Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:42])[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:41])[CH2:21][CH2:22][NH:23][C:24]([C:26]3[C:27]([C:37]([F:40])([F:39])[F:38])=[N:28][N:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:30]=3)=[O:25])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1>C1COCC1.CO.O>[C:31]1([N:29]2[CH:30]=[C:26]([C:24]([NH:23][CH2:22][CH2:21][C:20]([NH:19][C:16]3[CH:15]=[CH:14][C:13]([C@H:10]4[CH2:9][CH2:8][C@H:7]([CH2:6][C:5]([OH:42])=[O:4])[CH2:12][CH2:11]4)=[CH:18][CH:17]=3)=[O:41])=[O:25])[C:27]([C:37]([F:40])([F:39])[F:38])=[N:28]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3cn(-c4ccccc4)nc3C(F)(F)F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3cn(-c4ccccc4)nc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
NaOH (71.9 mg, 1.8 mmol) was added to trans-[4-(4-{3-[(1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)amino]propionylamino}phenyl)cyclohexyl]acetic acid methyl ester (100 mg, 0.18 mmol) dissolved in THF/MeOH/water (25 mL, 3:2:1). The reaction mixture was stirred at 25° C. for 5 hours and concentrated under vacuum. The residue was acidified with 1M HCl up to pH of 2 and extracted with ethyl acetate. The extract was washed with brine and dried with anhydrous sodium sulfate and concentrated under vacuum. Acetonitrile was added thereto and cooled to obtain a filtrate, and the filtrate was filtered and separated to obtain the desired compound (95 mg, 98%) as a white solid.
Reaction SMILES: CO[C:3](OC)([N:5]([CH3:7])[CH3:6])[CH3:4].[NH2:10][C:11]([NH2:13])=[S:12]>C(Cl)Cl>[NH2:10][C:11](/[N:13]=[C:3](/[N:5]([CH3:7])[CH3:6])\[CH3:4])=[S:12]
Reactant: NC(N)=S
Reactant: COC(C)(OC)N(C)C
Solvent: ClCCl
Product: C/C(=N\C(N)=S)N(C)C
Yield: 76.5 %

Procedure:
N,N-Dimethyl acetamide dimethyl acetal (75 g, 0.56 mole) was added to a suspension of thiourea (33.0 g, 0.43 mole) in methylene chloride. The mixture was heated under reflux for 4 h. The solvent was removed and the residue was crystallized from 5% MeOH and diethyl ether affording (1E)-N′-(aminocarbonothioyl)-N,N-dimethylethanimidamide (47.8 g, 76% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][CH2:14][N:15]([CH3:19])[C:16](=[O:18])[CH3:17])[N:5]=[CH:4][N:3]=1.[CH3:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[O:28][C:29]1[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=1)[NH2:24]>C(O)(C)C>[CH3:19][N:15]([CH2:14][CH2:13][O:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([NH:24][C:23]1[CH:25]=[CH:26][C:27]([O:28][C:29]3[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=3)=[C:21]([CH3:20])[CH:22]=1)=[N:3][CH:4]=[N:5]2)[C:16](=[O:18])[CH3:17]
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Reactant: CC(=O)N(C)CCOc1cccc2ncnc(Cl)c12
Solvent: CC(C)O
Product: CC(=O)N(C)CCOc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12

