Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([CH2:31][NH:32][S:33]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:26][C:27]([O:29]C)=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1.CC#N.[Li+].[OH-].C(O)(C(F)(F)F)=O>O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([CH2:31][NH:32][S:33]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)CC(CNS(=O)(=O)c1ccc(C)cc1)NC(=O)CNC(=O)c1cccc(NC=NN)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)NCC(CC(=O)O)NC(=O)CNC(=O)c2cccc(NC=NN)c2)cc1
Reaction time: 2 h
Yield: 56.8 %

Procedure:
A solution of the product of Example 64 (180 mg) in 1:1 CH3CN:H2O (4 ml) was treated with LiOH (100 mg). After 2 hours, the reaction was acidified with TFA and purified by HPLC (RP--CH3CN/H2O). The title compound (100 mg) was isolated as a white solid. MS, 1H-NMR and CHN analysis were consistent with the desired product.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:21])=[O:20])[CH:14]=1>[Pd].CCOC(C)=O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)(=[O:21])=[O:20])[CH:14]=1
Reactant: O=S(=O)(c1cccc(C#CCCOCCCCCCBr)c1)C1CCCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=S(=O)(c1cccc(CCCCOCCCCCCBr)c1)C1CCCC1
Reaction time: 19 h

Procedure:
To an evacuated flask, containing palladium on carbon [50% water by weight] (43 mg) was added a solution of 1{4-[(6-bromohexyl)oxy]-1-butyn-1-yl}-3-(cyclopentylsulfonyl) benzene (304 mg) in EtOAc (10 ml). The mixture was hydrogenated for 19 h. The catalyst was filtered off and the filtrate was concentrated in vacuo to afford title compound. LCMS RT=3.92 min
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([F:35])[CH:34]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16]([C:18]1[C:23]([NH:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:22][C:21](F)=[CH:20][N:19]=1)=[O:17].[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>CCOC(C)=O>[F:35][C:33]1[CH:32]=[C:4]([CH:3]=[C:2]([F:1])[CH:34]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16]([C:18]1[C:23]([NH:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:22][C:21]([N:40]2[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]2)=[CH:20][N:19]=1)=[O:17]
Reactant: CN1CCNCC1
Reactant: O=C(Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12)c1ncc(F)cc1NC1CCOCC1
Solvent: CCOC(C)=O
Product: CN1CCN(c2cnc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)CC1

Procedure:
A solution of N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-5-fluoro-3-(tetrahydro-2H-pyran-4-ylamino)pyridine-2-carboxamide (925 mg, 1.92 mmol) and N-methylpiperazine (20 mL) was stirred at 60° C. for 48 hours. The reaction mixture was then diluted with EtOAc and washed with NaHCO3 sat. sol. The organic layer was dried over sodium sulfate, filtered and evaporated. The crude was purified by flash chromatography on silica gel using DCM/EtOH/NH3 5N in MeOH 100:5:0.5 as the eluant, affording 600 mg of the title compound.
Reaction SMILES: C(OC(=O)C(C#N)=[C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:17]C)=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([CH3:20])([CH3:19])[CH2:7]1)C.[C-]#N.[Na+].CN(C)C=[O:30]>>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9]([C:8]([CH3:20])([CH3:19])[CH2:7][C:6]2=[O:30])=[CH:10][C:11]=1[OH:17]
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(C#N)=C1CC(C)(C)c2cc(OC)c(OC)cc21
Agent: [C-]#N
Agent: [Na+]
Product: COc1cc2c(cc1O)C(C)(C)CC2=O
Temperature: 100 °C
Reaction time: 40 h

Procedure:
In a three necked reaction flask equipped with a reflux condenser, a mixture of 5 g of 2,3-dihydro-5,6-dimethoxy-3,3-dimethyl-1H-inden-1-one (see example 1) and 5.5 g of sodium cyanide in 44.5 ml of dimethyl formamide was stirred at 100° C. for 40 hours. Then, the mixture was pored on an aqueous NaH2PO4 solution and extracted 4 times with ethyl acetate, dried over Na2CO3, and concentrated. The raw product was chromatographed in methylene chloride containing 1% of methanol to yield 2.5 g of white crystals. m.p. 105-107° C. MS: 206(M+), 191(100%), 163, 131, 103.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([CH2:23][O:24][C:25]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:44]1([S:50](Cl)(=[O:52])=[O:51])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>N1C=CC=CC=1.ClCCl.C(Cl)(Cl)Cl>[CH2:1]([O:19][CH2:20][CH:21]([CH2:23][O:24][C:25]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[O:22][S:50]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)(=[O:52])=[O:51])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.9 %

