Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([S:8]([N:11]2[C:16]3[CH:17]=[C:18]([C:21]([OH:23])=O)[CH:19]=[CH:20][C:15]=3[O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[NH2:59][C:60]1[CH:67]=[CH:66][C:63]([C:64]#[N:65])=[CH:62][CH:61]=1>ClCCl>[C:64]([C:63]1[CH:66]=[CH:67][C:60]([NH:59][C:21]([C:18]2[CH:19]=[CH:20][C:15]3[O:14][CH2:13][CH2:12][N:11]([S:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:24][CH3:25])(=[O:10])=[O:9])[C:16]=3[CH:17]=2)=[O:23])=[CH:61][CH:62]=1)#[N:65]
Reactant: N#Cc1ccc(N)cc1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ccc(C(=O)O)cc21
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ccc(C(=O)Nc3ccc(C#N)cc3)cc21
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
A solution of 4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid (example 1, steps 1 to 4) (1.0 g, 2.6 mmol) in dichloromethane (50 mL) was treated with N,N-diisopropyl ethyl amine (0.34 g, 2.6 mmol) and cooled to 0° C. Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (2.4 g, 5.2 mmol) was added, and the mixture was stirred at 0° C. for 1 min. 4-Aminobenzonitrile (1.2 g, 10.4 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was evaporated, and the crude was purified by flash chromatography (heptane/ethyl acetate gradient) yielding 4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid (4-cyano-phenyl)-amide as a white solid, 0.18 g (14%), MS (ISP): m/e=482.0 (M−H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].CO.[Br:14]N1C(=O)CCC1=O>[H-].[Na+].C(Cl)Cl>[Br:14][C:7]1[CH:6]=[C:5]([O:9][CH3:10])[C:4]([OH:11])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cccc(OC)c1O
Reactant: O=C1CCC(=O)N1Br
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(Br)cc(OC)c1O
Temperature: -45 °C
Yield: 63.5 %

Procedure:
To a 2 liter flask equipped with a magnetic stirrer, thermometer, and nitrogen inlet, was added 77 g (0.5 mol) of pyrogallol 1,3-dimethyl ether, 5.8 ml of MeOH, and 750 ml of CH2Cl2. To this solution was added 126 mg (5 mmol) of NaH (95%). The solution was stirred while cooling to −45° C. with a dry-ice acetone bath. 94 g (0.53 mol) of powdered N-bromosuccinimide was added rapidly. The reaction mixture was then stirred for 1 hour at −35° C., heated to room temperature over next 30 min, and finally refluxed for 30 min. The CH2Cl2 was removed under reduced pressure and the residue solidified. The tan solid was broken up and stirred well with 1 liter of ether. This was filtered and the residue was washed well with ether. The ether was evaporated under reduced pressure to yield a tan solid. The solid was placed in a 5 liter flask with 3 liters of ligroin (bp: 90-110° C.) and heated with stirring to 80° C. The hot solution was decanted from the brown oil and the hot yellow solution was allowed to cool at room temperature for 3 hr. The white needles was filtered off and dried to yield 74 g (63%) of 17.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([C:15]2[CH:19]=[CH:18][O:17][C:16]=2[CH2:20][OH:21])=[CH:13][CH:12]=[C:11]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[H][H]>O1CCOCC1.C(O)(=O)C.[OH-].[OH-].[Pd+2]>[C:1]([NH:4][C:5]1[C:14]([C@H:15]2[CH2:19][CH2:18][O:17][C@H:16]2[CH2:20][OH:21])=[CH:13][CH:12]=[C:11]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)ccc(-c2ccoc2CO)c1NC(C)=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc([C@H]2CCO[C@H]2CO)c1NC(C)=O
Reaction time: 8 h
Yield: 69.3 %

