Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1CN2C(=O)C[C@H]2S1.[I:10][CH:11]1[CH2:16][N:15]2[C:17](=[O:19])[CH2:18][C@H:14]2[S:13][CH2:12]1>>[I:10][CH2:11][CH:12]1[CH2:16][N:15]2[C:17](=[O:19])[CH2:18][C@H:14]2[S:13]1
Reactant: O=C1C[C@H]2SCC(I)CN12
Agent: CC1CN2C(=O)C[C@H]2S1
Product: O=C1C[C@H]2SC(CI)CN12

Procedure:
A mixture of benzhydryl 3-phenoxymethyl-4-thia-2,6-diazabicyclo[3.2.0]hept-2-ene-7-one-6-isopropenyl acetate, 2, (150 mg., 0.3 mmole) and iodine (127 mg., 0.5 mmols) in methylene chloride (9 ml) was stirred at ambient temperature for 15 mins. Water (9 ml) was then added to the stirred solution and air bubbled through the solution. After a reaction time of 45 mins the reaction mixture was washed with aqueous sodium thiosulfate, then water, and the organic layer dried over magnesium sulfate. Filtration and concentration gave the product as a pale yellow foam. Analysis of the foam by nmr spectroscopy showed a mixture of the 2-methylpenam, 1 (R=φOCH2, R1 =CHφ2, R2 =H, 69.4%), the starting material 2 (16.7%), and the 3-iodocepham, 6 (13.8%). The 2-iodomethylpenam could be isolated by thick layer chromatography. On standing (in solution or as a foam) at room temperature the 2-iodomethylpenam 1 is slowly converted to the thermodynamically more stable 3-iodocepham, 6. If the iodination reaction is allowed to run for longer periods of time, increasing amounts of 6 are obtained and after 10 hrs to a week, the major product is 6.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:10]=[CH:11][CH:12]=1.[CH3:26]OCOC.C(Cl)Cl>C1(C)C=CC=CC=1.CCOCC>[Br:6][C:7]1[CH:8]=[C:9]2[C:10](=[CH:11][CH:12]=1)[CH2:26][N:15]([S:16]([C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1)(=[O:18])=[O:17])[CH2:14][CH2:13]2
Reactant: Cc1ccc(S(=O)(=O)NCCc2cccc(Br)c2)cc1
Reactant: COCOC
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N2CCc3cc(Br)ccc3C2)cc1
Reaction time: 15 h
Yield: 90 %

Procedure:
To a stirred solution of sulfuric acid (60% w/w, 20 g) in 32 mL of toluene at r.t. was added 7.60 g of N-[2-(3-bromo-phenyl)-ethyl]-4-methyl-benzenesulfonamide, followed by 32 mL of dimethoxymethane. The reaction mixture was heated over an oil bath set at 50° C. externally with stirring under nitrogen for 15 h. LC/MS: retention time=4.549 min, MS 366/368. TLC (DCM): SM Rf=0.35, product Rf=0.65. The reaction was complete as judged by TLC. The reaction mixture was cooled to r. t. and diluted with ether (100 mL). The two layers were separated and the aqueous layer was extracted with ether (25 mL). The combined ethereal solution was washed with water (25 mL), saturated sodium bicarbonate (25 mL) and brine (20 mL), sequentially. Then, the ethereal solution was dried over anhydrous granular potassium carbonate, filtered, and concentrated in vacuo. The crude product, a solid after standing, was re-crystallized from ether (75 mL) and pentane (100 mL). The material was collected by suction filtration and dried under vacuum to obtain 6.6 g (90%) of the title compound as a white crystalline solid:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([CH:14]([O:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25](I)=[C:24]([CH3:30])[CH:23]=2)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:13]=1)=[O:8].[CH:32]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)([CH3:34])[CH3:33].[F-].[K+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([CH:14]([O:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25]([C:38]3[CH:39]=[CH:40][C:35]([CH:32]([CH3:34])[CH3:33])=[CH:36][CH:37]=3)=[C:24]([CH3:30])[CH:23]=2)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:13]=1)=[O:8]
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCC(F)(F)F)Oc2cc(C)c(I)c(C)c2)s1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)CCNC(=O)c1ccc(C(CCC(F)(F)F)Oc2cc(C)c(-c3ccc(C(C)C)cc3)c(C)c2)s1
Temperature: 25 °C

