Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][P:4]([CH2:16][C:17]([N:19]1[CH:23]([C:24]([O:26][CH:27]([O:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:25])[CH2:22][C:21]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[N:20]1)=[O:18])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])C.Br[Si](C)(C)C>ClCCl>[OH:5][P:4]([CH2:16][C:17]([N:19]1[CH:23]([C:24]([O:26][CH:27]([O:33][C:34](=[O:39])[C:35]([CH3:37])([CH3:38])[CH3:36])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:25])[CH2:22][C:21]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[N:20]1)=[O:18])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:3]
Reactant: CCOC(=O)C(OC(=O)C1CC(c2ccccc2)=NN1C(=O)CP(=O)(CCCCc1ccccc1)OCC)OC(=O)C(C)(C)C
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CCOC(=O)C(OC(=O)C1CC(c2ccccc2)=NN1C(=O)CP(=O)(O)CCCCc1ccccc1)OC(=O)C(C)(C)C
Reaction time: 8 h

Procedure:
A solution of 2.0 g of the diester product from part (b) in 25 ml. of dry dichloromethane under argon is treated at ambient temperature with 0.6 g. of bromotrimethylsilane. After stirring overnight, the volatiles are removed in vacuo and the residue, dissolved in ethyl acetate, is washed with 5% sodium dihydrogen phosphate, water and saturated brine. The organic fraction is dried (MgSO4) and concentrated in vacuo. The residue is triturated with acetonitrile or purified by flash chromatography to give (+)-4,5-dihydro-1-[[hydroxy(4-phenylbutyl)phosphinyl]acetyl]-3-phenyl-1H-pyrazole-5-carboxylic acid, 1-(2,2-dimethyl-1-oxopropoxy)-2-ethoxy-2-oxoethyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C@H:5]([CH3:34])[CH2:6][C@H:7]([NH:21][C:22](=[O:33])[C:23]1[CH:28]=[C:27]([F:29])[C:26]([O:30]C)=[C:25]([F:32])[CH:24]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:35])[C@H:5]([CH3:34])[CH2:6][C@H:7]([NH:21][C:22](=[O:33])[C:23]1[CH:24]=[C:25]([F:32])[C:26]([OH:30])=[C:27]([F:29])[CH:28]=1)[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(F)c(OC)c(F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(F)c(O)c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.3 %

Procedure:
Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-methoxy-benzoylamino)-2-methyl-pentanoic acid ethyl ester (125 mg, 0.260 mmol) in DCM (2.6 mL) is slowly added BBr3 (2.60 mL, 2.60 mmol) under nitrogen. The reaction is stirred for 18 hours at rt. The reaction is quenched with MeOH, diluted with EtOAc, washed with H2O and brine, dried over MgSO4, and concentrated under reduced pressure. The obtained material is purified by preparative silica gel thin-layer chromatography (7% MeOH in DCM) to give 100 mg (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-hydroxy-benzoylamino)-2-methyl-pentanoic acid ethyl ester. Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-hydroxy-benzoylamino)-2-methyl-pentanoic acid ethyl ester (30 mg, 0.064 mmol) in MeOH (2 mL) at room temperature is added aqueous 1M NaOH (4 mL, 4.0 mmol). After stirring for 1 hour the reaction is quenched with aqueous 1M HCl (4 mL, 4.0 mmol). The mixture is concentrated under reduced pressure and filtered to remove NaCl salt. The obtained residue is purified by preparative silica gel thin-layer chromatography (7% MeOH in DCM) to give 17.1 mg of (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-hydroxy-benzoylamino)-2-methyl-pentanoic acid. HPLC Retention time 1.56 minutes (condition G); MS 440 (M+1); 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 1.19 (d, J=7.07 Hz, 3 H) 1.55 (ddd, J=14.27, 10.74, 3.79 Hz, 1 H) 1.90-1.96 (m, 1 H) 2.54-2.71 (m, 1 H) 2.91 (dd, J=6.69, 3.16 Hz, 2 H) 4.25-4.43 (m, 1 H) 6.49 (d, J=9.60 Hz, 2 H) 6.93 (d, J=8.84 Hz, 1 H) 7.33-7.42 (m, 3 H) 7.49 (t, J=7.71 Hz, 2 H) 7.61 (d, J=8.34 Hz, 2 H) 7.67 (dd, J=8.34, 1.26 Hz, 2 H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=O)=[N:4][CH:5]=[CH:6][CH:7]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:15]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:3]2[N:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1cccnc1Nc1ccccc1C(=O)c1cccs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: c1csc(C2=Nc3cccnc3Nc3ccccc32)c1

