Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[C:24](Cl)(=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1.Cl.CCOCC>C1COCC1>[ClH:1].[Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][N:10]([C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=4)=[O:33])[CH2:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(C(=O)N2CCc3[nH]c4ncc(Cl)cc4c3C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.2 %

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol) and DIEA (0.05 mL, 0.29 mmol) were dissolved in THF (2 mL). m-Anisoyl chloride (0.04 mL, 0.29 mmol) was added dropwise, and the reaction solution was stirred at room temperature for 1 h. The crude reaction mixture was concentrated, and converted to the HCl salt by dissolving the crude material in MeOH (2 ml) and adding 1 M HCl/ether (2 equiv). The resulting solution was refrigerated overnight. The resulting precipitate was filtered and dried under vacuum to provide 25 (50 mg, 55% yield) as an off white solid. LC-MS (M+H=342, obsd.=342).
Reaction SMILES: [N:1]([C:4](=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][Cl:18])=[C:11]([O:19][CH3:20])[CH:10]=1)[C:5]([O-:7])=[O:6])=[N+]=[N-].[C:21]1(C)C(C)=CC=CC=1>>[Cl:18][CH2:17][CH2:16][O:15][C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[C:4]([C:5]([O:7][CH3:21])=[O:6])[NH:1]2)=[CH:10][C:11]=1[O:19][CH3:20]
Reactant: Cc1ccccc1C
Reactant: COc1cc(C=C(N=[N+]=[N-])C(=O)[O-])ccc1OCCCl
Product: COC(=O)c1cc2cc(OC)c(OCCCl)cc2[nH]1
Yield: 52 %

Procedure:
A warmed (40° C.) solution of the above azidocinnamate (5.08 g, 16.3 mmol) in xylenes (140 mL) was added to boiling xylenes (60 mL) over 1 h. After a further 15 min at reflux, most of the xylene was removed by distillation. The precipitate that formed in the cooled residue was isolated by filtration, washed with CHCl3 and hexanes, and crystallized from MeOH to give methyl 6-(2-chloroethoxy)-5-methoxyindole-2-carboxylate (2.423 g, 52%) as fluffy white needles, mp 164-166° C. (sublimes 110° C.). 1H NMR [(CD3)2SO] δ 11.65 (br s, 1 H, NH), 7.13 (s, 1 H, H-4), 7.03 (d, J=1.6 Hz, 1 H, H-3), 6.91 (s, 1 H, H-7), 4.24 (t, J=5.2 H, 2 H, OCH2), 3.98 (t, J=5.2 H, 2 H, CH2Cl), 3.84 3.78 (2×s, 3 H each, OCH3); 13C NMR δ 161.5 (CO2), 147.8, 145.8, 132.4, 125.5, 120.3 (C-2, 3a, 5, 6, 7a), 107.8 (C-3), 103.0 (C-4), 96.3 (C-7), 68.9 (OCH2), 55.7 (OCH3), 51.4 (CO2CH3), 42.9 (CH2Cl).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6]
Reactant: ClCc1ccccc1
Reactant: O=C(O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
4.14 g (30 mmol) of 3-hydroxybenzoic acid was dissolved in 250 ml of N,N-dimethylformamide, and 2.49 g (18 mmol) of potassium carbonate and 3.8 ml (33 mmol) of benzyl chloride were added, followed by stirring at room temperature overnight. After the reaction solution was concentrated under vacuum, the residue was dissolved in ethyl acetate and 5% aqueous solution of sodium hydrogencarbonate. The organic layer was washed with 5% aqueous solution of sodium hydrogencarbonate, distilled water, and then with saturated brine, dried over anhydrous magnesium sulfate. This solution was concentrated under vacuum and the residue was crystallized from ethyl acetate-hexane to obtain 3.96 g of benzyl 3-hydroxybenzoate (yield 58%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH:29]=[CH2:30]>C(#N)C>[CH2:30]([O:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])[CH:29]=[CH2:28]
Reactant: O=C(OCc1ccccc1)c1ccc([N+](=O)[O-])c(O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1cc(C(=O)OCc2ccccc2)ccc1[N+](=O)[O-]
Yield: 94.2 %

