Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][NH2:2].[F:3][C:4]([F:15])([F:14])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1>C(O)C>[F:3][C:4]([F:15])([F:14])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[N:1][NH2:2])=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: NN
Solvent: CCO
Product: NN=Cc1ccc(OC(F)(F)F)cc1
Reaction time: 0.75 h
Yield: 91 %

Procedure:
Hydrazine (3.3 mL, 105 mmol) was dissolved in ethanol (10 mL) at room temperature. To this solution was added 4-trifluoromethoxybenzaldehyde (5.0 mL, 35 mmol) dropwise over 25 min. The reaction mixture was stirred an additional 45 min and concentrated under vacuum. The residue was dissolved in ethyl ether (20 mL) and washed with water (10 mL). The water layers were extracted with ethyl ether (3×15 mL), and the combined organic layer was dried over magnesium sulfate, filtered and concentrated to give [4-(trifluoromethoxy)benzylidene]hydrazine (XX) as a yellow oil (6.5 g, 91% yield). 1H NMR (DMSO-d6): δ 7.69 (s, 1H); δ 7.56 (d, J=8.7 Hz, 2H) δ 7.30 (d, J=7.8 Hz, 2H); δ 6.94 (bs, 2H); GC-MS m/z 204 (M+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C@H:15]([C:31]#[N:32])[CH:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[CH:5][CH:4]=1.[O:33]1[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][C@@H:41]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([S:57]([NH2:60])(=[O:59])=[O:58])=[CH:53][C:52]=2[S:61]([C:64]([F:67])([F:66])[F:65])(=[O:63])=[O:62])[CH2:42][S:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:35][CH2:34]1>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C@H:15]([C:31]#[N:32])[CH:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:23]=[CH:24][C:25]([C:26]([NH:60][S:57]([C:54]4[CH:55]=[CH:56][C:51]([NH:50][C@H:41]([CH2:40][CH2:39][N:36]5[CH2:37][CH2:38][O:33][CH2:34][CH2:35]5)[CH2:42][S:43][C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)=[C:52]([S:61]([C:64]([F:67])([F:65])[F:66])(=[O:63])=[O:62])[CH:53]=4)(=[O:58])=[O:59])=[O:27])=[CH:29][CH:30]=3)[CH2:18][CH2:17]2)=[CH:7][CH:8]=1
Reactant: N#C[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: NS(=O)(=O)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Agent: Cl
Product: N#C[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(N[C@H](CCN4CCOCC4)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)cc2)CC1
Yield: 20.5 %

Procedure:
The title product (19.8 mg, yield: 20%) was prepared using a procedure similar to the one described for the synthesis of EXAMPLE 14. (R)-4-(4-((4′-Chlorobiphenyl-2-yl)(cyano)methyl)piperidin-1-yl)benzoic acid, hydrochloride salt (INTERMEDIATE 84, 44.9 mg, 0.1 mmol) and (R)-4-(4-morpholino-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 69, 54.4 mg, 0.1 mmol) were used as starting materials. The resulting product was purified by column chromatography (ISCO, 4 g silica gel column, eluting with 0→5% MeOH/DCM) followed by further purification by column chromatography (ISCO, 4 g silica gel column, eluting first with 0→100% EtOAc/hexanes and then with 0→5% MeOH/DCM), providing the title product.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([CH2:12][OH:13])[O:7][C:6]=2[CH:5]=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:28][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:13][CH2:12][C@@H:8]2[O:7][C:6]3[CH:5]=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=[C:2]([F:1])[C:11]=3[O:10][CH2:9]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)O[C@@H](CO)CO2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1

Procedure:
Preparation according to Preparation 10 using [[(2S)-5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methanol (0.97 g, 3.7 mmol), DCM (20 ml), p-toluenesulfonyl chloride (1.06 g, 5.6 mmol), TEA (0.78 ml, 5.6 mmol) and 4-DMAP (0.46 g, 3.7 mmol). Yield: 1.47 g. MS m/z (rel. intensity, 70 eV) 416 (M+, 40), 244 (bp), 243 (26), 231 (19), 91 (50).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:11][C:10]=1[C:19]([CH3:23])([CH3:22])[C:20]#[N:21])C1C=CC=CC=1>CO>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([C:19]([CH3:23])([CH3:22])[C:20]#[N:21])[CH:11]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1ccc(OCc2ccccc2)c(C(C)(C)C#N)c1
Solvent: CO
Product: CC(C)(C)c1ccc(O)c(C(C)(C)C#N)c1

