Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[CH:16]=[CH:15][C:14]4[CH2:18][CH2:19][CH2:20][CH2:21][C:13]=4[C:12]=3[NH:11][C:10](=[O:22])[C:9]2=[O:23])[CH:5]=[CH:6][CH:7]=1.[Br:24][C:25]1[CH:26]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>>[Br:24][C:25]1[CH:26]=[C:27]([S:31]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N:8]3[C:17]4[CH:16]=[CH:15][C:14]5[CH2:18][CH2:19][CH2:20][CH2:21][C:13]=5[C:12]=4[NH:11][C:10](=[O:22])[C:9]3=[O:23])[CH:3]=2)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: Nc1cccc(-n2c(=O)c(=O)[nH]c3c4c(ccc32)CCCC4)c1
Product: O=c1[nH]c2c3c(ccc2n(-c2cccc(NS(=O)(=O)c4cccc(Br)c4)c2)c1=O)CCCC3
Yield: 29 %

Procedure:
4-(3-Aminophenyl)-1,4,7,8,9,10-hexahydrobenzo[f]quinoxaline-2,3-dione (30 mg, 0.097 mmol) and 3-bromobenzenesulfonyl chloride (21 μL, 0.146 mmol) were used in a process similar to Example 9 to give the titled compound (a white crystal, 15 mg, yield 29%).
Reaction SMILES: C(S([C:11]1[C:12]2[CH:19]=[CH:18][N:17]([C@H:20]3[CH2:36][C@@H:23]4[O:24][CH:25]([C:28]5[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=5)[O:26][CH2:27][C@@H:22]4[CH2:21]3)[C:13]=2[N:14]=[CH:15][N:16]=1)(=O)=O)C1C=CC=CC=1.[NH2:37][C@H:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][CH2:39]1.CCN(C(C)C)C(C)C>C(O)C>[C@H:38]1([NH:37][C:11]2[C:12]3[CH:19]=[CH:18][N:17]([C@H:20]4[CH2:36][C@@H:23]5[O:24][CH:25]([C:28]6[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=6)[O:26][CH2:27][C@@H:22]5[CH2:21]4)[C:13]=3[N:14]=[CH:15][N:16]=2)[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][CH2:39]1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: COc1ccc(C2OC[C@@H]3C[C@@H](n4ccc5c(S(=O)(=O)Cc6ccccc6)ncnc54)C[C@@H]3O2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1ccc(C2OC[C@@H]3C[C@@H](n4ccc5c(N[C@@H]6CCc7ccccc76)ncnc54)C[C@@H]3O2)cc1
Temperature: 110 °C
Yield: 73.3 %

