Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].CN(C=O)C.C(O)(C)C>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:13]([F:12])[CH:14]=2)[N:3]=1
Reactant: Nc1cccc(F)c1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CN(C)C=O
Solvent: CC(C)O
Solvent: CCCCO
Product: Fc1cccc(Nc2nc(Cl)nc3nc[nH]c23)c1

Procedure:
2 g (10.58 mmol) of 2,6-dichloro-purine and 5.9 g (52.9 mmol) of 3-fluoro-aniline (Fluka, Buchs, Switzerland) are stirred in 60 ml of n-butanol and 3 ml of DMF at 80° C. for 5 h. The cooled reaction mixture is treated with isopropanol and the crystal mass which has precipitated out is filtered off and dried. 2-Chloro-6-(3-fluoro-phenyl-amino)-purine is obtained; m.p.>250° C.; FAB-MS: (M+H)+=264; Rf=0.3 (CH2Cl2:methanol 9:1).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:31][C:32]([CH3:36])([CH3:35])[CH2:33]O.C(N(CC)CC)C>C(#N)C.CCCCCC.C(OCC)(=O)C.ClC(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]2[O:9][CH2:33][C:32]([CH3:36])([CH3:35])[N:31]=2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: CC(C)(N)CO
Reactant: CCc1ccc(C(=O)O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCc1ccc(C2=NC(C)(C)CO2)cc1
Reaction time: 18 h

Procedure:
To a solution of 4-ethylbenzoic acid (3.80 g) in anhydrous acetonitrile (100 mL) was added under a nitrogen atmosphere, triphenylphosphine (20 g), 2-amino-2-methyl-1-propanol (2.74 mL) and triethylamine (28.2 mL). The mixture was cooled on an ice bath and then tetrachloromethane (5.36 mL) was added. The reaction mixture was allowed to stand at room temperature and stirred for 18 hours. To the reaction mixture was added ethyl acetate and hexane and the precipitate was removed by filtration. The concentration of the filtrate left a residue, which was purified by column chromatography on silica gel (hexane/ethyl acetate/=9/1/ to 6/1) to give the subject compound (1.15 g).
Reaction SMILES: [OH:1][NH:2][C:3]([NH2:5])=[O:4].CO.[CH3:8][C:9](=O)[CH2:10][C:11](=O)[CH2:12][CH3:13].O.[ClH:17]>>[ClH:17].[CH2:12]([C:11]1[CH:10]=[C:9]([CH3:8])[N:5]=[C:3]([OH:4])[N+:2]=1[O-:1])[CH3:13]
Reactant: NC(=O)NO
Reactant: CCC(=O)CC(C)=O
Agent: Cl
Solvent: O
Solvent: CO
Product: CCc1cc(C)nc(O)[n+]1[O-]
Temperature: -15 °C
Reaction time: 2 h

Procedure:
0.12 mol (9.13 g) hydroxy urea were dissolved in 50 ml 2 M HCl, 20 ml of methanol were added and 0.10 mol (11.41 g) 2,4-hexanedione were added dropwise under cooling by approximately −15° C. Further 30 ml of water and 10 ml of methanol were added. The two-phase reaction mixture was allowed to warm up slowly to room temperature and was stirred at room temperature for further 2 h, then evaporated until dryness. The residue was suspended with 50 ml of acetone, the mixture was cooled in an ice/ethanol bath, the solid filtered off and washed with a little ice-cold acetone. After drying 7.88 g crude product were obtained which were recrystallized from 45 ml ethanol wherefrom first an insoluble salt compound was hot filtered off and the product was subsequently recrystallized from the filtrate at −18° C. 3.0 g product were obtained which were again recrystallized from 28 ml ethanol. Finally 2.26 g of the title compound were obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[CH2:12][O:11][CH2:10][CH2:9][C:7]=2[N:8]=1.[F:14][C:15]1[CH:32]=[CH:31][C:18]([C:19]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28](O)=[O:29])[CH2:23][CH2:22]2)=[O:20])=[CH:17][CH:16]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([CH:21]2[CH2:22][CH2:23][N:24]([CH2:27][C:28]([NH:1][CH2:2][C:3]3[NH:4][C:5](=[O:13])[C:6]4[CH2:12][O:11][CH2:10][CH2:9][C:7]=4[N:8]=3)=[O:29])[CH2:25][CH2:26]2)=[O:20])=[CH:31][CH:32]=1
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CN1CCC(C(=O)c2ccc(F)cc2)CC1)NCc1nc2c(c(=O)[nH]1)COCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.5 %

