Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[SH:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:5]2[N:6]([C:8]3[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:10][CH:9]=3)[CH:7]=[C:3]([CH2:2][S:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[Cl:25])[N:4]=2)=[CH:19][CH:20]=1
Reactant: Sc1ccccc1Cl
Reactant: CS(=O)(=O)c1ccc(-n2cc(CCl)nc2-c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-n2cc(CSc3ccccc3Cl)nc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
To a solution of 4-chloromethyl-2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole (Example 159, Step 1) (250 mg, 0.656 mmol) and 2-chlorothiophenol (190 mg, 1.31 mmol) in 5 ml of dimethylformamide was added potassium carbonate (226 mg, 1.64 mmol). The mixture was stirred rapidly overnight at room temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, the combined organic extracts were washed with brine, and dried-over sodium sulfate. The solution was filtered and then concentrated. Chromatography of the residue over silica gel using 50% ethyl acetate in hexane as the eluent followed by crystallization gave the title compound as a pure white crystalline solid (147 mg): mp (DSC) 153° C. Anal. Calc'd. for C23H18Cl2N2O2S2 (MW 489.44): C, 56.44; H, 3.71; N, 5.72. Found: C, 56.51; H, 3.54; N, 5.57.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C@@H:6]1[C@H:10]([OH:11])[C@@H:9]([CH2:12][OH:13])[O:8][C@H:7]1[N:14]1[CH:21]=[C:20]([CH3:22])[C:18](=[O:19])[NH:17][C:15]1=[S:16].C(N(CC)CC)C.[F:30][C:31]([F:38])([F:37])[C:32](OCC)=[O:33]>CO>[F:30][C:31]([F:38])([F:37])[C:32]([NH:1][CH2:2][CH2:3][CH2:4][O:5][C@@H:6]1[C@H:10]([OH:11])[C@@H:9]([CH2:12][OH:13])[O:8][C@H:7]1[N:14]1[CH:21]=[C:20]([CH3:22])[C:18](=[O:19])[NH:17][C:15]1=[S:16])=[O:33]
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCCN)c(=S)[nH]c1=O
Reactant: CCOC(=O)C(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCCNC(=O)C(F)(F)F)c(=S)[nH]c1=O

Procedure:
2′-O-Aminopropyl-5-methyl-2-thiouridine is dissolved in MeOH and 5 equivalents of triethylamine are added followed by 10 equivalents of ethyl trifluoroacetate. The title compound is isolated after purification.
Reaction SMILES: [C@@H:1]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].C[C:22]([OH:25])([CH3:24])C>CN(C=O)C.CC(OC(C)=O)=O.N1C=CC=CC=1>[C:2]([O:3][C@@H:2]1[C@H:4]([O:5][C:4](=[O:5])[CH3:6])[C@@H:6]([CH2:7][O:8][C:22](=[O:25])[CH3:24])[O:9][C@H:1]1[N:10]1[C:20]2[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=2[N:12]=[CH:11]1)(=[O:3])[CH3:1]
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: CC(C)(C)O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 2.5 h

Procedure:
To a suspension of guanosine (1) (Dried in vacuo over P2O5 for 2 days at 100°, 10.6 g, 37.6 mmole) in DMF (distilled from P2O5,30 ml), Ac2O (re-distilled, 22.4 ml) and pyridine (distilled from KOH, 11.2 ml) were added. The mixture was heated with stirring at 75°. The mixture became clear solution after 1.5 h. Heating was continued for another 2.5 h. The resulting clear solution is filtered while hot, cooled to temperature, and evaporated in vacuo to afford a heavy, crystalline suspension. A portion (35 ml) of 2-methyl-2-propanol was added. The suspension is filtered, and the filter cake was washed with 2-methyl-2-propanol and dried. This crystalline is the hemi-solvate with HCONMe2, and was added to boiling 2-methyl-2-propanol, and the suspension was boiled under reflux for 5 min, cooled and refrigerated for 10 h at −5°. After filtration, the white crystalline was dried in air overnight, dried in vacuo over P2O5 for 2 days at 80°, to give white powder (12.0 g, 78.4%, mp:227-230°, lit. 226-231°).
