Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C1C=C(Cl)C=C(C(OO)=[O:32])C=1>>[O-:32][N+:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:6]2[N:5]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:4]([CH2:1][CH2:2][CH3:3])=[N:16][C:7]=2[CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCC(=O)OCC
Product: CCCc1nc2c[n+]([O-])c3ccccc3c2n1CCC(=O)OCC

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate ethyl 3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propionate (3.30 g, 10.6 mmol) by reaction with m-CPBA (4.63 g) to provide ethyl 3-(5-oxido-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propionate followed by reaction with p-toluenesulfonyl chloride (3.53 g, 18.6 mmol) and ammonium hydroxide solution (50 mL) to provide ethyl 3-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propionate as an off-white solid after recrystallization from aqueous methanol, mp 156-157° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8].[Cl-].[Al+3].[Cl-].[Cl-].[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccccc1
Reactant: N#CCCCCCBr
Agent: [Al+3]
Agent: [Cl-]
Product: N#CCCCCCc1ccccc1
Temperature: 25 °C
Yield: 86 %

Procedure:
A solution of 50.0 g (.284 mole) of 6-bromocapronitrile in 550 ml of benzene was cooled to 5° C. and to this was added 77.3 g (.580 mole) of anhydrous aluminum chloride in portions over a 10 minute period. The ice bath was removed and the vigorously stirred mixture was warmed slowly to reflux. After 2 hours at reflux, the mixture was cooled to room temperature, then poured slowly into a mixture of 50 ml of concentrated hydrochloric acid and 250 ml of ice water. The layers were separated and the aqueous portion was extracted twice with 125 ml portions of ether. The combined organic extracts were washed with 100 ml of saturated sodium bicarbonate solution, 100 ml of saturated sodium chloride solution, then dried over sodium sulfate, filtered, and evaporated leaving 53 g of a crude red/brown oil. Distillation under reduced pressure afforded 42.4 g (86%) of the nitrile as a pale yellow oil, bp 136°-140° C./2.5 mm of Hg.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1)[CH2:7][C:8]([OH:10])=[O:9].[CH3:20]O>>[NH2:5][CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1)[CH2:7][C:8]([O:10][CH3:20])=[O:9]
Reactant: CO
Reactant: NC(CC(=O)O)c1cccc([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: COC(=O)CC(N)c1cccc([N+](=O)[O-])c1
Temperature: -20 °C
Reaction time: 16 h

Procedure:
Thionyl chloride (1.11 ml) and 3-amino-3-(3-nitrophenyl)propionic acid (0.7 g) were added in turn to stirred methanol (5 ml) which had been cooled -20° C. The mixture was stirred at -20° C. for 10 minutes and at laboratory temperature for 16 hours. The mixture was evaporated to give methyl 3-amino-3-(3-nitrophenyl)propionate (0.83 g), as a solid.
Reaction SMILES: C([Li])CCC.[F:6][C:7]([F:29])([F:28])[C:8]1[N:13]=[C:12]([O:14][CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH:11]=[CH:10][CH:9]=1.[O:30]1[CH2:34][CH2:33]OS1(=O)=O.Cl.O.C(=O)(O)[O-].[Na+]>O1CCCC1.[Cl-].[Na+].O>[NH:18]1[CH2:17][CH2:16][CH:15]([O:14][C:12]2[CH:11]=[C:10]([CH2:33][CH2:34][OH:30])[CH:9]=[C:8]([C:7]([F:6])([F:28])[F:29])[N:13]=2)[CH2:20][CH2:19]1
Reactant: O=S1(=O)OCCO1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C(F)(F)F)n2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: OCCc1cc(OC2CCNCC2)nc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2.5 M n-Butyllithium in hexanes (1.2 mL, 2.9 mmol) was added dropwise to a solution of tert-butyl 4-{[6-(trifluoromethyl)pyridin-2-yl]oxy}piperidine-1-carboxylate (0.50 g, 1.4 mmol, from Step 1) in tetrahydrofuran (8.0 mL) at −78° C. The reaction was stirred at this temperature for 1.5 hours, and 1,3,2-dioxathiolane 2,2-dioxide (0.36 g, 2.9 mmol, Aldrich) in Tetrahydrofuran (2.0 mL) was added. The mixture was allowed to warm to room temperature and stir overnight. 