Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.C(#N)C.[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([S:35]([C:38]1[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=1)(=[O:37])=[O:36])[C:30]([Sn](C)(C)C)=[CH:29]2>C(Cl)(Cl)Cl>[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([S:35]([C:38]1[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=1)(=[O:37])=[O:36])[C:30]([F:21])=[CH:29]2
Reactant: Cc1ccc(S(=O)(=O)n2c([Sn](C)(C)C)cc3cc(Cl)ccc32)cc1
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)n2c(F)cc3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.7 %

Procedure:
N-fluoro-N′-(chloromethyl)triethylenediamine bis(tetrafluoroborate) (2.33 g) was added to an acetonitrile solution (88 ml) containing 5-chloro-1-tosyl-2-(trimethylstannyl)-1H-indole (2.05 g) obtained in the 2nd step in a nitrogen atmosphere, followed by stirring at room temperature for 16 hours. Chloroform was added to the reaction solution, an insoluble precipitate was removed, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=0:1 to 1:100), and a light yellow solid of 5-chloro-2-fluoro-1-tosyl-1H-indole (520 mg) was thus obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[C:26]([CH2:29][NH:30][C:31](=[O:44])[CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1)(=[O:28])[NH2:27]>ClCCl.C(N(CC)CC)C>[C:26]([CH2:29][NH:30][C:31](=[O:44])[CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([N:21]2[C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=[C:17]2[S:15]([CH2:14][C:3]2[C:2]([CH3:1])=[C:7]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[CH:6]=[CH:5][N:4]=2)=[O:16])(=[O:41])=[O:42])=[CH:36][CH:35]=1)(=[O:28])[NH2:27]
Reactant: NC(=O)CNC(=O)COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2n1S(=O)(=O)c1ccc(OCC(=O)NCC(N)=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (185 mg) was dissolved in 20 ml of dichloromethane and 0.5 ml of triethylamine, and N-(carbamoylmethyl)-2-[4-(chlorosulfonyl)phenoxy]acetamide (158 mg) was added. The reaction mixture was stirred at room temperature for 24 hr. Dichloromethane (100 ml) was added to the reaction mixture. The reaction mixture was washed with saturated NaCl solution, and 0.1N sodium bicarbonate solution. Dichloromethane layer was separated and dried over anhydrous magnesium sulfate. Dichloromethane was evaporated under reduced pressure to give syrupy material, which was lyophilized in vacuo. 237 mg of the titled product was obtained.
Reaction SMILES: C(O[C:6](=[O:26])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][C:17](=[O:19])[NH2:18])[C:12]2[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:11]=2[O:10][C@@H:9]1[CH3:25])(C)(C)C.N[C@@H]1C(=O)N(CC(N)=O)C2C=C(F)C=CC=2O[C@@H]1C.[CH3:46][C:47](C)([C:51]([NH:53][CH2:54][C:55]([F:61])([F:60])[C:56]([F:59])([F:58])[F:57])=[O:52])[C:48](O)=O>>[C:17]([CH2:16][N:13]1[C:12]2[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:11]=2[O:10][C@H:9]([CH3:25])[C@H:8]([NH:7][C:6](=[O:26])[C:47]([CH3:48])([CH3:46])[C:51]([NH:53][CH2:54][C:55]([F:60])([F:61])[C:56]([F:59])([F:57])[F:58])=[O:52])[C:14]1=[O:15])(=[O:19])[NH2:18]
Reactant: C[C@H]1Oc2ccc(F)cc2N(CC(N)=O)C(=O)[C@H]1NC(=O)OC(C)(C)C
Reactant: CC(C)(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Agent: C[C@H]1Oc2ccc(F)cc2N(CC(N)=O)C(=O)[C@H]1N
Product: C[C@H]1Oc2ccc(F)cc2N(CC(N)=O)C(=O)[C@H]1NC(=O)C(C)(C)C(=O)NCC(F)(F)C(F)(F)F

Procedure:
((6R,7S)-9-Carbamoylmethyl-2-fluoro-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid tert-butyl ester was deprotected according to the procedure in example 42b. The resulting 2-((6R,7S)-7-amino-2-fluoro-6-methyl-8-oxo-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-acetamide was reacted with 2,2-dimethyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid in analogy to the procedure described in example 2b to yield N-((6R,7S)-9-carbamoylmethyl-2-fluoro-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-2,2-dimethyl-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide, MS m/e (%): 511.3 (M−H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10][N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:7][C:6]=2[CH:17]=1.[N+](C1C=CC(NC2CC[CH:31]([O:34]CC(O)=O)[CH2:30]C2)=CC=1C(F)(F)F)([O-])=O.CCN=C=NCCCN(C)C.[ClH:54].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>O.ClCCl>[Cl:54][CH2:30][C:31]([N:14]1[CH2:13][CH2:12][N:11]([CH2:10][CH:8]2[CH2:7][C:6]3[CH:17]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:9]2)[CH2:16][CH2:15]1)=[O:34]