Procedure:
To a solution of 2-aminomethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (1.7 g, 9.6 mmol) and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid (2.7 g, 10 mmol) in dichloromethane (50 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.2 g, 11 mmol), 1-hydroxybenzotriazole (1.5 g, 9.6 mmol) and triethylamine (4.0 mL, 29 mmol). The mixture was stirred at ambient temperature for 24 hours. The reaction mixture was washed with ammonium chloride solution, concentrated in vacuo and purified via flash column chromatography (ethyl acetate:hexane, 10:90 to 100:0, methanol:dichloromethane, 1:99 to 10:90) to provide the title compound (2.2 g, 54% yield). 1H NMR (400 MHz, CDC3) δ 11.12 (s, 1H), 8.07 (s, 1H), 7.99 (dd, J=9.0, 5.5 Hz, 2H), 7.18 (t, J=8.5 Hz, 2H), 4.58 (s, 2H), 4.41 (d, J=6.0 Hz, 2H), 3.97 (t, J=5.5 Hz, 2H), 3.22-3.35 (m, 1H), 3.10-3.22 (m, 2H), 2.94-3.07 (m, 2H), 2.66-2.75 (m, 2H), 2.31-2.48 (m, 2H), 1.80-1.99 (m, 4H). HRMS calculated for C22H23N4O4 429.1938. found (ESI, [M+H]+), 429.1925. MS m/z 429.3 (M+1), retention time=1.28 min.
Reaction SMILES: C(OC([N:6]1[CH:11]2[CH:12]([O:14]C3CCCCO3)[CH2:13][CH:7]1[CH2:8][CH:9]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:10]2)=O)C.C[Si](I)(C)C.[OH-].[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:21]([CH:9]1[CH2:10][CH:11]2[NH:6][CH:7]([CH2:13][CH:12]2[OH:14])[CH2:8]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)N1C2CC(Cc3ccccc3)CC1C(OC1CCCCO1)C2
Agent: C[Si](C)(C)I
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: OC1CC2CC(Cc3ccccc3)CC1N2

Procedure:
A solution of the 3-benzyl-6-(tetrahydro-pyran-2-yloxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester and 0.5 mL of trimethylsilyl iodide in 25 mL of chloroform was kept at room temperature for 48 h, shaken with 25 mL of 6N NaOH and dilute sodium sulfite and dried over magnesium sulfate. Removal of solvents gave 0.2 g of a resin.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.CC(C)([O-])C.[K+].CN(P(N(C)C)(N(C)C)=O)C.O>O1CCCC1.C(OCC)C>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH:7]1[CH2:2][CH2:3][CH2:4][CH2:5][S:6]1
Reactant: ClCCCCSCc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: c1ccc(C2CCCCS2)nc1
Reaction time: 0.75 h
Yield: 74.3 %