12 N Hydrogen chloride in water (0.72 mL, 8.7 mmol) was added to the mixture. The mixture was stirred at room temperature for 4 hours. The mixture was then treated with saturated sodium bicarbonate to pH between 7 and 8, and brine was added. The mixture was then extracted with DCM four times. The combined extracts were dried over sodium sulfate, filtered and concentrated. Preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) was used to purify the product. It was the second peak to elute having the desired mass. 1H NMR (300 MHz, CD3OD) δ 7.24 (s, 1H), 6.86 (s, 1H), 5.16 (tt, J=8.4, 3.9 Hz, 1H), 3.80 (t, J=6.3 Hz, 2H), 3.06 (dt, J=12.6, 4.6 Hz, 2H), 2.85 (t, J=6.3 Hz, 2H), 2.73 (ddd, J=12.7, 9.5, 3.2 Hz, 2H), 2.13-1.93 (m, 2H), 1.68 (dtd, J=13.0, 9.1, 3.9 Hz, 2H). 19F NMR (282 MHz, CD3OD) δ −70.29 (s). LCMS (M+H)+: 291.1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:17]=1[F:25]>CN(C=O)C.CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[F:25]
Reactant: COc1cc2ncnc(Nc3ccc([N+](=O)[O-])cc3F)c2cc1OC
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(N)cc3F)c2cc1OC
Reaction time: 3 h
Yield: 64.9 %

Procedure:
(6,7-Dimethoxy-quinazolin-4-yl)-(2-fluoro-4-nitro-phenyl)-amine (673 mg, 1.95 mmol) was dissolved in a combination of DMF (20 ml) and MeOH (20 ml), to which was added 10% Pd/C (227 mg). The mixture was shaken under an atmosphere of H2 on a Parr hydrogenator at 40 psi for 3 hrs. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo. The resulting residue was triturated in EtOAc/Et2O. The resulting solids were filtered, washed with Et2O, and dried under vacuum to give N1-(6,7-dimethoxy-quinazolin-4-yl)-2-fluoro-benzene-1,4-diamine (398 mg, 65%) which was used in the next reaction without further purification. 1H-NMR (400 MHz, DMSO): 10.80 (br s, 1H), 10.30 (br s, 1H), 8.63 (s, 1H), 8.15 (s, 1H), 7.33 (s, 1H), 7.15 (m, 1H), 6.45 (m, 1H), 3.96 (s, 6H). LC/MS Calcd for [M+H]+ 315.1, found 315.4.
Reaction SMILES: [C:1]1([O:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:26])C=1>ClCCl>[C:1]1([O:11][C:12]2[CH:17]=[CH:16][N+:15]([O-:26])=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc2c(Oc3ccncc3)cccc2c1
Solvent: ClCCl
Product: [O-][n+]1ccc(Oc2cccc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of Example 136 A (6.62 g; 29 9 mmol) in dichloromethane (40 ml) is treated with m-chloroperbenzoic acid, 80% strength (7 10 g; 32 9 mmol), stirred at room temperature for 24 h and then heated to reflux for a further 2 h The reaction mixture is washed twice with satd aqueous NaHCO3 solution. The combined aqueous phases are extracted with dichloromethane and the combined dichloromethane phases are dried (Na2SO4) and concentrated in vacuo. The residue is crystallized from dichloromethane/petroleum ether.
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[Na+].Cl[C:16]1[N:24]=[C:23]2[C:19]([N:20]=[CH:21][N:22]2[CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[C:18]([NH2:31])[N:17]=1>COCCOC.O>[CH:1]1([CH2:7][O:8][C:16]2[N:24]=[C:23]3[C:19]([N:20]=[CH:21][N:22]3[CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)=[C:18]([NH2:31])[N:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Reactant: OCC1CCCCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1nc(OCC2CCCCC2)nc2c1ncn2C1CCCCO1
Temperature: 93 °C

Procedure:
Cyclohexylmethanol (4.5784 g) was diluted with 1,2-dimethoxyethane (99%+) (20 mL) before sodium tert-butoxide (3.853 g) was added gradually with stirring under nitrogen. An exotherm was observed on addition of sodium tert-butoxide. 2-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (2.5428 g) was added and the resultant mixture was heated to reflux at 93° C. (internal). A further quantity of 1,2-dimethoxyethane (99%+) (20 mL) was added to help dissolution and refluxed overnight. The reaction mixture was dissolved in water (100 mL) and extracted with ethyl acetate (100 mL, twice). The combined organic extracts were washed with brine (100 mL) before the organic layer was separated and dried by passing through a hydrophobic frit. Evaporated volatiles under reduced pressure and then azeotroped with toluene (50 mL, twice) to give mobile amber oil. This material was purified by silica chromatography (ISCO) eluting with 0-100% ethyl acetate: cyclohexane). This gave the title compound after placing under vacuo as pale yellow foam (1.0364 g) (94% purity by LCMS, 6% 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine) and was used in next step without further purification.