Procedure:
To a stirred solution of (rac)-1-O-octadecyl-3-O-trityl-glycerol (30.52 g) in a mixture of pyridine (41.08 g) and dichloromethane (250 ml) was dropwise added a solution of benzenesulfonyl chloride (18.36 g) in chloroform (50 ml) during a period of 10 minutes below 10° C. After stirring for 2 days at ambient temperature, the reaction mixture was refluxed for 8 hours. To the reaction mixture, were dropwise added pyridine (12.75 g) and benzenesulfonylchloride (5.7 g) successively. After stirring for 2 hours at room temperature, the reaction mixture was allowed to stand for 2 days. The reaction mixture was washed with water, 0.5N aqueous sulfuric acid, water, aqueous sodium bicarbonate and water, successively. The solution was dried over magnesium sulfate and evaporated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (450 g, elution by benzene) to give 37.4 g of (rac)-1-O-octadecyl-2-O-benzenesulfonyl-3-O-trityl-glycerol as an oil.
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[NH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([Br:19])[C:13]=1[NH2:20]>>[Br:19][C:14]1[CH:15]=[C:16]([F:18])[CH:17]=[C:12]2[C:13]=1[NH:20][C:2](=[O:4])[C:1](=[O:8])[NH:11]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1cc(F)cc(Br)c1N
Product: O=c1[nH]c2cc(F)cc(Br)c2[nH]c1=O
Temperature: 25 °C

Procedure:
The title compound was prepared using an adaptation of the method of Cheeseman (Cheeseman, G. W. H., J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (3.31 mL, 24.4 mmol) and 1,2-diamino-3-bromo-5-fluorobenzene (500 mg, 2.44 mmol) was heated to reflux under N2 for 5 h. The reaction mixture was dark brown. The reaction was allowed to cool to room temperature and the solid collected by vacuum filtration and rinsed with EtOH (30 mL). The brown solid was air dried for 1 hr to give 250 mg (39.6% crude yield). A portion of this solid was removed and dissolved in 1N NaOH (10 mL) and a few insoluble particles were removed by gravity filtration. The solution was treated with decolorizing carbon and the mixture was filtered through a pad of celite and the resulting solution acidified with 1N HCl. White crystals formed that were isolated by vacuum filtration and washed with water (20 mL). The crystals were dried in a drying pistol (0.05 torr, 78° C.) to yield 54.1 mg, mp 308°-310° C. (dec). 1H NMR (d6 -DMSO) δ 6.2 (dd, 1H, JH6-8 =2.7, JH-F =9.3, ArH), 7.35 (dd, 1H, JH6-8 =2.4, JHF =8.4 Hz), 11.1 (br s, 1H, NH), 12.1 (brs, 1H, NH). EIHRMS calc. for C8H4BrFN2O2 : 257.9440, found 257.9455.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:13][CH:14]=[CH2:15].[C:16](OC(=O)C)(=[O:18])[CH3:17]>N1C=CC=CC=1>[C:16]([O:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:13][CH:14]=[CH2:15])(=[O:18])[CH3:17]
Reactant: C=CCc1cc(C(=O)OC)cc(C)c1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C=CCc1cc(C(=O)OC)cc(C)c1OC(C)=O
Temperature: 25 °C

Procedure:
A solution of methyl 4-hydroxy-3-allyl-5-methylbenzoate (157 mg) in pyridine (5 mL) was cooled in an ice-bath under a nitrogen atmosphere and treated with acetic anhydride (1 mL). The reaction was stirred in the ice-bath for one hour and was then warmed to room temperature for 4 hours. The solvent was then removed under reduced pressure and the residue was suspended in anhydrous toluene (5-10 mL) and evaporated to dryness. The crude product was dissolved in ethyl acetate (30 mL) and washed with saturated aqueous ammonium chloride. It was then dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to give a brown oil. Yield=0.176 g (quantitative).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]1([CH:19]([CH2:23][CH3:24])[C:20]([OH:22])=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]2[N:33]=[CH:32][N:31]([CH2:34][C:35]3[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][C:36]=3[O:45][CH3:46])[C:30]=2[CH:47]=1>ClCCl>[CH3:46][O:45][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][C:35]=1[CH2:34][N:31]1[C:30]2[CH:47]=[C:26]([NH:25][C:20](=[O:22])[CH:19]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:23][CH3:24])[CH:27]=[CH:28][C:29]=2[N:33]=[CH:32]1)[C:39]([O:41][CH3:42])=[O:40]
Reactant: COC(=O)c1ccc(Cn2cnc3ccc(N)cc32)c(OC)c1
Reactant: CCC(C(=O)O)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCC(C(=O)Nc1ccc2ncn(Cc3ccc(C(=O)OC)cc3OC)c2c1)c1ccccc1
Yield: 24.9 %

