Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:10][CH2:11]Br)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[K+].[N:21]12[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:25][NH:24][CH2:23][CH2:22]2.[OH-].[K+]>C(OCC)C.O>[C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:10][CH2:11][N:24]2[CH2:25][CH:26]3[N:21]([CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:23]2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CC2CNCCN2C1
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: N#CC(CCN1CCN2CCCC2C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a stirred mixture of 78.5 parts of 2,2-diphenyl-4-bromobutyronitrile, 19.7 parts of potassium iodide and 30.0 parts of 1,4-diazabicyclo[4.3.0]nonane is added 70 parts of water and 19.3 parts of potassium hydroxide under a nitrogen atmosphere. The mixture is stirred and heated to 75° - 80° C. and then further heated to reflux (108° - 112° C.). After 3.5 hours of heating at reflux, the mixture is cooled to about 25° C. and 180 parts of ethyl ether added. The resulting organic layer is extracted once with a 20% solution of hydrochloric acid in water followed by a further extraction with 6% solution of hydrochloric acid in water. The aqueous extracts are then combined and basified to pH 11.0 with a 50% solution of sodium hydroxide in water. The resulting oil is extracted with three 110 parts portions of ethyl ether. The ether extracts are combined, dried over anhydrous potassium carbonate, and stripped of solvent under reduced pressure. The resulting product, 2,2-diphenyl-4-(1,4-diazabicyclo[4.3.0]non-4-yl)butyronitrile, is obtained in 89% yield. Correction of this yield to reflect the purity of the 1,4-diazabicyclo[4.3.0]nonane (96%) results in a yield of 93% for this reaction. This product boils at about 190° - 210° C. at 0.1 mm. pressure and is represented by the following structural formula. ##STR9##
Reaction SMILES: [CH:1]1([S:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[CH:15][C:16]([N:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22](C(O)=O)[CH2:21][CH2:20]4)=[N:17][CH:18]=3)[CH2:9][CH2:8]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.ClCCl>[CH:1]1([S:4]([N:7]2[CH2:8][CH2:9][N:10]([C:13]3[CH:14]=[CH:15][C:16]([N:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[NH:22][CH2:21][CH2:20]4)=[N:17][CH:18]=3)[CH2:11][CH2:12]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(O)N1CCN(c2ccc(N3CCN(S(=O)(=O)C4CC4)CC3)cn2)c2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=S(=O)(C1CC1)N1CCN(c2ccc(N3CCNc4ccccc43)nc2)CC1
Reaction time: 5 h

Procedure:
6.14 g of tert-butyl ester of 4-[5-(4-cyclopropanesulfonyl-piperazin-1-yl)pyridin-2-yl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid is put in a 1-liter three-necked flask under nitrogen atmosphere. 102 ml of dichloromethane is added, it is cooled in an ice bath and 92 ml of a 4M solution of hydrochloric acid in dioxane is added dropwise. The temperature of the reaction mixture is allowed to return slowly to room temperature and then it is stirred for 5 h. The reaction mixture is diluted with dichloromethane, then cooled in an ice bath. Then a saturated solution of NaHCO3 is added to pH=8. It is decanted and the aqueous phase is extracted with dichloromethane. The water-based organic phases are washed, dried over Na2SO4, filtered on a frit and concentrated. 4.92 g of 1-[5-(4-cyclopropanesulfonyl-piperazin-1-yl)pyridin-2-yl]-1,2,3,4-tetrahydroquinoxaline is obtained in the form of a white solid.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:22][C@H:21]([CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[N:8]2[C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N+:12]([O-])=[CH:11][C:10]=3[N:20]=[C:7]2[CH2:6]1)(=[O:4])=[O:3].[NH4+:34].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl>[NH2:34][C:11]1[C:10]2[N:20]=[C:7]3[CH2:6][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:22][C@H:21]([CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[N:8]3[C:9]=2[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@H]1CN(S(C)(=O)=O)Cc2nc3c[n+]([O-])c4ccccc4c3n21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NCCC[C@H]1CN(S(C)(=O)=O)Cc2nc3c(N)nc4ccccc4c3n21
Reaction time: 3 h