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reactant: Cl
Reactant: Fc1ccc2c(c1)CC(CN1CCNCC1)O2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCN(CC2Cc3cc(F)ccc3O2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 114.2 %

Procedure:
Into a 50 ml round-bottomed flask containing 20 ml of dichloromethane was added 1-(5-fluoro-2,3-dihydro-benzofuran-2-ylmethyl)-piperazine (100 mg, 0.42 mmol), 2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]acetic acid (230 mg, 0.63 mmol, 1.5 eq), EDAC.HCl (122 mg, 0.64 mmol, 1.5 eq), HOBt (86 mg, 0.64 mmol, 1.5 eq) and triethylamine (128 mg, 1.26 mmol, 3.0 eq). The solution was stirred at room temperature for 16 hours. The crude contents were diluted with water and then extracted with 3×50 ml of ethyl acetate. The organic fractions were combined, dried over magnesium sulfate, filtered, and then concentrated under vacuum. The crude material was then chromatographed on silica gel using methanol/dichloromethane to elute. The product-containing fractions were then combined and concentrated to provide 150 mg of the amide as a light yellow solid (57%). (ES, m/z): [M+H]+ 581.3; 1H NMR (300 MHz, CDCl3): δ 8.02 (d, J=9 Hz, 1H), 6.75-6.91 (m, 3H), 6.60-6.71 (m, 2H), 5.00 (broad s, 1H), 4.48 (d, J=7.5 Hz, 1H), 3.66 (s, 2H), 3.48-3.80 (broad m, 4H), 3.22-3.50 (broad m, 3H), 2.95 (m, 1H), 2.75-2.90 (m, 1H), 2.50-2.75 (broad m, 4H), 2.16 (d, J=8.7 Hz, 4H), 1.38-1.58 (dd, J=10.5, 22.5 Hz, 2H), 1.22-1.34 (dd, J=−10.9, 22.5 Hz, 2H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([I:15])=[C:11]([F:16])[CH:10]=2)[CH2:4]1.[F:17][CH:18]([F:22])[C:19](O)=[O:20].C(N(CC)C(C)C)(C)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:17][CH:18]([F:22])[C:19]([NH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([I:15])=[C:11]([F:16])[CH:10]=2)[CH2:4]1)=[O:20]
Reactant: O=C(O)C(F)F
Reactant: NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1)C(F)F
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
A suspension of (5S)-5-Aminomethyl-3-(3-fluoro-4-iodo-phenyl)-oxazolidin-2-one (1022, 5.0 g, 14.88 mmol) in methylene chloride (CH2Cl2, 50 mL) was treated with difluoroacetic acid (2.14 g, 1.41 mL, 22.32 mmol, 1.5 equiv) and N,N-diisopropylethylamine (DIEA or Hunig's base, 3.85 g, 5.18 mL, 29.76 mmol, 2.0 equiv), and the resulting reaction mixture was cooled down to 0-5° C. before being treated with EDCl (4.30 g, 22.32 mmol, 1.5 equiv) at 0-5° C. The reaction mixture was subsequently stirred at 0-5° C. for 1 h before being gradually warmed up to room temperature for 12 h. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was quenched with H2O (50 mL) and CH2Cl2 (50 mL). The two layers were then separated, and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed H2O (50 mL) and the saturated aqueous NaCl solution (50 mL), dried over MgSO4, and concentrated in vacuo to afford the crude (5 S) 2,2-difluoro-N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide (1026, 5.64 g, 6.16 g theoretical, 91.6%) as off-white powders, which by HPLC/MS and 1H NMR was found to be essentially pure and was directly used in the subsequent reactions without further purification. For 1026: 1H NMR (300 MHz, DMSO-d6) δ 3.54 (t, 2H, J=5.5 Hz), 3.77 (dd, 1H, J=6.3, 9.2 Hz), 4.15 (t, 1H, J=9.2 Hz), 4.77-4.86 (m, 1H), 6.25 (t, 1H, J=53.52 Hz, —CHCF2), 7.18 (dd, 1H, J=2.4, 8.7 Hz), 7.55 (dd, 1H, J=2.4, 8.7 Hz), 7.84 (t, 1H, J=8.5 Hz), 9.19 (t, 1H, J=5.5 Hz, —CONH); C12H10F3IN2O3, LCMS (EI) m/e 415 (M++H), 456 (M++H+CH3CN).