Procedure:
Pd (OH)2/C (2.0 g) and compound 7 (20.0 g, 0.104 mol) were stirred in MeOH (150 mL) at room temperature under hydrogen at 10 psi pressure for 16-18 hours. The mixture was then filtered through a pad of Celite®, and the filtrate was concentrated to give compound 15, which was used in the next reaction without further purification. 1H NMR (DMSO-d6; 400 MHz) δ 9.83 (s), δ 7.24 (s), δ 7.18 (m), δ 6.80 (m), δ 1.71 (s), δ 1.24 (s).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][OH:11])[C:4]1=[O:12].C(N(CC)CC)C.O=C1CCC(=O)N1[C:27]1[C:35]2[C:30](=[CH:31][C:32]([C:45]([O-])=[O:46])=[C:33]([O:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=3[F:44])[CH:34]=2)[N:29]([CH2:48][CH:49]([CH3:51])[CH3:50])[N:28]=1>CN(C)C=O.C(OCC)(=O)C>[F:44][C:38]1[CH:39]=[C:40]([F:43])[CH:41]=[CH:42][C:37]=1[O:36][C:33]1[CH:34]=[C:35]2[C:30](=[CH:31][C:32]=1[C:45]([NH:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][OH:11])[C:4]1=[O:12])=[O:46])[N:29]([CH2:48][CH:49]([CH3:51])[CH3:50])[N:28]=[CH:27]2
Reactant: N[C@H]1CCCN(CCO)C1=O
Reactant: CC(C)Cn1nc(N2C(=O)CCC2=O)c2cc(Oc3ccc(F)cc3F)c(C(=O)[O-])cc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H]3CCCN(CCO)C3=O)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.8 %

Procedure:
(S)-3-Amino-1-(2-hydroxyethyl)piperidin-2-one hydrochloride (52 mg, 0.27 mmol) was dissolved in triethylamine (0.075 mL, 0.54 mmol) and N,N-dimethylformamide (1 mL). To this was added 2,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylate (prepared according to Example 16, Step A; 119 mg, 0.268 mmol), and the reaction mixture was allowed to stir at ambient temperature for 48 hours. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography on a silica gel column, eluting with 50% acetone/hexanes to yield pure (S)-5-(2,4-difluorophenoxy)-N-(1-(2-hydroxyethyl)-2-oxopiperidin-3-yl)-1-isobutyl-1H-indazole-6-carboxamide (1 h) (104 mg, 80%). Mass spec: 487 (M+1). 1H NMR (CDCl3) δ 8.57 (brd, 1H), 8.32 (s, 1H), 7.87 (s, 1H), 7.14 (m, 1H), 7.03 (s, 1H), 7.00 (m, 1H), 6.89 (m, 1H), 4.47 (ddd, 1H), 4.22 (d, 2H), 3.82 (m, 2H), 3.68 (m, 1H), 3.47 (m, 3H), 2.90 (m, 1H), 2.62 (m, 1H), 2.36 (m, 1H), 2.00 (m, 2H), 1.74 (m, 1H), 0.93 (d, 6H).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:8][CH:7]([C:9]([O:11]CC2C=CC=CC=2)=[O:10])[CH2:6]1)=[N+]=[N-]>[Pd].CO>[NH2:1][CH2:4][CH:5]1[CH2:8][CH:7]([C:9]([OH:11])=[O:10])[CH2:6]1
Reactant: [N-]=[N+]=NCC1CC(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: NCC1CC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.6 %