Procedure:
tert-Butyl 3-[(11S)-9-(methylsulfonyl)-5-oxido-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-11-yl]propylcarbamate (6.37 g, 13.4 mmol) was dissolved in 120 mL of CH2Cl2 and treated with 12 mL of concentrated NH4OH solution. The mixture was stirred rapidly and then p-toluenesulfonyl chloride (2.81 g, 14.7 mmol) was carefully added. Rapid stirring was continued for 3 hours. The reaction mixture was treated with 100 mL of CH2Cl2 and 25 mL of H2O. The layers were separated and the organic portion was washed successively with 2% Na2CO3 solution (3×50 mL), H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 33% CMA/CHCl3) gave tert-butyl 3-[(11S)-6-amino-9-(methylsulfonyl)-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-11-yl]propylcarbamate (5.41 g) as light-orange foam.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C@:8]2([CH2:12][C:13]([OH:15])=[O:14])[CH3:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:21](=O)(O)[O-].[Na+]>CO>[OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C@:8]2([CH2:12][C:13]([O:15][CH3:21])=[O:14])[CH3:11])=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: C[C@@]1(CC(=O)O)CCc2ccc(O)cc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C[C@]1(C)CCc2ccc(O)cc21
Reaction time: 3 h
Yield: 67 %

Procedure:
(S)-5-(6-Methoxy-1-methyl-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1,3-dioxane-4,6-dione (290 mg, 960 μmol) was dissolved in N-methylpyrrolidinone (2 mL). Water (17.2 μL, 960 μmol) was added, and the reaction was heated and stirred at 125° C. for one hour to give the intermediate anisole carboxylic acid. The reaction was cooled and NaOH (170 mg, 4.3 mmol) and 1-dodecanethiol (0.80 mmol, 3.3 mmol) were added. The reaction was reheated to 125° C. and stirred for 2.5 days. Another 2.25 equivalents of NaOH was added along with 1.75 equivalents of the thiol. The resulting mixture was stirred at 125° C. for an additional 16 hours. The reaction was then cooled to room temperature and diluted with water (about 25 mL). The resulting mixture was extracted with diethyl ether (2×50 mL) and then the aqueous layer was acidified with hydrochloric acid. The aqueous layer was extracted with EtOAc (2×75 mL). The combined EtOAc layers were washed with water (2×75 mL) and brine (1×25 mL) and dried over magnesium sulfate. The organic layer was filtered and the solvent was removed. The residue was used directly in the next step (S)-2-(6-hydroxy-1-methyl-2,3-dihydro-1H-inden-1-yl)acetic acid (370 mg, 190% yield) (contains residual NMP). The (S)-2-(6-hydroxy-1-methyl-2,3-dihydro-1H-inden-1-yl)acetic acid (197 mg, 955 mmol) was dissolved in MeOH (10 mL) and a catalytic amount of sulfuric acid was added. The mixture was heated at reflux and stirred for three hours. The reaction was cooled, basified with saturated sodium bicarbonate, and the solvent was removed. The residue was then partitioned between EtOAc and water, and the layers were separated. The aqueous layer was extracted with EtOAc (1×50 mL), and the combined organic layers were washed with brine (1×25 mL) and dried over magnesium sulfate. After filtration and solvent removal, the residue was purified by medium pressure chromatography (silica, 0 to 15% EtOAc:DCM) to give (S)-methyl 2-(6-hydroxy-1-methyl-2,3-dihydro-1H-inden-1-yl)acetate (141 mg, 67% yield). LCMS ESI (neg.) m/e: 219.1 (M−1)−. Chiral Analytical HPLC (ChiralPak AD-H column, 8% isopropanol:hexanes): retention time=18.1 minutes (second peak).
Reaction SMILES: [I-:1].F[C:3]1[CH:12]=[CH:11][C:10]2[N:9]3[C:13]4[CH:22]=[CH:21][C:20]5[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=5[N+:14]=4[CH:23]=[C:8]3[CH:7]=[CH:6][C:5]=2[CH:4]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>CO>[I-:1].[N:24]1([C:3]2[CH:12]=[CH:11][C:10]3[N:9]4[C:13]5[CH:22]=[CH:21][C:20]6[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=6[N+:14]=5[CH:23]=[C:8]4[CH:7]=[CH:6][C:5]=3[CH:4]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Fc1ccc2c(ccc3c[n+]4c5ccccc5ccc4n32)c1
Reactant: C1CCNC1
Agent: [I-]
Solvent: CO
Product: c1ccc2c(c1)ccc1n3c(ccc4cc(N5CCCC5)ccc43)c[n+]21
Temperature: 190 °C