Reaction SMILES: [CH3:1][C:2]([N:12]1[CH:16]=[C:15]([NH:17][C:18](=[O:24])[CH:19]([NH2:23])[CH2:20][CH2:21][CH3:22])[N:14]=[CH:13]1)([CH3:11])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[F:25][C:26]1[CH:27]=[C:28]2[C:33](=[C:34]([F:36])[CH:35]=1)[CH2:32][C:31](=O)[CH2:30][CH2:29]2>>[CH3:1][C:2]([N:12]1[CH:16]=[C:15]([NH:17][C:18](=[O:24])[CH:19]([NH:23][CH:31]2[CH2:30][CH2:29][C:28]3[C:33](=[C:34]([F:36])[CH:35]=[C:26]([F:25])[CH:27]=3)[CH2:32]2)[CH2:20][CH2:21][CH3:22])[N:14]=[CH:13]1)([CH3:11])[CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CCN2CCOCC2)cn1
Reactant: O=C1CCc2cc(F)cc(F)c2C1
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CCN2CCOCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-3-morpholin-4-yl-propyl)-1H-imidazol-4-yl]-amide was reacted with 6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to provide the title compound: 13C NMR 14.2, 19.5, 19.6, 28.2, 28.3, 28.5, 28.6, 28.6, 28.7, 28.8, 29.7, 29.8, 30.8, 36.5, 36.6, 39.8, 52.3, 52.7, 54.0, 57.2, 57.3, 60.3, 60.8, 67.1, 100.8, 101.1, 101.3, 104.6, 104.7, 110.5, 110.6, 110.8, 110.9, 130.5, 137.6, 137.7, 139.9, 159.7, 162.3, 172.3, 172.5; MS m/z 504.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][N:4]([NH:7][C:8](=[O:19])[C@@H:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH3:10])[C:3]=1[C:20]([O:22]C)=O.[CH3:24][O:25][C:26]1[CH:38]=[CH:37][C:29]([CH2:30][N:31]2[CH:35]=[C:34]([NH2:36])[CH:33]=[N:32]2)=[CH:28][CH:27]=1>>[Br:1][C:2]1[CH:6]=[CH:5][N:4]([NH:7][C:8](=[O:19])[C@@H:9]([NH:11][C:12](=[O:13])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH3:10])[C:3]=1[C:20](=[O:22])[NH:36][C:34]1[CH:33]=[N:32][N:31]([CH2:30][C:29]2[CH:37]=[CH:38][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)[CH:35]=1
Reactant: COc1ccc(Cn2cc(N)cn2)cc1
Reactant: COC(=O)c1c(Br)ccn1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Product: COc1ccc(Cn2cc(NC(=O)c3c(Br)ccn3NC(=O)[C@H](C)NC(=O)OC(C)(C)C)cn2)cc1
Yield: 60 %

Procedure:
This compound was prepared starting from (S)-methyl 3-bromo-1-(2-(tert-butoxycarbonylamino)propanamido)-1H-pyrrole-2-carboxylate (300 mg, 0.77 mmol) and 1-(4-methoxybenzyl)-1H-pyrazol-4-amine (469 mg, 2.31 mmol) following the experimental procedure described in Preparation 27a to afford 271 mg (96% purity, 60% yield) of the title compound after purification by flash chromatography (0% to 70% AcOEt/hexanes).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6](=[O:9])[C:7]=1[OH:8].[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CO.[OH-].[Na+]>O>[CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6](=[O:9])[C:7]=1[O:8][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCc1ccccc1
Reactant: Cc1occc(=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1occc(=O)c1OCc1ccccc1
Yield: 93.7 %

Procedure:
20.0 g (159 mmol) of 2-methyl-3-hydroxy-4-pyranone and 22.1 g (175 mmol, 1.1 eq.) of benzyl chloride are introduced into 200 mL of methanol; then 6.98 g (175 mmol) of NaOH in 22 mL of water are added. The reaction medium is reflux agitated for 6½ hours. The solvent is subsequently evaporated and the residue retaken up with 100 mL of dichloromethane. This solution is then washed with a 5% aqueous solution of soda (2×80 mL) and with water (2×80 mL). The organic phases are collected, dried on sodium sulphate, filtered and evaporated under reduced pressure; 32.3 g (149 mmol) of 2-methyl-3-benzyloxy-4-pyranone are isolated. Yield: 94%.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17](=[S:19])[NH2:18])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[CH2:20](N(CC)CC)[CH3:21].ClCC=O.O>C(O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:17]4[S:19][CH:20]=[CH:21][N:18]=4)=[CH:15][CH:16]=3)[N:10]=2)[CH:7]=1
Reactant: NC(=S)c1ccc(-c2cn3cc(I)ccc3n2)cc1
Reactant: CCN(CC)CC
Agent: O=CCCl
Solvent: O
Solvent: CCO
Product: Ic1ccc2nc(-c3ccc(-c4nccs4)cc3)cn2c1

Procedure:
4-(6-Iodoimidazo[1,2-a]pyridin-2-yl)-1-benzenecarbothioamide (249 mg) was dissolved in ethanol (10 mL). Triethylamine (91 μL) and chloroacetaldehyde (155 μL) were added to the solution, and the mixture was refluxed for 18 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane-methanol. The solvent was evaporated, and the residue was purified through silica gel column chromatography (dichloromethane:methanol=100:5), followed by concentration under reduced pressure, to thereby yield the title compound (103 mg).
Reaction SMILES: CCCCN(C(NC(C1C=C(OC)C(OC)=C(OC)C=1)=[O:14])=S)CCCC.[CH2:27]([O:30][N:31]([CH:44]1[CH2:49][N:48]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@H:47]([CH2:57][O:58][Si:59]([C:62]([CH3:65])([CH3:64])[CH3:63])([CH3:61])[CH3:60])[CH:46]=[C:45]1[CH2:66][C:67]#[N:68])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N+:41]([O-:43])=[O:42])(=[O:34])=[O:33])[CH:28]=[CH2:29].C(=NO)C.CO>O>[CH2:27]([O:30][N:31]([CH:44]1[CH2:49][N:48]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@H:47]([CH2:57][O:58][Si:59]([C:62]([CH3:65])([CH3:64])[CH3:63])([CH3:60])[CH3:61])[CH:46]=[C:45]1[CH2:66][C:67]([NH2:68])=[O:14])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N+:41]([O-:43])=[O:42])(=[O:34])=[O:33])[CH:28]=[CH2:29]
Reactant: C=CCON(C1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1CC#N)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CCCCN(CCCC)C(=S)NC(=O)c1cc(OC)c(OC)c(OC)c1
Solvent: CO
Solvent: CC=NO
Solvent: O
Product: C=CCON(C1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1CC(N)=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 15 h

Procedure:
4 Å molecular sieves (MS-4 Å) were impregnated with the corresponding metal salt (CuCl2-2H2O) as follows: 1 mmol of the salts was dissolved in 100 ml of deionized H2O and stirred with 1 g of MS-4 Å at room temperature for 6 h. The solid was filtered, washed with deionized H2O and acetone, and dried in an oven at 150° C. for 1 h. (2S)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(cyanomethyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 172, 3.60 g, 5.78 mmol), Cu(II)Cl2-4 Å catalyst (200 mg), acetaldoxime (1.762 mL, 28.90 mmol, 5.0 eq) and MeOH (40.0 mL) were stirred at 60° C. for 15 h. The solid was filtered, washed with MeOH and the filtrate was evaporated to afford crude product.