Procedure:
Benzyl 3-hydroxy-4-nitro-benzoate 29a (4.50 g, 16.47 mmol) was dissolved in 75 mL of anhydrous acetonitrile. The resulting solution was added with potassium carbonate (6.83 g, 49.41 mmol) and 3-bromopropene (2.9 mL, 32.94 mmol) successively, heated to reflux for 3 hours, then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound benzyl 3-allyloxy-4-nitro-benzoate 29b (4.86 g, yield: 94.2%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.Cl[CH2:14][CH2:15][N:16]([CH3:18])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Oc1ccc2c(Cl)nccc2c1
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CN(C)CCOc1ccc2c(Cl)nccc2c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 120.6 %

Procedure:
To a solution of 1-chloro-isoquinolin-6-ol (300 mg, 1.67 mmol) in acetonitrile (16 ml) was added (2-Chloro-ethyl)-dimethyl-amine (289 mg, 2.0 mmol) and cesium carbonate (1.2 g, 3.67 mmol). The reaction was stirred at 65° C. overnight. The solvent was removed and the residue dissolved in ethyl acetate. The organic solution was washed with saturated sodium bicarbonate, dried over magnesium sulfate and concentrated. The crude product was purified using reverse phase HPLC to afford 505 mg (83%) of [2-(1-chloro-isoquinolin-6-yloxy)-ethyl]-dimethyl-amine as a white amorphous solid. LCMS found 251.04 [M+H]+.
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[C:18]([Br:19])=[CH:17][C:16]2[C:11](=[C:12]([Cl:21])[CH:13]=[C:14](Br)[CH:15]=2)[CH:10]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([Mg]Br)=[CH:26][CH:25]=1>C1COCC1.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>[C:1]([Si:5]([O:8][C:9]1[C:18]([Br:19])=[CH:17][C:16]2[C:11](=[C:12]([Cl:21])[CH:13]=[CH:14][CH:15]=2)[C:10]=1[C:27]1[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc([Mg]Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc2c(Cl)cc(Br)cc2cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2c(O[Si](C)(C)C(C)(C)C)c(Br)cc3cccc(Cl)c23)cc1
Yield: 68.8 %

Procedure:
A solution of tert-butyl[(3,6-dibromo-8-chloro-2-naphthyl)oxy]dimethylsilane (1.95 g, 4.32 mmol), 4-methoxyphenylmagnesium bromide (13.8 mL of 0.5 N solution, 6.9 mmol), and tetrakis(triphenylphosphine)palladium (0.25 g, 0.21 mmol) in THF (10 mL) were stirred at reflux for 8 hr. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with water, dried with sodium sulfate, filtered, evaporation of the solvent, and purified on a silica column (5% ethyl acetate-hexanes) to yield 1.42 g (69%) of the title compound as a white solid: 1H NMR (CDCl3): δ 0.36 (6H, s), 1.10 (9H, s), 3.87 (3H, s), 7.01 (2H, d, J=8.78 Hz), 7.33(1H,d, J=1.36 Hz), 7.58 (2H, d J=8.75 Hz), 7.73 (1H, s), 7.78 (1H, d, J=1.62 Hz), 8.10 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:13])=[C:5]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:4]=1[CH3:20].Br[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:13])=[C:5]([N:14]2[CH2:19][CH2:18][N:17]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[CH2:16][CH2:15]2)[C:4]=1[CH3:20]
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: COc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)C2
Product: COc1c(C)c(N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c(C)c2c1OC(C)C2
Yield: 55.1 %

Procedure:
By using 1-(7-methoxy-2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (552 mg, 2.0 mmol) synthesized in Reference example 88 and 1-bromo-4-(trifluoromethyl)benzene (900 mg, 4.0 mmol), the reaction was carried out in the same manner as Example 23 to synthesize the title compound 463 mg (yield 55%). Melting point was 142 to 145° C. (ethanol-water).
Reaction SMILES: C([O:5][C:6](=[O:20])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:19])[CH2:13][CH2:14][S:15]C(=O)C)(C)(C)C.N>>[SH:15][CH2:14][CH2:13][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:20])=[O:5])=[O:19]
Reactant: CC(=O)SCCC(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: N
Product: O=C(O)[C@@H]1CCCN1C(=O)CCS