Procedure:
3-({5-[4,4,4-Trifluoro-1-(4-iodo-3,5-dimethyl-phenoxy)-butyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (300 mg, 0.53 mmol) was dissolved in toluene (1.5 mL), followed by palladium tetrakis triphenylphosphine (30 mg, 0.03 mmol), 4-isopropyl-phenyl boronic acid (173 mg, 1.05 mmol), and potassium fluoride (61.2 mg, 1.05 mmol). The reaction was purged with nitrogen and heated to reflux, then water (1.5 mL) was added. The reaction was monitored by HPLC, and upon completion, allowed to cool to room temperature. The reaction was diluted with EtOAc and then Celite® added, followed by water. This mixture was then filtered through a pad of Celite®. The solution was separated in a separatory funnel and the organic layer was washed with 0.1N sodium hydroxide, water, and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The product was purified by flash column chromatography (225 mg). MS(ES): 562.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[OH-].[K+].[CH3:16]I>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]([CH3:16])[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11]
Reactant: CI
Reactant: COCCCNC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Product: COCCCN(C)C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 72 h
Yield: 37 %

Procedure:
A suspension of carbamate 270 (5.0 g, 26.4 mmol), crushed KOH (3.8 g, 67.7 mmol) in MeI (15 mL) was stirred at 20° C. for 72 h under N2. The solution was filtered through Celite, washed with DCM (2×50 mL) and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (30-50%) of EtOAc/pet. ether, to give carbamate 271 (2.0 g, 37%) as a colourless oil: 1H NMR δ 3.38 (t, J=6.3 Hz, 2H, CH2N), 3.33 (s, 3H, OCH3), 3.28 (t, J=7.0 Hz, 2H, CH2O), 2.85 (s, 3H, NCH3), 1.78 (tt, J=7.0, 6.3 Hz, 2H, CH2), 1.46 [s, 9H, C(CH3)3]; MS (APCI) m/z 104 (MH+-tBuCO2, 100%); HRMS (FAB+) calcd for C10H22NO3 (MH+) m/z 204.1600, found 204.1605.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Br:13]Br.ClCCl>C(Cl)(Cl)Cl>[Br:13][C:6]1[CH:5]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Oc1ccc(OC(F)(F)F)cc1Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cooled (0° ) solution of 4-trifluoromethoxyphenol (35.6 g, 0.2 mol) in chloroform (280 ml) was added dropwise a solution of bromine (32 g, 0.2 mol) in chloroform (50 ml). The solution was stirred at 0° C. for 1 h. and at room temperature for 2 h. Dichloromethane (200 ml) and waster (400 ml) ware added and the organic phase was washed further with water (400 ml), brine (200 ml) and dried (MgSO4). The solvent was removed and the residue was purified by distillation at reduced pressure to give the title compound. 1H NMR (250 MHz, CDCl3) δ7.38 (1H, d, J 2.1 Hz), 7.13 (1H, dd, J 9.1, 2.1 Hz), 7.03 (1H, d, J 9.1 Hz), and 5.53 (1H, s).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[C:24](#[N:32])[C:25]1[C:26](=[CH:28][CH:29]=[CH:30][CH:31]=1)[NH2:27].[OH-].[Na+]>O1CCCC1.C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[N:27][C:26]1[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=1[C:24]#[N:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCN1Cc1ccccc1
Reactant: N#Cc1ccccc1N
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: N#Cc1ccccc1N=C1CCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.1 %

Procedure:
The compound 2-(1-Benzyl-pyrrolidin-2-ylideneamino)benzonitrile (Compound 24) was synthesized by mixing chloroform (25 mL), tetrahydrofuran (25 mL), 1-benzyl-2-pyrrolidinone (5.16 g, 29.4 mmol), phosphorus oxychloride (5.2 mL) and tin(IV) chloride (1.0 mL), stirring at room temperature for 1.5 hours, and adding anthranilonitrile (3.3 g, 27.9 mmol) in portions. The mixture was then stirred at 50° C. for 5 hours under heating and ice-water (15 mL) and 10% aqueous sodium hydroxide solution was added to make weak alkaline. The organic solvent was removed under reduced pressure and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and condensed under vacuum. The crude product was purified by flash chromatography (chloroform-methanol, 100:1) to yield 7.0 g (91%) Compound 24 as slightly yellow needles; mp 59-61° C.; IR (KBr): 2217, 1628, 1439, 1279 cm−1; 1H NMR (DMSO-d6): δ 7.06-7.69 (m, 9H), 4.83 (s, 2H), 3.46 (t, 2H), 2.60 (t, 2H), 2.10 (m, 2H); 13C NMR (CDCl3): δ 162.8, 156.3, 137.6, 133.7, 132.9, 128.7, 128.3, 127.4, 122.8, 121.7, 118.8, 105.9, 48.3, 47.3, 27.7, 19.6. Anal. Calcd. for C18H17N3(275.35): C, 78.52; H, 6.22; N, 15.26. Found: C, 78.37; H, 6.20; N, 15.17.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH:12]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:11][C:10]([CH3:20])([CH3:19])[C:9]=2/[CH:21]=[CH:22]/[CH:23]=[O:24])=[CH:4][C:3]=1[CH3:25].[Li+].CC([N-]C(C)C)C.[C:34]([O:40][CH3:41])(=[O:39])[CH2:35][C:36]([CH3:38])=[O:37].C(B(CC)CC)C.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH:12]([N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:11][C:10]([CH3:19])([CH3:20])[C:9]=2/[CH:21]=[CH:22]/[CH:23]([OH:24])[CH2:38][CH:36]([OH:37])[CH2:35][C:34]([O:40][CH3:41])=[O:39])=[CH:4][C:3]=1[CH3:25]
Reactant: Cc1cc(C2=C(/C=C/C=O)C(C)(C)CC(N3CCCC3)C2)ccc1F
Reactant: COC(=O)CC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: CCB(CC)CC
Agent: [BH4-]
Solvent: CO
Product: COC(=O)CC(O)CC(O)/C=C/C1=C(c2ccc(F)c(C)c2)CC(N2CCCC2)CC1(C)C