Procedure:
In a 0.5-2 mL microwave vial, 4-(benzylsulfonyl)-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-6-yl]-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.198 mmol), (R)-(−)-1-aminoindan (0.127 mL, 0.989 mmol), and DIPEA (0.172 mL, 0.989 mol) were dissolved in ethanol (1.22 mL). The vial was sealed and heated to 110° C. overnight. The solution was then concentrated in vacuo and the resulting material was purified via silica gel chromatography eluting with a gradient of 20 to 50% EtOAc in hexanes to afford the product as an orange oil (70.0 mg, 73%). LC/MS: Rt=1.42 min, ES+ 483 (FA standard).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([C:52]([OH:54])=[O:53])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.S(=O)(=O)(O)O.[C:62](=O)(O)[O-].[Na+]>O1CCCC1>[CH3:62][O:53][C:52]([C@:10]12[O:32][C@:13]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][C:48]([F:49])([F:50])[F:51])=[CH:43][CH:42]=4)[CH:34]=3)([O:12][CH2:11]1)[C@H:14]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:15]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:9]2[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:54]
Reactant: O=C([O-])O
Reactant: O=C(O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OC(F)(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OC(F)(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Temperature: 45 °C
Reaction time: 20 h
Yield: 66.5 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-(trifluoromethoxy) phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-carboxylic acid 16a (0.49 g, 0.64 mmol) in tetrahydrofuran (2 mL) were added methanol (8 mL) and concentrated sulphuric acid (0.24 mL) at room temperature. The mixture was stirred at 45° C. for 20 hours. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate till pH becomes 7 and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with saturated aqueous sodium chloride (10 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=20/1 to give the title compound 16b as a white solid (322 mg, 66.5%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.48 (d, 1H), 7.44-7.38 (m, 2H), 7.32 (m, 7H), 7.26 (m, 3H), 7.21 (d, 1H), 7.16 (m, 4H), 7.05 (d, 2H), 6.87 (d, 2H), 4.90-4.81 (m, 2H), 4.79 (d, 1H), 4.63 (d, 1H), 4.53 (d, 1H), 4.32 (d, 1H), 4.20 (dd, 2H), 4.10 (t, 2H), 4.02 (dd, 1H), 3.89 (d, 1H), 3.74 (d, 1H), 3.71 (s, 3H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[O:6]1[CH2:11][CH2:10][NH:9][C:8]2[CH:12]=[N:13][CH:14]=[CH:15][C:7]1=2.[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([N+:28]([O-:30])=[O:29])[C:25]=1[O:26][CH3:27])[C:20](O)=[O:21].[OH-].[Na+]>>[Cl:16][C:17]1[CH:18]=[C:19]([C:20]([N:9]2[CH2:10][CH2:11][O:6][C:7]3[CH:15]=[CH:14][N:13]=[CH:12][C:8]2=3)=[O:21])[CH:23]=[C:24]([N+:28]([O-:30])=[O:29])[C:25]=1[O:26][CH3:27]
Reactant: COc1c(Cl)cc(C(=O)O)cc1[N+](=O)[O-]
Reactant: c1cc2c(cn1)NCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1c(Cl)cc(C(=O)N2CCOc3ccncc32)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To phosphorus oxychloride (3.00 ml), 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (177 mg, 1.30 mmol) and 3-chloro-4-methoxy-5-nitro benzoic acid (200 mg, 0.87 mmol) were added and then stirred at 95□ for 16 hours. After completion of the reaction, the reaction mixture was poured into ice water and neutralized with saturated solution of sodium hydroxide, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate
Reaction SMILES: Br[CH:2]([CH:11]([OH:18])[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[H-].[Na+]>C1COCC1.C(OCC)(=O)C>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH:11]2[CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])[O:18]2)[CH:13]=1
Reactant: COC(=O)CCCCC(Br)C(O)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CCCCC1OC1c1cccnc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
16.3 g of methyl 6-bromo-7-hydroxy-7-(3-pyridyl)-heptanoate is dissolved in 200 ml of THF and 4.5 g of 50% sodium hydride in mineral oil added in portions. After stirring at room temperature for 3 h, the reaction mixture is diluted with ethyl acetate, filtered and concentrated to give crude product which is further purified by column chromatography on silica gel using ethyl acetate as eluent to yield 2-(3-pyridyl)-3-(4-methoxycarbonylbutyl)-oxirane.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.C(N(CC)CC)C.Cl.[C:21]([NH:25][NH2:26])([CH3:24])([CH3:23])[CH3:22]>CN(C=O)C>[C:21]([NH:25][NH:26][C:4]1[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)NN
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1csc2c(NNC(C)(C)C)nc(Cl)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To 6 ml of a solution of 438 mg (2.0 mol) of 2,4-dichloro-7-metylthieno[3,2-d]pyrimidine and 445 mg (4.4 mmol) of triethylamine in DMF was added 249 mg (2.0 mmol) of t-butylhydrazine hydrochloride under ice cooling. The reaction mixture was stirred at the same temperature for one hour and then allowed to resume room temperature, followed by stirring for further 16 hours. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1:2) to give 314 mg (yield: 58.0%) of the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.[N:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1[N:14]1[CH2:30][CH2:29][C:17]2([CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[CH2:16][CH2:15]1>C(Cl)Cl>[N:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1[N:14]1[CH2:30][CH2:29][C:17]2([CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(c3ncccn3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cnc(N2CCC3(CCNC3)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (1 ml) is added to a solution of tert-butyl 8-(pyrimidin-2-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (0.53 mmol, 1.0 eq.) in methylene chloride (5 ml) at 0° C. and the reaction mixture is stirred at 25° C. for 1 h. When the reaction was complete, the solvent was removed in vacuo in order to obtain the desired amine (AMN-25).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1)=[CH:8]2)=[O:4].[NH2:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:33])[C:5]([C:3]([NH:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:32])[F:31])[CH:24]=2)[C:10]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NCCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3cccc(C(F)(F)F)c3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCCNC(=O)c1ncc2c(cc(-c3cccc(C(F)(F)F)c3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 38.9 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-(3-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (40 mg, 0.088 mmol), 4-aminobutyric acid (726 mg, 7.0 mmol) and NaOMe solution (10.6 mL, 5.3 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-50% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2, and the resulting precipitate was isolated by filtration to give 18 mg of the title compound. MS: (+) m/z 526.32 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C-]#N.[K+].[CH:26]1(O)[CH2:30]CC[CH2:27]1>>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH:19]3[CH2:30][CH2:26][CH2:27][CH2:20]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Reactant: OC1CCCC1
Agent: [C-]#N
Agent: [K+]
Product: CN1Cc2c(C(=O)OC3CCCC3)ncn2-c2cccc(Cl)c2C1=O