Procedure:
N-{2-[(4-Chloroquinazolin-5-yl)oxy]ethyl}-N-methylacetamide (38 mg, 0.136 mmol) and 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (obtained as described in Example 103, preparation of stating materials, 32 mg, 0.150 mmol) were dissolved in iso-propanol, and the mixture heated to reflux for 1 hour. The mixture was concentrated in vacuo, and the residue purified by chromatography, eluting with 0 to 5.5% (10:1 methanol/conc. NH3(aq)) in ethyl acetate. Evaporation of the appropriate fractions gave N-methyl-N-(2-{[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}ethyl)acetamide as a dry film (24 mg, 39%); NMR Spectrum (DMSO-d6, 400 MHz), 373K 1.96 (s, 3H), 2.24 (s, 3H), 2.46 (s, 3H), 2.94 (s, 3H), 3.90 (t, 2H), 4.50 (t, 3H), 6.94 (d, 1H), 7.18 (d, 1H), 7.21 (m, 2H), 7.36 (d, 1H), 7.63 (dd, 1H), 7.68 (d, 1H), 7.71 (dd, 1H), 8.17 (dd, 1H), 8.47 (s, 1H), 9.76 (s, 1H); Mass spectrum MH+ 458.4.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]2[O:17][CH2:16]2)=[CH:11][CH:10]=1)([CH3:3])[CH3:2].[NH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=2)=[CH:26][C:25]=1[CH3:37]>>[CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=3)=[CH:26][C:25]=2[CH3:37])=[CH:11][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OCCOCc1ccc(OCC2CO2)cc1
Reactant: Cc1cc(C2=NNC(=O)CC2)ccc1OCCN
Product: Cc1cc(C2=NNC(=O)CC2)ccc1OCCNCC(O)COc1ccc(COCCOC(C)C)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isopropoxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C@@:10]3([C@@H:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27](O)=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=[O:30])[NH:12][C@H:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:5]2=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:52][O:53][CH2:54][CH2:55][S:56]([NH2:59])(=[O:58])=[O:57].[H-].[Na+].Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C@@:10]3([C@@H:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH3:25])([CH3:26])[C:27]([NH:59][S:56]([CH2:55][CH2:54][O:53][CH3:52])(=[O:58])=[O:57])=[O:28])[CH2:14][C:13](=[O:30])[NH:12][C@H:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:5]2=[CH:4][CH:3]=1
Reactant: COCCS(N)(=O)=O
Reactant: Cc1ccc(F)cc1[C@@H]1NC(=O)C[C@H](c2cc(Cl)ccc2OC(C)(C)C(=O)O)[C@@]12C(=O)Nc1cc(Cl)ccc12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: COCCS(=O)(=O)NC(=O)C(C)(C)Oc1ccc(Cl)cc1[C@H]1CC(=O)N[C@@H](c2cc(F)ccc2C)[C@]12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
A solution of chiral (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (50 mg, 0.09 mmol) prepared in Example 12a and CDI (32 mg, 0.2 mmol) in DMF (2 mL) was heated at 60° C. for 2 h. Then to this solution was added a mixture of 2-methoxy-ethanesulfonic acid amide (139 mg, 1 mmol) and NaH (35 mg, 60%, 0.9 mmol) in DMF (2 mL), which had been stirred at room temperature for 3 h. After the resulting mixture was stirred at room temperature for 1 h, it was poured into water and the aqueous solution was acidified to “pH” 1-2 by addition of concentrated HCl. After the aqueous phase was extracted with EtOAc twice, the combined organic phases were dried over anhydrous Na2SO4, concentrated and the residue was purified by flash column to give the title compound as a white solid (10 mg).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=1.Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>C1COCC1.[Na+].[Cl-]>[Br:13][C:14]1[C:15]([Si:23]([CH3:26])([CH3:25])[CH3:24])=[C:16]([F:21])[C:17]([F:20])=[CH:18][CH:19]=1
Reactant: Fc1ccc(Br)cc1F
Reactant: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)c1c(Br)ccc(F)c1F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Diisopropylamine (2.62 g, 25.9 mmol) was added drop wise to a solution of n-BuLi (2.5 M in hexane, 10.4 mL, 26.0 mmol) in anhydrous THF (19 mL) at −78° C., then the solution was stirred at −78° C. for 15 minutes. To this solution was added 4-bromo-1,2-difluorobenzene (5.00 g, 25.9 mmol), then the mixture was stirred at −78° C. for 2 hours. Freshly distilled chlorotrimethylsilane (2.81 g, 25.9 mmol) was added, then the mixture was allowed to warm to room temperature slowly over two hours. The mixture was diluted with saturated NaCl (aq) then extracted with EtOAc (3×40 mL). The combined organic layers were dried over MgSO4, filtered, then concentrated to afford the title compound as a light yellow oil. This material was used directly in the next step without further purification. 1H NMR (500 MHz, CDCl3): δ 7.27 (ddd, J=8.7, 4.0, 1.7 Hz, 1H); 7.00 (q, J=8.9 Hz, 1H); 0.47 (s, 9H).
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].C(N(CC)CC)C>ClCCl>[CH:1]1([C:5]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCC1
Reactant: CCOC(=O)CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)C1CCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
Cyclobutane carbonyl chloride (5 ml, 43.8 mmol) was slowly added to a solution of ethyl glycinate (5.86 g, 42 mmol) in dichloromethane (100 ml) and triethylamine (14.6 ml, 105 mmol) at 0° C. The mixture was then stirred at ambient temperature for 14 hours. The reaction mixture was washed with 1.0 N hydrochloric acid and the organic phase separated, dried (magnesium sulphate) and evaporated in vacuo to yield a yellow solid. Recrystallisation from dichloromethane:petroleum ether, yielded ethyl N-(cyclobutylcarbonyl)glycinate as a white solid (7.78 g, 100% yield):
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH:5]([N:17]([CH3:19])[CH3:18])[C:6]1([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[CH2:9][CH2:8][CH2:7]1)[CH3:3].[C:20]([OH:26])(=[O:25])[CH2:21][C:22]([OH:24])=[O:23]>C(OCC)(=O)C>[CH3:3][CH:2]([CH2:4][CH:5]([N:17]([CH3:18])[CH3:19])[C:6]1([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[CH2:7][CH2:8][CH2:9]1)[CH3:1].[C:20]([O-:26])(=[O:25])[CH2:21][C:22]([O-:24])=[O:23]
Reactant: O=C(O)CC(=O)O
Agent: CC(C)CC(N(C)C)C1(c2ccc(Cl)cc2)CCC1
Solvent: CCOC(C)=O
Product: O=C([O-])CC(=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
15 g of sibutramine was dissolved in 60 ml of ethyl acetate. Malonic acid (5.72 g) dissolved in 20 ml ethyl acetate was slowly added in droplets to the sibutramine solution at room temperature and agitated for 2 hrs. The resulting solution was cooled to 0° C., agitated for about 2 hrs, and filtered to collect a deposited crystal. The crystal was washed with 50 ml of isopropyl ether and vacuum-dried at 50° C., thus obtaining 19 g (yield: 92.6%) of a white target compound.
Reaction SMILES: C[Mg]I.[C:4]1(C)C=C(C)C=C(C)C=1N1C=CN(C2C(C)=CC(C)=CC=2C)C1=[Cu-2]Cl.Cl[CH2:30][CH:31]=[C:32]([CH:34]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([Br:50])=[CH:46][CH:45]=1)[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([Br:42])=[CH:38][CH:37]=1)[CH3:33].[Cl-].[NH4+]>CCOCC>[CH3:33][C:32]([CH:34]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([Br:50])=[CH:46][CH:45]=1)[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([Br:42])=[CH:38][CH:37]=1)([CH:31]=[CH2:30])[CH3:4]
Reactant: CC(=CCCl)C(Cc1ccc(Br)cc1)Cc1ccc(Br)cc1
Reactant: Cc1cc(C)c(-n2ccn(-c3c(C)cc(C)cc3C)c2=[Cu-2]Cl)c(C)c1
Agent: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C=CC(C)(C)C(Cc1ccc(Br)cc1)Cc1ccc(Br)cc1
Reaction time: 0.17 h
Yield: 485.6 %