Procedure:
In a manner similar to Scheme I, 33 (2.27 g, 6.65 mmol) was treated with the LDA derived anion of methyl acetoacetate (7.98 mmol) followed by triethylborane, methanol, and NaBH4 . Workup and purification by HPLC. using 1% Et3N in EtOAc as eluent provided the oily product.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[Cl:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>>[Cl:24][C:25]1[CH:26]=[C:27]([NH:28][C:1]([C:4]23[CH2:5][CH2:6][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:10][CH2:11]2)[CH2:8][CH2:9]3)=[O:3])[CH:29]=[CH:30][CH:31]=1
Reactant: Nc1cccc(Cl)c1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3cccc(Cl)c3)(CC1)CC2

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 3-chloroaniline (36.0 μL) were used to obtain (2S,4S)-1-[[N-[4-[N-(3-chlorophenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (23.3 mg).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[CH2:13]([O:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([NH:27][NH2:28])=[O:26])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(=O)C>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:27][N:28]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[O:26])=[CH:29][CH:30]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NNC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 100 °C
Yield: 90 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-(benzyloxy)benzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 247 mg of the title compound (90%) as a yellow powder in 98.9% purity by HPLC (Rt: 5.03, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[N:6]=[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:4]=1.C(=O)([O-])O.[Na+].[CH2:26]([O:33][C:34](Cl)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>C(OCC)(=O)C.O>[CH3:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:34]([O:33][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:35])=[CH:13][CH:14]=2)[N:6]=[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:4]=1
Reactant: CCOC(=O)c1cc(C)cc(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C)cc(-c2ccc(NC(=O)OCc3ccccc3)cc2)n1
Reaction time: 0.75 h
Yield: 75 %

Procedure:
To a mixture of ethyl 4-methyl-6-(4-aminophenyl)-2-pyridinecarboxylate hydrochloride (6 g), water (150 ml), sodium hydrogen carbonate (6 g) and ethyl acetate (150 ml) is added under ice-cooling with agitation benzyloxycarbonyl chloride (4.2 g), and the mixture is agitated for 45 minutes. The reaction mixture is made acidic with diluted hydrochloric acid, and the resulting crystals are collected by filtration, washed with water and dried. The organic layer is separated from the filtrate, washed with water and dried, and then the solvent is distilled off therefrom under reduced pressure. To the resulting residue is added ethyl acetate, and the precipitated crystals are collected by filtration and combined with the crystals obtained above to give ethyl 4-methyl-6-(4-benzyloxycarbonylaminophenyl)-2-pyridinecarboxylate (6 g). M.P. 184°-185° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.Br[CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[C:18]([CH:20]2[CH2:25][CH2:24][N:23]([CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)[CH2:22][CH2:21]2)=[O:19])=[CH:4][CH:3]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: O=C(c1nc2ccccc2n1Cc1ccc(F)cc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CCN2CCC(C(=O)c3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a stirred, room temperature, mixture of [1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]-4-piperidinylmethanone, mono (trifluoroacetate) (1.82 g, 4.03×10-3 mole), potassium carbonate (1.39 g, 1.00×10-2 mole), and sieve dry DMF (15 ml) was added 1-(2-bromoethyl)-4-methoxybenzene (0.87 g, 4.04×10-3 mole). The reaction was then immersed in an oil bath which had been preheated to ca. 90° C. After being stirred at between 80°-90° C. for 22 hours, the reaction was allowed to cool to room temperature. The reaction was poured into a separatory funnel containing H2O and a 2:1 mixture of ethyl acetate:toluene. The two phases were mixed and the aqueous layer was separated. The organic layer was washed two times with H2O and once with saturated aqueous NaCl before being dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure leaving an oil which was purified by flash chromatography (ethyl acetate). Crystallization from cyclohexane afforded [1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl][1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]methanone as off white matted needles: 1.08 g (5%). This material was spectroscopically identical with the previously described product of Example III.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][Br:15].[OH-].[Na+]>O>[Br:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:7][CH2:1][CH2:2][CH2:3][CH2:4][C:5]#[CH:6]
Reactant: C#CCCCCO
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C#CCCCCOCCCCCCBr
Reaction time: 22 h