Procedure:
A solution of pyrid-2-ylmethyl 4-chlorobutyl sulphide (82 g) in anhydrous tetrahydrofuran (100 cc) is added dropwise, in the course of 15 minutes and whilst keeping the temperature below 30° C., to a solution of potassium tert.-butoxide (66 g) in a mixture of anhydrous hexamethylphosphorotriamide (100 cc) and anhydrous tetrahydrofuran (530 cc). After stirring for 1 hour at a temperature of about 20° C., potassium tert.-butoxide (20 g) is added and stirring is continued for 45 minutes at the same temperature. The reaction mixture is added to a mixture of distilled water (1000 cc) and diethyl ether (600 cc); after decantation, the aqueous phase is extracted twice with diethyl ether (400 cc in total). The ether extracts are combined, washed three times with distilled water (3000 cc in total), dried over anhydrous sodium sulphate and filtered and the filtrate is concentrated under reduced pressure (20 mm Hg; 2.7 kPa) at 35° C. 2-(Pyrid-2-yl)-tetrahydrothiopyran (50.6 g) is thus obtained in the form of a brown oil.
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=2)[N:11]([CH2:22][C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[CH3:32])[N:25]([CH3:33])[CH:24]=2)[C:10]1=[O:34])[CH2:5][CH2:6][CH2:7][CH3:8]>O1CCOCC1.O>[CH3:33][N:25]1[C:26]2[C:31](=[C:30]([CH3:32])[CH:29]=[CH:28][CH:27]=2)[C:23]([CH2:22][N:11]2[C:12]3[C:17](=[CH:16][C:15]([O:20][CH3:21])=[CH:14][CH:13]=3)[C:18](=[O:19])[N:9]([C@@H:4]([CH2:5][CH2:6][CH2:7][CH3:8])[C:3]([OH:35])=[O:2])[C:10]2=[O:34])=[CH:24]1
Reactant: CCCC[C@@H](C(=O)OC)n1c(=O)c2cc(OC)ccc2n(Cc2cn(C)c3cccc(C)c23)c1=O
Solvent: C1COCCO1
Solvent: O
Product: CCCC[C@@H](C(=O)O)n1c(=O)c2cc(OC)ccc2n(Cc2cn(C)c3cccc(C)c23)c1=O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-2-[1-(1,4-dimethyl-1H-indol-3-ylmethyl)-6-methoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-hexanoic acid methyl ester (124 mg, 0.26 mmol) in dioxane (2.5 ml) is added a solution of LiOH monohydrate (50 mg, 1.19 mmol) in H2O (2.5 mL). The solution is stirred at 60° C. for 4 hours. The reaction mixture is allowed to cool to room temperature, quenched with 4M HCl in dioxane (500 μL) and concentrated. The resulting residue is triturated with H2O and MeOH to afford the title compound. LCMS (ESMS): m/z 464.87 (M+H+)
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][S:8](Cl)(=[O:10])=[O:9])(=O)C.[CH3:12][NH:13][CH3:14]>>[OH:4][CH2:5][CH2:6][CH2:7][S:8]([N:13]([CH3:14])[CH3:12])(=[O:10])=[O:9]
Reactant: CC(=O)OCCCS(=O)(=O)Cl
Reactant: CNC
Product: CN(C)S(=O)(=O)CCCO

Procedure:
Using 3-acetoxy-1-propanesulfonylchloride and dimethylamine, substantially the same reaction was conducted as in reference example 47 and 48 to produce the title compound.
Reaction SMILES: C(OC(=O)CC)(=O)CC.[CH3:10][O:11][C:12]([C@@H:14]1[CH2:27][C@H:26]([OH:28])[C:25](=[O:29])[C@H:24]2[C@@:15]1([CH3:37])[CH2:16][CH2:17][C@H:18]1[C@:23]2([CH3:30])[CH2:22][C@@H:21]([C:31]2[CH:35]=[CH:34][O:33][CH:32]=2)[O:20][C:19]1=[O:36])=[O:13].[C:38](Cl)(=[O:42])[CH:39]([CH3:41])[CH3:40]>>[CH3:10][O:11][C:12]([C@@H:14]1[CH2:27][C@H:26]([O:28][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[C:25](=[O:29])[C@H:24]2[C@@:15]1([CH3:37])[CH2:16][CH2:17][C@@H:18]1[C@:23]2([CH3:30])[CH2:22][C@@H:21]([C:31]2[CH:35]=[CH:34][O:33][CH:32]=2)[O:20][C:19]1=[O:36])=[O:13]
Reactant: COC(=O)[C@@H]1C[C@H](O)C(=O)[C@@H]2[C@@]3(C)C[C@@H](c4ccoc4)OC(=O)[C@H]3CC[C@]21C
Reactant: CC(C)C(=O)Cl
Agent: CCC(=O)OC(=O)CC
Product: COC(=O)[C@@H]1C[C@H](OC(=O)C(C)C)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Yield: 62 %