Procedure:
MeMgI (3.21 mL, 1.4 M in ether, 4.5 mmol) was added at 0° C. to a mixed liquid containing (1,3-dimesityl-1H-imidazol-2(3H)-ylidene)copper(I)chloride (244 mg, 0.60 mmol) in ether (5 mL), and the resulting mixture was stirred for 10 minutes. A solution containing 4,4′-(2-(4-chlorobut-2-en-2-yl)propane-1,3-diyl)bis(bromobenzene) (1.33 g, 3.0 mmol) in ether (4 mL) was then added, and the resulting mixed liquid was stirred at 0° C. for 12 hours. A saturated aqueous solution of ammonium chloride was added to the mixed liquid, and the mixture was extracted with ether. The thus obtained organic layer was washed with a saturated saline solution, and dried using MgSO4. The organic layer was then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography, yielding the title compound (4n) (1.23 g) in a yield of 97%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:18]=[C:19]([NH:27][C:28]2[N:37]=[CH:36][C:35]3[N:34]([CH3:38])[C:33](=[O:39])[CH2:32][N:31]([CH:40]([CH3:42])[CH3:41])[C:30]=3[N:29]=2)[CH:20]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:22]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13](=[O:15])[NH:16][C:17]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:20]=[C:19]([NH:27][C:28]2[N:37]=[CH:36][C:35]3[N:34]([CH3:38])[C:33](=[O:39])[CH2:32][N:31]([CH:40]([CH3:42])[CH3:41])[C:30]=3[N:29]=2)[CH:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(N)cc(S(C)(=O)=O)c3)nc21
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(NC(=O)[C@H]4CCCN4C(=O)OC(C)(C)C)cc(S(C)(=O)=O)c3)nc21
Yield: 29.5 %

