Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(C=CC(O)=CC=1)O.[C:18]([OH:22])(=[O:21])[CH:19]=[CH2:20].[OH-].[Na+]>CC(C)=O.CO>[CH2:1]([NH:9][CH2:20][CH2:19][C:18]([OH:22])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN
Reactant: C=CC(=O)O
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Product: CCCCCCCCNCCC(=O)O
Temperature: 25 °C
Yield: 78 %

Procedure:
To a mixture of n-octylamine (516 g, 4.0 mols), hydroquinone (200 mg) and methanol (400 ml), acrylic acid (144 g, 2.0 mols) was added dropwise with stirring while cooling with ice. After addition, the mixture was refluxed while heating for 4 hours. After cooled to room temperature, NaOH (80 g, 2.0 mols) was added. The reaction mixture was despersed in 6 liters of acetone, and filtration and drying were carried out to obtain the Na salt of N-n-octyl-β-alanine as white crystals having a melting point (dec.) of 242° C. (349 g Yield: 78%).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[Br:16][C:17]1[C:18](Cl)=[N:19][C:20]([Cl:23])=[N:21][CH:22]=1>C1COCC1>[Br:16][C:17]1[C:18]([O:13][CH:10]2[CH2:11][CH2:12][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]2)=[N:19][C:20]([Cl:23])=[N:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2nc(Cl)ncc2Br)C1
Temperature: 25 °C
Reaction time: 19 h
Yield: 79.2 %

Procedure:
To a solution of N-Boc-3-hydroxypyrrolidine (2.06 g, 11 mmol) in anhydrous THF (50 mL), was added NaH (60% oil dispersion, 0.44 g, 11 mmol). The mixture was stirred at room temperature for 19 h. The reaction mixture was cooled to −0° C. and was added slowly to a solution of 5-bromo-2,4-dichloropyrimidine (2.28 g, 10 mmol) in anhydrous THF (20 mL) at −5° C. The resulting mixture was stirred at −0° C. for 5 h and quenched with water. The aqueous solution was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified on ISCO (hexane/ethyl acetate gradient, 0-20%) to give the title compound (3.0 g, 79.2%) as colorless oil. MS (ESI) m/z: Found: 378.0 (M++1); Calc. 377.0 (M+)
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[N:7]1[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH3:16])=[N:8]1.[N:17]1[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=1>>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[N:7]1[C:11]2=[N:12][C:23]([C:20]3[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=3)=[N:15][C:13](=[O:14])[C:10]2=[C:9]([CH3:16])[NH:8]1
Reactant: Cc1nn(C2CCCC2C)c(N)c1C(N)=O
Reactant: O=Cc1ccncc1
Product: Cc1[nH]n(C2CCCC2C)c2nc(-c3ccncc3)nc(=O)c1-2
Temperature: 120 °C
Reaction time: 1 h
Yield: 32.6 %