Procedure:
A mixture of 4.14 g. of 10-fluoroimidazo[1,2-a:3,4-a']diquinolin-15-ium iodide, 3.6 g. of pyrrolidine and 100 ml. of methanol is stirred and heated in a pressure vessel at 190° C. for 24 hours, then cooled and evaporated at reduced pressure. The resulting precipitate of 10-(1-pyrrolidinyl)imidazo[1,2-a:3,4-a']diquinolin-15-ium iodide is collected and washed with cold methanol; m.p. 350°-355° C., after crystallization from dimethylformamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]([NH2:20])=O)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[O:9]2)=[CH:4][CH:3]=1.[CH3:21][C:22]([NH2:26])([CH3:25])[CH2:23]N.C1(C)C=CC=CC=1>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:9])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[N:20]3[CH2:21][C:22]([CH3:25])([CH3:23])[N:26]=[C:18]23)=[CH:6][CH:7]=1
Reactant: CC(C)(N)CN
Reactant: NC(=O)C1(c2ccc(F)cc2)OC(=O)c2ccccc21
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)CN2C(=O)c3ccccc3C(O)(c3ccc(F)cc3)C2=N1
Temperature: 25 °C

Procedure:
A mixture of 1-(4-fluorophenyl)-3-oxo-1,3-dihydro-2-benzofuran-1-carboxamide (25 g) (Step 1 of Example 2), 2-methyl-1,2-diaminopropane (40 mL), and toluene (125 mL) was heated at reflux for 18 h in a flask equipped with a water separator. The mixture was cooled to ambient temperature and extracted with water. The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was slurried with ethanol. The solid was collected by filtration and dried to give the title compound (26 g) as a white solid, m.p. 168-170° C. Anal. for C19H17N2O2F: Calculated: C, 70.35; H, 5.28; N, 8.64. Found: C, 70.16; H, 5.35; N, 8.55.
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)=O)=[N:17][C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])=[C:13]2[CH2:12][NH:11][C:10]1=[O:31].[CH3:32][CH2:33][O-:34].[Na+]>CCO>[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]([O:34][CH2:33][CH3:32])=[N:17][C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])=[C:13]2[CH2:12][NH:11][C:10]1=[O:31]
Reactant: CC[O-]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(-c2ccc(F)cc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2

Procedure:
The product of Example 3 (0.0658 g, 0.147 mmol) was suspended in EtOH (2 mL) and stirred under argon. A 0.5 M solution of NaOEt in EtOH (0.587 mL, 0.294 mmol) was added. After 15 min the solvent was removed in vacuo, and the residue partitioned between EtOAc and H2O. The organic phase was washed with H2O (2×), satd aq NaCl (1×), dried over anhydrous Na2SO4, filtered, and evaporated to give the crude product. Flash chromatography on silica gel eluted with 0-5% EtOAc/CH2Cl2 gave the title compound as a white-amorphous solid. mp 191-194° C., LC MS m/z=415 (MH+) Rt=2.15 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([C:20](=[O:32])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]([OH:31])=O)[CH:22]=2)=[N:8][CH:7]=1)=[O:5])C.C(Cl)Cl.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>>[CH3:17][O:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[O:18][CH3:19])[C:9]([C:20](=[O:32])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]([N:40]3[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]3)=[O:31])[CH:22]=1)=[N:8][CH:7]=[C:6]2[C:4]([OH:3])=[O:5]
Reactant: CCOC(=O)c1cnc(C(=O)c2cccc(OCC(=O)O)c2)c2cc(OC)c(OC)cc12
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OCC(=O)N4CCN(C)CC4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
The 1-(3-carboxymethoxybenzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid ethyl ester (119 mg, 0.23 mmol) was suspended in 8 ml of methylene chloride containing 10 equivalent of N-methylpiperizine, 1.1 equivalent of HBTU and 4.0 equivalent of triethylamine. The mixture was stirred at room temperature overnight and then evaporated to remove solvents. The residue was extracted with ethyl acetate and water. The organic layer was dried and solvents were evaporated. The residue was dissolved in 4 ml of methanol and aqueous lithium hydroxide was added (0.5N, 1 ml). The mixture was stirred overnight until all starting material disappeared. The reaction was loaded on a preparative HPLC for purification to give 6,7-Dimethoxy-1-{3-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethoxy]-benzoyl}-isoquinoline-4-carboxylic acid as a fluffy solid (39 mg, 35%). ES-MS calcd for C26H27N3O7 (m/e) 493.5, obsd 494.4 (M+H).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH3:13][O:14][C:15]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[C:23]([OH:26])[CH:22]=[CH:21][CH:20]=2)=[O:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:46][C:47]([CH3:51])([CH3:50])[CH2:48]O>C1COCC1>[CH3:13][O:14][C:15]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[C:23]([O:26][CH2:46][C:47]([CH3:51])([CH3:50])[CH3:48])[CH:22]=[CH:21][CH:20]=2)=[O:16]
Reactant: COC(=O)c1cc2c(O)cccc2[nH]1
Reactant: CC(C)(C)CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc2c(OCC(C)(C)C)cccc2[nH]1
Reaction time: 20 h