Procedure:
Starting from (R)pyrrolidine-1,2-dicarboxylic acid tert butyl ester (74 mg; 0.346 mmol) and 2-(3-amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (90 mg; 0.230), 40 mg (0.068 mmol; 29.5% yield) of the desired compound were obtained.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH:18]1([N:13]2[C:12]([C:35]3[CH:36]=[CH:37][C:32]([CH3:31])=[CH:33][CH:34]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: Cc1ccc(-c2c3c(nn2C2CCCC2)CCNCC3)cc1
Yield: 52.9 %

Procedure:
The title compound (70.4 mg) was prepared as in Example 177, Steps C and D, using 204.3 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 180, Step A) and 204.1 mg of 4-methylphenylboronic acid. MS (ESI): exact mass calculated for C19H25N3, 295.42; found, m/z 296.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.37 (d, J=7.9 Hz, 2H), 7.21 (d, J=7.9 Hz, 2H), 4.50 (m, 1H), 3.43-3.40 (m, 2H), 3.32-3.28 (m, 2H), 3.20-3.17 (m, 2H), 2.80-2.77 (m, 2H), 2.43 (s, 3H), 2.04-1.86 (m, 6H), 1.64-1.55 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@H:14]([NH:15][C:16]([C:18]2[NH:19][CH:20]=[CH:21][N:22]=2)=[O:17])[CH2:13][CH2:12][N:11]([C:23]2[S:24][C:25]([C:28]([O:30]CC)=[O:29])=[CH:26][N:27]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>CO.ClCCl>[CH2:1]([O:8][C@H:9]1[C@@H:14]([NH:15][C:16]([C:18]2[NH:22][CH:21]=[CH:20][N:19]=2)=[O:17])[CH2:13][CH2:12][N:11]([C:23]2[S:24][C:25]([C:28]([OH:30])=[O:29])=[CH:26][N:27]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc(N2CC[C@H](NC(=O)c3ncc[nH]3)[C@H](OCc3ccccc3)C2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: O=C(N[C@H]1CCN(c2ncc(C(=O)O)s2)C[C@H]1OCc1ccccc1)c1ncc[nH]1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 63.8 %

Procedure:
Ethyl cis(±)-2-{3-(benzyloxy)-4-[(1H-imidazol-2-ylcarbonyl)amino]piperidin-1-yl}-1,3-thiazole-5-carboxylate obtained in Example (90f) (0.25 g, 0.55 mmol) was dissolved in methanol (5 mL) and dichloromethane (1 mL). A 2 N aqueous lithium hydroxide solution (5 mL, 10 mmol) was added, and the mixture was stirred at 70° C. for 20 minutes. The organic solvent was evaporated under reduced pressure, and 1 N hydrochloric acid was added until the pH of the solution was about 4. Purification by reverse phase chromatography (elution solvent: acetonitrile/water=1/1, 4/1) gave 0.15 g of the title compound as a white solid (66%).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([S:13][CH2:14][CH2:15][C:16]1[CH:17]=[N:18][N:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH:25]2[C:34]3[C:29](=[CH:30][C:31]([OH:35])=[CH:32][CH:33]=3)[CH2:28][CH2:27][C:26]2([C:37]2[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=2)[CH3:36])[CH:20]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>O.CO.O1CCCC1>[CH2:7]([S:13]([CH2:14][CH2:15][C:16]1[CH:17]=[N:18][N:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH:25]2[C:34]3[C:29](=[CH:30][C:31]([OH:35])=[CH:32][CH:33]=3)[CH2:28][CH2:27][C:26]2([C:37]2[CH:38]=[CH:39][C:40]([OH:43])=[CH:41][CH:42]=2)[CH3:36])[CH:20]=1)=[O:2])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCCCCCSCCc1cnn(CCCCC2c3ccc(O)cc3CCC2(C)c2ccc(O)cc2)c1
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCS(=O)CCc1cnn(CCCCC2c3ccc(O)cc3CCC2(C)c2ccc(O)cc2)c1
Reaction time: 16 h