Procedure:
Following the procedure of Example 20, [2-[(3-amino-2-pyridinyl)amino]phenyl](2-thienyl)methanone is heated with para toluene sulfonic acid catalyst in organic solvent while removing water in a Dean-Stark trap to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH2:16])[N:3]=1.[NH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>>[NH2:16][C:4]1[N:3]=[C:2]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=1
Reactant: Cc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Reactant: N#Cc1ccc(N)cc1
Product: Cc1ccc(Cl)cc1-c1cc(Nc2ccc(C#N)cc2)nc(N)n1
Yield: 71 %

Procedure:
Following the method described in Example 26, 4-chloro-6-(5-chloro-2-methyl-phenyl)-pyrimidin-2-yl-amine and 4-amino-benzonitrile provided the title compound (71% yield). 1H NMR (DMSO-d6) δ 2.36 (s, 3H, CH3), 6.19 (s, 1H, Ar), 6.61 (s, 2H, NH2), 7.32 (d, 1H, J=8.2 Hz, Ar), 7.38 (dd, 1H, J=8.2 Hz, J=2.3 Hz, Ar), 7.43 (d, 1H, J-2.3 Hz, Ar), 7.72 (d, 2H, J=8.8 Hz, Ar), 8.00 (d, 2H, J=8.8 Hz, Ar), 9.73 (s, 1H, NH).
Reaction SMILES: Cl[C:2](Cl)([O:4][C:5](=[O:11])[O:6][C:7](Cl)(Cl)Cl)Cl.[Br:13][C:14]1[CH:23]=[C:22]([Br:24])[C:21]([CH2:25]CO)=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2>O1CCOCC1>[Br:13][C:14]1[CH:23]=[C:22]([Br:24])[C:21]([CH2:25][CH2:2][O:4][C:5]([O:6][CH3:7])=[O:11])=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: OCCc1c(Br)cc(Br)c2cccnc12
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: COC(=O)OCCc1c(Br)cc(Br)c2cccnc12
Reaction time: 8 h

Procedure:
Triphosgene, 740 mg (2.5 mmol) was dissolved in 5 mL of anhydrous dioxane and stirred at ambient temperature while 5,7-dibromo-8-(2-hydroxyethyl)quinoline was added in several portions. The mixture was stirred overnight and capped to protect from atmospheric moisture. The solvent and excess reagent were removed under a stream of dry argon. Residue was redissolved in 10 mL of methanol, stirring for 1 hr., and the solvent was removed. The residue was recrystallized from methanol/water. Melting point: 102.5104.5° C.
Reaction SMILES: FC(F)(F)C(O)=O.C[O:9][C:10](=[O:23])[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[S:18][C:19]([NH2:22])=[N:20][N:21]=2)=[CH:13][CH:12]=1.[OH-].[Na+]>O>[NH2:22][C:19]1[S:18][C:17]([C:14]2[CH:13]=[CH:12][C:11]([C:10]([OH:23])=[O:9])=[CH:16][CH:15]=2)=[N:21][N:20]=1
Reactant: COC(=O)c1ccc(-c2nnc(N)s2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(-c2ccc(C(=O)O)cc2)s1
Yield: 99.7 %

