Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@:2]12[C@@H:21]([OH:22])[CH2:20][C@@:19]3([CH3:23])[C@@H:12]([CH2:13][CH:14]=[C:15]3[C:16](=[O:18])[CH3:17])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:25])[CH:4]=[CH:5][C:6](=[O:24])[CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:38]([O-])(=[O:40])[CH3:39].[Na+]>C(O)(=O)C.C(OC(=O)C)(=O)C>[C:38]([O:22][C@H:21]1[CH2:20][C@@:19]2([CH3:23])[C@@H:12]([CH2:13][CH:14]=[C:15]2[C:16](=[O:18])[CH3:17])[C@H:11]2[C@@:2]1([F:1])[C@:3]1([CH3:25])[C:8]([CH2:9][CH2:10]2)=[CH:7][C:6](=[O:24])[CH:5]=[CH:4]1)(=[O:40])[CH3:39]
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Reactant: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1C[C@]2(C)C(C(C)=O)=CC[C@H]2[C@@H]2CCC3=CC(=O)C=C[C@]3(C)[C@@]12F
Temperature: 25 °C
Reaction time: 60 h
Yield: 80.2 %

Procedure:
A solution of 9-fluoro-11β-hydroxypregna-1,4,16-triene-3,20-dione (1.0g) in a mixture of acetic acid (70 ml) and acetic anhydride (70 ml) containing p-toluenesulfonic acid hydrate (500 mg) is stirred at room temperature for 60 hours. Sodium acetate (2.0g) is added and the mixture is concentrated in vacuo. The residue is mixed with water and washed with a dilute sodium bicarbonate solution and water, dried and the residue is crystallized from ethyl acetate-hexane to afford 0.9g of the title compound, melting point 202°-203° C.
Reaction SMILES: [OH-].[Na+].[Cl:3]Cl.Cl[O-].[Na+].[OH:8][C:9]1[N:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]>>[Cl:3][C:15]1[CH:14]=[C:10]([C:11]([OH:13])=[O:12])[C:9]([OH:8])=[N:17][CH:16]=1
Reactant: O=C(O)c1cccnc1O
Reactant: ClCl
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Product: O=C(O)c1cc(Cl)cnc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydroxide, 336 g of 50% solution (4.2 mole) in 1 kg of ice was treated with bubbling chlorine gas while stirring until 78 g (1.1 mole) of chlorine was taken into the solution. To the resulting cold, basic sodium hypochlorite solution was added 142 g (1.0 mole) of 2-hydroxynicotinic acid in one portion. Within 1/2 hr the temperature had risen to 35° C. and dissolution had occurred. The mixture was stirred overnight after which time 13CNMR analysis indicated the ratio of starting material to desired product (as the disodium salt) was about 30:70%. Another solution of basic sodium hypochlorite was prepared by the above procedure by absorbing 35 g (0.5 mole) of chlorine gas in a mixture of 100 g of 50% solution (1.25 mole) of sodium hydroxide and 278 g of ice. This hypochlorite solution was added to the main reaction mixture and stirring was continued overnight. 13CNMR analysis indicated the starting 2-hydroxynicotinic acid had all reacted and the desired 5-chloro-2-hydroxynicotinic acid was present as the disodium salt. Sodium bisulfite, 14 g was added and stirring was continued for 1.5 hr. The reaction mixture was gradually added to a cooled, stirred solution of 337 ml of concentrated (37%) hydrochloric acid. The maximum temperature of the acidified mixture was 25° C. The yield of title compound on separation and drying was 146 g (84%).