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5](Cl)[C:4]=1[C:19]([O:21][CH3:22])=[O:20].[CH:24]1([SH:29])[CH2:28][CH2:27][CH2:26][CH2:25]1>C1COCC1>[CH:24]1([S:29][C:5]2[C:4]([C:19]([O:21][CH3:22])=[O:20])=[C:3]([CH:2]([F:23])[F:1])[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: SC1CCCC1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1SC1CCCC1
Yield: 107.1 %

Procedure:
This compound was prepared as described in Example 108: 3 g (0.0083 mol) of product of Example 103, 1.02 g (0.01 mol) of cyclopentylmercaptan and 0.36 g (0.009 mol) of 60NaH in 50 ml of dry THF were reacted affording 3.8 g of a red oil. Crude was purified by HPLC using 1ethyl acetate/cyclohexane as eluting solvent to give 2.5 g of a light yellow oil which gas chromatography showed to be 94% pure. This material was passed through a spinning plate preparative chromatograph in two different portions of 1.25 g each (eluting solvent: 40CH2Cl2 /cyclohexane) to give, after kugelrohr distillation at 105-125° C./106 Pa, 1.95 g (55%) of product as a clear oil; nD25 1.4831.
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:4]([CH3:18])=[N:3]1.C(N(CC)CC)C.[Cl:26][C:27]([Cl:33])=[C:28]([Cl:32])[C:29](Cl)=[O:30].O>C1C=CC=CC=1>[CH3:1][N:2]1[C:6]([O:7][C:29](=[O:30])[C:28]([Cl:32])=[C:27]([Cl:33])[Cl:26])=[C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:4]([CH3:18])=[N:3]1
Reactant: O=C(Cl)C(Cl)=C(Cl)Cl
Reactant: Cc1nn(C)c(O)c1C(=O)c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccccc1
Product: Cc1nn(C)c(OC(=O)C(Cl)=C(Cl)Cl)c1C(=O)c1ccc(Cl)cc1Cl
Yield: 74.6 %

Procedure:
2.85 g of 1,3-dimethyl-4-(2,4-dichlorobenzoyl)-5-hydroxy pyrazole and 1.01 g of triethylamine were dissolved in 20 ml of benzene. 1.94 g of trichloroacrylic acid chloride were dropped into the solution. The reaction mixture was stirred for 3 hours at the reflux temperature of benzene. After the completion of the reaction, water was added to the reaction mixture, the organic layer was separated and dried. Benzene was distilled off under reduced pressure to give 3.3 g of 1,3-dimethyl-4-(2,4-dichlorobenzoyl)-5-trichloroacryloyloxy pyrazole as colorless crystals of melting point 141° to 142° C.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH3:7][O:8][C:9]1[CH:35]=[CH:34][C:12]([CH2:13][N:14]2[C:23]3[C:18](=[CH:19][C:20]([B:24]4[O:28]C(C)(C)C(C)(C)[O:25]4)=[CH:21][CH:22]=3)[CH:17]=[CH:16][C:15]2=[O:33])=[CH:11][CH:10]=1.Cl>C1COCC1.O>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[C:23]3[C:18](=[CH:19][C:20]([B:24]([OH:28])[OH:25])=[CH:21][CH:22]=3)[CH:17]=[CH:16][C:15]2=[O:33])=[CH:34][CH:35]=1
Reactant: COc1ccc(Cn2c(=O)ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)ccc3cc(B(O)O)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
Sodium periodate (5.9 g, 28 mmol) was added to a solution of 1-(4-methoxybenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2(1H)-one (3.6 g, 9.2 mmol) in THF/H2O (4/1, 40 mL). The reaction mixture was stirred at RT for 30 min, after which 2N HCl (9.2 mL) was added and the solution was then stirred at RT for 3 h. The solution was extracted with EtOAc (3×50 mL) and the organic layer was dried (MgSO4), and concentrated to yield crude 1-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinolin-6-ylboronic acid (2.6 g, 90% yield) which was used without further purification. 1H NMR (400 MHz, DMSO-d6): δ 8.10 (brs, 1H), 7.96 (d, J=9.2 Hz, 1H), 7.88 (dd, J=1.6, and 8.8 Hz, 1H), 7.39 (d, J=9.2 Hz, 1H), 7.16 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 6.69 (d, J=9.6 Hz, 1H), 5.45 (brs, 2H), 3.69 (s, 3H); LC-MS (EI) m/z: 310.0 (M+H+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[C:34](Cl)(=[O:43])[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1>>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:27][CH2:28][N:29]([C:34]([C:35]5[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=5)=[O:43])[CH2:30][CH2:31]4)[N:24]=[CH:25][C:18]=23)=[CH:32][CH:33]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)N2CCC(n3ncc4c(Oc5ccc(S(C)(=O)=O)cc5)ncnc43)CC2)cc1