Procedure:
A solution of 1,1'-carbonyldiimidazole (0.23 g.) and 2-phenylbutyric acid (0.22 g.) in dichloromethane (3 ml.) was heated under reflux for 30 minutes and then treated with a solution of (J) (0.41 g.) in dichloromethane (3 ml.). The mixture was heated under reflux for an additional 10 minutes and then diluted with dichloromethane. This mixture was washed successively with 10% v/v hydrochloric acid, water, and brine, then dried (MgSO4) and evaporated. The resultant residue was purified by flash chromatography on a 5×25 cm. silica gel column using 3:97 v/v methanol:dichloromethane as the eluent to give the title compound (0.15 g., 25%): partial NMR: 2.0(br m,2H, CH3CH2), 3.4(t,1H, CH2CH), 7.3(s,5H, Ar).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8](Br)[S:7][CH:6]=1)=[O:4].[CH3:11][N:12]1[C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>COCCOC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:16]2[N:12]([CH3:11])[N:13]=[CH:14][CH:15]=2)[S:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1csc(Br)c1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1csc(-c2ccnn2C)c1
Temperature: 140 °C
Yield: 84.3 %

Procedure:
5-Bromo-thiophene-3-carboxylic acid methyl ester (0.193 g, 0.87 mmol) was combined with 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.2 g, 0.96 mmol), caesium carbonate (0.424 g, 1.3 mmol), and palladium tetrakis(triphenylphosphine) (0.1 g, 0.09 mmol) in DME (10 mL), IMS 2 mL) and water (1 mL). The reaction mixture was degassed then heated by microwave irradiation to 140° C. for 20 minutes. The mixture was diluted with water then extracted with DCM (×3) then the organic solution was dried over sodium sulfate, filtered and the solvent evaporated. The residue was purified by chromatography on a 5 g silica II cartridge, eluting with 5-30% ethyl acetate in cyclohexane to give 5-(2-methyl-2H-pyrazol-3-yl)-thiophene-3-carboxylic acid methyl ester as a brown oil (0.163 g). LCMS m/z 223.24 [M+H]+ R.T.=3.24 min (Analytical Method 6).
Reaction SMILES: [CH2:1]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]#[N:10])[CH2:4][CH2:3][CH2:2]1>[Ni].CCO>[N:5]1([CH2:8][CH2:9][NH2:10])[CH2:6][CH2:7][CH2:1][CH2:2][CH2:3][CH2:4]1
Reactant: N#CCN1CCCCCC1
Agent: [Ni]
Solvent: CCO
Product: NCCN1CCCCCC1
Reaction time: 16 h
Yield: 35.3 %

Procedure:
A mixture of nitrile 290 (5.58 g, 40.4 mmol) and Raney Nickel (50% w/w in water, ca. 5 mL) in EtOH (50 mL) and cNH3 (4 mL) was stirred under H2 (60 psi) for 16 h. The mixture was filtered through Celite, washed with EtOH (3×10 mL) and the solvent evaporated to give crude diamine 291 as an oil (2.03 g, 35%) which was used without further purification: 1H NMR δ 2.72 (t, J=6.1 Hz, 2H, CH2N), 2.60-2.68 (m, 4H, 2×CH2N), 2.53 (t, J=6.1 Hz, 2H, CH2N), 1.55-1.66 (m, 10H, 4×CH2, NH2).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH2:32]>>[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH:32][C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1
Reactant: CN1CCN(c2nccn3c(-c4ccnc(S(C)(=O)=O)n4)cnc23)CC1
Reactant: NCc1cccc(Cl)c1
Product: CN1CCN(c2nccn3c(-c4ccnc(NCc5cccc(Cl)c5)n4)cnc23)CC1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
The mixture of 3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine (from Example 46 supra) (150 mg, 0.402 mmol) and 3-chlorobenzylamine (228 mg, 1.608 mmol) was heated at 140° C. with stirring for 2 hours. The resulting oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 30:1 to 10:1) to afford the crude product (120 mg). Then the crude product was purified by prep-HPLC. Several drops concentrated HCl were added to the fractions with product. After sonicating for several minutes, solution was concentrated under reduced pressure to afford (3-chloro-benzyl)-{4-[8-(4-methyl-piperazin-1-yl)-imidazo [1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-amine; hydrochloride. (Yield 45 mg, 25.8%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13])[C:5]([NH:14][C:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]2)=O)=[CH:4][CH:3]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:9][CH2:10][CH2:11][O:12][CH3:13])[C:15]([CH:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[N:14][C:5]2=[CH:4][CH:3]=1
Reactant: COCCCNc1nc(Cl)ccc1NC(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COCCCn1c(C2CCCNC2)nc2ccc(Cl)nc21
Yield: 10 %