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Cl.O>CS(C)=O>[NH2:3][CH2:4][CH2:5][CH2:6][N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([Cl:14])[CH:16]=1
Reactant: NCCCNc1ccccn1
Reactant: ClCc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: NCCCN(Cc1cccc(Cl)c1)c1ccccn1
Reaction time: 1 h
Yield: 60.5 %

Procedure:
Sodium hydride (1.32 g) was dissolved in DMSO (25 ml) at 70°-75° C. under nitrogen. The solution was cooled and 2-(3-aminopropylamino)pyridine (7.56 g) in DMSO (20 ml) added at room temperature. 3-Chlorobenzyl chloride (8.86 g) in DMSO (15 ml) was added dropwise maintaining the temperature at 20°-25° C. After a further 1 hour, water was added (200 ml) and the mixture extracted with ether. The ether extracts were washed with 2N hydrochloric acid and the aqueous layer adjusted to pH 3.5. After extracting with chloroform the pH was raised to 14 and extracted with ether. After drying (K2CO3), the final ether extracts were stripped to give 2-[N-(3-aminopropyl)-N-(3-chlorobenzyl) amino]pyridine (8.34 g) as an oil which was used without further purification. (ii) 2-[N-(3-aminopropyl)-N-(3-chlorobenzyl)amino]pyridine (1.65 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one (1.3 g) were heated together under reflux in pyridine (15 ml) for 20 hr. On cooling, the mixture was stripped, the residue triturated with wet ether and recrystallised twice from ethanol/water to give 2-[3-[N-(3-chlorobenzyl)-N-pyrid-2-ylamino]propylamino]-5-(6-methylpyrid-3-ylmethyl) pyrimid-4-one 0.6H2O, 1.29 g (53%) mp 100°-104° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:51]([NH2:62])[C:52]1[CH:61]=[CH:60][C:57]([O:58][CH3:59])=[C:54]([O:55][CH3:56])[CH:53]=1>CN(C=O)C>[CH3:56][O:55][C:54]1[CH:53]=[C:52]([CH:61]=[CH:60][C:57]=1[O:58][CH3:59])[CH2:51][NH:62][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([I:1])[CH:3]=[CH:4][C:5]=1[NH:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: COc1ccc(CN)cc1OC
Reactant: O=C(O)c1cc(I)ccc1NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNC(=O)c2cc(I)ccc2NC2CCOCC2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A mixture of 14.22 g of 5-iodo-2-(tetrahydro-2H-pyran-4-ylamino)benzoic acid, 18.4 g of HBTU, 21.28 g of DIEA and 9.18 g of veratrylamine in 200 ml of DMF is stirred overnight at room temperature. The reaction medium is evaporated under reduced pressure. The residue is taken up in 3000 mL of EtOAc. The solution is washed with aqueous 0.5N HCl solution, with saturated aqueous NaHCO3 solution, and then with saturated aqueous NaCl solution. The organic phase is dried over MgSO4, filtered and evaporated under reduced pressure to give 18 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=2)=[CH:4][CH:3]=1.[Br:33][CH2:34][CH2:35]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[Br:33][CH2:34][CH2:35][N:13]1[C:14](=[O:16])[C:15]2[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:32][CH:31]=3)[C:8]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:28])[F:29])[CH:21]=3)=[N:9][C:10]=2[N:11]([CH3:18])[C:12]1=[O:17]
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCBr)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (100 mg, 0.215 mmol, Intermediate 9) in DMF (3 mL) was added 1,2-dibromoethane (100 mg, 0.532 mmol), followed by potassium carbonate (60 mg, 0.429 mmol). The mixture was stirred at 80° C. overnight. The mixture was diluted with ethyl acetate and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give crude product, which was purified by recrystallization from ethanol to give 1-(2-bromoethyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (120 mg, 97.6% yield) as white solid. LCMS retention time 2.103 min; LCMS MH+ 573.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].Cl[C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1>O1CCCC1>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: Clc1nc2ccccc2o1