Reaction SMILES: [OH:1][CH:2]([CH:4]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=O)[CH3:3].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC.[NH2:48][CH:49]([C:52]1[C:53](=[O:70])[NH:54][C:55]([CH2:58][C:59]2[CH:64]=[CH:63][C:62]([O:65][CH3:66])=[C:61]([O:67][CH2:68][CH3:69])[CH:60]=2)=[N:56][N:57]=1)[CH2:50][CH3:51]>>[CH2:68]([O:67][C:61]1[CH:60]=[C:59]([CH:64]=[CH:63][C:62]=1[O:65][CH3:66])[CH2:58][C:55]1[NH:54][C:53](=[O:70])[C:52]([CH:49]([NH:48][C:5](=[O:7])[CH:4]([CH:2]([OH:1])[CH3:3])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:50][CH3:51])=[N:57][N:56]=1)[CH3:69]
Reactant: CCOc1cc(Cc2nnc(C(N)CC)c(=O)[nH]2)ccc1OC
Reactant: CC(O)C(CCCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(Cc2nnc(C(CC)NC(=O)C(CCCc3ccccc3)C(C)O)c(=O)[nH]2)ccc1OC

Procedure:
423 mg (1.90 mmol) of 2-(1-hydroxyethyl)-5-phenylpentanoic acid, are reacted analogously to Example 39A with 257 mg (1.90 mmol) of 1-hydroxy-1H-benzotriazole, 328 mg (2.54 mmol) of N-ethyldiisopropylamine, 365 mg (1.90 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 432 mg (1.27 mmol) of 6-(1-aminopropyl)-3-(3-ethoxy-4-methoxybenzyl)-1,2,4-triazin-5(4H)-one to give N-{1-[3-(3-ethoxy-4-methoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}2-(1-hydroxyethyl)-5-phenylpentanamide.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][CH:20]2[S:24]C(=O)N[C:21]2=[O:26])=[CH:17][CH:16]=1)[CH3:11].Cl.[OH-:30].[Na+]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][CH:20]([SH:24])[C:21]([OH:26])=[O:30])=[CH:27][CH:28]=1)[CH3:11]
Reactant: CN(CCOc1ccc(CC2SC(=O)NC2=O)cc1)c1nc2ccccc2o1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CN(CCOc1ccc(CC(S)C(=O)O)cc1)c1nc2ccccc2o1

Procedure:
A solution of 5-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]benzyl]-2,4-thiazolidinedione (Eur. Patent Appl., Publication No. 0306228) (1.0 g) in 10% aqueous sodium hydroxide solution (25 mL) was heated at reflux under a nitrogen atmosphere for 1.75 hrs. The mixture was cooled, acidified to pH3 with concentrated hydrochloric acid and extracted with ethyl acetate (300 mL). The organic solution was washed with brine (100 mL), dried (MgSO4) and evaporated. The residue was redissolved in boiling ethyl acetate, filtered and allowed to cool and crystallise to afford the title compound, mp 154°-6° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[CH:4]=[CH:3]1.[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:7][CH:5]1[CH2:6][C:2](=[O:1])[CH:3]=[CH:4]1
Reactant: C1=COCCC1
Reactant: O=C1C=CC(O)C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1C=CC(OC2CCCCO2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
A solution of 4-hydroxy-2-cyclopentenone (1.41 g, 14.4 mmol) in tetrahydrofuran (24 mL) is treated with 3,4-dihydro-2H-pyran (2 mL) and pyridinium p-toluenesulfonate (500 mg, PPTS). The reaction is stirred at room temperature for 18 hours. The reaction mixture is then diluted with ethyl acetate (25 mL) and washed with 50% saturated brine (2×30 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The resulting crude brown oil is purified by filtration through a plug of silica gel (25 g, 33% ethyl acetate/hexane) to provide the title compound as a yellow oil (2.00 g, 76%); 1H NMR (CDCl3) δ7.46 (2×dd, 1H, J=16.3, 5.7 Hz), 6.2 (m, 1H), 4.9 (m, 1H), 4.80 (d appt, 1H, J=23.8, 2.9 Hz), 3.9 (m, 1H), 3.6 (m, 1H), 2.73 (2×dd, 1H, J=18.4, 6.2 Hz), 2.35 (2×d, 1H, J=18.4 Hz), 1.8 (m, 1H), 1.6 (m, 4H); IR (neat) νmax 2944, 2870, 2855, 1723, 1348, 1202, 1182, 1152, 1128, 1078, 1032 cm-1 ; MS (CI) m/e (% relative intensity) 183 (M+H+, 28), 85(100).