Procedure:
Compound 35B (crude material, 2.84 mmol max) prepared in Step 13 was added to a 50 trLL round-bottomed flask equipped for stirring under nitrogen. Glacial acetic acid (10 mL) was then added and the resultant solution was stirred at reflux under nitrogen for 16 hr. The reaction solution was concentrated in-vacuo to give a brownish oil. Toluene (30 mL) was added and the subsequent solution was concentrated in vacuo; this was repeated three times to remove any trace quantities of acetic acid affording the title compound as a brown oil. This oil was then purified by preparative LC/MS (5-50% CH3CN in H2O) to afford 5-chloro-3-(3-methoxypropyl)-2-(piperidin-3-yl)-3H-imidazo[4,5-b]pyridine (35C) as a tan oil. (088 mmol, 0.122 g, 10% yield over 3-steps). Subsequent analysis of a later derivative of this compound revealed that the chiral center had been epimerized during this reaction sequence. ESI-MS: m/z 309.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][C:6]=1[C:12]1[C:20]2[C:15](=[C:16]([O:21][CH3:22])[N:17]=[CH:18][CH:19]=2)[N:14]([CH3:23])[CH:13]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C.[OH-].[Na+]>ClCCl.O1CCOCC1>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:7][C:6]=1[C:12]1[C:20]2[C:15](=[C:16]([O:21][CH3:22])[N:17]=[CH:18][CH:19]=2)[N:14]([CH3:23])[CH:13]=1
Reactant: COc1nccc2c(-c3cc(N)ccc3Oc3ccc(F)cc3F)cn(C)c12
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1nccc2c(-c3cc(NS(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c12
Temperature: 80 °C

Procedure:
A mixture of Example 2D (0.05 g, 0.131 mmol), methanesulfonyl chloride (0.031 mL, 0.393 mmol), and triethylamine (0.080 g, 0.787 mmol) in dichloromethane (3 mL) was stirred at room temperature for 2 hours. The solvent was removed, and the residue was treated with sodium hydroxide (0.656 mL, 1.31 mmol) and dioxane (3 mL). The reaction mixture was heated at 80° C. for 3 hours. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][S:18]([C:21]4[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1>[Pd].C(O)C>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][S:18]([C:21]4[CH:22]=[CH:23][C:24]([NH2:27])=[CH:25][CH:26]=4)(=[O:20])=[O:19])[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)c4ccc([N+](=O)[O-])cc4)cc23)CC1
Agent: [Pd]
Solvent: CCO
Product: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)c4ccc(N)cc4)cc23)CC1
Reaction time: 1 h
Yield: 78.4 %

Procedure:
A mixture of 4-nitrobenzenesulfonic acid 3-(1-methylpiperidin-4-yl)-1H-indol-5-yl ester (800 mg, 1.92 mmol) and 5% palladium on carbon (230 mg) in ethanol (100 mL) was hydrogenated at atmospheric pressure at ambient temperature for 1 h. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 10, 11, 12, 15% 2M ammonia in methanol/methylene chloride) to give 580 mg (78%) of homogeneous product as a yellow oil that crystallized upon standing: mp=217-219° C. dec; MS(m/e): 386 (M+1), 384 (M−1); Calculated for C20H23N3O3S: C, 62.32; H, 6.01; N, 10.90. Found: C, 62.30; H, 5.91; N, 10.69.
Reaction SMILES: [CH:1]1(/[CH:7]=[C:8](/[CH2:12][P:13]([OH:19])([CH2:15][CH:16]([CH3:18])[CH3:17])=[O:14])\[C:9]([OH:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>Cl.C(OCCCC)(=O)C>[CH:1]1(/[CH:7]=[C:8](\[CH2:12][P:13]([OH:19])([CH2:15][CH:16]([CH3:17])[CH3:18])=[O:14])/[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)CP(=O)(O)C/C(=C/C1CCCCC1)C(=O)O
Agent: Cl
Solvent: CCCCOC(C)=O
Product: CC(C)CP(=O)(O)C/C(=C\C1CCCCC1)C(=O)O
Yield: 54 %