Procedure:
To a flask charged with 10% palladium on carbon (0.20 g, 0.19 mmol) was added a solution of benzyl 3-(azidomethyl)cyclobutanecarboxylate (2.00 g, 8.15 mmol, prepared using IIII from benzyl 3-(hydroxymethyl)cyclobutanecarboxylate (Parkway Scientific), JJJJ with sodium azide) in MeOH (100 mL). The reaction mixture was sparged with hydrogen and an atmosphere of hydrogen was maintained via a balloon. The reaction mixture was stirred for about 4 h at ambient temperature and then was filtered through a pad of Celite®, washed with MeOH and concentrated in vacuo to give the crude 3-(aminomethyl)cyclobutanecarboxylic acid (1.08 g, 100%) which was used without further purification: LC/MS (Table 1, Method r) Rt=2.41 min (ELSD); MS m/z: 130 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@H:33]6[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[N:56]([CH2:59][CH3:60])=[C:57]=[O:58]>O1CCCC1>[CH2:59]([NH:56][C:57](=[O:58])[O:39][C@H:36]1[CH2:37][CH2:38][C@H:33]([C:30]2[CH:31]=[CH:32][C:27]([C:23]3[N:22]=[C:21]4[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:18]([O:17][C@@H:16]5[CH2:15][O:14][C@@H:13]6[C@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH2:10][O:11][C@H:12]56)=[N:19][C:20]4=[CH:25][C:24]=3[Cl:26])=[CH:28][CH:29]=2)[CH2:34][CH2:35]1)[CH3:60]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](O)CC4)cc3)nc2n1COCC[Si](C)(C)C
Reactant: CCN=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)O[C@H]1CC[C@H](c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O[Si](C)(C)C(C)(C)C)n4COCC[Si](C)(C)C)cc2)CC1
Reaction time: 12 h

Procedure:
(trans)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-Butyldimethylsilyloxy)hexahydrofuro[3,2-b]-furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]py-ridin-5-yl)phenyl)cyclohexanol (50 mg) and triethylamine (20 μL) are dissolved in tetrahydrofurane (2 mL), treated with isocyanatoethane (8 μL) and stirred for 12 hours. Triethylamine (20 μL) and isocyanatoethane (8 μL) are added and the mixture is stirred for 48 hours. The mixture is partitioned between ethylacetate and saturated aqueous NH4Cl solution. The organic phase is dried (MgSO4) and concentrated. The residue is purified by HPLC on reversed phase to give the title compound. LC (method 5): tR=1.26 min; Mass spectrum (ESI+): m/z=787 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:9].[O-]S([O-])(=O)=O.[Mg+2].CO[C:28](OC)([CH3:30])[CH3:29].CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[Br:7][C:5]1[S:4][C:3]2[C:8](=[O:9])[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:28]([CH3:30])([CH3:29])[NH:1][C:2]=2[CH:6]=1
Reactant: COC(C)(C)OC
Reactant: COc1ccc(CNC(=O)c2sc(Br)cc2N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)N(C)C
Product: COc1ccc(CN2C(=O)c3sc(Br)cc3NC2(C)C)cc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
A mixture of 3-amino-5-bromo-N-(4-methoxybenzyl)thiophene-2-carboxamide (160 mg, 0.47 mmol), MgSO4 (60 mg), 2,2-dimethoxypropane (0.5 mL), PTSA (8.6 mg, 0.050 mmol) and DMA (0.5 mL) was stirred at 120° C. for 1 h by using microwave reactor. Then, the mixture was poured into saturated aqueous NaHCO3. The organic materials were extracted with AcOEt. The combined extracts were washed with water and brine, and then dried over Na2SO4. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (silica gel, 90:10 hexane/EtOAc to 40:60 hexane/EtOAc) to give the title compound (112 mg, 62%) as a pale brown solid:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O-:3])=[O:2].IC.[C:26]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:26][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:8]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1[nH]c2ccc([N+](=O)[O-])cc2c1-c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1C
Reaction time: 16 h