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][CH2:17][C:18](OCC)=[O:19])=[CH:11][C:10]=2[F:23])=[C:5]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[S:4][N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[Cl:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][CH2:17][CH2:18][OH:19])=[CH:11][C:10]=2[F:23])=[C:5]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[S:4][N:3]=1
Reactant: CCOC(=O)CCc1cc(F)c(OCc2c(Cl)nsc2-c2ccc(Cl)cc2)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCc1cc(F)c(OCc2c(Cl)nsc2-c2ccc(Cl)cc2)c(F)c1
Temperature: 0 °C

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 3-(4-[[3-chloro-5-(4-chlorophenyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl)propanoate (250 mg, 0.53 mmol, 1.00 equiv), tetrahydrofuran (10 mL). This was followed by the addition of a solution of LAH (60 mg, 1.58 mmol, 2.99 equiv) in tetrahydrofuran (2 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 20 min at 25° C. The reaction was then quenched by the addition of sodium sulfate.H2O. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (30/70). The collected fractions were combined and concentrated under vacuum. This resulted in 103 mg (45%) of 3-(4-[[3-chloro-5-(4-chlorophenyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl)propan-1-ol as a off-white solid. 1H-NMR (300 MHz, CDCl3) δ: 7.62 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H), 6.71-6.91 (m, 1H), 5.01 (s, 2H), 3.64 (t, J=7.5 Hz, 2H), 2.61-2.69 (m, 2H), 1.70-1.90 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C19H15C12F2NO2S, 430.0 (M+H). found 430.0
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[C:19]([CH3:25])[C:18]=2[OH:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.[Br:27]Br>C(O)(=O)C>[Br:27][C:21]1[C:20]([CH3:24])=[C:19]([CH3:25])[C:18]([OH:26])=[C:17]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:22]=1[CH3:23]
Reactant: BrBr
Reactant: Cc1cc(C)c(C(CCCCCC(=O)O)c2ccc(F)cc2)c(O)c1C
Solvent: CC(=O)O
Product: Cc1c(C)c(Br)c(C)c(C(CCCCCC(=O)O)c2ccc(F)cc2)c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-(4-fluorophenyl)-7-(2-hydroxy-3,4,6-trimethylphenyl)heptanoic acid (1.32 g) in acetic acid (10 ml) was added dropwise a solution of bromine (0.19 ml) in acetic acid (2 ml) with ice cooling. After completion of addition, the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted by addition of water and ethyl acetate. The organic layer was separated and washed in turn with water and saturated saline and dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to obtain 7-(5-bromo-2-hydroxy-3,4,6-trimethylphenyl)-7-(4-fluorophenyl)heptanoic acid (1.04 g) (Compound 12). The physical properties and spectrum data thereof are shown in Tables 3 and 4.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([C:26]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=2)=[O:27])[CH:23]=[CH:22][C:3]=1[C:4]([NH:6][C@H:7]([C:19]([OH:21])=[O:20])[CH2:8][NH:9][C:10](=[O:18])[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15]C[CH2:13]1)=[O:5].ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(=O)CC1C=CC=CC=1)=O.ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(=O)CC1C=CC(OC)=CC=1)=O.ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(=O)CC1C=CC([N+]([O-])=O)=CC=1)=O.ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(=O)CC1C=CC=C(C(F)(F)F)C=1)=O.[N+](C1C=C(CC(NC[C@@H](C(O)=O)N)=O)C=C([N+]([O-])=O)C=1)([O-])=O.ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(=O)CC1SC=CC=1)=O.ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(=O)CC1C=NC=CC=1)=O.ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(=O)CC1C=CC2C(=CC=CC=2)C=1)=O.ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(=O)CC1C2C=CC=CC=2C2C1=CC=CC=2)=O.S1C2C=CC=CC=2[NH+]=C1>>[Cl:1][C:2]1[CH:25]=[C:24]([C:26]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=2)=[O:27])[CH:23]=[CH:22][C:3]=1[C:4]([NH:6][C@H:7]([C:19]([OH:21])=[O:20])[CH2:8][NH:9][C:10](=[O:18])[CH2:11][CH:12]1[CH2:13][CH2:15][CH2:16][CH2:17]1)=[O:5]
