Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]([F:15])([F:14])[F:13].CN(C)[CH:18]=[O:19].Cl>O1CCCC1>[OH:4][C:5]1[C:6]([O:11][C:12]([F:13])([F:14])[F:15])=[CH:7][CH:8]=[CH:9][C:10]=1[CH:18]=[O:19]
Reactant: COCOc1ccccc1OC(F)(F)F
Reactant: CN(C)C=O
Agent: Cl
Solvent: C1CCOC1
Product: O=Cc1cccc(OC(F)(F)F)c1O
Reaction time: 1 h

Procedure:
1-methoxymethoxy-2-trifluoromethoxybenzene (12.21 g) was dissolved in tetrahydrofuran (120 mL), and a 1.59M n-butyllithium-n-cyclohexane solution (40 mL) was added to the solution at −60° C. over 15 minutes under an argon gas flow, and then the mixture was stirred for 1 hour. N,N-dimethylformamide (6.30 mL) was added to the solution, and then the mixture was stirred at room temperature for 30 minutes. 2N hydrochloric acid (100 mL) was added to the solution, and then the mixture was stirred at 60° C. for 15 hours. The organic solvent was distilled off under reduced pressure, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (10.38 g) as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.C(=O)([O-])O.[Na+].[CH2:14]=[C:15]1[CH2:20][O:19][C:17](=[O:18])[CH2:16]1>C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:14][CH:15]2[CH2:20][O:19][C:17](=[O:18])[CH2:16]2)[CH:7]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: C=C1COC(=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C1CC(Cn2cc(Cl)cnc2=O)CO1
Reaction time: 2 h
Yield: 24 %

Procedure:
A suspension of 5-chloropyrimidin-2-one (1.007 g) and sodium hydrogen carbonate (647 mg) in 3-methylene-γ-butyrolactone (1.208 g) and ethanol (50 ml) was stirred and heated at reflux. After 2 h, the suspension was cooled and filtered. The filtrate was evaporated and the residue and solid were combined and boiled in ethyl acetate (150 ml). The resulting suspension was filtered and the filtrate evaporated to a pale cream solid. The solid from the filtration was treated with water (50 ml) and the resulting suspension filtered to give a solid which was combined with the pale cream solid and recrystallised from methanol to give white crystals of the title pyrimidinone (424 mg), m.p. 283°-284° C., λmax (EtOH) 229.5 nm (ε 7,700), 332 nm (ε 2,100).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:7]=12.[CH2:13](I)[CH:14]=[CH2:15]>>[CH2:15]([N:8]1[C:7]2=[C:2]([Cl:1])[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]1[CH3:12])[CH:14]=[CH2:13]
Reactant: C=CCI
Reactant: Cc1[nH]c2c(Cl)nccc2c1C
Product: C=CCn1c(C)c(C)c2ccnc(Cl)c21
Yield: 75 %

Procedure:
In accordance with the same procedures as in Step 2 of Example 198, except for using 7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 198 and allyl iodide, the titled compound was obtained as a white solid. (Yield: 75%)
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH3:10].[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[C:11]1([S:17]([O:1][C:2]2[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=2[CH3:10])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1c(O)c(=O)ccn1C
Solvent: c1ccncc1
Product: Cc1c(OS(=O)(=O)c2ccccc2)c(=O)ccn1C
Yield: 43 %

Procedure:
3-Hydroxy-1,2-dimethylpyridin-4(1H)-one (0.5 g, 3.6 mmol) was reacted with benzenesulfonyl chloride (0.51 mL, 4.0 mmol) in 40 mL of pyridine to afford PZBG-3a in 43% yield (0.43 g, 1.5 mmol). 1H NMR (500 MHz, CDCl3) δ=8.19 (d, J=6.9 Hz, 2H), 7.66 (t, J=7.5 Hz, 1H), 7.57 (t, J=7.5 Hz, 2H), 7.23 (d, J=8 Hz, 1H), 6.34 (d, J=8.1 Hz, 1H), 3.63 (s, 3H, NCH3), 2.49 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ=171.3, 144.8, 140.7, 139.9, 137.3, 134.3, 129.0, 128.9, 118.3, 41.8, 14.7. ESI-MS(+): m/z 280.09 [M+H]+.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH2:29]([N:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[CH2:29]([N:36]1[CH2:41][CH2:40][CH:39]([CH:2]=[O:3])[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=CC1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 248.9 %