Procedure:
To a solution of 1-(2-methylcyclopentyl)-3-methyl-5-amino-1H-pyrazole-4-carboxamide (2.3 g, 10.4 mmol) in xylenes (8.0 ml) under argon was added 4-pyridinecarboxaldehyde (1.5 ml, 15.5 mmol). The reaction mixture was warmed to 120° C. and stirred for 1 hour at which time the mixture became homogeneous. The reaction mixture was then heated to 160° C. for 24 hours and then cooled to room temperature. A solid precipitated which was collected by filtration through a glass frit. The solid was washed with ether, saturated NaHCO3 then water and was recrystallized from DMF. The solid was collected on a glass frit and was washed with methanol, then ether and dried at 110° C. for 72 hours in high vacuum to afford 1.05 g (33%) of 1-(2-methylcyclopentyl)-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one as white crystals m.p. 290°-291° C.
Reaction SMILES: Cl.CC(Cl)=O.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([NH:27][C:28]([NH:30][C:31]3[CH:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=3)=[O:29])[CH:21]=2)[CH2:15][CH2:14]1)=[O:12])(C)(C)C>O1CCOCC1>[CH3:6][O:10][C:11]([N:13]1[CH2:14][CH2:15][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([NH:27][C:28]([NH:30][C:31]3[CH:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=3)=[O:29])[CH:21]=2)[CH2:17][CH2:18]1)=[O:12]
Reactant: Cc1ccc(NC(=O)Nc2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)ccc2F)cn1
Agent: Cl
Solvent: CC(=O)Cl
Solvent: C1COCCO1
Product: COC(=O)N1CCN(Cc2ccc(F)c(NC(=O)Nc3ccc(C)nc3)c2)CC1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
To 1.0 eq of 4-{4-fluoro-3-[3-(6-methyl-pyridin-3-yl)-ureido]-benzyl}-piperazine-1-carboxylic acid tert-butyl ester (2D) in MeOH (about 0.1 M 2D in MeOH) was added 2 volumes of HCl in dioxane (4 N) and the reaction mixture stirred at 50° C. for 15 min and evaporated to a solid. The solid was combined with DCM and treated with approximately 5 eq of TEA and split into 3 equal portions of reaction mixture A. One portion of the reaction mixture A was treated with 1.2 eq of methyl carbonyl chloride and stirred overnight. The resultant mixture was concentrated and purified by reversed phase HPLC to afford 4-{4-fluoro-3-[3-(6-methyl-pyridin-3-yl)-ureido]-benzyl}-piperazine-1-carboxylic acid methyl ester. MS 402 (M+H). A second portion of the reaction mixture A was treated with 1.2 eq of dimethylsulfamoyl chloride and stirred overnight. The resultant mixture was concentrated and purified by reversed phase HPLC to afford 4-{4-fluoro-3-[3-(6-methyl-pyrdin-3-yl)-ureido]-benzyl}-piperazine-1-sulfonic acid dimethylamide. MS 451 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]=[C:11]=[O:12].C([N:15](CC)CC)C.Cl>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]([NH2:15])=[O:12]
Reactant: CCN(CC)CC
Reactant: O=C=Nc1c(Cl)cc(Cl)cc1Cl
Agent: Cl
Solvent: CC#N
Product: NC(=O)Nc1c(Cl)cc(Cl)cc1Cl
Reaction time: 1 h
Yield: 143.8 %

Procedure:
To a stirred mixture of CC-16313 (0.450 g, 1.22 mmol) and 2,4,6-trichlorophenyl isocyanate (0.271 g, 1.22 mmol) in acetonitrile (10 mL), was added triethylamine (0.34 mL, 2.44 mmol) at room temperature under nitrogen. After 1 h, 1N aq. HCl (10 mL) was added and the mixture was stirred for 10 min. The product was isolated by filtration, washed with 1N aq. HCl (20 mL), acetonitrile (20 mL) and dried overnight in vacuo to give 1-[2-(2,6-Dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-(2,4,6-trichloro-phenyl urea as a white solid (0.42 g, 69% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.22 min (99.7%); mp: 264-266° C.; 1H NMR (DMSO-d6) δ 1.91-2.06 (m, 1H, CH), 2.31-2.47 (m, 1H, CH), 2.60 (d, J=17.0 Hz, 1H, CH), 2.83-3.02 (m, 1H, CH), 4.21-4.54 (m, 4H, CH2, CH2), 5.11 (dd, J=4.9, 13.2 Hz, 1H, NCH), 7.01 (t, J=5.9 Hz, 1H, NH), 7.44 (d, J=7.9 Hz, 1H. Ar), 7.51 (s, 1H, Ar), 7.66-7.75 (m, 311, Ar), 8.24 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.48, 31.20, 43.02, 47.07, 51.56, 121.66, 122.87, 126.72, 128.09, 130.23, 131.24, 133.34, 134.87, 142.29, 144.84, 154.97, 167.95, 170.99, 172.86; LCMS: MH=495, 497; Anal Calcd for C21H17N4O4Cl3: C, 50.51; H, 3.45; N, 11.22; Cl, 22.01. Found: C, 50.28; H, 3.17; N, 11.13; Cl, 21.96.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:9](=[O:21])[C:8]=1[Br:22])(=O)=O.[K+].[Br-:26]>CN(C)C(=O)C>[Br:22][C:8]1[C:9](=[O:21])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH:11]=[CH:12][C:7]=1[Br:26]
Reactant: [Br-]
Reactant: O=c1c(Br)c(OS(=O)(=O)C(F)(F)F)ccn1Cc1cccc(F)c1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=c1c(Br)c(Br)ccn1Cc1cccc(F)c1
Yield: 50.6 %