Procedure:
DEAD (0.414 ml, 2.66 mmol) is slowly added to a solution of 4-Hydroxy-1H-indole-2-carboxylic acid methyl ester 75 (363 mg, 1.9 mmol), triphenylphosphine (698 mg, 2.66 mmol) and 2,2-Dimethyl-propan-1-ol (228 mg, 2.58 mmol) in 8 ml of THF. Stirring is continued for 20 hours and the solvent is then evaporated. The crude mixture is purified by chromatography on silicagel using cyclohexane/EtOAc (9/1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:14][N:15]1[CH:19]=[C:18]([CH:20]=O)[CH:17]=[N:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[Cl:1][C:2]1[C:3]([N:8]2[CH2:9][CH2:10][N:11]([CH2:20][C:18]3[CH:17]=[N:16][N:15]([CH3:14])[CH:19]=3)[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: Cn1cc(C=O)cn1
Reactant: Clc1nccnc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(CN2CCN(c3nccnc3Cl)CC2)cn1
Reaction time: 6 h
Yield: 102.9 %

Procedure:
Dissolve 3′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (3.43 g, 17.3 mmol) in tetrahydrofuran (100 mL). Add 1-methyl-1H-pyrazole-4-carbaldehyde (2.244 g, 20.38 mmol) in dry tetrahydrofuran (5 mL), stir for 10 min. at room temperature, add sodium triacetoxyborohydride (4.32 g, 20.4 mmol), subject the reaction to ultrasound and stir for 6 hr. at room temperature. Add saturated aq. sodium hydrogen carbonate (100 mL) then 2 N sodium hydroxide (10 mL) to the mixture and extract with DCM (2×200 mL). Pass the combined DCM extracts through an IST Phase Separator Frit®, concentrate and purify (silica gel chromatography, eluting with 0:100 to 8:92 methanol:DCM), to give 3′-chloro-4-(1-methyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl as a crystalline solid (5.21 g, 92%). MS (ES): m/z=293.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH2:4][C@@H:5]([NH2:35])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:34])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])=[O:23])=[C:17]([O:32][CH3:33])[CH:16]=2)=[CH:8][CH:7]=1.[C:37]1(=[O:44])[O:43][C:41](=[O:42])[CH2:40][CH2:39][CH2:38]1>O1CCCC1>[CH3:1][O:2][C:3](=[O:36])[CH2:4][C@@H:5]([NH:35][C:37](=[O:44])[CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])[C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:34])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])=[O:23])=[C:17]([O:32][CH3:33])[CH:16]=2)=[CH:10][CH:11]=1
Reactant: O=C1CCCC(=O)O1
Reactant: COC(=O)C[C@@H](N)c1ccc(NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Solvent: C1CCOC1
Product: COC(=O)C[C@@H](NC(=O)CCCC(=O)O)c1ccc(NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 108.2 %