Procedure:
A solution of ethyl 5-nitro-3-phenyl-1H-indole-2-carboxylate (1.0 g, 3.23 mmol) and iodomethane (2.5 mL, 40.2 mmol) in DMF (25 mL) was treated with Cs2CO3 (3.26 g, 10 mmol) and stirred for 16 h. The reaction was quenched by addition of water and the solid was collected and dried to yield ethyl 1-methyl-5-nitro-3-phenyl-1H-indole-2-carboxylate (I13064-48) as a yellowish solid (1.1 g, 100%): 1H NMR (DMSO-d6) δ 1.03 (t, J=7.0 Hz, 3 H), 4.09 (s, 3 H), 4.18 (q, J=7.0 Hz, 2 H), 7.40-7.55 (m, 5 H), 7.90 (d, J=9.2 Hz, 1 H), 8.23 (dd, J=9.2, 2.3 Hz, 1H), 8.32 (d, J=2.3 Hz, 1 H); MS (EI) m/z 325.2 (MH+).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]=O)=[CH:12][CH:11]=1>>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:20][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(CN)OCC
Reactant: O=Cc1ccnc2ccccc12
Product: CCOC(CNCc1ccnc2ccccc12)OCC
Reaction time: 8 h
Yield: 109.3 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-2 with the modification that the reaction was carried out overnight, 2,2-diethoxyethanamine (3.64 ml, 25 mmol) was reacted with 4-quinolinecarboxaldehyde (3.14 g, 20 mmol) to obtain the title compound (6.0 g, 88%).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([C:24]3[CH:29]=[C:28]([CH3:30])[C:27]([O:31][Si](C(C)(C)C)(C)C)=[C:26]([CH3:39])[CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:9][C:8]=1[CH3:40])(C)(C)C.B(O)(O)[C:44]1[CH:45]=[CH:46][C:47]([CH3:50])=[CH:48][CH:49]=1.C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.O.ClCCl>[OH:31][C:27]1[C:28]([CH3:30])=[CH:29][C:24]([C:14]2([C:10]3[CH:11]=[C:12]([CH3:13])[C:7]([OH:6])=[C:8]([CH3:40])[CH:9]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:44]3[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=3)[C:15]2=[O:23])=[CH:25][C:26]=1[CH3:39]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Cc1cc(C2(c3cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c3)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(N2C(=O)C(c3cc(C)c(O)c(C)c3)(c3cc(C)c(O)c(C)c3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
Combine 3,3-Bis-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1,3-dihydro-indol-2-one (0.886 g, 1.47 mmol), p-tolylboronic acid (0.40 g, 2.94 mmol), copper (II) acetate (0.267 g, 1.47 mmol), triethylamine (0.41 mL, 2.94 mmol), 4 angstrom molecular sieves, and dichloromethane (20 mL). Stir at room temperature overnight under ambient atmosphere. Filter the reaction through Celite. Elute through a column of silica gel with 70% dichloromethane in hexanes and concentrate. Dissolve the resulting compound (0.340 g, 0.492 mmol), in THF (2 mL). Add a solution of tetrabutylammonium fluoride (1.0 M) in THF (1.23 mL). Stir for 1 h. Add 1N aqueous HCl(10 mL), water (40 mL), and ethyl acetate (50 mL). Separate the layers and concentrate the organic layer in vacuo. Chromatograph on silica gel eluting with ethyl acetate to give 0.215 g (32%) of the title compound: mass spectrum (FAB): m/z=464(M+1); 1H NMR(DMSO-d6): δ8.23 (s, 2H), 7.37-7.28 (m, 5H), 7.21 (td, 1H), 7.08 (td, 1H), 6.74-6.73 (m, 5H), 2.37 (s, 3H) 2.07 (s, 12H).
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.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([O:23][CH3:22])[CH:25]=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: COc1cccc(C(=O)Cl)c1
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccccc2)cc1
Product: COc1ccc(-c2nc(NC(=O)c3cccc(OC)c3)sc2Cc2ccccc2)cc1
Yield: 56.8 %

Procedure:
A procedure similar to that in Example 4 was used. 5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 1 and m-methoxybenzoyl chloride prepared in the step 1 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to obtain a crude product, which was purified by a silica gel column chromatography eluted with a gradient of dichloromethane and ethyl acetate (100:0-10:1) to obtain a product as a white solid in a yield of 56.8%, mp: 71-72 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.80 (3H, s, OCH3), 3.81 (3H, s, OCH3), 4.23 (2H, s, CH2), 6.85 (2H, d, J=8.80 Hz, ArH), 7.05 (1H, d, J=2.30 Hz, ArH), 7.20˜7.42 (10H, m, ArH); EI-MS m/e (%): 430.1 (M+, 100), 135.0 (85); HREI-MS Calcd. for C25H22N2O3S: 430.1351. found: 430.1352.
Reaction SMILES: [C:1]1([C:7]2[S:11][CH:10]=[C:9]([CH:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[OH:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]1([C:7]2[S:11][CH:10]=[C:9]([C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(C(O)c2csc(-c3ccccc3)c2)cc(OC)c1OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1cc(C(=O)c2csc(-c3ccccc3)c2)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
To a solution of 40f (0.260 g, 0.73 mmoL) in 20 mL anhydrous CH2Cl2 was added Dess-Martin reagent (0.465 g, 1.36 mmol). The mixture was allowed to stir for 30 min and quenched with sat. Na2S2O3 solution, extracted with ethyl acetate and dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to give pure compound 1f as light yellow crystals (60.9%). 1H NMR (CDCl3) δ 7.97 (d, 1H, J=1.5 Hz), 7.82 (d, 1H, J=1.5 Hz), 7.59-7.57 (m, 2H), 7.45-7.34 (m, 3H), 7.19 (s, 2H), 3.95 (s, 3H), 3.93 (s, 6H); MS (ESI) m/z 355.1 (M+H)+.
Reaction SMILES: [N:1]#[C:2]Br.[C:4]1([C:10]2([CH2:19][CH2:20][N:21](C)[CH3:22])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][CH2:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)(Cl)Cl>[C:4]1([C:10]2([CH2:19][CH2:20][N:21]([C:2]#[N:1])[CH3:22])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)CCC1(c2ccccc2)COc2ccccc21
Reactant: N#CBr
Solvent: ClC(Cl)Cl
Product: CN(C#N)CCC1(c2ccccc2)COc2ccccc21
Yield: 83.5 %