Procedure:
To a solution of 4-(5-amino-1,3,4-thiadiazol-2-yl)benzoic acid methyl ester trifluoroacetic acid salt (8 g) in water was added 1N sodium hydroxide and the mixture was adjusted to pH 8. The precipitate was collected by filtration to give 4-(5-amino-1,3,4-thiadiazol-2-yl)benzoic acid (5.05 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([CH3:18])([CH3:17])[CH2:6][CH2:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])[CH3:2].[BrH:20]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:19])[C:5]([CH3:18])([CH3:17])[CH2:6][CH2:7][CH2:8][CH:9]([Br:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])[CH3:2]
Reactant: CCOC(=O)C(C)(C)CCC=Cc1ccccc1Cl
Reactant: Br
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(C)CCCC(Br)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 80.14 %

Procedure:
6-(2-Chlorophenyl)-2,2-dimethylhex-5-enoic acid ethyl ester (15 g, 53.6 mmol) was dissolved in glacial acetic acid (150 mL). The solution was cooled in an ice-bath (ca. 15° C.) while dry hydrogen bromide was passed into the solution for 8 h. The reaction mixture was poured into ice-water (250 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with saturated NaHCO3 solution (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product (18 g) was purified by column chromatography (silica gel, ethyl acetate/heptane=1/20 to 1/10) to provide 6-bromo-6-(2-chlorophenyl)-2,2-dimethylhexanoic acid ethyl ester (15.5 g, 80.14%) as a yellow oil. 1H NMR (Field: 300 MHz, Solvent: CDCl3/TMS) δ (ppm): 7.58 (d, 1H, J=7.8 Hz), 7.34 (t, 1H, J=7.8 Hz), 7.27 (d, 1H, J=7.2 Hz), 7.21 (t, 1H, J=7.2 Hz), 5.45 (t, 1H, J=8.1 Hz), 4.09 (q, 2H, J=6.9 Hz), 2.19 (m, 2H), 1.55 (m, 2H), 1.24 (t, 3H, J=6.9 Hz), 1.14 (s, 6H). 13C NMR (Field: 75 MHz, Solvent: CDCl3/TMS) δ (ppm): 177.45, 139.25, 132.64, 129.64, 129.27, 128.75, 127.43, 60.36, 49.97, 42.17, 39.84, 39.51, 25.41, 25.20, 23.67, 14.43. MS (GC-CI): Calculated for C16H22BrClO2 (MH)+: 361.0564; found 361.0547.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22](OCC)=[O:23])[C:4]1=[O:27])[CH3:2].[NH2:28][CH2:29][CH:30]([OH:32])[CH3:31]>>[CH2:1]([N:3]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22]([NH:28][CH2:29][CH:30]([OH:32])[CH3:31])=[O:23])[C:4]1=[O:27])[CH3:2]
Reactant: CC(O)CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC)c1=O
Product: CCn1c(=O)c(C(=O)NCC(C)O)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 38 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-ethyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (30 mg, 0.081 mmol) and 1-amino-2-propanol (0.05 mL) was prepared 1-ethyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxypropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (12 mg, 38% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.49 (s, 1 H), 8.56 (s, 1 H), 7.37 (s, 1 H), 7.18 (m, 2 H), 7.05-7.07 (m, 2 H), 4.23-4.06 (m, 5 H), 3.62 (m, 1 H), 3.38 (m, 1 H), 1.29-1.22 (m, 6 H); HRMS m/z calcd for C21H23FN3O4: 400.1667. Found: 400.1673.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:12](N1C=CN=C1)([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[S:13]>C(#N)C>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([NH:11][C:12]([N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)=[S:13])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc2c(Cl)cccc2s1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: S=C(Nc1nc2c(Cl)cccc2s1)n1ccnc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 18.5 %