Procedure:
To a suspension of 4.08 g of (methoxymethyl)triphenyl-phosphonium chloride in 20 mL of THF was added 8.11 mL of n-butyllithium(1.6 M in hexane) at 0° C. The reaction was stirred at 0° C. for 0.5 h. To the resulting solution was added 2.05 g of 1-benzyl-4-piperidone at 0° C. After stirring at rt for 1 h, the reaction was refluxed for 3 h. The reaction was cooled to rt and partitioned between EtOAc and H2O. The organic layer was washed with sat'd NaCl, dried over MgSO4 and concentrated to afford 5.48 g of viscous oil. The oil was dissolved in 20 mL of formic acid (96%). After stirring at rt for 4 h, the mixture was concentrated. The residue was dissolved in EtOAc and washed with sat'd NaHCO3 followed by sat'd NaCl. The organic layer was dried over MgSO4 and concentrated. The residue was purified by flash chromatography eluting with 1:1 v/v hexanes/EtOAc followed by EtOAc to give 877 mg of the title compound.
Reaction SMILES: COC(=O)C1C=CC=C(N[C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])C=1.C1(C2C3C=CC=CC=3N([CH2:57][C:58](C3CCCC3)=[O:59])C(=O)N(CC(O)=O)N=2)CCCCC1.C(OC(=O)CSC1C=CC=C(N)C=1)C.C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[CH2:58]([O:59][C:11](=[O:38])[CH2:12][N:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C:14]1=[O:37])[CH3:57]
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: O=C(O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: CCOC(=O)CSc1cccc(N)c1
Agent: COC(=O)c1cccc(N)c1
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 22, step a) and (3-amino-phenylsulfanyl)-acetic acid ethyl ester were used instead of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively in step e, followed by reaction of the product obtained, in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester (Example 1, step c), according to the method of Example 1, step d. 1H NMR (CDCl3) 8.41 (1H, s), 7.45 (2H, m), 7.31-7.17 (4H, m), 7.08 (2H, m), 6.12 (1H, br s), 4.66 (1H, d), 4.21 (1H, d), 4.23 (1H, d), 4.19 (1H, d), 3.65 (2H, s), 2.96 (1H, m), 2.79 (1H, m), 1.82-1.62 (13H, m), 1.29 (5H, m). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C, 52.82; H, 7.43; N, 8.12%; C31H36N4O5S.C7H17NO5.5.0H2O requires: C, 52.95; H, 7.36; N, 8.04%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH2:19]C(Cl)C(OC)=O)[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Br:26]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[Br:26][CH2:19][C:14]1[CH:13]=[C:12]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=2)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: COC(=O)C(Cl)Cc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1cnc(-c2ccc(Cl)c(CBr)c2)c(Cl)c1

Procedure:
A solution of 9.6 g (31.4 mmol) of 3-chloro-2-(4-chloro-3-methylphenyl)5-trifluoromethylpyridine (prepared as in Example 16) and 5.6 g (31.5 mmol) of N-bromosuccinimide in 150 ml of tetrachloromethane was irradiated with a 150 W high-pressure Hg lamp for one hour. For the workup, the precipitated succinimide was removed, and the filtrate was concentrated under reduced pressure. The residue was taken up in cyclohexane. The solids were removed and discarded, and the cyclohexane solution was concentrated again. The crude product was purified by chromatography on silica gel (mobile phase: n-pentane/methyl tert-butyl ether 20:1). Yield: 6.2 g (51%) of colorless crystals of melting point 71°-72° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.[C:20]([C:22]1[N:26]([CH3:27])[C:25](B(O)O)=[CH:24][CH:23]=1)#[N:21].[F-].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:20]([C:22]1[N:26]([CH3:27])[C:25]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]3[CH2:15][CH2:14][CH2:13]3)(=[O:10])=[O:9])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=2)=[CH:24][CH:23]=1)#[N:21]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: O=S(=O)(NC1CCC1)c1ccc(Br)cc1C(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc(S(=O)(=O)NC2CCC2)c(C(F)(F)F)c1
Reaction time: 16 h
Yield: 56.8 %