Procedure:
The product from Example 2, 3-acetylthiopropanoyl-L-proline-t-butyl ester, 0.5 g, was mixed with 4.5 ml of 5.5 N methanolic ammonia at room temperature under nitrogen for one hour to remove the acetyl group. The solvent was then removed at 25° C. with a rotary evaporator. After the product was taken up in methanol and reevaporated twice more in the rotary evaporator, the clear oily residue was dissolved in ethyl ether, washed twice with 5% potassium bisulphate and once with saturated NaCl, dried over MgSO4 and filtered. Residual solvent was removed in vacuo to yield a clear oily product, migrating as a single spot on thin layer chromatography in three separate solvent systems. The t-butyl ester protecting group was removed by reaction with trifluoroacetic acid in anisole.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:12][CH:13]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:23]=1)[CH2:14][NH:15][C:16]([NH:18][NH2:19])=S>C1COCC1>[C:1]([NH:9][C:10]1[S:11][C:16]([NH:15][CH2:14][CH:13]([OH:12])[CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[CH:23]=2)=[N:18][N:19]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=S)NCC(O)COc1cccc(CN2CCCCC2)c1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1nnc(NCC(O)COc2cccc(CN3CCCCC3)c2)s1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.33 g (2 mmol) of benzoyl isothiocyanate are added to 0.68 g (2 mmol) of N-[2-hydroxy-3-[3-(1-piperidinylmethyl)phenoxy]propyl]-hydrazine carbothioamide in 20 ml of THF and the reaction mixture is stirred overnight at room temperature. After removal of the THF by evaporation, the solid residue is washed with ether and dissolved in 30 ml of ethanol with heating, and 1 ml of 30% hydrogen peroxide is added. The sulphur which separates is filtered off, the filtrate is concentrated by evaporation and the oily residue is purified by preparative layer chromotography.
Reaction SMILES: [C:1]([O:5][O:6][C:7]([O:11][O:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH2:9]C)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(OO)(C1C=CC=CC=1)(C)C>>[C:13]([O:12][O:11][C:7]([O:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:9])[CH3:8])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCC(C)(OOC(C)(C)C)OOC(C)(C)C
Agent: CC(C)(OO)c1ccccc1
Product: CC(C)(C)OOC(C)(C)OOC(C)(C)C

Procedure:
2,2-di(t-butylperoxy) butane or cumyl hydroperoxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[O:9].[I-:17].[K+].II>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[C:14]([I:17])[CH:15]=1)=[O:9]
Reactant: [I-]
Reactant: O=C(c1ccc(O)cc1)c1ccccc1F
Agent: II
Agent: [K+]
Product: O=C(c1ccc(O)c(I)c1)c1ccccc1F