Procedure:
To 4-chlorobenzo[d]thiazol-2-amine (1.12 g, 6.07 mmol) in acetonitrile (30 mL) was added 1,1′-thiocarbonyldiimidazole (1.405 g, 7.89 mmol). The reaction mixture was stirred at 50° C. for 18 hours. The reaction was cooled to room temperature and the precipitate was filtered and washed with acetonitrile (2×50 mL). The yellow powder was dried in a vacuum oven (40° C.) for 1 hour to yield N-(4-chlorobenzo[d]thiazol-2-yl)-1H-imidazole-1-carbothioamide (0.33 g, 1.12 mmol, 18.5% yield) and then used in the next step without any further purification or characterization.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:22][CH2:21][CH:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:19][CH:18]=2)=[CH:13][CH:12]=1)C1C=CC=CC=1>CCOC(C)=O>[C:27]([Si:24]([CH3:26])([CH3:25])[O:23][CH:20]1[CH2:19][CH2:18][CH:17]([C:14]2[CH:13]=[CH:12][C:11]([NH2:10])=[CH:16][CH:15]=2)[CH2:22][CH2:21]1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)OC1CC=C(c2ccc(NC(=O)OCc3ccccc3)cc2)CC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC1CCC(c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
{4-[4-(tert-Butyl-dimethyl-silanyloxy)-cyclohex-1-enyl]-phenyl}-carbamic acid benzyl ester (Intermediate 16) (350 mg, 0.8 mmol) was dissolved in EtOAc (35 mL). After de-gas by vacuum/nitrogen exchange, Pd—C (70 mg) was added. The reaction mixture was first purged with nitrogen and then hydrogen introduced by vacuum/hydrogen purge cycle. The reaction mixture was stirred at rt overnight when TLC (30% EtOAc in heptane, UV) could not detect the starting material. The reaction mixture was filtered through a celite pad, rinsed with EtOAc. The filtrate was concentrated in vacuo. The residue was purified on a silica gel column, eluted with 10-20% EtOAc in heptane to obtain the title compound as an oil which solidified on standing 130 mg (0.42 mmol, 53% yield).
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:11][C:12]([CH3:14])=O>>[CH3:11][C:12](=[N:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[CH3:14]
Reactant: NNC(=O)c1ccncc1
Reactant: CC(C)=O
Product: CC(C)=NNC(=O)c1ccncc1
Temperature: 20 °C

Procedure:
A four neck flask (1 liter) equipped with a thermometer, a reflux condenser and a stirrer was charged with 68.5 g (0.5 mol) of isonicotinohydrazide and 500 ml of acetone and then heated under reflux for 24 hours. The reaction liquid was cooled down to 20° C. or lower, and then crystal was filtered off and dried under reduced pressure, whereby the intended compound (white crystal) was obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([S:17][CH2:18][CH3:19])[N:14]3[CH:20]=[CH:21][N:22]=[C:13]3[CH:12]=2)=[CH:7][C:6]=1[O:23][CH3:24].[OH-:25].[Na+]>N1CCOCC1>[CH2:18]([S:17][C:15]1[N:14]2[CH:20]=[CH:21][N:22]=[C:13]2[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:14]3[CH2:20][CH2:21][O:25][CH2:12][CH2:13]3)=[C:6]([O:23][CH3:24])[CH:7]=2)[N:16]=1)[CH3:19]
Reactant: [OH-]
Reactant: CCSc1nc(-c2ccc(OCCCl)c(OC)c2)cc2nccn12
Agent: [Na+]
Solvent: C1COCCN1
Product: CCSc1nc(-c2ccc(OCCN3CCOCC3)c(OC)c2)cc2nccn12
Temperature: 25 °C
Yield: 71 %