Procedure:
3-bromo-1-(3-fluorobenzyl)-2-oxo-1,2-dihydropyridin-4-yl trifluoromethanesulfonate (2.00 g, 4.65 mmol), KBr (5.53 g, 46.49 mmol), and 18-Crown-6-(0.10 g, 0.38 mmol) were dissolved in N,N-dimethylacetamide (26 mL). The reaction mixture was then heated at reflux for 16 hours. The reaction was concentrated and the resulting residue was partition between water (50 mL) and ethyl acetate (3×50 mL). The combined organics were washed with H2O (2×30 mL), brine (50 mL), dried over MgSO4, concentrated, and subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexane) to afford a brown solid (0.850 g, 51%).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[OH-].[Na+].Cl[CH2:9][C@@H:10]1[CH2:12][O:11]1.Cl>O>[O:11]1[CH2:12][C@@H:10]1[CH2:9][NH:5][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(N)(=O)=O
Reactant: ClC[C@@H]1CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)NC[C@H]1CO1
Reaction time: 2 h
Yield: 15.7 %

Procedure:
To a cold solution of methanesulfonamide (10 g, 0.105 mol) in water (100 mL) in an ice bath was added sodium hydroxide as pellets (8.4 g, 0.21 mol) and then (S)-2-chloromethyloxirane (12.4 g, 0.158 mol). The mixture was stirred at the same temperature for 2 h, and at room temperature for 12 h and then concentrated hydrochloric acid (18 mL) was added. The product was isolated by extracting the aqueous layer with dichloromethane (2×300 mL). The organic layer was dried over MgSO4 and then evaporated to dryness, yielding a colorless liquid (2.5 g), which was used directly in the next step.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[NH:13][C:12]=2[CH:20]=O)[CH2:4][CH2:3]1.[CH2:22]([S:24]([C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31](=[O:36])[CH2:30]2)(=[O:26])=[O:25])[CH3:23]>>[CH2:22]([S:24]([C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31](=[O:36])/[C:30]/2=[CH:20]\[C:12]1[NH:13][C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=2[C:11]=1[CH2:10][CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)(=[O:25])=[O:26])[CH3:23]
Reactant: CN1CCN(CCCc2c(C=O)[nH]c3c2CCCC3)CC1
Reactant: CCS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CCS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCCN1CCN(C)CC1)CCCC3)C(=O)N2

Procedure:
3-[3-(4-Methylpiperazin-1-yl)-propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde, prepared as described in Example 2, was condensed with 5-ethylsulfonyloxindole (Example 5) following the procedure described in Example 1 above. The reaction mixture was purified by flash chromatography and eluting with (dichloromethane: methanol 30/1, 20/1, 15/1) to give the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][Se:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[NH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl>[C:42]1([NH:41][C:10](=[O:12])[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[Se:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:18][CH:17]=2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccc(C[Se]c2ccccc2C(=O)O)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C[Se]c2ccccc2C(=O)Nc2ccccc2)cc1