Procedure:
According to general procedure B, 4-bromo-N-cyclobutyl-2-(trifluoromethyl)benzenesulfonamide (200 mg, 0.56 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (100 mg, 0.67 mmol), potassium fluoride (107 mg, 1.85 mmol), and tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (83 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclobutyl-2-(trifluoromethyl)benzenesulfonamide (122 mg, 57%) was provided after purification. MS (ESI) m/z 383. HPLC purity 99.3% at 210-370 nm, 10.9 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [Si]([O:8][CH:9]([CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)[CH:10]=[CH:11][CH:12]1[CH:16]([CH:17]([OH:27])[C:18]#[C:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:15](=[O:28])[CH:14]=[CH:13]1)(C(C)(C)C)(C)C.C(O)(=O)C.O1CCCC1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[OH:8][CH:9]([CH:29]1[CH2:30][CH2:31][CH2:32][CH2:33]1)[CH:10]=[CH:11][CH:12]1[CH:16]([CH:17]([OH:27])[C:18]#[C:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:15](=[O:28])[CH:14]=[CH:13]1
Reactant: COC(=O)CCCC#CC(O)C1C(=O)C=CC1C=CC(O[Si](C)(C)C(C)(C)C)C1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)CCCC#CC(O)C1C(=O)C=CC1C=CC(O)C1CCCC1
Reaction time: 20 h
Yield: 79.3 %