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].N1C=CC=CC=1.[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[C:21](Cl)=[O:22]>C(Cl)Cl>[OH:3][CH2:2][CH2:1][O:4][C:21]([C:12]1[CH:13]=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=1)=[O:22]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: OCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCCO)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
15.6 g (252 mmol) of ethylene glycol (manufactured by TOKYO CHEMICAL INDUSTRY CO., LTD.) was dissolved in 100 mL of dehydrated methylene chloride (manufactured by Kanto Chemical Co., Inc.) and 3.49 g (44.0 mmol) of pyridine was added to the solution followed by cooling down with ice water. To this solution, a solution in which 8.00 g (42.0 mmol) of 2-naphthalene carbonyl chloride (manufactured by TOKYO CHEMICAL INDUSTRY CO., LTD.) was dissolved in 80 mL of methylene chloride was dripped in one hour while being stirred. Subsequent to two hour stirring, the resultant was stirred for six hours at room temperature. The reaction solution was rinsed with water and thereafter the organic phase was isolated followed by drying with magnesium sulfate (manufactured by Kanto Chemical Co., Inc.) and the solvent was distilled away. The remainder was refined by silica gel column chromatography with a solvent mixture of a methylene chloride (manufactured by JUNSEI CHEMICAL CO., LTD.) and methanol (manufactured by Kanto Chemical Co., Inc.) with a volume ratio of 97:3 serving as an eluent to obtain 6.88 g of 2-naphthoic acid 2-hydroxyethyl ester.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][CH2:8][CH:7]([CH2:10][N:11]=[N+]=[N-])[O:6]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][CH:5]1[CH2:9][CH2:8][CH:7]([CH2:10][NH2:11])[O:6]1
Reactant: [N-]=[N+]=NCC1CCC(CN=[N+]=[N-])O1
Agent: [Pd]
Solvent: CO
Product: NCC1CCC(CN)O1
Yield: 75.6 %

Procedure:
Methanesulphonyl chloride (307.8 g, 2.7 mol) is added dropwise to a solution of tetrahydrofuran-2,5-dimethanol (118.8 g, 900 mmol) and of triethylamine (454.5 g, 4500 mmol) in 1.54 L of dichloromethane at 0° C. The reaction medium is maintained at 0° C. for 1 hour, ice-cold water is then added and the organic phase is separated out and washed with 500 mL of dilute (1 M) hydrochloric acid solution. The organic phase is separated out and then washed with 500 mL of saturated aqueous NaHCO3 solution. The organic phase is finally separated out and concentrated to give 236.7 g of (tetrahydrofuran-2,5-diyl)bis(methylene) dimethanesulphonate in the form of a brown oil in a purity equal to 96% (determined by LCMS). Reaction yield: 91.0%. A solution of (tetrahydrofuran-2,5-diyl)bis(methylene) dimethanesulphonate (236.7 g, 821.7 mmol) and NaN3 (270.0 g, 4.1094 mol) in DMSO (1.350 L) is heated at 95° C. and stirred overnight. The reaction medium is added to ice-cold water and extracted with 3 times 700 mL of ethyl acetate. The extracts (phase containing ethyl acetate) are successively washed with water, saturated aqueous NaHCO3 solution and dried overnight on MgSO4 and then filtered to remove the MgSO4. The phase containing the ethyl acetate is concentrated to give 166.5 g of 2,5-bis(azidomethyl)tetrahydrofuran in the form of a brown oil. A mixture of 2,5-bis(azidomethyl)tetrahydrofuran (166.5 g) and of Pd-C (10%, 10.8 g) in methanol (2.7 L) is stirred overnight at room temperature under 1 atm of H2. The reaction medium is filtered and the filtrate is concentrated under vacuum to give 90.0 g of 2,5-bis(aminomethyl)tetrahydrofuran in the form of a yellow oil. The total yield for the 3 successive reactions is 75%. The process for synthesizing 2,5-bis(aminomethyl)tetrahydrofuran gives a 90/10 mixture of the cis/trans isomers according to 13C NMR analysis in deuterated methanol.