Procedure:
Using a procedure similar to that described in Example 4 except replacing the propionic anhydride used therein with the requisite anhydride, the title compound 10 (0.04 g, 62%) was prepared as a white solid, mp 209-211° C.; 10 was synthesized as described for 9 from 8a using isobutyryl chloride to afford 0.04 g (62%) of 10 as a white solid, mp 209-211° C.; 1H NMR (CDCl3): δ 1.13 (3H, s, H-19); 1.24 (3H, d, J=6.9 Hz, CH3CH(CH3)CO2); 1.26 (3H, d, J=6.9 Hz CH3CH(CH3)CO2,); 1.46 (3H, s, H-20); 1.52-1.78 (3H, m, H-7α,β and H-11β); 1.80 (1H, ddd, J=3.0, 3.0, 9.9 Hz, H-6α); 2.12 (2H, m, H-3α and H-8); 2.20. (1H, s, H-10); 2.25-2.35 (2H, m, H-3β and H-6β); 2.51 (1H, dd, J=5.1, 13.2 Hz, H-11α); 2.68 (1H, sept, J=6.9 Hz, CH3CH(CH3)CO2); 2.77 (1H, dd, J=8.4, 8.4 Hz, H-4); 3.74 (3H, s, CO2CH3); 5.15 (1H, dd, J=9.9, 10.3 Hz, H-2); 5.52 (1H, dd, J=5.3, 11.9 Hz, H-12); 6.39 (1H, dd, J=0.9, 1.5 Hz, H-14); 7.40 (1H, dd, J=1.5, 1.5 Hz, H-15); 7.42 (1H, dd, J=0.9, 1.5 Hz, H-16).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([NH2:10])[CH:4]=1.[CH:13](O)=O>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:8]=[CH:7][C:6]2[N:9]=[CH:13][NH:10][C:5]=2[CH:4]=1
Reactant: O=CO
Reactant: Nc1ccc(C(F)(F)F)cc1N
Product: FC(F)(F)c1ccc2nc[nH]c2c1
Yield: 83 %

Procedure:
A mixture of 10 g (60 mmol) of 4-(trifluoromethyl)-1,2-phenylenediamine (Lancaster) and 50 mL of formic acid was refluxed for 2 h. Excess formic acid was then removed in vacuo. To the resultant concentrate was added 200 mL of water during which time a precipitate was discerned. This was filtered and discarded. The filtrate was concentrated in vacuo and redissolved in EtOAc. After repeated washing with saturated NaHCO3, the EtOAc solution was dried over MgSO4 and concentrated. The concentrate was put on a vacuum pump overnight. This resulted in 9.27 g (83%) of a yellow solid. 1H NMR (DMSO-d6) δ7.5 (d,1H, aromatic), 7.8 (d, 1H, aromatic), 8 (s, 1H, aromatic), 8.4 (s, 1H, CH), 12.8 (br s, 1H, NH).
Reaction SMILES: Cl.[C:2](=[NH:6])([NH2:5])[CH2:3][CH3:4].C[O-].[Na+].[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([C:30](=O)[CH2:31][CH2:32][CH3:33])[C:26](OC)=[O:27])=[CH:20][CH:19]=1)#[N:11]>CO>[CH2:3]([C:2]1[NH:6][C:26](=[O:27])[C:25]([CH2:24][C:21]2[CH:22]=[CH:23][C:18]([C:13]3[C:12]([C:10]#[N:11])=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:19][CH:20]=2)=[C:30]([CH2:31][CH2:32][CH3:33])[N:5]=1)[CH3:4]
Reactant: CCC(=N)N
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCc1nc(CC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 74.5 %

Procedure:
A solution of propanimidamide hydrochloride (20 g), 28% sodium methoxide (56 mL) and methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (34 g) in methanol (350 mL) was stirred overnight. The solvent was evaporated under reduced pressure, and water and 1 M hydrochloric acid were added. The precipitated solid was collected by filtration, and washed with water and diethyl ether to give the title compound (27 g, 82%) as a pale-yellow solid.
Reaction SMILES: C([O:4][C:5](=[O:21])[CH2:6][C:7]1[O:11][N:10]=[C:9]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:8]=1)(C)C>OS(O)(=O)=O>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]([C:9]2[N:8]=[C:7]([CH2:6][C:5]([OH:21])=[O:4])[O:11][N:10]=2)=[O:20])=[CH:18][CH:17]=1
Reactant: CC(C)OC(=O)Cc1nc(C(=O)c2ccc(F)cc2)no1
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1nc(C(=O)c2ccc(F)cc2)no1
Temperature: 0 °C
Yield: 82.9 %