Procedure:
A solution of sodium metaperiodate (0.1 g.) in water (2 ml.) was added to a stirred solution of (1RS,2RS)-1-{4-[4-(2-hexylthioethyl)pyrazol-1-yl]butyl}-1,2,3,4-tetrahydro-2-p-hydroxyphenyl-2-methylnaphth-6-ol (Example 1; 0.23 g.) in a mixture of methanol (4 ml.) and tetrahydrofuran (4 ml.) and the mixture was stirred at laboratory temperature for 16 hours, diluted with water (20 ml.) and extracted three times with methylene chloride (10 ml. each time). The combined extracts were dried and evaporated to dryness and the residue was purified by chromatography on a silica gel column using a 49:1 v/v mixture of ethyl acetate and ethanol as eluent. There was thus obtained as an oil (1RS,2RS)-1-{4-[4-(2-hexylsulphinylethyl)pyrazol-1-yl]butyl}-1,2,3,4-tetrahydro-2-p-hydroxyphenyl-2-methylnaphth-6-ol.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][C:12]([C:14]2[N:15]=[C:16]([CH2:19][NH2:20])[S:17][CH:18]=2)=[O:13])[CH:6]=[CH:7][CH:8]=1.[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]N)=[CH:26][CH:25]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.C(O)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][C:12]([C:14]2[N:15]=[C:16]([CH2:19][NH:20][CH2:28][C:27]3[CH:30]=[CH:31][C:24]([O:23][C:22]([F:21])([F:32])[F:33])=[CH:25][CH:26]=3)[S:17][CH:18]=2)=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: NCc1nc(C(=O)NCCc2cccc(Cl)c2)cs1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(NCCc1cccc(Cl)c1)c1csc(CNCc2ccc(OC(F)(F)F)cc2)n1

Procedure:
2-Aminomethyl-thiazole-4-carboxylic acid [2-(3-chlorophenyl)ethyl]amide hydrochloride (0.10 g, 0.3 mmol) and 4-(trifluoromethoxy)benzyl amine (0.06 g, 0.3 mmol) were mixed with sodium cyanoborohydride (1 M in THF, 0.6 mL), ethanol (5 mL), and a catalytic amount of acetic acid (2 drops). The mixture was heated at reflux for 24 hours. The mixture was concentrated in vacuo, diluted with water and extracted with methylene chloride. The combined organic layers were washed with sodium carbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude amine was purified by flash chromatography (EtOAc/hexane), treated with HCl in dioxane, and concentrated in vacuo to afford the title compound: 1H NMR (400 MHz, d6-DMSO): 9.83 (br s, 2H), 8.43 (t, 1H), 8.32 (s, 1H), 7.66 (d, 2H), 7.44 (d, 2H), 7.25 (m, 4H), 4.58 (s, 2H), 4.37 (s, 2H), 3.53 (m, 2H), 2.86 (t, 2H); MS (ESI-LCMS) for C21H20ClF3N3O2S: 470 (MH+).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[I:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:14]=1[O:15]C)[C:11](=[O:17])[CH2:10][CH2:9]2>C1(C)C=CC=CC=1>[OH:15][C:14]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][C:11]2=[O:17])=[CH:7][C:6]=1[I:5]
Reactant: COc1cc2c(cc1I)CCC2=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1CCc2cc(I)c(O)cc21