Procedure:
(2-Fluorophenyl)(4-hydroxyphenyl)methanone, potassium iodide and iodine were processed as described in Example 68A to provide the title compound. MS (DCI) m/z 343 (M+H)+, 360 (M+NH4)+.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([NH:15][C:16]([N:18]2[CH2:23][CH2:22][O:21][C:20]3[CH:24]=[C:25]([O:28][C:29]4[C:38]5[C:33](=[CH:34][C:35]([O:41][CH3:42])=[C:36]([O:39][CH3:40])[CH:37]=5)[N:32]=[CH:31][CH:30]=4)[CH:26]=[CH:27][C:19]2=3)=[O:17])[CH:11]=1)(C(C)(C)C)(C)C.[ClH:43]>CCO>[ClH:43].[CH3:40][O:39][C:36]1[CH:37]=[C:38]2[C:33](=[CH:34][C:35]=1[O:41][CH3:42])[N:32]=[CH:31][CH:30]=[C:29]2[O:28][C:25]1[CH:26]=[CH:27][C:19]2[N:18]([C:16]([NH:15][C:12]3[CH:11]=[C:10]([CH2:9][OH:8])[O:14][N:13]=3)=[O:17])[CH2:23][CH2:22][O:21][C:20]=2[CH:24]=1
Reactant: COc1cc2nccc(Oc3ccc4c(c3)OCCN4C(=O)Nc3cc(CO[Si](C)(C)C(C)(C)C)on3)c2cc1OC
Agent: Cl
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc4c(c3)OCCN4C(=O)Nc3cc(CO)on3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
To N-(5-((tert-butyldimethylsilyloxy)methyl)isoxazol-3-yl)-7-(6,7-dimethoxyquinolin-4-yloxy)-2,3-dihydrobenzo[b][1,4]oxazine-4-carboxamide (7) (50 mg, 0.084 mmol) was added 2 N HCl in EtOH (5 mL) at RT. After 15 min, the solid had dissolved and the solution was stirred at RT for an additional 2 hrs at which time a white precipitate formed. The mixture was cooled to 0° C., filtered, and the isolated solid was washed with cold EtOH. The solid was dried in vacuo to afford 7-(6,7-dimethoxyquinolin-4-yloxy)-N-(5-(hydroxymethyl)isoxazol-3-yl)-2,3-dihydrobenzo[b][1,4]oxazine-4-carboxamide hydrochloride (33 mg, 83% yield). MH+=479.2.
Reaction SMILES: [C:1](=[N:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:23]1[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[CH:24]=1.C(=O)([O-])[O-:31].[K+].[K+]>CC(C)=O>[C:1](=[N:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[O:31][C:23]1[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[CH:24]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1C=C(Cl)CCC1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccccc1N=C(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1C=C(Oc2cccc(N=C(c3ccccc3)c3ccccc3)c2)CCC1

Procedure:
A suspension of the (benzhydrylidene-amino)-phenol (10.47 g, 38.3 mmol), 3-chloro-cyclohex-2-enone (5.00 g, 38.3 mmol) and potassium carbonate (5.82, 42.1 mmol) in 150 mL of acetone was heated at reflux overnight. The cooled reaction mixture was filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting hexanes/EtOAc (2:1). In this manner, 3-[3-(benzhydrylidene-amino)phenoxy]-cyclohex-2-enone was obtained as a yellow solid, (8.82 g, 63%): 1H NMR (CDCl3) δ 7.78 (d, 2H, J=7.0 Hz), 7.50 (d, 1H, J=7.1 Hz), 7.45 (d, 2H, J=7.7 Hz), 7.347.10 (m, 6H), 6.69 (d, 1H, J=8.0 Hz), 6.61 (d, 1H, J=8.0 Hz), 6.38 (s, 1H), 4.89 (s, 1H), 2.55 (t, 2H, J=6.2 Hz), 2.34 (t, 2H, J=6.2 Hz), 2.06 (m, 2H). Anal. Calc. for C25H21NO2 0.2H2O: C, 80.92; H, 5.81; N, 3.78. Found: C, 81.12; H, 5.81; N, 3.72.