Procedure:
3.19 g (10 mmol) of ethyl 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate, 70 mg of powdered potassium cyanide and 10 ml of cyclopentanol are stirred at 120° overnight, subsequently evaporated and the residue is chromatographed on silica gel while eluting with ethyl acetate. By recrystallization from ethyl acetate there is obtained cyclopentyl 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 162°-163°.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]([CH2:8][O:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH:5]([CH3:29])[C:4]1=[O:30])[CH3:2].[CH:31]([N-]C(C)C)(C)C.[Li+].IC>O1CCCC1>[CH2:1]([N:3]1[CH:7]([CH2:8][O:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:5]([CH3:31])([CH3:29])[C:4]1=[O:30])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CCN1C(=O)C(C)CC1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCN1C(=O)C(C)(C)CC1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 2M solution of lithium diisopropylamide in tetrahydrofuran (1.912 ml, 3.82 mmol) at −78° C. was added, drop-wise, a solution of 1-ethyl-5-{[(triphenylmethyl)oxy]methyl}-2-pyrrolidinone (1.34 g, 3.48 mmol) in tetrahydrofuran (10 ml) and the resulting mixture was stirred for 1 hr at −78° C. Iodomethane (0.239 ml, 3.82 mmol) was then added and after stirring for a further 1 hr at −78° C. the mixture was allowed to warm to room temperature over 3 hrs. The mixture was then re-cooled to −78° C. and treated, drop-wise, with a further aliquot of a 2M solution of lithium diisopropylamide in tetrahydrofuran (1.912 ml, 3.82 mmol). After stirring for an additional 1 hr at −78° C. the mixture was again treated with iodomethane (0.239 ml, 3.82 mmol) and then the mixture was allowed to warm to room temperature and stirred overnight. The mixture was quenched with saturated aqueous ammonium chloride and then extracted with ethyl acetate (2×). The combined organic extracts were then washed with water (3×) and then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated to a crude oily solid (1.7 g). The crude solid was purified by automated flash silica-gel column chromatography (Biotage SP4), eluting with a 0-100% gradient of ethyl acetate in hexane, to give pure product fractions (i.e. 1-ethyl-3,3-dimethyl-5-{[(triphenylmethyl)oxy]methyl}-2-pyrrolidinone (0.468 g)) as well as pure monoalkylated material (i.e. 1-ethyl-3-methyl-5-{[(triphenylmethyl)oxy]methyl}-2-pyrrolidinone (0.524 g)) and a mixture of these two (0.240 g). The desired product was set aside while the 1-ethyl-3-methyl-5-{[(triphenylmethyl)oxy]methyl}-2-pyrrolidinone and the mixed material were combined and dissolved in tetrahydrofuran (20 ml). This solution was then added drop wise to a 2M solution of lithium diisopropylamide in tetrahydrofuran (1.912 ml, 3.82 mmol) at −78° C. and stirring at this temperature was continued for 1 hr. Iodomethane (0.239 ml, 3.82 mmol) was then added to the mixture and the mixture was allowed to warm to room temperature over 4 hrs. Workup as described above gave an additional batch of 1-ethyl-3,3-dimethyl-5-{[(triphenylmethyl)oxy]methyl}-2-pyrrolidinone (0.846 g) as an oil which was combined with the material set aside earlier (total mass=1.08 g) and used in the next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([Cl:22])[CH:13]=1)[O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]1.[OH-].[K+]>C(O)C.O>[Cl:22][C:14]1[CH:13]=[C:12]([CH:4]([O:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]2)[C:3]([OH:23])=[O:2])[CH:17]=[CH:16][C:15]=1[S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: COC(=O)C(OC1C=CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(C(OC2C=CCCC2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
A solution of rac-(3-chloro-4-methanesulfonyl-phenyl)-(cyclohex-2-enyloxy)-acetic acid methyl ester (350 mg, 0.98 mmol) in ethanol (15 mL) at 25° C. was treated with a solution of potassium hydroxide (273 mg, 4.88 mmol) in water (2.5 mL) and the solution was stirred at 25° C. After 3 h, the reaction was diluted with water and concentrated under reduced pressure. The concentrate was acidified to pH 2 with an aqueous solution of 1N hydrochloric acid and extracted with dichloromethane (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure. The residual material was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate plus 1% acetic acid) to give rac-(3-chloro-4-methanesulfonyl-phenyl)-(cyclohex-2-enyloxy)-acetic acid (265 mg, 79% yield) as a colorless oil: EI-HRMS m/e calcd for C15H17ClSO5 (M+) 344.0485, found 344.0494.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13][C:14](O)=[O:15].CS(O)(=O)=O>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5]2[C:4]=1[CH2:11][CH:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13][C:14]2=[O:15]
Reactant: COc1cccc(CC(CC(=O)O)c2ccccc2)c1OC
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1OC)CC(c1ccccc1)CC2=O
Yield: 77 %