Procedure:
A mixture of 5-hexyn-1-ol (5 g), 1,6-dibromohexane (37.29 g), TAB (1 g) and 50% sodium hydroxide solution (20 ml) was stirred under nitrogen for 22 h. The mixture was diluted with water (100 ml) and extracted with diethyl ether (2×150 ml). The combined organic extracts were dried and evaporated in vacuo to give an oil. Purification by FCC eluting with hexane followed by hexane:ether (95:5) gave the title compound as a colourless oil. (7.7 g), t.l.c. (hexane:ether 2:1) Rf 0.80.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](O)=O)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[BH4-].[Na+].[Cl:14]C1C(CO)=NC(Cl)=CC=1.S(Cl)(Cl)=O.Cl.N1C=CC=CC=1>O.CO>[Cl:1][C:2]1[C:3]([CH2:9][Cl:14])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: OCc1nc(Cl)ccc1Cl
Reactant: O=C(O)c1nc(Cl)ccc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: ClCc1nc(Cl)ccc1Cl

Procedure:
The haloalkylpyridine reactants employed as starting materials in the present invention are readily available or can be prepared according to known procedures or procedures analogous thereto. For example, the 3,6-dichloro-2-chloromethyl pyridine is prepared by converting the methyl ester of 3,6-dichloropyridine carboxylic acid to the corresponding alcohol by reaction with NaBH4 and methanol in the presence of water. The 3,6-dichloro-2-hydroxymethylpyridine product is then reacted with thionyl chloride in the presence of a catalytic amount of pyridine hydrochloride at temperatures of about 65° C. for a period of from about 15 to about 20 minutes. The thionylchloride is then removed by evaporation and the residue cooled, mixed with ice and then extracted with hexane. The desired 3,6-dichloro-2-chloromethyl pyridine reactant is obtained as a light yellow oil. Other haloalkyl pyridine starting materials can be prepared in an analogous manner.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[NH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22]>>[O:14]=[C:6]1[C:5]2[CH:15]=[CH:16][C:2]([NH:17][C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=3)[C:21]#[N:22])=[CH:3][C:4]=2[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Reactant: N#Cc1cccc(N)c1
Product: N#Cc1cccc(Nc2ccc3c(=O)[nH]c4ncccc4c3c2)c1
Yield: 16 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (50 mg, 0.22 mmol) and 3-aminobenzonitrile (38 mg, 0.33 mmol) to provide 233 (11 mg, 16% yield) as a white solid. LC-MS (M+H=313, obsd.=313).
Reaction SMILES: [CH3:1][C:2]1([CH2:6][OH:7])[CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17].O>ClCCl>[CH3:1][C:2]1([CH2:6][O:7][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:5][O:4][CH2:3]1
Reactant: CC1(CO)COC1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(COS(C)(=O)=O)COC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
Step A To a solution of 3-methyl-3-oxetanemethanol (Aldrich) (3.5 g, 34 mmol) and triethylamine (10 g, 103 mmol) in dichloromethane (100 mL) at 0° C. was added a dichlormethane solution (20 mL) of methanesulfonyl chloride (Aldrich) (5.08 g, 45 mmol). The reaction mixture was stirred at 0° C. for 2 h. Water was added. Organic layer was separated, the aqueous layer was extracted with dichlormethane. The combined organic layers were washed with diluted aqueous HCl solution, saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated to give methanesulfonic acid 3-methyl-oxetan-3-ylmethyl ester as a yellow oil (6 g, 97%).
Reaction SMILES: [O:1]=[C:2]([N:26]1[CH2:31][CH2:30][CH:29]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=2)[CH2:28][CH2:27]1)[CH2:3][NH:4][C:5]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18]CC2C=CC=CC=2)[O:9][N:8]=1)=[O:6]>CO.[Pd]>[O:1]=[C:2]([N:26]1[CH2:31][CH2:30][CH:29]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:40])([F:41])[F:42])[CH:34]=2)[CH2:28][CH2:27]1)[CH2:3][NH:4][C:5]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[O:9][N:8]=1)=[O:6]
Reactant: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cc(-c2ccccc2OCc2ccccc2)on1
Agent: [Pd]
Solvent: CO
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cc(-c2ccccc2O)on1
Reaction time: 3 h
Yield: 19.2 %