Reactant: O=C(CC1CCCCC1)NC[C@H](NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl)C(=O)O
Agent: COc1ccc(CC(=O)NC[C@H](NC(=O)c2ccc(C(=O)NCc3cccc(O)c3)cc2Cl)C(=O)O)cc1
Agent: N[C@@H](CNC(=O)Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)C(=O)O
Agent: O=C(CC1c2ccccc2-c2ccccc21)NC[C@H](NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl)C(=O)O
Product: O=C(CC1CCCC1)NC[C@H](NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl)C(=O)O

Procedure:
N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(cyclohexylacetyl)amino-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(phenylacetyl)amino-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(4-methoxyphenylacetyl)amino-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(4-nitrophenylacetyl)amino-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(3-trifluoromethylphenylacetyl)amino-L-alanine; N-[2-chloro-4-[[[3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(3,5-dinitrophenylacetyl)amino-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(2-thienylacetyl)amino-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(3-pyridylacetyl)amino-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(2-naphthylacetyl)amino-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(9H-fluoren-9-ylacetyl)amino-L-alanine; 3-[[(2S)-2-carboxy-2-[2-chloro-4-[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoylamino]ethylaminocarbonyl]methyl]benzothiazol-3-ium salt)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[CH:14]=O)[CH3:2].[O-]CC.[Na+].S(=O)(=O)(O)O.[OH-].[Na+]>CCO>[Br:13][C:10]1[CH:11]=[CH:12][C:7]2[O:6][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:16])=[CH:14][C:8]=2[CH:9]=1
Reactant: CCOC(=O)COc1ccc(Br)cc1C=O
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc2cc(Br)ccc2o1
Temperature: 25 °C
Yield: 27.1 %

Procedure:
The compound was prepared according to a literature procedure. (Yoo et al., Bioorg. Med. Chem. 5:445, 1997). To ethyl (4-bromo-2-formylphenoxy)acetate (Example 1, 14.3 g, 49.7 mmol) was added, under Ar, 115 mL absolute EtOH. To this mixture was added 5.28 g (77.7 mmol) sodium ethoxide and the reaction allowed to reflux overnight. Sulfuric acid (conc., 2 mL) was then added, and the reaction allowed to reflux an additional 2 hours. The mixture was then cooled to rt, 50 mL was added and the pH adjusted to neutrality with 1 N NaOH. The mixture was then extracted with 150 mL EtOAc, and the combined organic phase was washed with brine (2×150 mL), dried over Na2SO4, and filtered. The solvent was removed in vacuo. Purification by Biotage® separation using 5% EtOAc/hexanes provided 3.62 g (27%) of the desired compound. 1H-NMR (CDCl3, 67 ): 1.43 (t, 3H), 4.45 (q, 2H), 7.46-7.57 (m, 3H), 7.82 (s, 1H); LRMS (GC/MS/EI) 268 [M]+.