Procedure:
Then a solution of 7-[4-(2-Chloro-ethoxy)-3-methoxy-phenyl]-5-ethylsulfanyl-imidazo[1,2-c]pyrimidine (800 mg, 2.2 mmol) in morpholine (10 ml) was stirred at 100° C. overnight. After cooling to room temperature, the mixture was poured into a dilute NaOH solution and extracted with CH2Cl2. The combined organic extract was dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography to give 5-Ethylsulfanyl-7-[3-methoxy-4-(2-morpholin-4-yl-ethoxy)-phenyl]-imidazo[1,2-c]pyrimidine (650 mg, 71%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18]OS(C)(=O)=O)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][NH:28][C:24]([CH3:27])([CH3:26])[CH3:25])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(OCCOS(C)(=O)=O)c2c1C
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1oc2cccc(OCCNC(C)(C)C)c2c1C
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4-(2-Methanesulfonyloxy-ethoxy)-3-methyl-benzofuran-2-carboxylic acid ethyl ester (20 mg) and tert-butylamine (0.3 ml) were dissolved in THF (2 ml) and stirred overnight at 60° C. The reaction mixture was dissolved in ethyl acetate and washed with saturated ammonium chloride solution and water. The organic solvent was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by preparative thin layer chromatography (using dichloromethane:MeOH=10:1 as a developing solvent) to afford 4-(2-tert-butylamino-ethoxy)-3-methyl-benzofuran-2-carboxylic acid ethyl ester (11 mg) as a colorless oil. FAB-MS: m/z 320 (MH+); 1H-NMR (CDCl3): δ 1.20 (9H, s), 1.44 (3H, t, J=7 Hz), 2.75 (3H, s), 3.08 (2H, t, J=5 Hz), 4.23 (2H, t, J=5 Hz), 4.44 (2H, q, J=7 Hz), 6.62 (1H, d, J=8 Hz), 7.11 (1H, d, J=8 Hz), 7.29 (1H, t, J=8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH:19]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([NH:24][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][N:17]=[CH:18][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NC1CCCC1
Product: O=C(NC1CCCC1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N-cyclopentyl-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.45 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.57 mmol of cyclopentylamine. LC/MS [9.55 min; 426 (M+1)]
Reaction SMILES: [C:1]12([C:11]3[S:15][CH:14]([C:16]([O:18]CC)=[O:17])[N:13]([C:21](=[O:25])[CH2:22][CH2:23][SH:24])[N:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH-].[K+]>>[C:1]12([C:11]3[S:15][CH:14]([C:16]([OH:18])=[O:17])[N:13]([C:21](=[O:25])[CH2:22][CH2:23][SH:24])[N:12]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CCOC(=O)C1SC(C23CC4CC(CC(C4)C2)C3)=NN1C(=O)CCS
Agent: [K+]
Agent: [OH-]
Product: O=C(O)C1SC(C23CC4CC(CC(C4)C2)C3)=NN1C(=O)CCS

Procedure:
The product of step (d) was treated with potassium hydroxide by the process of Example 3, step (c) to give the title product as white solid. mp 183°-184°. Mass spectrum (FAB) showed M+ 355 (base peak 221). C16H22N2O3S2 requires MWt 354.
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[CH:8]1[CH:12]=[C:11]([CH2:13][C:14]([Cl:16])=O)[S:10][CH:9]=1.[O:17]1CCOCC1>>[Cl:16][CH2:14][C:13]([C:11]1[S:10][CH:9]=[CH:8][CH:12]=1)=[O:17]
Reactant: C1COCCO1
Reactant: O=C(Cl)Cc1cccs1
Agent: C[Si](C)(C)C=[N+]=[N-]
Product: O=C(CCl)c1cccs1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42 %