Solvent: C1CCOC1
Product: Fc1ccc(Nc2nc3ccccc3o2)cc1C(F)(F)F

Procedure:
To a solution of 17.9 g. (0.1 mole) of 4-fluoro-3-(trifluoromethyl)aniline in 200 ml. of tetrahydrofuran was added dropwise 15.4 g. (0.1 mole) of 2-chlorobenzoxazole in 150 ml. of tetrahydrofuran with vigorous agitation. Following the addition, the reaction mixture was heated on a steam bath under reflux for 16 hours. Then the tetrahydrofuran solvent was removed by distillation under vacuum, and 100 ml. of water was added to the residue. The residue was an oily liquid which solidified on the addition of the water. The residue was removed by filtration and dried in vacuo. The dried residue was dissolved in a minimum amount of warm acetone, and about 200 ml. of water was added to the solution, resulting in the crystallization of the reaction product. The precipitate was filtered and dried and 24.5 g. of 2-[4-fluoro-3-(trifluoromethyl)anilino]benzoxazole having a melting point of 190°-191° C. was recovered.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12](S(C2C=NC=CC=2)(=O)=O)[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[C:29]([F:36])[CH:28]=1.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>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:30]2[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][C:29]=2[F:36])[NH:12][CH:11]=1)[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
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+]
Product: CN(Cc1c[nH]c(-c2ccc(Cl)cc2F)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (4-chloro-2-fluorophenyl)boronic acid (243 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (220 mg), the title compound was obtained as a colorless oil (yield 127 mg, 54%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:14][CH:15]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[C:16]([F:19])([F:18])[F:17])=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.O.O.[Sn](Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(O)C>[F:19][C:16]([F:17])([F:18])[CH:15]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[O:14][C:5]1[C:4]([NH2:1])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: O=[N+]([O-])c1cc2ccccc2nc1OC(c1cccnc1)C(F)(F)F
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc2ccccc2nc1OC(c1cccnc1)C(F)(F)F
Temperature: 90 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
3-Nitro-2-[2,2,2-trifluoro-1-(pyridin-3-yl)ethoxy]quinoline (253 mg, 0.720 mmol) obtained in Step 3 was dissolved in ethanol (12.7 mL). To this, tin chloride dihydrate (817 mg, 3.62 mmol) was added and the mixture was stirred at 90° C. for 1 hour. By addition of an aqueous sodium bicarbonate solution to neutralize the reaction mixture, the reaction was stopped. Then, extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0 to 3/1) to give Compound HF (182 mg, yield: 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[CH:16][CH2:17][CH2:18]Br)[C:6]=2[CH:20]=1.[O:21]=[C:22]1[C:30]2([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[N:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH:24]2[NH:23]1.[ClH:36]>C(O)C>[ClH:1].[ClH:36].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[CH:16][CH2:17][CH2:18][N:33]3[CH2:32][CH2:31][C:30]4([N:25]5[CH2:26][CH2:27][CH2:28][CH2:29][CH:24]5[NH:23][C:22]4=[O:21])[CH2:35][CH2:34]3)[C:6]=2[CH:20]=1