Procedure:
A stirred suspension of (R)-3-amino-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]-phenylacetylamino}phenyl)-propanoic acid methyl ester (0.75 g, Reference Example 30) in anhydrous tetrahydrofuran (25 ml), under an atmosphere of argon, was treated with glutaric anhydride (0.18 g). After stirring at ambient temperature for 4 hours the reaction mixture was evaporated to give the title compound (1.0 g) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[CH:9]1([C:12]2[C:13]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([C:29]4[CH:34]=[CH:33][C:32](I)=[CH:31][C:30]=4[F:36])=[O:28])[CH2:23][CH2:22]3)=[N:14][CH:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)[CH2:11][CH2:10]1>>[CH:9]1([C:12]2[C:13]([N:21]3[CH2:22][CH2:23][N:24]([C:27]([C:29]4[CH:34]=[CH:33][C:32]([N:7]5[C@H:3]([CH2:2][OH:1])[CH2:4][CH2:5][C:6]5=[O:8])=[CH:31][C:30]=4[F:36])=[O:28])[CH2:25][CH2:26]3)=[N:14][CH:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)[CH2:10][CH2:11]1
Reactant: O=C(c1ccc(I)cc1F)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: O=C1CC[C@@H](CO)N1
Product: O=C(c1ccc(N2C(=O)CC[C@H]2CO)cc1F)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 40.6 %

Procedure:
Using (S)-5-hydroxymethylpyrrolidin-2-one (94 mg) and [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](2-fluoro-4-iodophenyl)methanone (400 mg) described in Preparation Example 164 and by the reaction and treatment in the same manner as in Example 1, the title compound (158 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)([CH3:8])/[CH:3]=[CH:4]/B(O)O.[Na].B(O)O.[NH2:23][C:24]1[N:29]=[C:28]([NH2:30])[C:27](I)=[C:26]([CH3:32])[N:25]=1>C(O)C>[NH2:23][C:24]1[N:29]=[C:28]([NH2:30])[C:27](/[CH:4]=[CH:3]/[C:2]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)([CH3:8])[CH3:1])=[C:26]([CH3:32])[N:25]=1
Reactant: CC(C)(/C=C/B(O)O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1nc(N)nc(N)c1I
Agent: OBO
Agent: [Na]
Solvent: CCO
Product: Cc1nc(N)nc(N)c1/C=C/C(C)(C)c1ccc(C(F)(F)F)cc1

Procedure:
Example 17, wherein U is alkenylene [e.g., --CH=CHC(CH3)2 --], teaches a desirable method for preparing Compound 68, in which a substituted phenylmethyl halide, for example, 4-trifluoromethylphenylmethyl bromide, is treated with potassium cyanide in water, yielding the corresponding substutited phenylacetonitrile. The so-prepared acetonitrile may then be treated with potassium tert.-butoxide in tetrahydrofuran, then reacted with a lower alkyl halide, for example iodomethane, yielding the corresponding 2-alkyl-2-(substituted phenyl)propanenitrile. The propanenitrile is then treated with diisobutylaluminium hydride which converts it to the corresponding propanaldehyde, for example, 2-methyl-2-(4-trifluoromethylphenyl)propanaldehyde. The propanaldehyde may then be reacted with bromomethyl triphenylphosphonium bromide and potassium tert.-butoxide in tetrahydrofuran, affording the cis/trans-1-bromo-3-alkyl-3-(substituted phenyl)-1-butene intermediate. This compound, in turn can be dehydrohalogenated with potassium tert.-butoxide in tert.-butanol, affording the corresponding butyne, for example, 3-methyl-3-(4-trifluoromethylphenyl)-1-butyne. Using methods taught by G. W. Kabaika et al. [Synthetic Communications, 11(3), 247-251 (1981) and Synthetic Communications, 13(12), 1027-1032 (1983)], the 1-butyne is reacted with 1,3,2-benzodioxaborole to form a boronic acid, in the present case, trans-3-methyl-3-(4-trifluoromethylphenyl)-1-butenylboronic acid. The sodium salt of the boronic acid may in turn be reacted with 2,4-diamino-5-iodo-6-methylpyrimidine in the presence of tetrakistriphenylphosphine palladium(0) in ethanol, yielding the targeted trans-2,4-diamino-6-methyl-5-[3-(4-trifluoromethylphenyl)-3-methyl-1-butenyl]pyrimidine (Compound 68).
Reaction SMILES: [C:1]([CH:4]([C:10](=[O:12])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2].[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=[CH2:15]>N12CCCN=C1CCCCC2.C(O)(=O)C>[CH2:8]([O:7][C:5](=[O:6])[C:4]([C:10](=[O:12])[CH3:11])([C:1](=[O:3])[CH3:2])[CH2:15][CH2:14][C:13]([O:17][CH2:18][CH3:19])=[O:16])[CH3:9]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Solvent: CC(=O)O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CCC(C(C)=O)(C(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.4 %