Procedure:
A solution of methyl 2-acetylamino-6-(2,2-dimethylpropionylamino)-3-(2-hydroxymethylfuran-3-yl)benzoate (Intermediate 38, 0.2 g) in dioxane (4 mL) and acetic acid (1 mL) was treated under an atmosphere of nitrogen with palladium hydroxide on carbon (10%, 0.03 g). The nitrogen was replaced by hydrogen and the mixture was stirred under an atmosphere of hydrogen overnight. The mixture was filtered through Celite and the pad was washed thoroughly with ethyl acetate. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of methanol and ethyl acetate with a gradient of 0-10% to give methyl 2-acetylamino-6-(2,2-dimethylpropionylamino)-3-[cis-(2RS,3RS)-2-(hydroxymethyl)tetrahydrofuran-3-yl]benzoate (0.14 g) as a white solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:25]3[C:26]([O:31]CC4C=CC(OC)=CC=4)=[N:27][CH:28]=[CH:29][CH:30]=3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.O1CCOCC1>C(Cl)Cl.O.C([O-])(O)=O.[Na+]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[C:24]([C:25]3[C:26](=[O:31])[NH:27][CH:28]=[CH:29][CH:30]=3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:16][CH:17]=1)=[O:11]
Reactant: COc1ccc(COc2ncccc2-c2nccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(c1ccc(Oc2nccnc2-c2ccc[nH]c2=O)cc1)c1nc2ccccc2[nH]1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a suspension of (1H-benzo[d]imidazol-2-yl)(4-(3-(2-(4-methoxybenzyloxy)pyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone (0.050 g, 0.094 mmol) in DCM/water in a 50 mL round bottom flask was added DDQ (0.026 g, 0.113 mmol) and dioxane (1 mL). The mixture was stirred at 60° C. for 16 h. The mixture was diluted with saturated NaHCO3 and extracted with DCM (3×25 mL). The combined organic layer was washed with saturated NaHCO3 and brine. The insoluble material was collected, washed with ethanol, filtered and dried in vacuo to give 3-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)pyridin-2(1H)-one. MS (ESI, pos. ion) m/z: 410.2 (M+1). IC50 (uM) +++++.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=1)[OH:4].[C:22]([O:26][C:27](=[O:48])[NH:28][C:29]([C:31]1[S:32][C:33]([S:46][CH3:47])=[C:34]([S:36]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41](Br)[CH:40]=2)(=[O:38])=[O:37])[CH:35]=1)=[NH:30])([CH3:25])([CH3:24])[CH3:23].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.CCO>[C:22]([O:26][C:27](=[O:48])[NH:28][C:29](=[NH:30])[C:31]1[S:32][C:33]([S:46][CH3:47])=[C:34]([S:36]([C:39]2[CH:44]=[C:43]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([CH:3]([OH:4])[C:2]([F:1])([F:20])[F:21])[CH:6]=3)[CH:42]=[CH:41][CH:40]=2)(=[O:38])=[O:37])[CH:35]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC1(C)OB(c2cccc(C(O)C(F)(F)F)c2)OC1(C)C
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2cccc(C(O)C(F)(F)F)c2)c1

Procedure:
Following the same procedure in Example 1, step c, reaction of 2,2,2-trifluoro-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethanol (123 mg, 416 mmol, as prepared in Example 28, step b), {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (100 mg, 0.2 mmol, as prepared in Example 27, step c), tetrakis(triphenylphosphine)palladium(0) (59 mg, 0.05 mmol, Strem Chemicals Inc, Newburyport, Mass.), Na2CO3 (800 μL, 2M aqueous), and toluene/EtOH mixture (2:1, 2.4 mL) afforded 100 mg (85%) after purification (SiO2, flash elution: 30% EtOAc in hexanes) of the title compound as a white foam. 1H-NMR (CDCl3; 400 MHz) δ 8.20 (t, 1H, J=1.7 Hz), 7.94–7.99 (m, 2H), 7.77–7.81 (m, 1H), 7.67 (br s, 1H), 7.57 (m, 1H), 7.27–7.34 (m, 1H), 7.15–7.21 (m, 2H), 5.11 (q, 1H, J=6.8 Hz), 2.51 (s, 3H), 1.49 (s, 9H). 19F-NMR (CDCl3; 400 MHz) δ −78.51 (d, J=6.9 Hz). ESI-MS (m/z): Calcd. for C25H25F3N2O5S3: 586.7; found: 586.7.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]([N:14]3[CH2:19][CH2:18][C:17]4([C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[CH2:21][O:20]4)[CH2:16][CH2:15]3)=[O:13])=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[F:30][C:31]([F:45])([F:44])[C:32]1[CH:33]=[C:34]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:35]Br>CN(C)C=O>[F:30][C:31]([F:44])([F:45])[C:32]1[CH:33]=[C:34]([CH:37]=[C:38]([C:40]([F:43])([F:41])[F:42])[CH:39]=1)[CH2:35][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:12]([N:14]2[CH2:15][CH2:16][C:17]3([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][O:20]3)[CH2:18][CH2:19]2)=[O:13])=[C:7]1[CH3:11]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: Cc1[nH]c2cc(Cl)ccc2c1C(=O)N1CCC2(CC1)OCc1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N2CCC3(CC2)OCc2ccccc23)c2ccc(Cl)cc2n1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 16 h
Yield: 41.2 %