Procedure:
To a solution of 1.58 g (0.00517 mol) 2-(4-methylbenzylseleno)benzoic acid (example 2) and 0.58 g (0.00573 mol) triethylamine in 10 ml dichloromethane which has been cooled to 0° C. is added 1.32 g (0.00517 mol) solid bis[2-oxo-3-oxazolidinyl]phosphoryl chloride in one portion. After stirring for 30 minutes a solution of 0.48 g aniline (0.47 ml; 0.00517 mol) in 10 ml dichloromethane and 0.74 g (1.02 ml; 0.00573 mol) triethylamine in 10 ml dichloromethane is added dropwise with stirring. The reaction mixture is stirred for 20 hours at room temperature and treated with 20 ml distilled water. The organic phase is separated and extracted successively with 20 ml water, two 25 ml portions of 10% hydrochloric acid and two 25 ml portions of 10% sodium hydroxide solution and dried. The solvent is then removed and the residue purified by column chromatography (silica gel/dichloromethane).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH2:9]Br)=[CH:7][N:6]=[C:5]([C:11]#[N:12])[CH:4]=1.[CH3:13][Si:14]([CH3:30])([CH3:29])[CH2:15][CH2:16][O:17][CH2:18][N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21][C:20]1=[O:28].C(=O)([O-])[O-].[Cs+].[Cs+].C(O)(=O)C>CN(C=O)C>[O:28]=[C:20]1[N:19]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:30])([CH3:29])[CH3:13])[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[C:21]21[CH2:9][C:8]1[CH:7]=[N:6][C:5]([C:11]#[N:12])=[CH:4][C:3]=1[CH2:2]2
Reactant: N#Cc1cc(CBr)c(CBr)cn1
Reactant: C[Si](C)(C)CCOCN1C(=O)Cc2cccnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: C[Si](C)(C)CCOCN1C(=O)C2(Cc3cnc(C#N)cc3C2)c2cccnc21
Reaction time: 0.08 h

Procedure:
To a solution of 4,5-bis(bromomethyl)pyridine-2-carbonitrile from Step B (729 mg, 2.52 mmol) and 1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (665 mg, 2.52 mmol, described in Intermediate 1) in DMF (75 mL) was added cesium carbonate (2.46 g, 7.55 mmol), portionwise, over 5 min. After 2 h, acetic acid (0.15 mL) was added and the mixture was concentrated to a volume of about 25 mL, then partitioned between CHCl3 (100 mL), saturated aqueous NaHCO3 (30 mL) and brine (50 mL). The organic layer was removed and the aqueous layer was extracted further with CHCl3 (100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 0:100, to give the title compound. MS: m/z=393 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:6]=1.[S-:19][C:20]#[N:21].[K+].BrBr>CO>[NH2:1][C:2]1[S:3][C:4]([S:19][C:20]#[N:21])=[C:5]([CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:6]=1
Reactant: N#C[S-]
Reactant: CC(C)(C)OC(=O)NCCSCc1csc(N)n1
Agent: BrBr
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCSCc1nc(N)sc1SC#N
Reaction time: 0.75 h

Procedure:
To a stirred solution of 2-amino-4-(2-t-butyloxycarbonylaminoethylthiomethyl)-1,3-thiazole (4.27 g, 14.8 mmol) and potassium thiocyanate (2.87 g, 29.5 mmol) in methanol (30 mL) cooled to 0° C. was added dropwise bromine (3.55 g, 0.022 mol) and stirring was continued for 45 min. Reaction mixture was partitioned between ethyl acetate and water. Organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford solid residue of title product in quantitative yield. Crude product was used in next step without further purification.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[S:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[C:22]([C:45]5[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=5)=[N:23][N:24]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:25]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:5])=[O:4].[CH2:52](Br)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>>[CH2:52]([N:2]([CH3:1])[S:3]([C:6]1[S:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[C:22]([C:45]5[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=5)=[N:23][N:24]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH:25]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:5])=[O:4])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: CNS(=O)(=O)c1ccc(-c2ncnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc23)s1
Reactant: BrCc1ccccc1
Product: CN(Cc1ccccc1)S(=O)(=O)c1ccc(-c2ncnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc23)s1

Procedure:
100 mg 5-{6-[3-(4-fluorophenyl)-1-trityl-1H-pyrazol-4-yl]quinazolin-4-yl}thiophen-2-sulfonic acid methylamide (compound in Example 745) and 18 μL benzyl bromide were reacted in the same manner as in Example 746, to give 64 mg 5-{6-[3-(4-fluorophenyl)-1-trityl-1H-pyrazol-4-yl]quinazolin-4-yl}thiophen-2-sulfonic acid benzyl-methylamide. This product was subjected to the same reaction as in Example 618, dissolved in dichloromethane/methanol and recrystallized from ethanol/ether, to give 11 mg of the title compound as orange crystals.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16].[Br:17][C:18]1[N:19]=[C:20]([C:25](O)=[O:26])[NH:21][C:22]=1[CH2:23][CH3:24].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Br:17][C:18]1[N:19]=[C:20]([C:25]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH3:16])=[O:26])[NH:21][C:22]=1[CH2:23][CH3:24]
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: CCc1[nH]c(C(=O)O)nc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)nc1Br
Yield: 92 %