Procedure:
AlCl3 (10.66 g; 80.0 mmol) is added to a mixture of 5-iodo-6-methoxyindan-1-one (7.68 g; 26.66 mol) in toluene (130 ml).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13](=[O:19])[C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([O:20][CH3:21])[CH:3]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:11]([N:8]1[C:9]2[C:5](=[C:4]([O:20][CH3:21])[CH:3]=[C:2]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:10]=2)[C:6]([C:13](=[O:19])[C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[CH:7]1)[CH3:12]
Reactant: OB(O)c1ccccc1
Reactant: CCn1cc(C(=O)C(=O)N(C)C)c2c(OC)cc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCn1cc(C(=O)C(=O)N(C)C)c2c(OC)cc(-c3ccccc3)cc21
Temperature: 100 °C
Yield: 80.5 %

Procedure:
To a sealable vessel was added 36-3 (100 mg, 0.28 mmol), phenylboronic acid (1042 mg, 0.86 mmol), Pd(PPh3)4 (66 mg, 10 mol %), and potassium carbonate (117 mg, 0.85 mmol). Dioxane (1.5 mL) was added and the reaction heated at 100° C. two days. The reaction mixture was diluted with ethyl acetate, filtered through celite and concentrated. The resulting residue was purified on silica gel column chromatography eluting with hexanes/ethylacetate (50-100%) to afford 79 mg of 36-4. LCMS: calc 350.2 and found: 351.1 [MH]+.
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH2:11]>C(OCC)C>[CH3:3][C@H:4]([CH2:5][CH:6]=[CH2:7])[CH2:9][O:11][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCc1ccccc1
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: C=CC[C@@H](C)COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89 %

Procedure:
A 250-mL round-bottomed flask, equipped with a magnetic stirring bar and a thermometer was fitted with a septum and a nitrogen inlet. The apparatus was charged with 1.60 g (40.0 mmol) of a 60% dispersion of sodium hydride in mineral oil. The sodium hydride was washed with 3×20 mL of dry hexane and then suspended in 40 mL of dry N,N-dimethylformamide and cooled to 0° C. To the stirred suspension was added 4.32 mL (6.21 g, 36.3 mmol) of benzyl bromide followed by dropwise addition of 3.47 g (34.6 mmol) of ketone 2 (via cannula) dissolved in 10 mL of diethyl ether over 15 min maintaining the reaction temperature at 6° C. or less. The reaction mixture was stirred for 20 minutes at 0° C., then warmed to room temperature. After 12 hours, 10 mL of water was cautiously added and the mixture was transferred to a 250-mL separatory funnel. The aqueous Phase was extracted with 3×100 mL of ethyl acetate. The organic layers were individually washed with 100 mL of brine, combined, dried over sodium sulfate, filtered, concentrated and chromatographed (6 cm×33 cm column, 9:1 hexane:dichloromethane) to afford 5.93 g (89%) of benzyl ether 3 as a clear, colorless liquid: Rf =0.20 (9:1 hexane:dichloromethane). [a]54622 --1.6° (c 2.21, CH2Cl2). IR(film): 3080m, 3070m, 3035m, 3005w, 2980s, 2960s, 2930s, 2910s, 2880s, 2860s, 2975w, 1645m, 1605w, 1495m, 1480w, 1455s, 1445m, 1415w, 1375m, 1365m, 1310w, 1255w, 1205w, 1160w, 1100s, 1040m, 995m, 915s, 745s, 695s, 605m. 1H-NMR: 7.36-7.24 (m, 5H, ArH); 5.85-5.72 (m, 1H, CH=CH2); 5.06-5.00 (m, 2H, CH=CH2); 4.51 (s, 2H, ArCH2O); 3.33 (dd, J=9.1, 6.2, 1H, one of CH2OBn); 3.28 (dd, J=9.1, 6.2, 1H, one of CH2OBn); 2.27-2.19 (m, 1H, CHCH3); 1.98-1.84 (m, 2H, CH2CH=CH2); 0.93 (d, J=6.5, 3H, CHCH3). 13C NMR: 138.7, 136.8, 128.2, 127.4, 127.3, 115.8, 75.2, 72.9, 38.0, 33.3, 16.7. Anal. Calcd. for C13H18O: C, 82.06; H, 9.53. Found: C, 82.08; H, 9.49.