Procedure:
To a solution of 0.031 g (0.080 mmol) 1′-[(6-chloro-2-methyl-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (5) in 1 ml dry N,N-dimethylformamide were added 0.004 g (0.08 mmol) sodium hydride (50% in oil). After stirring for 20 min 0.015 ml (0.08 mmol) 3,5-bis(trifluoromethyl)benzyl bromide were added. After stirring for 16 h the reaction mixture was quenched with water and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with water (2×30 ml) and brine (1×30), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (n-heptane/ethyl acetate) to give the title compound (0.020 g; 41%) as a white solid. MS m/e (%): 607 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[CH3:25][O:26][CH2:27]Cl.O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:25][O:26][CH3:27])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:5])[CH3:2]
Reactant: COCCl
Reactant: CCOC(=O)c1cc2ccc(OCc3ccccc3)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(OCc3ccccc3)cc2n1COC
Reaction time: 0.25 h
Yield: 101.7 %

Procedure:
To a solution of 6-benzyloxy-1H-indole-2-carboxylic acid ethyl ester (3.00 g, 10 mmol) in DMF (30 ml) was added 60% sodium hydride in oil (0.49 g, 12 mmol) under ice cooling and the mixture was stirred for 15 minutes. Then to the mixture was added chloromethyl methyl ether (1.0 ml, 13 mmol) under ice cooling and stirred for 0.5 hour. Water (60 ml) was added to the reaction mixture and extracted with AcOEt, the organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous sodium sulfate and evaporated to give the title compound (3.45 g) as a pale brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]#[N:12])=[CH:4][CH:3]=1.[C:13]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14]1.[Si]([C:23]#[N:24])(C)(C)C>C(OCC)(=O)C>[C:23]([C:13]1([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]#[N:12])=[CH:6][CH:7]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1)#[N:24]
Reactant: N#CCCCc1ccc(N)cc1
Reactant: O=C1CCCC1
Reactant: C[Si](C)(C)C#N
Solvent: CCOC(C)=O
Product: N#CCCCc1ccc(NC2(C#N)CCCC2)cc1
Temperature: 80 °C
Reaction time: 13 h
Yield: 102.3 %

Procedure:
A mixture of 4-(4-Aminophenyl)butanenitrile (97) (52 mg, 0.27 mmol), cyclopentanone (0.07 mL, 0.55 mmol) and TMSCN (0.05 mL, 0.55 mmol) was heated to 80° C. and stirred for 13 h. To the medium was added ethyl acetate (2×20 mL) and then washed with water (2×20 mL). The organic layer was dried over MgSO4, concentrated and the residue was purified with silica gel column chromatography (hexane:ethyl acetate, 1:1) to give 4-[4-(1-Cyanocyclopentyl amino)phenyl]butanenitrile (93) (70 mg, quant.) as a white solid.
Reaction SMILES: [OH:1][CH:2]([CH2:22][OH:23])[CH2:3][N:4]1[CH:9]=[CH:8][C:7](=[O:10])[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]1[C:19]([OH:21])=[O:20].[C:24]([O-])(O)=O.[Na+].S(OC)(OC)(=O)=O.Cl.[Na+].[Cl-]>[Cl-].[Na+].O.O.CN1C(=O)CCC1>[OH:1][CH:2]([CH2:22][OH:23])[CH2:3][N:4]1[CH:9]=[CH:8][C:7](=[O:10])[C:6]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:5]1[C:19]([O:21][CH3:24])=[O:20]
Reactant: O=C(O)c1c(OCc2ccccc2)c(=O)ccn1CC(O)CO
Reactant: O=C([O-])O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1c(OCc2ccccc2)c(=O)ccn1CC(O)CO
Temperature: 0 °C