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1e) (0.39 g, 1.67 mmol), 4-bromo-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (25b) (0.18 g, 0.82 mmol), WSC hydrochloride (0.49 g, 2.53 mmol) and HOBT (0.11 g, 0.84 mmol), to obtain 0.33 g of the title compound as a white solid (92%).
Reaction SMILES: Br[CH:2]([C:4]1[CH:5]=[C:6]([C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:10][C:9]2=[O:20])[CH3:3].C(N(CC)C1C=CC=CC=1)C.[C:37]([C:39]1[CH:40]=[C:41]([CH:44]=[C:45]([F:47])[CH:46]=1)[NH:42][CH3:43])#[CH:38]>CN(C=O)C>[C:37]([C:39]1[CH:40]=[C:41]([N:42]([CH3:43])[CH:2]([C:4]2[CH:5]=[C:6]([C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH:7]=[C:8]3[C:13]=2[O:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][C:9]3=[O:20])[CH3:3])[CH:44]=[C:45]([F:47])[CH:46]=1)#[CH:38]
Reactant: C#Cc1cc(F)cc(NC)c1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Solvent: CCN(CC)c1ccccc1
Solvent: CN(C)C=O
Product: C#Cc1cc(F)cc(N(C)C(C)c2cc(C(=O)N(C)C)cc3c(=O)cc(N4CCOCC4)oc23)c1
Yield: 34 %

Procedure:
8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (185 mg, 0.37 mmol), N,N-diethylaniline (174 μl, 1.10 mmol) and 3-ethynyl-5-fluoro-N-methylaniline (60 mg, 0.40 mmol) in DMF (1043 μl) were stirred at 50° C. for 2 days. Purification was done using an analogous procedure to the one described in Example 3.03 to give 8-(1-((3-ethynyl-5-fluorophenyl)(methyl)amino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (60 mg, 34%) as a white solid. Mass Spectrum: M+H+ 478. NMR Spectrum (DMSOd6): 1.55 (d, 3H), 2.62 (s, 3H), 2.92 (bs, 3H), 3.01 (bs, 3H), 3.18-3.27 (m, 2H), 3.28-3.33 (m partially hidden by H2O, 2H), 3.40-3.48 (m, 2H), 3.48-3.57 (m, 2H), 4.21 (s, 1H), 5.54 (q, 1H), 5.62 (s, 1H), 6.52 (d, 1H), 6.73 (d, 1H), 6.80 (s, 1H), 7.72 (d, 1H), 7.89 (d, 1H).
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[CH:9]=[C:8]([CH3:20])[N:7]=1)=[O:5])C.[NH2:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]#[N:29])[CH:23]=1>>[C:28]([C:24]1[CH:23]=[C:22]([NH:21][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=3)[CH:9]=[C:8]([CH3:20])[N:7]=2)=[O:5])[CH:27]=[CH:26][N:25]=1)#[N:29]
Reactant: N#Cc1cc(N)ccn1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(F)c2)cc(C)n1
Product: Cc1cc(-c2cc(F)cc(F)c2)cc(C(=O)Nc2ccnc(C#N)c2)n1

Procedure:
The title compound, was prepared from 4-(3,5-Difluorophenyl)-6-methyl-pyridine-2-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 4-Amino-pyridine-2-carbonitrile instead of 3-chloroaniline to yield the final compound as a white crystalline, MS (ISP): m/e=351.2 (M+H)+.
Reaction SMILES: O[CH:2]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=1)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:39]>C(Cl)Cl>[Cl:39][CH:2]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=1)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7]
Reactant: CSc1nccc(C(O)c2cccc(C#N)c2)n1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CSc1nccc(C(Cl)c2cccc(C#N)c2)n1
Reaction time: 4 h