Procedure:
A solution of 13 mg (0.045 millimole) of (E)-3-cyclohexyl-2-(hydroxyisobutylphosphinoyl)methylpropenoic acid in 0.13 ml of 4.3 N hydrogen chloride-butyl acetate was heated at 100° C. in a sealed tube for 24 hours. After cooling, the solvent was evaporated under reduced pressure. The residue was dissolved in 0.2 ml of ethanol, and 0.1 ml of 6 N sodium hydroxide was added. The mixture was heated under reflux for 1.5 hours. After cooling, 5 ml of water was added and hydrochloric acid was also added to acidify the mixture. The mixture was then extracted three times with 5 ml of ethyl acetate each time. The combined ethyl acetate layers were washed with 5 ml of a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to give 7 mg (yield 54%) of (Z)-3-cyclohexyl-2-(hydroxyisobutylphosphinoyl)methylpropenoic acid as colorless crystals. Its melting point and IR and 1H-NMR data were identical with those of the product obtained in Example 5 (b).
Reaction SMILES: [CH3:1][C:2]1[N:41]=[C:5]2[N:6]([C@H:29]3[CH2:34][CH2:33][C@H:32]([O:35][CH2:36][C:37]4([CH3:40])[CH2:39][O:38]4)[CH2:31][CH2:30]3)[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[FH:59].F.[F-]>ClC1C=CC=CC=1>[F:59][CH2:39][C:37]([OH:38])([CH3:40])[CH2:36][O:35][C@H:32]1[CH2:33][CH2:34][C@H:29]([N:6]2[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:18][CH:19]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]3[N:3]=[C:2]([CH3:1])[N:41]=[C:5]23)[CH2:30][CH2:31]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(C)CO3)CC2)c2nc(C)nn12
Reactant: F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: Clc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(O)CF)CC2)c2nc(C)nn12
Temperature: 120 °C
Reaction time: 20 h

Procedure:
A mixture of 4′-[(2-methyl-4-{trans-4-[(2-methyloxiran-2-yl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.19 g), tetra-n-butylammonium dihydrogentrifluoride (0.65 g) and chlorobenzene (0.5 mL) was stirred at 120° C. for 20 hr. The reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.094 g, 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5][N:6]1[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1.[F:17][C:18]([F:33])([F:32])[O:19][C:20]1[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([NH:28][NH2:29])=[O:27])=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:29][NH:28][C:26](=[O:27])[CH2:25][O:24][C:23]2[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:33])[F:32])=[CH:31][CH:30]=2)[CH2:8][CH2:7]1
Reactant: O=C1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: NNC(=O)COc1ccc(OC(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(COc1ccc(OC(F)(F)F)cc1)NNC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1

Procedure:
The title compound was prepared from 3,4-dichlorobenzyl-4-piperidone (J. Med. Chem, 1999, 42, 3629; 100 mg), 2-[4(trifluoromethoxy)phenoxy]acetohydrazide (100 mg), sodium triacetoxyborohydride (100 mg), and 0.02 ml acetic acid, stirred together for 2 hours in dichloromethane by the method of Example 369 step ii. MS [M+H]+ (ES+) 492 1H NMR: (CDCl3) δ 1.4-1.6 (3H, m) 1.7 (2H, m), 2.0 (2H, m) 2.7-2.9 (2H, m), 3.4 (2H, m), 4.4 (3H, m), 5.3 (1H, s) 6.9 (2H, m), 7.2-7.5 (4H, m), 7.8 (1H, d).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:21]=CC(C=O)=[CH:16][C:15]=2[F:22])=[CH:9][C:8]=1[C:23]([F:26])([F:25])[F:24]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH:3]([C:2]1[CH:1]=[CH:21][C:14]([O:13][C:10]2[CH:11]=[CH:12][C:7]([Cl:6])=[C:8]([C:23]([F:25])([F:26])[F:24])[CH:9]=2)=[C:15]([F:22])[CH:16]=1)=[CH2:4]
Reactant: [Li]CCCC
Reactant: O=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (6.73 g, 18.83 mmol) in anhydrous THF (20 mL) was added dropwise n-butyllithium (11.77 mL, 18.83 mmol) under −78° C. over 30 min. It was stirred for 1 h, then was added by 4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-3-fluorobenzaldehyde (5.0 g, 15.69 mmol). It was warmed slowly to room temperature and stirred for overnight at room temperature. Purification via a flash column chromatography then afforded the title compound (4.0 g, 80% yield). LCMS: rt=5.7 min, [M+H+]=316