Procedure:
A reactor was charged with 1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic acid 6 (4.302 kg, 13.47 mol) followed by charging with NaHCO3 (1.69 kg, 20.09 mol) and 242 g of deionized water. To this was added 21.4 kg of NMP and the mixture was stirred and temperature brought to 28-35° C. Dimethyl sulfate (2.34 kg, 18.30 mol) was added dropwise via an addition funnel to the reaction mixture over 1-3 hours keeping the temperature at 28-33° C. The slurry was agitated at this temperature for 14 h. When deemed complete, the reaction mixture was cooled to 5° C. or below and the mixture was neutralized to pH 6 by the addition of HCl (561 mL of conc HCl in 2806 g of deionized water). The reaction vessel was slowly charged with cold 20% brine solution composed of 8.7 kg NaCl, 20 kg of deionized water and 14.8 kg of ice at a maximum temperature of 10° C. The mixture was agitated at 0-10° C. for 2.5 h. The slurry was filtered under vacuum and the cake washed with 15 kg of deionized water two times. The wet solid product was dried at 45-55° C. under vacuum until constant weight was obtained. The desired product methyl 1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate 7 was obtained as a light yellow solid (3.77 kg, 99.42% purity by HPLC, 84%). 1H NMR (300 MHz, DMSO-d6) δ 7.60 (d, J=7.5 Hz, 1H), 7.36 (m, 5H), 6.28 (d, J=7.5 Hz, 1H), 5.23 (d, J=5.4 Hz, 1H), 5.10 (Abq, J=10.8 Hz, 2H), 4.85 (m, 1H), 3.98 (dd, J=14.3, 2.4 Hz, 1H), 3.79 (s, 3H), 3.70 (dd, J=14.3, 9.0 Hz, 1H), 3.58 (m, 1H), 3.23 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:20]=[CH:19][NH:18][C:17](=[O:21])[CH:16]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[C:23](=O)([O-])[O-].[K+].[K+].CI>COCCOC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:20]=[CH:19][N:18]([CH3:23])[C:17](=[O:21])[CH:16]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cc[nH]c(=O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: COCCOC
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1ccn(C)c(=O)c1
Temperature: 25 °C
Reaction time: 30 h
Yield: 59.5 %

Procedure:
To a solution of 85 mg (0.274 mmol) of 4-[4-(3-chloro-phenylethynyl)-2-methyl-imidazol-1-yl]-1H-pyridin-2-one in 6 ml of DME were added 76 mg (0.55 mmol) of potassium carbonate and 0.034 ml (0.55 mol) of methyl iodide. The suspension was stirred at room temperature for 30 h. The mixture was diluted with 20 ml of ethyl acetate, filtered and concentrated in vaccuo. After purification by flash chromatography on silicagel one obtains 53 mg (0.163 mmol, 60%) of the title compound, as a crystalline yellow solid, MS: m/e=324.2, 326.2 (M+H+).
Reaction SMILES: [CH3:1][C:2](O)([CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH:3]=[CH2:4].P(Br)(Br)[Br:18].O>CCCCCC.N1C=CC=CC=1>[Br:18][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: BrP(Br)Br
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)C
Solvent: O
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CC(=CCBr)CCCC(C)CCCC(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 189.9 %

Procedure:
In 300 ml of hexane were dissolved 50 g of 3,7,11-trimethyl-1-dodecen-3-ol and 0.87 g of pyridine, and 30.8 g of phosphorus tribromide was added dropwise to the solution at 0° to -10° C. After 2 hours of stirring at 0° C., the reaction mixture was poured into water and extracted with hexane. The hexane layer was successively washed with aqueous sodium hydrogen carbonate and aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off to give 62.5 g of crude 1-bromo-3,7,11-trimethyl-2-dodecene. To a suspension of 14.2 g of zinc in 26 ml of acetic acid was added dropwise 62.5 g of the crude 1-bromo-3,7,11-trimethyl- 2-dodecene and the mixture was stirred at room temperature for 1 hour. Thereafter, the zinc was filtered off and the filtrate was poured into water and extracted with hexane. The hexane layer was washed with aqueous sodium hydrogen carbonate and aqueous sodium chloride in that order and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was further distilled under reduced pressure to give 10.6 g (yield 25%) of 3,7,11-trimethyl-1-dodecene. The physical constants of the compound are as follows.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:38][CH2:39]SC)[C:13]([NH:15][C@H:16]1[CH2:21][CH2:20][C@@H:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][C@H:17]1[CH2:30][S:31]([C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:33])=[O:32])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+]>IC.C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:38][CH2:39][N:15]([C@H:16]2[CH2:21][CH2:20][C@@H:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:18][C@H:17]2[CH2:30][S:31]([C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:32])=[O:33])[C:13]1=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)C[C@H]1CS(=O)(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](CS(=O)(=O)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.3 %