Procedure:
Trimethylsilyl diazomethane (TMSCHN2, 2M in hexanes, 100 ml, 0.200 mole) was added dropwise, over a period of 20 minutes, to an ice bath solution of thiophene-2-acetyl chloride (0.192 mole, 28.1 g) in 100 ml of dry 1,4-dioxane. The slush disappeared upon addition of TMSCHN2. The reaction mixture was slowly warmed to room temperature and stirred for 24 hours. The reaction mixture was cooled in an ice bath and HCl gas was bubbled for 0.5 hour and stirred at room temperature for 2 days. The solvent was removed under reduced pressure, the residue partitioned between 100 ml of aqueous saturated NaHCO3 solution and 250 ml of ethyl acetate and separated. The organic phase was washed with 100 ml of aqueous saturated NaHCO3 solution, dried (Na2SO4) and the solvent was removed under reduced pressure. The crude product was chromatographed on 200 g of silica packed with 2.5% EtOAc-hexanes and the column was eluted with increasing amounts of ethyl acetate in hexanes (2.5%, 1 L, 5%, 1 L; 7.5%, 1 L, 10%, 1 L; 12.5%, 1 L; 15%, 1 L) to give 12.8 g of the desired product which was slightly contaminated: 42% yield; 1H NMR (CDCl3) δ 7.80 (dd, 1H, J=0.9, 3.9 Hz), 7.74 (dd, 1H, J=0.9, 5.0 Hz average), 7.19 (dd, 1H, J=0.9, 5.0 Hz average), 4.61 (s, 2H). This product turned yellow and then brown over time and therefore was used in the formation of the 2-amino-1,3-thiazole derivatives as soon as possible.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[N:3]=1.[H-].[Na+].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30]Cl)[CH:25]=1.O>CN(C)C=O>[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][O:1][C:2]2[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:30][C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)=[CH:19][CH:20]=3)[N:3]=2)[CH:25]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1O
Reactant: ClCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3cccnc3)cc2)nc1OCc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a solution of ethyl 3-[3-hydroxy-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (435 mg) in N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 120 mg) was added at 0° C., and then the solution was stirred at room temperature for 30 minutes. 3-Picolyl chloride (574 mg) was added to the reaction mixture, which was stirred at room temperature for one hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-(3-pyridylmethoxy)-1-[4-(3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (533 mg, yield: 75%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate.
Reaction SMILES: C([O:5][C:6]1[C:7](=[O:37])[C:8](=[O:36])[C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[NH:18][C:19]([CH3:27])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])[CH:12]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[OH:36][C:8]1[C:7](=[O:37])[C:6](=[O:5])[C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[NH:18][C:19]([CH3:27])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])[CH:12]=1
Reactant: COc1ccc(C(NC(C)(C)c2ccccc2)c2cccc(Nc3c(OC(C)(C)C)c(=O)c3=O)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C(NC(C)(C)c2ccccc2)c2cccc(Nc3c(O)c(=O)c3=O)c2)cc1
Yield: 99.8 %

Procedure:
Following a similar procedure to that described in Example (55b), 1.40 g of 3-t-butoxy-4-{3-[(4-methoxyphenyl )-(1-methyl-1-phenylethylamino)methyl]phenylamino}-3-cyclobutene-1,2-dione [prepared as described in step (c) above], 10 ml of trifluoroacetic acid and 35 ml of dichloromethane were reacted, to obtain 1.24 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])=[CH2:5].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>C1COCC1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])[CH2:5][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNC1
Reactant: C=C(C(=O)OC)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)C(CN1CCCC1)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
To a solution of 2-(2,4-dichlorophenyl)acrylic acid methyl ester (0.70 mmol) in 2 mL THF was added pyrrolidine (0.77 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 50 min, diluted with DCM and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuo to give the desired compound as pinkish oil;
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([C:12]1[N:13]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)[N:14]=[C:15]2[C:20]=1[C:19](=[O:21])[N:18]([CH3:22])[C:17](=[N:23][C:24]([CH3:28])([CH3:27])[CH2:25]O)[NH:16]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[CH2:5]([C:12]1[N:13]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:32][CH:31]=2)[N:14]=[C:15]2[N:16]3[CH2:25][C:24]([CH3:28])([CH3:27])[N:23]=[C:17]3[N:18]([CH3:22])[C:19](=[O:21])[C:20]=12)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cn1c(=NC(C)(C)CO)[nH]c2nn(Cc3ccc(-c4ccccc4)cc3)c(Cc3ccccc3)c2c1=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CN1C(=O)c2c(nn(Cc3ccc(-c4ccccc4)cc3)c2Cc2ccccc2)N2CC(C)(C)N=C12
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
A 2.0 M solution of thionyl chloride (25 μL, 0.050 mmol) in CH2Cl2 is added into a solution of 3-benzyl-2-(biphenyl-4-ylmethyl)-6-(1-hydroxy-2-methylpropan-2-ylimino)-5-methyl-6,7-dihydro-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (5.0 mg, 0.010 mmol) in methylene chloride (1 mL). The reaction mixture is stirred at r.t. overnight, and then quenched with 5% NaHCO3. The resulting mixture is purified by chromatography to give 3.2 mg of the final product (Yield: 67%). MS (FAB) m/z 476.4 [M+H]+.