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=O)[CH:5]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:26][N:27]([CH3:38])[C:28]1[CH:37]=[CH:36][C:31]([C:32]([NH:34]O)=[NH:33])=[CH:30][N:29]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]2[O:9][N:33]=[C:32]([C:31]3[CH:30]=[N:29][C:28]([N:27]([CH3:38])[CH3:26])=[CH:37][CH:36]=3)[N:34]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: CN(C)c1ccc(C(=N)NO)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: [F-]
Product: COC(=O)c1cccc(-c2nc(-c3ccc(N(C)C)nc3)no2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 50 ml round flask, a mixture of 5.6 (31.1 mmol) of isophtalic acid monomethyl ester and 6.71 g (34.2 mmol, 1.1 eq.) of carbonyl-diimidazole is stirred for 1 h at rt. Then, 5.60 g (31.1 mmol) of 6-dimethylamino-N-hydroxy-nicotinamidine is added and the resulting mixture stirred for another 3 h. After completion of the reaction, the solvent is removed. The resulting residue is suspended in water, vigorously stirred and then filtered. The obtained solid is washed two times with diethyl-ether and dried. This yields 10.0 g (94%) of a light yellow solid. Mass spectrum: m/z (M+H)+: 343.1The crude intermediate (9.8 g (28.7 mmol) is then redissolved in 200 ml of THF and 1.81 g (5.7 mmol, 0.2 eq.) of tetrabutyl-ammonium fluoride tri-hydrate TBAF) is added. After 1.5 h, another 0.2 eq. of TBAF is and the mixture stirred at rt for 20 h. Then, solvent is removed under vacuo, and the residue taken up in 200 ml of dichloro-methane and washed twice with NaHCO3 (5%). The combined aqueous phases are extracted three times with dichloro-methane, the combined organic phases dried (Na2SO4) and concentrated. This yields the title compound as light yellow solid, which is used for the next step without purification. Mass spectrum: m/z (M+H)+: 325.2
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[O:16]CC1C=CC=CC=1>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:24])[C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([C:12]([F:13])([F:15])[F:14])=[CH:6][C:5]=1[OH:16]
Reactant: COC(=O)c1c(OC)cc(C(F)(F)F)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1c(O)cc(C(F)(F)F)cc1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 60 mg (0.176 mmol) 2-benzyloxy-6-methoxy-4-trifluoromethyl-benzoic acid methyl ester in 1 ml ethanol under nitrogen at room temperature, was added 8 mg (0.0071 mmol) Pd/C 10%. The mixture was stirred at room temperature under an hydrogen atmosphere for 4 hours. The catalyst was filtered, washed with dichloromethane and the filtrate was concentrated in vacuo to provide 38 mg (y: 86.1%) of the title compound as a white solid. MS (m/e): 249.0 (M−H).
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.Cl[C:9](Cl)([O:11][C:12](=[O:18])[O:13][C:14](Cl)(Cl)Cl)Cl.C(Cl)Cl.CO>C(Cl)Cl>[NH2:3][CH2:6][CH2:7][CH:9]1[CH2:14][O:13][C:12](=[O:18])[O:11]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: NCCC1COC(=O)O1