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH2:13])=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>CN(C1C=CN=CC=1)C.C1COCC1>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][C:30]([F:29])=[CH:31][CH:32]=2)=[N:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(NC(=O)c3ccc(F)cc3)sc2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a 50 ml eggplant-shaped flask were added 1.00 g (3.37 mmol) 5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 1, 0.68 g (6.75 mmol) triethylamine, 30 mg (0.25 mmol) DMAP and 25 ml THF, and then added dropwise 0.53 g (3.37 mmol) p-fluorobenzoyl chloride dissolved in 5 ml THF. The resulting mixture was stirred at room temperature for 2 hours, elevated to 35-40° C. and allowed to react for 10 hours, filtrated, washed with THF, the mother liquid was concentrated under a reduced pressure to give a pale brown oily crude product, separated with 50 ml ethyl acetate and 10 ml 1N HCl, the organic layer separated was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was recrystallized with ethyl acetate/petroleum ether (1:2) to obtain a 1.10 g product as a white solid in a yield of 78.0%, mp: 164-165 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.77 (3H, s, OCH3), 4.22 (2H, s, CH2), 6.76 (2H, d, J=7.84 Hz, ArH), 6.94 (2H, t, 3JFH=3JHH=8.40 Hz, ArH), 7.24˜7.36 (7H, m, ArH), 7.71 (2H, dd, 3JHH=7.56, 4JFH=5.32 Hz, ArH), 11.62 (1H, br, CONH); EI-MS m/e (%): 418.2 (M+, 100), 123.0 (86); HREI-MS Calcd. for C24H19FN2O2S: 418.1151. found: 418.1138. Anal. Calcd. for C24H19FN2O2S: C, 68.88; H, 4.58; N, 6.69. found: C, 68.77; H, 4.48; N, 6.84.
Reaction SMILES: CC1C=CC=C(C#CC=C2CCNCC2)N=1.[Br:17][C:18]1[N:23]=[C:22]([C:24]#[C:25][CH:26]=[C:27]2[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]2)[CH:21]=[CH:20][CH:19]=1>>[Br:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([C:24]#[C:25][CH:26]=[C:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=CC#Cc2cccc(Br)n2)CC1
Agent: Cc1cccc(C#CC=C2CCNCC2)n1
Product: Brc1cccc(C#CC=C2CCNCC2)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The title product was prepared following the method described for the Compound of Example 3 but using as starting material Compound 305a instead of the Compound of Example 2 and stirring at ambient temperature for 3 days. The reaction mixture was evaporated to dryness in vacuo, taking up the residue several times with chloroform to remove excess trifluoroacetic acid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([CH3:14])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].I[CH:24]([CH3:26])[CH3:25]>CN(C)C=O>[F:16][C:2]([F:1])([F:15])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([CH3:14])=[CH:11][CH:12]=2)[N:7]([CH:24]([CH3:26])[CH3:25])[CH:6]=1)=[O:4]
Reactant: CC(C)I
Reactant: Cc1ccc2c(C(=O)C(F)(F)F)c[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(C(=O)C(F)(F)F)cn(C(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
A solution of 2,2,2-trifluoro-1-(6-methyl-1H-indol-3-yl)-ethanone (1.5 g, 6.60 mmol) in N,N-dimethylformamide (15 mL) at 25° C. was treated with potassium carbonate (2.28 g, 16.51 mmol). The resulting mixture was stirred at 25° C. for 15 min and then treated with 2-iodopropane (0.99 mL, 9.90 mmol). The reaction was heated at 65° C. for 3 h. At this time, the reaction was cooled to 25° C. and was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic layer was then washed with a 1N aqueous hydrochloric acid solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 4/1 hexanes/ethyl acetate) afforded 2,2,2-trifluoro-1-(1-isopropyl-6-methyl-1H-indol-3-yl)-ethanone (1.61 g, 90.6%) as a pink solid: mp 65-68° C.; EI-HRMS m/e calcd for C14H14F3NO (M+) 269.1027, found 269.1037.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:19]([O:21][CH:22]=[CH2:23])=[O:20]>C(Cl)(Cl)Cl>[C:19](=[O:20])([O:21][CH:22]=[CH2:23])[O:11][CH:8]1[CH2:7][CH2:6][CH:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][CH2:9]1
Reactant: C=COC(=O)Cl
Reactant: CC(C)(C)C1CCC(O)CC1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: C=COC(=O)OC1CCC(C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.4 %

Procedure:
To a 250 mL 3-neck round bottom flask fitted with a magnetic stirrer, condenser, thermometer, ice water bath, dropping funnel, was added 10.0 g (64.0 mmol) of 4-t-butylcyclohexanol, 5.6 g (70.3 mmol) of pyridine and 100 mL of chloroform. The reaction mixture was cooled to less than 10° C. and 6.8 g (64.0 mmol) of vinyl chloroformate was added so that the temperature remained below 15° C. The reaction mixture was stirred at room temperature for 20 hours, then washed with 100 mL 2N HCl, 100 mL distilled water and dried over magnesium sulfate. The solvent was removed on a rotary evaporator and the resulting oil chromatographed (silica gel, methylene chloride) to afford 7.3 g (32.28 mmol, 50.4%) of an oil. FTIR (neat, capillary) 2949.85, 2867.24, 1753.81, 1650.71, 1478.96, 1468.77, 1452.57, 1393.73, 1385.90, 1361.15, 1325.03, 1296.75, 1246.94, 1193.82, 1178.29, 1155.10, 1118.52, 1106.53, 1083.32, 1041.01, 1016.58, 1005.94, 946.14, 923.71, 902.63, 867.23, 843.74, 804.43, 783.98, 758.83, 696.74, 668.14. NMR (CDCl3) δ 6.86-7.22 (1H,m), 4.37-4.97 (2H,m), 1.00-2.30 (10H,m), 0.85 (9H,S). ##STR42##
Reaction SMILES: [CH3:1][CH:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:23]C)[N:13]2[CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][O:19][CH2:18]2)=[C:9]([NH2:25])[N:8]=1)[CH2:3][O:4][CH3:5].Cl.[OH-].[Na+]>CO.O1CCOCC1.O>[NH2:25][C:9]1[N:8]=[C:7]([O:6][CH:2]([CH3:1])[CH2:3][O:4][CH3:5])[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:23])[N:13]2[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][O:19][CH2:18]1
Reactant: COCC(C)Oc1nc(N)c2nc(OC)n(CC3CCCOC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: COCC(C)Oc1nc(N)c2[nH]c(=O)n(CC3CCCOC3)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-{[1-methyl-2-(methoxy)ethyl]oxy}-8-(methyloxy)-9-(tetrahydro-2H-pyran-3-ylmethyl)-9H-purin-6-amine (290 mg) in dry methanol (12 ml) at room temperature and under nitrogen was added 4.0M hydrogen chloride in 1,4-dioxane (5.0 ml). The reaction was left to stir at room temperature for 1 hour. The reaction was concentrated in vacuo and the resulting residue purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (10-45%) to afford a white solid. This was taken up in water (15 ml) and neutralised by the addition of 2.0M sodium hydroxide solution. The solid was filtered and dried on the rotary evaporator (60° C.) for 30 minutes (50 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19](Br)=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].O.[C:32](OCC)(=[O:34])C>CO.N1C=CC=CC=1.[Cu](I)I>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([O:34][CH3:32])=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Agent: I[Cu]I
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: c1ccncc1
Product: COc1cncc2cccc(S(=O)(=O)N3CC[C@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 25 °C

Procedure:
A solution of Intermediate 1a (337 mg) obtained in Example 1-1, Step A in methanol (2.7 ml) and pyridine (2.7 ml) was added with a solution of 28% sodium methylate (847 mg) in methanol, and then with copper iodide (70 mg), and the mixture was stirred at 65° C. for 30 hours. The reaction mixture was cooled to room temperature, and added with water (30 ml) and ethyl acetate (30 ml), and the insoluble solids were removed by filtration through Celite. The organic layer of the filtrate was separated, and the aqueous layer was extracted 3 times with ethyl acetate (20 ml for each time). The combined organic layer was washed 3 times with saturated brine (30 ml for each time), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=30:1) to obtain the title compound (98 mg).