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[CH2:11][O:10][C:9](=[O:13])[C:8]=3[CH:7]=[CH:6][C:5]=2[CH:14]=[CH2:15])[CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C(Cl)Cl>[CH:1]1([C:4]2[C:12]3[CH2:11][O:10][C:9](=[O:13])[C:8]=3[CH:7]=[CH:6][C:5]=2[CH:14]2[CH2:15][O:24]2)[CH2:3][CH2:2]1
Reactant: C=Cc1ccc2c(c1C1CC1)COC2=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1OCc2c1ccc(C1CO1)c2C1CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-cyclopropyl-5-vinyl-2-benzofuran-1(3H)-one (440 mg, 2.2 mmol) in 50 mL of DCM was slowly added mCPBA (1.14 g, 6.6 mmol) in 50 mL of DCM at 0° C. After warming to room temperature, the mixture was stirred for 12 hours. The mixture was washed with aqueous Na2SO3 until potassium iodide (KI) indicator paper did not change color. The organic layers were combined, washed with brine and then concentrated. The residue was purified via prep-TLC to give the title compound: 1H-NMR (400 MHz, CDCl3) δ ppm 7.77 (d, J=8.6 Hz, 1H), 7.39 (d, J=7.8 Hz, 1H), 5.39 (s, 2H), 4.43-4.45 (m, 1H), 3.26-3.28 (m, 1H), 2.68-2.70 (m, 1H), 1.94-2.01 (m, 1H), 1.08-1.12 (m, 2H), 0.65-0.75 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:11]2[N:12]=[CH:13][NH:14][C:15](=[O:16])[N:10]2[N:9]=1.[I:18]N1C(=O)CCC1=O.O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([I:18])=[C:11]2[N:12]=[CH:13][NH:14][C:15](=[O:16])[N:10]2[N:9]=1
Reactant: O=c1[nH]cnc2cc(-c3ccccc3Cl)nn12
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: O=c1[nH]cnc2c(I)c(-c3ccccc3Cl)nn12
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
To a suspension of 7-(2-chlorophenyl)-3H-pyrazolo[1,5-a][1,3,5]-triazin-4-one (I-3A-9c; 2.59 g, 10.5 mmol) in chloroform (115 ml) cooled in an ice bath was added N-iodosuccinimide (2.36 g, 10.5 mmol), portionwise, over 15 minutes. After stirring for 3 hours, the reaction was added to stirring water and methylene chloride. A solution of saturated aqueous Na2S2O4 was added until the color remained light yellow. The solid precipitate that was dispersed in the aqueous phase was collected by vacuum filtration and then dried, in vacuo, to afford intermediate I-3A-9d as a solid (3.78 g, 97%): +APcI MS (M+1) 372.9; 1H NMR (400 MHz, CD3OD) δ 8.05 (s, 1H), 7.55-7.40 (m, 4H).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:10]([OH:22])[C:11]([F:21])([F:20])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:14]1([CH2:13][CH2:12][C:11]([F:20])([F:21])[CH:10]([OH:22])[C@@H:9]([NH2:8])[CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(O)C(F)(F)CCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccccc1)C(O)C(F)(F)CCc1ccccc1
Reaction time: 1 h

Procedure:
To 1 gm of the resultant product from Example 6 was added 5 ml of trifluoroacetic acid and 5 ml of dichloromethane. After one hour at room temperature, the solution was concentrated to an oil. The oil was dissolved in 100 ml EtOAc and washed with saturated NaHCO3 solution. The organic layer was dried with anhydrous Na2SO4 and evaporation of the solvent in vacuo provided a white solid, 740 mg (98%). Mass spectrum: (M+1)=306.
Reaction SMILES: [CH3:1][C:2]1([C:8]([NH2:10])=[O:9])[CH2:7][CH2:6][CH:5]=[CH:4][CH2:3]1.C(N(CC)CC)C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.[I:30]I>CCCCC.C(Cl)Cl>[I:30][CH:5]1[CH:6]2[CH2:7][C:2]([CH3:1])([C:8](=[O:9])[NH:10]2)[CH2:3][CH2:4]1
Reactant: CC1(C(N)=O)CC=CCC1
Reactant: II
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCCCC
Solvent: CCN(CC)CC
Product: CC12CCC(I)C(C1)NC2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-methylcyclohex-3-ene-1-carboxamide, 52b, (5.0 g, 35.9 mmol) dissolved in 100 mL of pentane and CH2Cl2 was cooled to 0° C. and treated with triethylamine (11.0 mL, 79.0 mmol) and trimethylsilyl-triflate (14.3 mL, 79.0 mmol) sequentially. The resulting mixture was stirred for 1 hour at room temperature. The lower layer was removed via pipette. The upper pentane layer was concentrated in vacuo and the resulting residue was dissolved in THF (100 mL). To the stirred reaction was added iodine (20.1 g, 79.02 mmol) and the reaction was allowed to stir overnight at room temperature. After quenching with Na2SO3 and NaHCO3, the reaction was partitioned between CH2Cl2 and water. The organic layers were combined, dried over Na2SO4, concentrated in vacuo to a dark yellow oil (9.5 g) that was used without further purification.