Procedure:
To a solution of the diol (9 g, 37.66 mmol) in CH2Cl2 (200 mL) was added triethylamine (15.2 g, 151 mmol) at −20˜30° C. under N2. After several minutes, triphosgene (5.5 g, 18.83 mmol) was added to the mixture dropwise at this temperature and stirred at −20˜30° C. for half an hour. Then the mixture was stirred at room temperature for 15 h. TLC (CH2Cl2/MeOH=10:1) showed the starting material was almost consumed. To the mixture was added water and extracted with ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C1(C)C(S(O[CH2:37][CH2:38][N:39]([CH3:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].O.C(O)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:37][CH2:38][N:39]([CH3:46])[C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)=[C:20]([O:25][CH3:26])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1O
Reactant: Cc1ccccc1S(=O)(=O)OCCN(C)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCCN(C)c1ccccc1
Temperature: 75 °C
Yield: 80 %

Procedure:
To a solution of 6-(4-chlorophenyl)-3-(4-hydroxy-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (96 mg, 0.25 mmol, the preparation of which may be found in Example K1) in DMF was added 2-(methylanilino)ethyl toluenesulfonate (153 mg, 0.50 mmol) and cesium carbonate (0.24 g, 0.75 mmol) and the mixture was stirred with heating at 75° C. for 12 h. The reaction was allowed to cool and a 10 mL solution of 20% water/ethanol was added. The resulting precipitate was filtered and dried in a vacuum oven to give the title compound (104 mg, 80%). 1H NMR (DMSO-D6) δ 3.01 (3H, s), 3.78 (5H, m), 4.18 (2H, t, J=3.7 Hz), 6.63 (1H, t, J=7.3 Hz), 6.78 (2H, d, J=7.2 Hz), 7.02-7.20 (5H, m), 7.60 (2H, d, J=8.6 Hz), 7.96 (3H, m), 8.39 (1H, s). LCMS m/z=518 (m+H+). Calcd. for C28H24ClN3O3S×1H2O: C, 62.74; H, 4.89; N, 7.84. Found: C, 62.76; H, 4.65; N, 7.82.
Reaction SMILES: C([O:5][C:6](=[O:47])[CH2:7][CH2:8][N:9]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[S:10]([C:13]1[CH:18]=[CH:17][C:16]([C@H:19]([C:26](=[O:39])[NH:27][C:28]2[S:29][C:30]3[C:35]([N:36]=2)=[CH:34][CH:33]=[C:32]([O:37][CH3:38])[N:31]=3)[CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=1)(=[O:12])=[O:11])(C)(C)C.[OH-].[Na+]>CO.O>[CH2:40]([N:9]([S:10]([C:13]1[CH:14]=[CH:15][C:16]([C@H:19]([C:26](=[O:39])[NH:27][C:28]2[S:29][C:30]3[C:35]([N:36]=2)=[CH:34][CH:33]=[C:32]([O:37][CH3:38])[N:31]=3)[CH2:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:17][CH:18]=1)(=[O:11])=[O:12])[CH2:8][CH2:7][C:6]([OH:47])=[O:5])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: COc1ccc2nc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(=O)(=O)N(CCC(=O)OC(C)(C)C)Cc4ccccc4)cc3)sc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2nc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(=O)(=O)N(CCC(=O)O)Cc4ccccc4)cc3)sc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title I compound, 3-(benzyl-{4-[(R)-2-cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-amino)-propionic acid tert-butyl ester (0.064 g, 0.0942 mmol) is dissolved in methanol (5 mL), to which a solution of sodium hydroxide (0.004 g, 0.0942 mmol) in water (2 mL) is added. The reaction mixture is stirred at RT overnight. The reaction mixture is then concentrated and the residue is partitioned between 1 M HCl/ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and concentrated to afford 3-(benzyl-{4-[(R)-2-cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-amino)-propionic acid as a white foam: 1H NMR (400 MHz-CDCl3) δ 1.17 (m, 2H) 1.50 (m, 2H) 1.66 (m, 4H) 1.78 (m, 1H) 2.28 (m, 1H) 2.43 (m, 2H) 3.23 (m, 1H) 3.50 (m, 1H) 3.85 (m, 2H) 4.00 (s, 3H) 4.37 (m, 1H) 4.77 (m, 1H) 6.79 (m, 1H) 7.36 (m, 5H) 7.52 (m, 2H) 7.67 (m, 1H) 7.95 (m, 2H); LC/MS 623.3 (M+1), 621.4 (M−1). EC50 in primary enzyme assay 0.27 μM
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]C)=[CH:6][C:5]([N:10]2[C:14](=[O:15])[N:13]([CH3:16])[C:12]([CH:17]([F:19])[F:18])=[N:11]2)=[C:4]([F:20])[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:10]2[C:14](=[O:15])[N:13]([CH3:16])[C:12]([CH:17]([F:18])[F:19])=[N:11]2)=[C:4]([F:20])[CH:3]=1
Reactant: COc1cc(-n2nc(C(F)F)n(C)c2=O)c(F)cc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1c(C(F)F)nn(-c2cc(O)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.1 %

Procedure:
To a stirred ice cold solution of 1.5 g (0.0048 mole) of 1-(4-chloro-2-fluoro-5-methoxyphenyl)-3-difluoromethyl-4,5-dihydro-4-methyl-1,2,4-triazol-5(1H)-one in 80 mL of methylene chloride was added dropwise 14.2 mL of a 1M solution of boron tribromide in methylene chloride. After complete addition the mixture was allowed to warm to room temperature and stir for approximately 18 hours. The mixture was poured into ice water and the resultant mixture stirred until the ice had melted. The organic phase was separated from the mixture and was washed with two portions of water. After washing, the organic phase was dried over anhydrous magnesium sulfate and filtered. Evaporation of the filtrate under reduced pressure yielded 1.2 g of 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-3-difluoromethyl-4,5-dihydro-4-methyl-1,2,4-triazol-5(1H)-one (mp 153°-155° C.), Compound 23.