Procedure:
A solution of 10.9 g (103 mmole) cyanogen bromide and 23 g (86 mmole) of 2-(3-phenyl-2,3-dihydrobenzofuran-3-yl)-N,N-dimethylethylamine in 500 ml CHCl3 was refluxed for 4 hours. The solvent was evaporated and the resultant oil warmed to reflux in 500 ml water. After cooling, the mixture was extracted with CH2Cl2 (2×1 liter), and the organics were washed with 1N HOAc (3×1 liter) and dried over K2CO3. Evaporation gave 20 g of an oil, which was chromatographed on 200 g silica gel using CH2Cl2 as an eluent to give 11 g of an oil which solidified on standing. Recrystallization from acetone/hexane gave 7.1 g (30%) of crystals, m.p. 88°-92°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[CH:29][C:30]([CH:33]2[CH2:35][CH2:34]2)=[N:31][CH:32]=1>>[CH:33]1([C:30]2[CH:29]=[CH:28][C:27]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]4[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]5[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=5)=[N:8][C:7]=34)=[CH:32][N:31]=2)[CH2:35][CH2:34]1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Brc1ccc(C2CC2)nc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(C#Cc4ccc(C5CC5)nc4)c3n2)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 5-bromo-2-cyclopropyl-pyridine (Example B.11) (257 mg, 1.3 mmol) according to general procedure II. Obtained as an orange solid (110 mg, 23%). MS (ISP) 473.0 [(M+H)+]; mp 138-140° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[NH2:5].[CH:12]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl.C1COCC1.N1C=CC=CC=1.C(Cl)Cl>[CH:12]1([C:18]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:2]([F:1])[CH:3]=2)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1ccc([N+](=O)[O-])c(F)c1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1ccc([N+](=O)[O-])c(F)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
3-Fluoro-4-Nitroaniline (1 mmol, 0.15 g) was dissolved in a 3:1 mixture of CH2Cl2/THF (4 mL) and pyridine (0.2 mL) was added to the mixture, which was cooled in an ice-water bath under nitrogen. Cyclohexanecarbonylchloride (1.1 mmol, 0.162 g) was dissolved in CH2Cl2 (1 mL) and added dropwise to the above solution at 4° C. and stirred at room temperature for 3 h. The reaction mixture was diluted with CH2Cl2 (50 mL) and washed with 1N HCl, 10% NaHCO3, brine and water, dried over Na2SO4 and the solvent evaporated to afford cyclohexyl-N-(3-fluoro-4-nitrophenyl)carboxamide (0.215 g) of product (Yield: 81%).
Reaction SMILES: [Br-].[CH2:2]([S+:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[F:16][C:17]([F:44])([S:40]([OH:43])(=[O:42])=[O:41])[C:18]([F:39])([F:38])[C:19]([F:37])([F:36])[C:20]([F:35])([F:34])[C:21]([F:33])([F:32])[C:22]([F:31])([F:30])[C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25]>>[F:44][C:17]([F:16])([S:40]([O-:43])(=[O:42])=[O:41])[C:18]([F:38])([F:39])[C:19]([F:37])([F:36])[C:20]([F:34])([F:35])[C:21]([F:33])([F:32])[C:22]([F:31])([F:30])[C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25].[CH2:2]([S+:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=S(=O)(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C(C[S+]1CCCC1)c1ccccc1
Agent: [Br-]
Product: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
Compound (III-3) was synthesized by salt exchange of phenacyltetrahydrothiophenium bromide with perfluorooctanesulfonic acid in the same manner as above.