Procedure:
To the solution of 3-{hydroxy[2-(methylthio)pyrimidin-4-yl]methyl}benzonitrile (1.65 g, 6.41 mmol) in CCl4 (10 mL) and CH2Cl2(10 mL) was added triphenylphophine (2.36 g, 8.98 mmol) and stirred for 4 h. The mixture was concentrated and the residue was purified by silica gel chromatography (20% EtOAc in hexane) to give 3-{chloro[2-(methylthio)pyrimidin-4-yl]methyl}benzonitrile. 1H-NMR (500 MHz, CDCl3) δ 8.58 (d, 1H, J=5.1), 7.79 (s, 1H), 7.70 (d, 1H, J=8.1), 7.62 (d, 1H, J=7.8), 7.49 (t, 1H, J=7.8), 7.25 (d, 1H, J=4.9), 5.92 (s, 1H), 2.51 (s, 3H). LRMS m/z (M+H) Calcd: 276.8, found: 276.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([CH3:22])=[C:6]([CH2:12][C:13]2[CH:14]=C(C=CC=2)C(O)=O)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:24]1CC[O:27][CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([CH3:22])=[C:6]([CH2:12][CH:13]2[CH2:14][O:27][CH2:26][CH2:25][NH:24]2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1COCCN1
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(CC2COCCN2)=C(C)C1=O
Yield: 55.6 %

Procedure:
3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)benzoic acid (85 mg, 0.27 mmol) obtained in Example 41 and morpholine (0.036 ml, 0.41 mmol) were used, and a method similar to that described in Example 42 was employed to obtain the title compound (57 mg, 0.15 mmol, yield 54%).
Reaction SMILES: [CH3:1][C:2]([CH3:22])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:21])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:20])=[CH:11]/[CH2:12][S:13][CH2:14][C@H:15]([NH2:19])[C:16]([OH:18])=[O:17].C([O-])([O-])=O.[K+].[K+].[C:29]1(=[O:35])[O:34][C:32](=[O:33])[CH2:31][CH2:30]1.Cl>C1COCC1>[C:16]([C@@H:15]([NH:19][C:29](=[O:35])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH2:14][S:13][CH2:12]/[CH:11]=[C:10](\[CH3:20])/[CH2:9][CH2:8]/[CH:7]=[C:6](\[CH3:21])/[CH2:5][CH2:4][CH:3]=[C:2]([CH3:22])[CH3:1])([OH:18])=[O:17]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NC(=O)CCC(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 5-trans, trans-farnesyl-L-cysteine (500 mg, 1.54 mmol) in THF and first portion of K2CO3 (2 mmol) was cooled to 5° C. with vigorous stirring. To this stirred solution was added succinic anhydride (308 mg, 3.1 mmol) drop wise while maintaining the PH at 9-10 with another portion of K2CO3 (4 mmol). The mixture was stirred at room temperature for 2 h, HPLC analysis showed completion of the reaction. The pH of the reaction mixture then adjusted to 2 by the addition of 2N HCl solution. The acidic solution was extracted three times with 10 ml of ethyl acetate. The combined organic extract was washed with water, brine and dried over sodium sulfate, the solvent was removed on rotary evaporator to afford crude product, which was further purified by preparative HPLC (535 mg, 82% yield): 1H-NMR (500 MHz, CDCl3) δ 1.59 (s, 6H), 1.66 (s, 6H), 2.05 (m, 8H), 2.60 (m, 2H), 2.48 (m, 2H), 2.86 (dd, 1H), 2.94 (dd, 1H), 3.10 (dd, 1H), 3.12 (dd, 1H), 4.68 (dd, 1H), 5.06 (m, 2H), 5.20 (t, 1H); 13C-NMR (125 MHz, CDCl3) δ 16.0, 16.1, 17.7, 25.7, 26.5, 26.7, 29.4, 29.8, 30.5, 32.6, 39.6, 39.7, 52.2, 119.3, 123.8, 124.3, 131.3, 135.4, 140.3, 173.4, 174.2, 176.8; ES-MS: mass calcd for Chemical Formula: C22H35NO5S 425.6 (M+). Found (M+Na) m/z 448.