Procedure:
10% Pd/C (50 mg) was added to a stirred solution of 5-(2-benzyloxy-phenyl)-isoxazole-3-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide (192 mg, 0.33 mmol) (prepared by the method used to generate Intermediate 43) in methanol (50 mL) and stirred under H2 atmosphere with pressure for 3 hrs. The reaction mixture was filtered through celite, the celite was washed with methanol and the filtrate was concentrated under reduced pressure. Washing with ethyl acetate afforded the residue. The residue was purified by preparative HPLC to afford 31 mg (19.1% Yield) of 5-(2-hydroxy-phenyl)-isoxazole-3-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 490, 96.83%. 1H NMR (300 MHz, DMSO-d6): δ10.8 (s, 1H), 8.68 (t, 1H), 7.8 (m, 1H), 7.5 (t, 1H), 7.3 (m, 4H), 7.18 (s, 1H), 7.04 (d, 1H), 6.94 (t, 1H), 4.8 (m, 1H), 4.2 (d, 2H), 3.8 (m, 1H), 3.7 (m, 1H), 3.4 (m, 1H), 3.25 (m, 1H), 1.9 (m, 2H), 1.65 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1.C#C.[C:15]1(C)[CH:20]=CC=[CH:17][CH:16]=1>[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Co+2]>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:20][N:11]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C#N)cc1
Reactant: Cc1ccccc1
Agent: [Co+2]
Agent: C#C
Agent: c1cc[cH-]c1
Product: COC(=O)c1ccc(-c2ccccn2)cc1
Temperature: 180 °C
Reaction time: 12 h

Procedure:
24.0 g (150 mmol) of 4-cyanobenzoic acid methyl ester (Fluka, Buchs, Switzerland) in 150 ml of toluene are placed under an acetylene atmosphere in an autoclave and 0.30 g (1.6 mmol) of cobaltocene (=dicyclopentadienylcobalt; Aldrich, Milwaukee, USA) is added. The mixture is then subjected to an acetylene pressure of 15 atm, heated at 180° C. and stirred for 12 hours. After cooling and release of the pressure, 9.5 g of active carbon are added to the black suspension; the mixture is diluted with 250 ml of toluene, stirred for 30 min, filtered and concentrated by evaporation. Crystallisation from warm ether by the addition of hexane yields the title compound: m.p. 96° C.; TLC (hexane/ethyl acetate 4:1): Rf=0.37; FAB MS (M+H)+=214. Further product can be obtained from the mother liquor by column chromatography (SiO2, hexane/ethyl acetate 19:1→4:1).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([CH:18]4[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]4)[CH2:13]3)=[N:6][C:5]=2[N:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:3]=1.[ClH:35]>>[ClH:35].[NH:20]1[CH2:21][CH:18]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:7]3[NH:8][C:9](=[O:11])[C:10]4[C:2]([CH3:1])=[N:3][N:4]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:5]=4[N:6]=3)[CH2:13]2)[CH2:19]1
Reactant: Cc1nn(-c2ccccc2)c2nc(C3CCCN(C4CN(C(=O)OC(C)(C)C)C4)C3)[nH]c(=O)c12
Agent: Cl
Product: Cc1nn(-c2ccccc2)c2nc(C3CCCN(C4CNC4)C3)[nH]c(=O)c12

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of tert-butyl 3-(3-(3-methyl-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperidin-1-yl)azetidine-1-carboxylate (200 mg, 0.43 mmol, 1.00 equiv) in hydrogen chloride (5 mL) at room temperature. The resulting solution was heated to reflux overnight. The resulting mixture was concentrated under vacuum. The resulting residue (150 mg) was purified by Prep-HPLC with the following conditions (Gilson Pre-HPLC): Column, SHISEIDO, CAPCELL PAK C18, 20 mm ID*250 mm, 5 u; mobile phase, methanol/H2O; Detector, UV 254 nm to yield 6-(1-(azetidin-3-yl)piperidin-3-yl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one hydrochloride as a white solid.