Procedure:
2.0 g of ethyl 2-acetyl-3-oxo-butyrate was mixed with 5 drops of 1,8-diazabicyclo-[5.4.0]-undec-7-ene. Over 10 minutes, 2.7 g of ethyl acrylate was added dropwise. The mixture was stirred for 30 hours at room temperature, 2 ml of acetic acid was added to neutralize the base, and the mixture was extracted with an aqueous sodium carbonate solution and water. Fractional distillation yields 1.5 g of 2,2-diacetyl-1,5-pentanedioic acid diethyl ester (purity: 70%; colorless).
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:7][CH2:6][CH2:5]1)=[O:3].C[O-].[Na+].[C:11](OC)(=[O:16])[C:12]([O:14][CH3:15])=[O:13]>CO>[CH3:15][O:14][C:12](=[O:13])[C:11](=[O:16])[CH2:1][C:2]([CH:4]1[CH2:7][CH2:6][CH2:5]1)=[O:3]
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)C1CCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=O)CC(=O)C1CCC1
Reaction time: 0.08 h
Yield: 53.2 %

Procedure:
To a solution of cyclobutyl methyl ketone (4 g, 40.8 mmol) in MeOH (60 mL) was added sodium methoxide (3.3 g, 61.2 mmol) at rt. After a 5 min stirring, dimethyl oxalate (4.8 g, 40.8 mmol) was added. The reaction mixture was stirred for 3 h at rt and concentrated. The residue was taked up in diluted HCl and extracted with EtOAc. The organic layers were concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc, 9:1) to provide 4 g of the title compound. Rf=0.46 (hexane/EtOAc, 1:1); 1H NMR (300 MHz, CDCl3) δ ppm 1.70-2.40 (m, 6H), 3.58 (quintet, 1H), 3.85 (s, 3H), 6.54 (s, 1H), 13.8-15.0 (br. s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20].Cl.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:28]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[O:35])=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]
Reactant: O=C(Cl)c1cccnc1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC(=O)c2cccnc2)cc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
To a stirred solution of the [4-amino-2-(2-methylphenyl)benzoyl]methionine methyl ester (85 mg, 0.23 mmol) in CH2Cl2 (5 mL) was added nicotinic acid chloride hydrochloride (81 mg, 0.46 mmol) and saturated NaHCO3 (2 mL). The reaction was stirred at ambient temperature for 2 hours. The reaction was diluted with CH2Cl2 (10 mL), the layers were separated and the organic layer washed with saturated aqueous NaHCO3 (5 mL), dried (MgSO4) and concentrated in vacuo. Flash chromatography (CH2Cl2-methanol 50:1) and crystallization from ethyl acetate gave the desired compound (87 mg, 80%) as a white powder. 1H NMR (300 MHz, CDCl3) δ 9.10 (dd, 1H, J=2.4, 1.0 Hz), 8.80 (dd, 1H, J=4.7, 1.7 Hz), 8.21 (ddd, 1H, J=7.8, 2.4, 1.7 Hz), 8.09-8.00 (m, 2H), 7.71-7.66 (m, 1H), 7.64-7.61 (m, 1H), 7.46 (ddd, 1H, J=7.8, 4.7, 1.0 Hz), 7.35-7.20 (m, 4H), 5.92 (bd, J=7.5 Hz), 4.67-4.57 (m, 1H), 3.66 (s, 3H), 2.23-2.01 (4 s and m, 8H), 2.00 (m, 1H), 1.65-1.52 (m, 1H). MS m/z 478 (M+1)+.