Procedure:
tert-Butyl (1R,3R,4S)-4-((S)-2-benzyloxycarbonylamino-4-(methylthio)butanamido)-3-(tert-butylsulfonylmethyl)cyclohexylcarbamate (6.2 g) was dissolved in iodomethane (60 mL) and CH2Cl2 (15 mL). The resulting solution was stirred at rt for 72 h before being concentrated in vacuo. The residue was dissolved in methylene chloride, and the resulting solution was concentrated; this was repeated to afford the salt. This material was dissolved in DMF (60 mL) and the solution was charged with Cs2CO3 (13.2 g). After 12 h, the reaction was partitioned between EtOAc and brine. The organic phase was dried (MgSO4), filtered, and concentrated to afford tert-butyl (1R,3R,4S)-4-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-3-(tert-butylsulfonylmethyl)cyclohexylcarbamate (5.5 g). MS found: (M+H)+=566.5.
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[P:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14].[CH2:23]([I:25])[CH3:24].P(=O)(O)(O)O>C1(C)C=CC=CC=1>[I-:25].[CH2:23]([P+:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:22])[CH3:24]
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Reactant: CCI
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1
Product: CC[P+](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Product: [I-]
Temperature: 27 °C

Procedure:
Into a 50 millimeter glass reactor equipped with a thermometer connected to a temperature controller, a heating mantle, a condenser and a magentic stirring bar, is charged 5 gms (0.0164 mole) of tri-o-tolyl phosphine and 23 gms of toluene. The slurry is heated to 27° C., then 3.08 gms (0.0177 mole) of ethyl iodide is added. This reaction mass is heated to 70° C. and maintained at that temperature for 17 hours, then heated to 100° C. and maintained at that temperature for 9 hours, then cooled to 70° C. and maintained at that temperature for 15 hours, then cooled to 26° C. and the resulting phosphonium salt collected by filtration. The salt is washed with 6 gms of toluene then vacuum dried. There if obtained 1.6 gms of catalyst which has a melting point of 247°-250° C. and a chemical shift of 28.5 ppm (phosphoric acid reference).
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](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39].[CH2:40]([N:42]([CH2:47][CH3:48])[CH2:43][CH2:44][CH2:45][NH2:46])[CH3:41]>C1COCC1>[CH2:40]([N:42]([CH2:47][CH3:48])[CH2:43][CH2:44][CH2:45][NH:46][C:16]1[N:17]=[C:18]([C:19]2[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=2[CH3:35])[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[O:23])[C:13]2[CH2:12][NH:11][C:10](=[O:39])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1)[CH3:41]
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CCN(CC)CCCN
Solvent: C1CCOC1
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)Nc3ccc(F)cc3)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 63 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (20 mg, 0.036 mmol) in THF (3 mL) was added N,N-diethyl-1,3-propanediamine (0.030 mL, 0.19 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (14 mg, 62%). LC-MS m/z 619 (M+H)+; 1H-NMR (MeOD) δ 1.00 (t, 6H), 1.55 (m, 2H), 2.38 (s, 3H), 2.55 (m, 6H), 3.10 (m, 2H), 4.11 (s, 2H), 7.15 (m, 4H), 7.53 (m, 2H), 7.72 (m, 2H), 7.82 (s, 1H), 7.98 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[N:18]1[CH2:23][CH2:22][CH:21]([C:24](Cl)=[O:25])[CH2:20][CH2:19]1.[CH2:27]([NH2:29])[CH3:28]>>[CH2:27]([NH:29][C:24]([CH:21]1[CH2:22][CH2:23][N:18]([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:6]=2)[CH2:19][CH2:20]1)=[O:25])[CH3:28]
Reactant: CCN
Reactant: O=C(Cl)C1CCN(c2cc(-c3ccccc3)nc3ccc(F)cc23)CC1
Product: CCNC(=O)C1CCN(c2cc(-c3ccccc3)nc3ccc(F)cc23)CC1

Procedure:
In a manner analogous to that of Example 1(e) but using 1-[(6-fluoro-2-phenyl-4-quinolinyl]-4-piperidinecarbonyl chloride and ethylamine as starting materials the named compound was obtained as cream-colored needles, mp 225°-227° dec after recrystallization from methanol.