a solution of 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}benzoyl chloride in THF (2 mL) with stirring under N2. The ice-water bath was removed and the reaction mixture was allowed to stir for 5 d. The pH of the reaction mixture was adjusted to ˜1 (litmus paper) with 1 N HCl and the acidic reaction mixture was partitioned between EtOAc and H2O. The organic phase was separated, washed with H2O (2×), dried over MgSO4, filtered, and the filtrate was concentrated to give the crude title compound. The crude product was purified by flash chromatography over SiO2 with CH2Cl2:MeOH (94:6) to give 0.133 g (69%) of compound 17 as an amorphous solid. 1H NMR (400 MHz; DMSO-d6): δ 1.42 (m, 2H), 1.80 (m, 2H), 2.17 (s, 3H), 2.93 (br s, 2H), 3.87 (s, 3H), 6.59 (d, J=8.6 Hz, 2H), 7.09 (dd, J=2.5 Hz, 9.2 Hz, 1H), 7.15 (m, 4H), 7.25 (m, 3H), 7.35 (d, J=2.4 Hz, 1H), 7.61 (d, J=9.1 Hz, 1H), 7.70 (s, 1H), 12.25 (br s, 1H). AP LRMS m/z 494 (M−H)−.
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([N:10]1[CH2:15][CH2:14][C:13]2([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([O:29]C)[C:23]=3[O:22][C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:12][CH2:11]1)[C:8]#[CH:9].[ClH:31].N1C=CC=CC=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O.N1C=CC=CC=1>[Cl:31][CH:9]=[CH:8][CH2:7][N:10]1[CH2:15][CH2:14][C:13]2([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:29])[C:23]=3[O:22][C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:12][CH2:11]1
Reactant: C#CCN1CCC2(CC1)c1ccccc1Oc1c(OC)cccc12
Reactant: Cl
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: Oc1cccc2c1Oc1ccccc1C21CCN(CC=CCl)CC1
Temperature: 200 °C

Procedure:
A mixture of 1'-(prop-2-ynyl)-4-methoxyxanthene-9-spiro-4'-piperidine hydrogen oxalate (1.3 g.) and pyridine hydrochloride prepared from pyridine (9 ml.) and concentrated hydrochloric acid (10 ml.) is heated at 200° C. for 10 minutes. The mixture is cooled and water (20 ml.) added. The solution is basified with dilute sodium carbonate solution and extracted with ether. The ether extract is washed with water, dried with MgSO4 and evaporated to dryness. The solid residue is recrystallised from ethyl acetate-petroleum ether (b.p. 80°-100° C.) to give 1'-(3-chloro-prop-2-enyl)-4-hydroxyxanthene-9-spiro-4'-piperidine, m.p. 153°-155° C.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=4[CH:18]([CH3:20])[CH2:19][C:8]=3[C@@H:7]1[CH2:6][CH2:5][C:4]12[O:26][CH2:25][CH2:24][O:23]1)[CH3:2].N.NC1C=CC=CC=1.[Li]>O1CCCC1>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=4[CH:18]([CH3:20])[CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]12[O:23][CH2:24][CH2:25][O:26]1)[CH3:2]
Reactant: CC[C@]12CCC3=C(CC(C)c4cc(OC)ccc43)[C@@H]1CCC21OCCO1
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: Nc1ccccc1
Product: CC[C@]12CC[C@@H]3c4ccc(OC)cc4C(C)C[C@H]3[C@@H]1CCC21OCCO1
Yield: 85.9 %

Procedure:
Add dl-13-ethyl-3-methoxy-6-methyl-17,17-ethylenedioxygona-1,3,5(10),8-tetraene (11.0 g) in tetrahydrofuran (160 ml) to liquid ammonia (600 ml) containing tetrahydrofuran (170 ml) and aniline (30 ml). Then add lithium (0.6 g) in small portions and stir for 2 hours. Work up in the usual way to obtain dl-13-ethyl-3-methoxy-6-methyl-17,17-ethylenedioxygona-1,3,5(10)-triene as a gum (9.5 g) that will crystallize on scratching. Recrystallize from isopropanol to obtain a product with m.p. 130°-134°; ultraviolet absorption peak at 280 mμ (ε1,976), no infrared absorption in the ketone region.