Reactant: Clc1ccc2c(c1)C(=CCCBr)c1ccccc1CC2
Reactant: O=C1NC2CCCCN2C12CCNCC2
Agent: Cl
Solvent: CCO
Product: O=C1NC2CCCCN2C12CCN(CCC=C1c3ccccc3CCc3ccc(Cl)cc31)CC2
Reaction time: 5 h

Procedure:
A mixture of 3.0 g of 3-chloro-5-(3-bromopropylidene)-10,11-dihydro-5H-dibenz[a,d]cycloheptene and 3.0 g of 1,2,3,5,6,7,8,8a-octahydro-2-oxoimidazo[1,2-a]pyridine-3-spiro-4'-piperidine in 20 ml of ethanol is boiled under reflux with stirring for 5 hours. The ethanol is then distilled off under reduced pressure, and the residue is dissolved in 30 ml of toluene. The toluene solution is washed with water and extracted with 30 ml of 5% hydrochloric acid. The aqueous layer is treated with activated charcoal and made alkaline. The separated oil is allowed to stand. The crystals thus obtained is dissolved in ethanol, and ethanolic hydrochloric acid is added to give 2.8 g of 1'-[3-(3-chloro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)propyl]-1,2,3,5,6,7,8,8a-octahydro-2-oxo-imidazo[1,2-a]-pyridine-3-spiro-4'-piperidine dihydrochloride as white crystals, m.p. 262° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([C@@H:32]2[C@@H:36]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:35][CH2:34][N:33]2C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)=[O:31])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.C(S)CCCCCCC.N12CCCN=C1CCCCC2>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([C@@H:32]2[C@@H:36]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:35][CH2:34][NH:33]2)=[O:31])[C:10]([N:12]2[CH2:13][CH2:14][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([CH3:28])(=[O:26])=[O:27])[CH2:16][CH2:17]2)=[O:11])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Nc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2[C@@H](c3ccccc3)CCN2C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Agent: CCCCCCCCS
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@H]2NCC[C@@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The title compound was prepared according to the procedure of Sheppeck, J. E., et al. (Tetrahedron Lett. 2000, 41, 5329-5333) using fluoren-9-ylmethyl 2-{N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl)piperidyl)-2-oxoethyl]carbamoyl}(2S, 3R)-3-phenylpyrrolidine carboxylate (Step a) (415 mg, 0.5 mmol), THF (10 mL), n-octanethiol (Aldrich) (876 mg, 6 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (Aldrich) (5 mg, 0.03 mmol). The reaction mixture was stirred for 5 h at 25° C. and the organic solvent was removed in vacuo. To the residue was added Et2O (20 mL) resulting in precipitation of the compound. The precipitate was collected by filtration and washed with hexane to provide a yellow solid. Purification by preparative reverse phase HPLC [Phenomenex; 5 μm 250×21.2 mm, 5% to 95% CH3CN (0.1% TFA) in H2O (0.1% TFA) over 30 min, then 100% CH3CN (0.1% TFA) for 2 min] provided the title compound (TFA salt) as a white foam (187 mg). MS (ESI, pos. ion) m/z: 609 (M+1); (ESI, neg. ion) m/z: 607 (M−1). Calc'd for C32H37ClN4O4S: 608.22. Anal. Calcd for C32H37ClN4O4S.1.4C2HF3O2: C, 54.37; H, 5.03; N, 7.29. Found: C, 54.26; H, 5.19; N, 7.41.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[CH:5][C:4]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[N:3]1.C(N(CC)C(C)C)(C)C.[F:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:30]=1[C:31](Cl)=[O:32]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:30]=1[C:31]([NH:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)[CH:5]=2)=[CH:12][CH:11]=1)=[O:32]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Cn1nc(-c2cccs2)cc1-c1ccc(N)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2cccs2)cc1-c1ccc(NC(=O)c2c(F)cccc2F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