Procedure:
4-(2',3'-Dimethoxyphenyl) 3-phenylbutyric acid (13.3 g, 44.3 mmol), from Step 4, was treated with 14 mL (216 mmol) of methanesulfonic acid and 200 mL of trifluoroacetic acid at 60° C. for 1.5 h. After cooling the reaction mixture, the trifluoroacetic acid was removed in vacuo and ice water was added to the residue. Methylene chloride was added and the layers separated. The organic layer was washed with 1N aqueous sodium hydroxide solution, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized three times from methanol to give 9.6 q (77% yield) of 5,6 dimethoxy 3-phenyl 1,2,3,4-tetrahydro-1-naphthalenone, m.p. 126°-128° C. 1H NMR spectrum was identical to the spectrum reported for the product of Step 6 of Method A, Example 1.
Reaction SMILES: [F:1][C:2](I)([F:4])[F:3].[Cl:6][CH2:7][C:8]([CH2:10][Cl:11])=[O:9].O>CN(C)C=O.[Zn]>[Cl:6][CH2:7][C:8]([C:2]([F:4])([F:3])[F:1])([OH:9])[CH2:10][Cl:11]
Reactant: FC(F)(F)I
Reactant: O=C(CCl)CCl
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: O
Product: OC(CCl)(CCl)C(F)(F)F

Procedure:
A mixture of commercial zinc powder (1.30 g, 0.02 mole), trifluoromethyl iodide (2.15 g, 11 mmole) and 1,3-dichloroacetone (5.6 g, 44 mmole) in 30 ml dimethylformamide (DMF) is irradiated in the water bath of an ultrasound laboratory cleaner (35 Watts, 32 KHz) for 30 minutes. The mixture is partitioned between 2% w/v aqueous hydrochloric acid and diethyl ether. The ether extract is dried (MgSO4) and the solvent evaporated to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12](/[CH:13]=[CH:14]/[C:15]2[CH:16]=[N:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pt]>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[N:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](/C=C/c2ccc(Cl)nc2)COC1(C)C
Agent: [Pt]
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(Cl)nc2)COC1(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.3 %

Procedure:
To a stirred suspension of (S)-4-[(E)-2-(6-chloro-pyridin-3-yl)-vinyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.0 g) in methanol (70 ml) was added platinum on charcoal (0.58 g, 10 wt %) and the mixture was stirred under an atmosphere of hydrogen at room temperature for 15 min. The mixture was then filtered through celite and the filtrate was concentrated in vacuo to give (S)-4-[2-(6-chloro-pyridin-3-yl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (949 mg, 94%) as a colourless oil. MS (ISP): 343.2 ([{37Cl}M+H]+), 341.1 ([{35Cl}M+H]+), 287.0 ([{37Cl}M+H—C4H8]+), 285.1 ([{35Cl}M+H—C4H8]+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[N:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[CH:20](=[O:22])[CH3:21].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH2:13][CH:20]([OH:22])[CH3:21])[N:15]=1
Reactant: CC=O
Reactant: Cc1cccnn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(O)Cc1cccnn1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 18.7 %