Procedure:
63 mg (0.133 mmole) of 4-(3-t-butyldimethylsilyloxy-3-cyclopentyl-1-propenyl)-5-(1-hydroxy-6-methoxycarbonyl-2-hexyn-1-yl)-2-cyclopentenone obtained in Example 25 was dissolved in 2 ml of a mixed solvent composed of acetic acid, tetrahydrofuran and water in a ratio of 3:2:2, and the solution was stirred for 20 hours. An aqueous solution of sodium bicarbonate and ethyl acetate were added to the reaction mixture to perform extraction. The organic layers were combined, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The dried product was filtered, concentrated and subjected to silica gel column chromatography (silica gel 5 g; eluent, hexane:ethyl acetate=5:1→1:1) to give 38 mg (yield 79%) of 4-(3-hydroxy-3-cyclopentyl-1-propenyl)-5-(1-hydroxy-6-methoxycarbonyl-2-hexyn-yl)-2-cyclopentenone. The resulting compound had the following spectral data.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[C:7](=[NH:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1C=CC=CC=1.[I-].[Zn+2].[I-]>[C:8]1([C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([NH2:20])[C:5]#[N:6])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: c1ccccc1
Product: N#CC(N)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 4.05 ml (0.03 mol) of trimethylsilylcyanide in 20 ml of dry benzene was treated with 0.44 gm (0.001 mol) zinc iodide and 4.63 ml (0.028 mol) of benzophenoneimine. The reaction mixture was stirred at room temperature for 10 min., whereupon a white precipitate formed. The reaction mixture was quenched with wet ether and stirred for 2 hours. The liquid phase was washed with saturated brine solution and dried over sodium sulfate and evaporated in vacuo. The residue was recrystallized from ether-hexane to afford 2.4 gm (38%). 1H NMR (CDCl3, 300 MHz) δ 7.7-7.6 (m, 4H), 7.4-7.28 (m, 6H); 13C NMR (CDCl3, 75.5 MHz ) δ 141.2, 128.9, 128.6, 125.8, 123.4, 60.8.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:17])[C:7]=2[C:6]([NH:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>C(Cl)(Cl)Cl>[CH2:22]([N:21]([CH2:24][CH3:25])[CH2:20][CH2:19][NH:18][C:6]1[C:7]2[C:8](=[O:17])[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[S:15][C:16]=2[C:3]([CH2:2][NH:1][S:41]([C:38]2[CH:37]=[CH:36][C:35]([O:34][CH3:33])=[CH:40][CH:39]=2)(=[O:43])=[O:42])=[CH:4][CH:5]=1)[CH3:23]
Reactant: CCN(CC)CCNc1ccc(CN)c2sc3ccccc3c(=O)c12
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN(CC)CCNc1ccc(CNS(=O)(=O)c2ccc(OC)cc2)c2sc3ccccc3c(=O)c12
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
A solution of 1.40 g (3.94 mmol) of 4-(aminomethyl)-1-[[2-(diethylamino)ethyl]amino]-thioxanthen-9-one (prepared by the method described in Example 4) in 30 mL of chloroform containing 1.5 mL of triethylamine was cooled to 0° C. and treated with p-methoxybenzenesulfonyl chloride (0.83 g, 4.02 mmol). After 10 min at 0° C. the reaction mixture was stirred at room temperature for 2 h. Chloroform was removed in vacuo, the residue dissolved in 100 mL of methylene chloride containing 1 mL of triethylamine and treated with additional p-methoxybenzenesulfonyl chloride (0.85 g) with stirring at room temperature. The mixture was concentrated in vacuo, the residue was purified by passing through a pad of silica gel (1% triethylamine/chloroform) affording 1.57 g of N-[[1-[[2-(diethylamino)ethyl]amino]-9-oxothioxanthen-4-yl]methyl]-p-methoxy-benzenesulfonamide. The sulfonamide was treated with methanesulfonic acid (0.3 g) in isopropanol/isopropyl acetate/methanol to afford 1.07 g of the methanesulfonate salt, m.p. 133°-137° C.
Reaction SMILES: [C:1]([NH:8][C:9]1[S:10][C:11]([CH:17]([CH3:19])[CH3:18])=[CH:12][C:13]=1[N+:14]([O-])=O)([C:3](OCC)=[O:4])=[O:2].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[CH:17]([C:11]1[S:10][C:9]2[NH:8][C:1](=[O:2])[C:3](=[O:4])[NH:14][C:13]=2[CH:12]=1)([CH3:19])[CH3:18]
Reactant: CCOC(=O)C(=O)Nc1sc(C(C)C)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1cc2[nH]c(=O)c(=O)[nH]c2s1
Yield: 8.8 %

Procedure:
2-Ethoxalylamino-5-isopropyl-3-nitrothiophene (i g, 3.5 mmol) was dissolved in 10 ml of dioxane at 50° C., 6 ml of water was added, and the solution was treated with 12.2 g (70 mmol) of sodium dithionite dissolved in 50 ml of warm water (50° C.) over a period of 30 minutes. The mixture was cooled and extracted with 4×25 ml of ethyl acetate. The combined organic phases were washed with water, dried (MgSO4), and concentrated to 15 ml, whereby a crop of crystals separated which was filtered off and dried to yield 65 mg (8%) of the title compound, melting over 300° C. 1H-NMR (DMSO-D6, δ): 1.2 (d, 6H) ,3.1 (m, 1H), 6.5 (s, 1H), 11.8 (broad, 1H), 12.2 (broad, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:10][C:11](=[O:38])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20]3[N:24]([CH:25]=2)[N:23]=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:28][CH:27]=2)[S:21]3)=[CH:14][CH:13]=1)C.CO.[OH-].[Na+].Cl>O1CCCC1>[CH2:33]([O:32][C:29]1[CH:28]=[CH:27][C:26]([C:22]2[S:21][C:20]3=[N:19][C:18]([C:15]4[CH:14]=[CH:13][C:12]([C:11]([OH:38])=[O:10])=[CH:17][CH:16]=4)=[CH:25][N:24]3[N:23]=2)=[CH:31][CH:30]=1)[CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCOc1ccc(-c2nn3cc(-c4ccc(C(=O)OCC)cc4)nc3s2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCOc1ccc(-c2nn3cc(-c4ccc(C(=O)O)cc4)nc3s2)cc1
Yield: 110.7 %