Procedure:
{4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-(4-methoxy-phenyl)-methanone was prepared according to General Procedure I by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 25) with p-anisoyl chloride (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 2.04-2.13 (m, 4H), 3.30 (methyl sulfonyl and water peak), 3.80 (m, 3H), 5.10-5.15 (m, 1H), 7.00-7.02 (m, 2H), 7.41-7.43 (m, 2H), 7.62-7.65 (m, 2H), 8.05-8.07 (m, 2H), 8.41 (s, 1H), 8.57 (s, 1H). Mass spectrum MH+=508.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])[CH:5]=[CH:6][CH:7]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>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.COCCOC>[C:2]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CCCC#Cc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: O=C1c2ccccc2C(=O)N1CCCC#Cc1cccc(-c2ccccc2)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2-(5-(3-Bromophenyl)pent-4-ynyl)isoindoline-1,3-dione (0.31 g, 0.84 mmol), phenyl boronic acid (206 mg, 1.68 mmol), and Pd (PPh3)4 (0.23, 0.2 mmol) were taken into DME (5 mL) and stirred at 80° C. for two hours. The reaction was then quenched with saturated NaHCO3 and the resulting mixture extracted with EtOAc, washed with brine, then dried over sodium sulfate and the solvent removed in vacuo. The resulting residue was purified on normal phase chromatography (Heptane/EtOAc) to yield 2-(5-(biphenyl-3-yl)pent-4-ynyl)isoindoline-1,3-dione. MH+ 366.3
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][CH2:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:11])=[O:7].C1CCNCC1.[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Cl)=[CH:34][CH:33]=1.C1(N=C=O)C=CC=CC=1>CC#N>[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][N:17]2[CH2:18][CH2:19][CH:14]([CH2:13][NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:20]=[CH:21][CH:22]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:4]=3)[CH2:15][CH2:16]2)=[CH:34][CH:33]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCNCC1
Solvent: O=C=Nc1ccccc1
Solvent: CC#N
Solvent: C1CCNCC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of 4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (30 mg, 0.087 mmol) in CH3CN (1.0 mL) and (piperidinomethyl)polystyrene (80 mg, 2.7 mmol base/g resin) were added to a solution of 4-chlorobenzyl chloride (11.7 mg, 0.073 mmol) in CH3CN (1.0 mL). The reaction mixture was stirred at 60° C. for 2 h. Phenyl isocyanate (10.4 mg, 0.087 mmol) was added to the cooled reaction mixture and the mixture was stirred at 25° C. for 1 h. The reaction mixture was loaded onto Varian™ SCX column and washed with CH3OH (20 mL). Product was eluted off using 2 N NH3 in CH3OH (6 mL) and concentrated to afford 1-(4-chlorobenzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine as a colorless oil used without purification. Iodomethane (28 mg, 0.20 mmol) was added to a solution of 1-(4-chlorobenzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine in CH3CN (2.0 mL) and the reaction mixture was stirred at 70° C. for 4 h. The solvent was removed under reduced pressure to afford 1-(4-chlorobenzyl)-1-methyl-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidinium iodide as a pale yellow oil (31.7 mg, 71%): The purity was determined by RPLC/MS (99%;); ESI/MS m/e 482.1 (M+, C24H28ClF3N3O2).