Procedure:
A solution of isopropyl[3-(4-fluorobenzoyl)-1,2,4-oxadiazol-5-yl]acetate (6.2 g) in 97% H2SO4 (40 ml) was stirred at room temperature for 15 minutes. The resulting solution was added slowly to a liter of ice water with mechanical stirring. The precipitated solid was collected by filtration and washed with water (5×300 ml). Drying under vacuum gave 4.4 g of a powder. Recrystallization from 25% hexane/acetone gave 2.5 g (47%) of crystals, m.p. 146°-148°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[N:13][CH:14]=1.FC(F)(F)C(O)=O.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)Cl>[CH3:42][S:43]([N:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:11]=[CH:10][C:9]([C:8]#[C:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:14][N:13]=2)[CH2:16][CH2:17]1)(=[O:45])=[O:44]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C#Cc3ccccn3)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2ccc(C#Cc3ccccn3)cn2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
To a stirred solution of tert-butyl 4-[5-(pyridin-2-ylethynyl)pyridin-2-yl]piperazine-1-carboxylate (3.8 g, 10.4 mmol) in CH2Cl2 (35 mL) at 0° C. was added trifluoroacetic acid (17.2 mL). The reaction was brought to room temperature and stirred for 30 minutes. Volatiles were removed in vacuo, and the residue was azeotroped with toluene (2×10 mL). The residue was then dissolved in CH2Cl2 and washed with aqueous sodium hydroxide solution (2M, 2×20 mL). The layers were then separated and the aqueous phase extracted with CH2Cl2 (3×10 mL). The combined organic extracts were then dried, (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in CH2Cl2 (50 mL), and cooled to 0° C. and treated sequentially with triethylamine (1.5 mL, 16.7 mmol) and methanesulfonyl chloride (1.1 mL, 13.5 mmol). The reaction was brought to RT and stirred for 1 hour. The reaction was then quenched with water (50 mL). The layers were separated and the aqueous phase extracted with CH2Cl2 (3×20 mL). The combined organic extracts were then dried, (MgSO4), filtered and concentrated in vacuo. The residue was then purified by flash chromatography (silica gel, 10% MeOH in EtoAc) to give 1-(methylsulfonyl)-4-[5-(pyridin-2-ylethynyl)pyridin-2-yl]piperazine as a brown solid (3.5 g, 10.2 mmol, 98%).
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[PH:9](=[O:12])([OH:11])[OH:10].[CH2:13]([C:15]([CH2:43][CH3:44])([CH:17](F)[C:18]1[N:22]=[CH:21][N:20]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:19]=1)C)[CH3:14].[Cl-].[NH4+]>>[PH:9](=[O:10])([OH:12])[OH:11].[CH2:13]([CH:15]1[CH:43]([CH2:44][CH3:1])[CH:17]1[C:18]1[N:22]=[CH:21][N:20]([C:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:19]=1)[CH3:14]
Reactant: CC(C)[N-]C(C)C
Reactant: CCC(C)(CC)C(F)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=[PH](O)O
Agent: [Cl-]
Agent: [Li+]
Product: CCC1C(CC)C1c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 5 h

Procedure:
Lithium diisopropylamide (0.91 ml, 1.5M in cyclohexane) was added dropwise under nitrogen to a stirred solution of diethyl 3-fluoro-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.35 g, prepared as described in Example 27) whilst maintaining the temperature below -60° C. After five hours, the mixture was allowed to warm then stand at room temperature overnight. It was then poured on to saturated ammonium chloride solution and extracted with ethyl acetate. The extracts were dried over magnesium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica, using dichloromethane-ethanol (19:1) as eluant, to give diethyl 2(1-trityl-1,2,4-triazol-3-yl)cyclopropane phosphonate (0.18 g). NMR (CDCl3): δ1.3(6H,2xt), 1.4-1.5(3H,m), 2.6-2.7(1H,m), 4.05-4.2(4H,m), 7.1-7.3(15H,m), 7.8(1H,s). M/S: M+ 487. The basic structure was confirmed by 13C, 19F, 31P, COSY and NOESY experiments but stereochemistry could not be assigned. Theoretical calculations suggested that the trans (1RS,2RS) isomer is likely to be much more stable and thus preferred.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([S:33]([C:36]2[CH:41]=[CH:40][C:39]([CH:42]([CH2:46][CH:47]3[CH2:51][CH2:50][CH2:49][CH2:48]3)[C:43](O)=[O:44])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:52][C:53]1[S:54][CH:55]=[CH:56][N:57]=1.N1C=CC=CC=1>C(Cl)Cl.O>[CH:28]1([S:33]([C:36]2[CH:37]=[CH:38][C:39]([CH:42]([CH2:46][CH:47]3[CH2:51][CH2:50][CH2:49][CH2:48]3)[C:43]([NH:52][C:53]3[S:54][CH:55]=[CH:56][N:57]=3)=[O:44])=[CH:40][CH:41]=2)(=[O:35])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(S(=O)(=O)C2CCCC2)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(S(=O)(=O)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 71.9 %