Procedure:
To a solution of 4-[2-(4-pentyloxyphenyl)imidazo-[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester trifluoroacetic acid salt (5.2 g) in the mixture of methanol (104 ml) and tetrahydrofuran (52 ml) was added 2N NaOH aq. (47 ml) and refluxed for 36 hours. The reaction mixture was adjusted to pH 1-2 with 1N HCl and the resulting precipitate was collected by filtration to give 4-[2-(4-pentyloxyphenyl)-imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid (4.27 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=2[S:9][C:10]=1[NH:11][C:12]([CH:14]1[CH2:16][CH2:15]1)=O)=O)C.[NH3:21]>>[CH:14]1([C:12]2[N:21]=[C:4]([OH:3])[C:6]3[C:7]4[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=4[S:9][C:10]=3[N:11]=2)[CH2:16][CH2:15]1
Reactant: N
Reactant: CCOC(=O)c1c(NC(=O)C2CC2)sc2ccccc12
Product: Oc1nc(C2CC2)nc2sc3ccccc3c12
Temperature: 90 °C
Reaction time: 24 h

Procedure:
A suspension of 10 millimol VII in 10 milliliter 25% aqueous NH3 was stirred at 90° C. for 24 hours in closed vial. The reaction mixture was cooled down to room temperature, and poured onto crushed ice with continuous stirring then collected by filtration. The product was washed with water and n-hexane, then dried.
Reaction SMILES: C1(=O)NC(=O)C2=CC=CC=C12.[OH:12][C@H:13]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][CH2:35][C:36]([OH:43])([CH2:40][CH2:41][CH3:42])[CH2:37]CC)[CH:29]=1)[C@@H:14]([CH3:27])[CH2:15][N:16]1C(=O)C2C(=CC=CC=2)C1=O>>[NH2:16][CH2:15][C@@H:14]([CH3:27])[C@H:13]([C:28]1[CH:29]=[C:30]([CH:31]=[CH:32][CH:33]=1)[CH2:34][CH2:35][C:36]1([OH:43])[CH2:37][CH2:42][CH2:41][CH2:40]1)[OH:12]
Reactant: CCCC(O)(CCC)CCc1cccc([C@@H](O)[C@@H](C)CN2C(=O)c3ccccc3C2=O)c1
Agent: O=C1NC(=O)c2ccccc21
Product: C[C@H](CN)[C@@H](O)c1cccc(CCC2(O)CCCC2)c1

Procedure:
Phthalimide cleavage of 2-((2S,3S)-3-hydroxy-3-(3-(3-hydroxy-3-propylhexyl)phenyl)-2-methylpropyl)isoindoline-1,3-dione is performed following the method described in Example 9 gives Example 180.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([C:10]([O:12]C)=[O:11])[C:7]([CH3:14])=[CH:6][CH:5]=1.CO>C1COCC1>[Cl:3][C:4]1[N:9]=[C:8]([C:10]([OH:12])=[O:11])[C:7]([CH3:14])=[CH:6][CH:5]=1
Reactant: COC(=O)c1nc(Cl)ccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(Cl)nc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
A solution of aqueous 1N NaOH (10.00 ml) is added to a stirred solution of methyl 6-chloro-3-methyl-pyridine-2-carboxylate (1.0 g, 5.39 mmoles) in THF:MeOH (10 ml:2 ml). The mixture is stirred at room temperature for 3 hours. The organic solvent is removed under reduced pressure and the semi-solid is dissolved in water and acidified to pH 1-2 with aqueous 1N HCl. The resulting precipitate is filtered, washed with water, and dried at 40° C. in vacuum oven for 12 hours to give the title compound as a white solid (780 mg, 84%). Mass spectrum (m/z): 172.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][N:31](C)[C:32](=O)C(F)(F)F)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([O:5][C:6](=[O:39])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][NH:31][CH3:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CN(C)C(=O)C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CNCc1cc(OCCc2nc(-c3ccccc3)oc2C)ccc1CCC(=O)OC(C)(C)C
Temperature: 55 °C