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:22][O:23][C:24]([CH:26]1[CH2:30][C:29](=O)[CH2:28][N:27]1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:25].CC(C)([O-])C.[K+].O>C1COCC1>[CH3:22][O:23][C:24]([CH:26]1[CH2:30][C:29](=[CH2:2])[CH2:28][N:27]1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:25]
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C1CC(=O)CN1C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C1CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of methyltriphenylphosphonium iodide (1.25 g, 3.08 mmol) in THF (20 ml) at 0° C., 4-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (500 mg, 2.05 mmol) and potassium ter-butoxide (460 mg, 4.11 mmol) was added. It was stirred for overnight at room temperature. Water was added and the compound was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over sodium sulphate, filtered and concentrated under vacuum. Purification by column chromatography offered 4-methylene-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as a colorless oil (0.23 g, 46%).
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5](=[O:8])[O:6][CH:7]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][CH2:2][C:3]2[O:4][C:5](=[O:8])[O:6][CH:7]=2)=[CH:12][CH:11]=1
Reactant: Fc1ccc(S)cc1
Reactant: O=c1occ(CBr)o1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1occ(CSc2ccc(F)cc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.1 %

Procedure:
In 30 ml of dichloromethane was dissolved 1.0 g of 4-bromomethyl-1,3-dioxol-2-one, and 0.8 g of 4-fluorobenzenethiol was added. Then, 0.6 g of triethylamine was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate. The insoluble materials were separated by filtration, and the solvent was evaporated under reduced pressure. The residue was subjected to medium-pressure silica gel column chromatography as in Example 1 [except that the column was eluted with a mixture of chloroform and n-hexane (2/1, v/v)]. The eluate was evaporated under reduced pressure, and the residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 0.52 g of the captioned compound as pale yellow crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]=[C:18]([CH3:28])[S:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:15])[CH:10]([CH2:29][C:30]2[NH:31][CH:32]=[C:33]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[N:34]=2)[CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O>[F:41][C:38]1[CH:39]=[CH:40][C:35]([C:33]2[N:34]=[C:30]([CH2:29][CH:10]3[CH2:9][NH:8][CH2:13][CH2:12][N:11]3[C:14]([C:16]3[N:17]=[C:18]([CH3:28])[S:19][C:20]=3[C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)=[O:15])[NH:31][CH:32]=2)=[CH:36][CH:37]=1
Reactant: Cc1nc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2Cc2nc(-c3ccc(F)cc3)c[nH]2)c(-c2ccc(F)cc2)s1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(C(=O)N2CCNCC2Cc2nc(-c3ccc(F)cc3)c[nH]2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-[4-(4-Fluorophenyl)-1H-imidazol-2-ylmethyl]-4-{1-[5-(4-fluorophenyl)-2-methylthiazol-4-yl]-methanoyl}-piperazine-1-carboxylic acid tert-butyl ester description 112 (0.130 g) was dissolved in TFA and stirred under argon at room temperature for 3 hours. The TFA was evaporated and the residue chromatographed over silica gel, eluting with a gradient of 0 to 10% [9:1 methanol/conc. ammonia solution] in dichloromethane. The title compound was obtained as a white foam (0.095 g), mass spectrum (API+) 480 [MH+], C25H23F2N5OS requires 479.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([OH:24])=O)[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].CN(C(O[N:51]1N=N[C:53]2[CH:54]=[CH:55]C=C[C:52]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(N)CCC>CN(C=O)C>[CH2:52]([NH:51][C:22](=[O:24])[C:21]1[CH:25]=[CH:26][C:27]([CH3:28])=[C:19]([C:18]2[C:13]3[CH:12]=[CH:11][C:10](=[O:42])[N:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[C:14]=3[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=2)[CH:20]=1)[CH2:53][CH2:54][CH3:55]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCCCN
Product: CCCCNC(=O)c1ccc(C)c(-c2nc(N3CCC(N4CCC(C)CC4)CC3)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and butylamine (8.19 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (18.7 mg, 55%). LC-MS m/z 629 (M+H)+.