Procedure:
A solution of triphenylphosphine (106 mg, 0.40 mmol) and N-bromosuccinimide (82 mg, 0.45 mmol) in methylene chloride (1.35 mL) was cooled to 0° C. and then treated with a solution of 2-(4-cyclopentanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (94.8 mg, 0.27 mmol) in methylene chloride. The reaction mixture was stirred at 25° C. for 45 min. At this time, the reaction was treated with 2-aminothiazole (35 mg, 0.35 mmol) and pyridine (0.03 ml, 0.40 mmol). The reaction was stirred at 25° C. for 18 h. The reaction was then diluted with water (100 mL) and extracted with chloroform (3×50 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 2-(4-cyclopentanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (84 mg, 71.8%) as a light-orange solid: mp 180-182° C.; EI-HRMS m/e calcd for C22H28N2O3S2 (M+) 432.1541 found 432.1543.
Reaction SMILES: Br[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:12]1(B(O)O)[CH2:14][CH2:13]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(OC)(C)C>[CH:12]1([C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:14][CH2:13]1
Reactant: FC(F)(F)c1cccnc1Br
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: COC(C)(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cccnc1C1CC1
Temperature: 80 °C
Yield: 9.7 %

Procedure:
2-bromo-3-trifluoromethylpyridine (5 g, 22.1 mmol), cyclopropyl boronic acid (2.09 g, 24.3 mmol), and tribasic potassium phosphate (14.1 g, 66.4 mmol) were suspended in a mixture of toluene (150 mL) and water (30 mL), with rapid stirring. The suspension was heated to 80° C., and the solvent de-gassed by direct bubbling of N2 gas through the suspension for 30 minutes. The reaction was then heated to 95° C., and tricyclohexyl phosphine (620 mg, 2.21 mmol) followed by palladium acetate (248 mg, 1.12 mmol) were added. The reaction was left to stir and heat at 95° C. for 6 hours. The reaction was cooled to room temperature, and filtered through a plug of Arbocel™, eluting with ethyl acetate. The solvent was removed to leave a dark yellow oil. TBME was added (300 mL), and the organic phase washed with 2M HCl solution (3×200 mL). The organics were discarded. TBME (300 mL) was added to the combined aqueous layers, and solid sodium bicarbonate was added until the aqueous layer reached pH 7. The organic layer was removed, and the aqueous layer was extracted with TBME (2×100 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 4:1 heptane:ethyl acetate, affording the title compound as a colourless oil (400 mg, 10%).
Reaction SMILES: [Br:1][C:2]1(Br)[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:5]=2[O:4][CH2:3]1.O.Cl>N1C=CC=CC=1>[Br:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:12][C:5]=2[O:4][CH:3]=1
Reactant: CS(=O)(=O)Nc1cc2c(cc1Oc1ccccc1)C(=O)C(Br)(Br)CO2
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc2occ(Br)c(=O)c2cc1Oc1ccccc1
Yield: 82.1 %

Procedure:
In 20 ml of pyridine was dissolved 4.81 g of 3,3-dibromo-2,3-dihydro-7-methylsulfonylamino-6phenoxy-4H-1-benzopyran-4-one. The solution was refluxed for 20 minutes. The reaction mixture was introduced into 200 ml of water. The mixture was adjusted to pH 4 with concentrated hydrochloric acid and then extracted with two 100-ml portions of ethyl acetate. The extracts (the organic layers) were combined, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting crystal was recrystallized from acetonitrile to obtain 3.30 g (yield: 82%) of 3-bromo-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one having a melting point of 215°-216° C.