Procedure:
A solution of 3-(4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2-{[methyl-(2,2,2-trifluoro-acetyl)-amino]-methyl}-phenyl)-propionic acid tert-butyl ester (111 mg, 0.20 mmol) in methanol (5 mL) and THF (5 mL) was treated with 2N NaOH (1.0 mL, 2.0 mmol) and heated at 55° C. for 1 h. The reaction mixture was cooled, concentrated, neutralized with 1N HCl and extracted into EtOAc. The organic layer was washed with saturated NaHCO3 solution and brine, dried (Na2SO4), and concentrated. The residue was purified by silica gel radial chromatography (CH2Cl2/methanol 95/5 to 90/10) to the title compound (37 mg, 42%). MS (ES) m/z 451.3 [M+1].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:11][C@H:10]2[NH:12][C:13]2[C:14]3[N:25]=[N:24][N:23]([C@H:26]4[C@@H:30]5[O:31]C(C)(C)[O:33][C@@H:29]5[C@@H:28]([O:36][CH2:37][CH2:38][OH:39])[CH2:27]4)[C:15]=3[N:16]=[C:17]([S:19][CH2:20][CH2:21][CH3:22])[N:18]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CO.Cl>[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:11][C@H:10]2[NH:12][C:13]2[C:14]3[N:25]=[N:24][N:23]([C@@H:26]4[CH2:27][C@H:28]([O:36][CH2:37][CH2:38][OH:39])[C@@H:29]([OH:33])[C@H:30]4[OH:31])[C:15]=3[N:16]=[C:17]([S:19][CH2:20][CH2:21][CH3:22])[N:18]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCCSc1nc(N[C@@H]2C[C@H]2c2ccc(F)c(F)c2)c2nnn([C@@H]3C[C@H](OCCO)[C@H]4OC(C)(C)O[C@H]43)c2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCSc1nc(N[C@@H]2C[C@H]2c2ccc(F)c(F)c2)c2nnn([C@@H]3C[C@H](OCCO)[C@@H](O)[C@H]3O)c2n1
Yield: 23.9 %

Procedure:
A solution of 2-((3aR,4S,6R,6aS)-6-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethanol (450 mg, 0.80 mmol, 1.00 equiv.) in methanol (4 mL) and 12N hydrochloric acid (1.5 mL) was stirred at ambient temperature for about 3 hours. The pH value of the solution was adjusted to 8-9 by adding potassium carbonate. Following standard extractive workup with ethyl acetate (3×20 mL), the resulting crude residue was purified by silica gel column chromatography (dichloromethane/methanol (50:1)) to give a semi-crude product (200 mg; yield=48%). The semi-crude product, which contained about 5% of other diastereoisomers, was then further purified by chiral-prep HPLC (column: Chiralpak IA2×25 cm, 5 umChiral-P(IA)004IA00CJ-MB003) to afford the title compound (100 mg). [α]D24.1-43.2° (c, 0.2 g/100 mL in MeOH). LC-MS: m/z=523.0 (MH)+, Retention time: 1.58 minute. 1H NMR (300 MHz, CD3OD) δ: 7.08-7.23 (m, 3H), 5.13 (q, 1H), 4.75-4.79 (m, 1H), 4.17-4.20 (m, 1H), 3.91-3.95 (m, 1H), 3.63-3.73 (m, 4H), 3.06-3.26 (m, 2H), 2.90-3.00 (m, 1H), 2.70-2.80 (m, 1H), 2.05-2.29 (m, 2H), 1.60-1.88 (m, 2H), 1.38-1.59 (m, 2H), 0.94 (t, J=7.5 Hz, 3H).