Procedure:
Diisopropylamine (8.52 ml) was dissolved in tetrahydrofuran (100 ml). To the solution was added dropwise, at 0° C., n-butyl lithium (a 1.64M hexane solution, 36.6 ml). The mixture was stirred for 30 minutes at the same temperature. The reaction mixture was cooled to −70° C., to which was added dropwise a solution of 3-methyl pyridazine (4.71 g) in tetrahydrofuran (10 ml). The mixture was stirred for 30 minutes at the same temperature, to which then added acetaldehyde (2.45 g). The mixture was wormed up to room temperature over 30 minutes, which was stirred for 6 hours at the same temperature. To the reaction mixture was added a saturated aqueous solution of ammonium chloride (10 ml). The mixture was concentrated under reduced pressure. The concentrate was purified by means of a silica gel chromatography (developing solvent: ethyl acetate-methanol 1:0→9:1) to afford the title compound (1.29 g).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH:2]=[C:3]=[CH2:4].[H-].[Na+].[CH3:26]I>O1CCCC1>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([N:15]([CH3:26])[CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[CH:10][CH:11]=1)[CH:2]=[C:3]=[CH2:4]
Reactant: CI
Reactant: C=C=CCOc1ccc(S(=O)(=O)NC(C(=O)OC)C(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C=CCOc1ccc(S(=O)(=O)N(C)C(C(=O)OC)C(C)C)cc1
Reaction time: 15 h
Yield: 83.9 %

Procedure:
A solution of product from Example 11 (400 mg, 1.18 mmol) in tetrahydrofuran (10 ml) was added to a suspension of 60% sodium hydride (57 mg, 1.42 mmol) in tetrahydrofuran (2 ml) and the resulting mixture was stirred for 30 minutes, at which time methyl iodide (335 mg, 2.36 mmol) was added. The resulting mixture was stirred for 15 hours and partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate and the crude residue was purified by flash chromatography to give 350 mg (84%) of the product.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([N:9]=O)[CH2:5][CH2:4]1)[CH3:2].O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[NH2:9][N:6]1[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]1
Reactant: CCN1CCN(N=O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCN1CCN(N)CC1
Reaction time: 8 h
Yield: 62.5 %

Procedure:
A solution of N-ethyl-N'-nitroso piperazine (4.0 g, 0.028 mole) in anhydrous freshly distilled tetrahydrofuran (80 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (1.5 g, excess) under nitrogen in anhydrous tetahydrofuran (160 ml) at 20°-25° C. After addition stirring was continued for a further 8 hours. Work up via controlled addition of water (1.5 ml), 10% sodium hydroxide (2.25 ml) and water (3.75 ml) gave N-amino-N'-ethyl piperazine (2.26 g, 63%) as a pale straw coloured oil.
Reaction SMILES: O[CH:2]([CH2:7][CH:8]([S:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[CH3:9])[CH2:3][C:4](=[O:6])[CH3:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([S:10][CH:8]([CH3:9])[CH2:7][CH:2]=[CH:3][C:4](=[O:6])[CH3:5])[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(SC(C)CC(O)CC(C)=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cccc(SC(C)CC=CC(C)=O)c1
Yield: 93.5 %

Procedure:
1.00 Gram of 4-hydroxy-6-(3-methoxyphenylthio)-2-heptanone was dissolved in 100 ml of toluene, and 0.02 g of p-toluene sulfonic acid was added thereto. The resulting mixture was refluxed for 1 hour with stirring. After having been cooled, the mixture was washed with a saturated aqueous sodium hydrogencarbonate solution and then saturated aqueous sodium chloride solution. Then the mixture was dried over anhydrous magnesium sulfate. Removing the solvent from the mixture under reduced pressure gave 1.05 g of 6-(3-methoxyphenylthio)-3-hepten-2-one. (trans : cis =4.8 : 1) (purity: 82.7%). The yield was 93.5%.