To a solution of 66 (20 mg, 0.08 mmol) in CH2Cl2 (10 ml) was added N,N-diisopropylethylamine (DIEA, 26 mg, 36 μL, 0.2 mmol), 4-dimethylaminopyridine (DMAP, 0.6 mg, 0.05 mmol). The 2,6-difluorobenzoyl chloride (15 mg, 0.08 mmol) was dropped into above solution. The mixture was stirred for 2 h at room temperature. The reaction was quenched with saturated NaHCO3 (20 ml) and extracted with EtOAc. The dicarboxamide was hydrolyzed with 1M NaOH in THF and MeOH (1:1). The product was purified by HPLC and afforded 67 (20.5 mg, 65%) as yellow solid. LC-MS: calcd. for C21H15F2N3OS: 396 (M+1). 1H NMR (DMSO-d6) δ 3.86 (s, 3H), 6.77 (s, 1H), 7.08-7.10 (m, 1H), 7.26-7.29 (m, 2H), 7.42 (dd, 1H, J=0.88, 3.5), 7.42 (dd, 1H, J=0.88, 4.9), 7.59 (d, 2H, J=8.6), 7.62-7.63 (m, 1H), 7.83 (d, 2H, J=8.6), 11.00 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5](=O)[CH2:6][C:7]([O:9]CC)=O)[CH3:2].Cl.[CH:17]1([C:20](=[NH:22])[NH2:21])[CH2:19][CH2:18]1.C[O-].[Na+]>CO>[CH:17]1([C:20]2[NH:22][C:5]([CH:4]([O:3][CH2:1][CH3:2])[O:13][CH2:14][CH3:15])=[CH:6][C:7](=[O:9])[N:21]=2)[CH2:19][CH2:18]1
Reactant: N=C(N)C1CC1
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCOC(OCC)c1cc(=O)nc(C2CC2)[nH]1
Reaction time: 8 h

Procedure:
To a mixture of ethyl 4,4-diethoxy-3-oxobutanoate (prepared according to the method of E. Graf, R. Troschutz, Synthesis, 1999, 7, 1216; 10.0 g, 46 mmol) and cyclopropanecarboximidamide monohydrochloride (Lancaster Synthesis, 5.0 g, 41 mmol) in methanol (100 mL) was added a methanol solution of sodium methoxide (5.4 M, 8.4 mL, 46 mmol). The reaction mixture was stirred overnight. The solvent was removed with a rotary evaporator. Dichloromethane was added and the mixture was filtered. The solvent from the filtrate was removed with a rotary evaporator. The residue was purified by medium pressure liquid chromatography (MPLC) (35→100% ethyl acetate in hexanes as eluant) to afford the title compound as a white solid (4.67 g).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)[CH3:11]>CC(N(C)C)=O>[CH2:10]([O:12][C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:16][N:17]1[CH2:18][CH2:19][CH:20]([NH:23][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:21][CH2:22]1)[CH3:11]
Reactant: N#Cc1ccc(F)cc1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Solvent: CC(=O)N(C)C
Product: CCOc1cc(CN2CCC(Nc3ccc(C#N)cc3)CC2)ccc1OC
Yield: 16 %

Procedure:
A solution of 4-fluoro-benzonitrile (36.3 mg, 0.30 mmol, 1.0 equiv; commercially available) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (95.2 mg, 0.36 mmol, 1.2 equiv; intermediate A1) in DMAc (2 mL) was heated by microwave irradiation to 210° C. for 3 h. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 17.8 mg (16%) of the title compound. MS (ISP): 366.4 [M+H]+.
Reaction SMILES: C(OC([N:8]([S:20]([C:23]1[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=1[CH3:31])(=[O:22])=[O:21])[C:9](=[NH:19])[NH:10][CH2:11][CH2:12][CH2:13][C@@H:14]([C:16]([OH:18])=[O:17])[NH2:15])=O)(C)(C)C.Cl.O1CCOC[CH2:34]1.O=S(Cl)Cl.CO>O1CCOCC1>[NH2:15][C@H:14]([C:16]([O:18][CH3:34])=[O:17])[CH2:13][CH2:12][CH2:11][NH:10][C:9](=[NH:19])[NH:8][S:20]([C:23]1[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=1[CH3:31])(=[O:22])=[O:21]
Reactant: C1COCCO1
Reactant: Cc1cc(C)c(S(=O)(=O)N(C(=N)NCCC[C@H](N)C(=O)O)C(=O)OC(C)(C)C)c(C)c1
Agent: Cl
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)CCCNC(=N)NS(=O)(=O)c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.10 g of Nω -t-butoxycarbonyl-Nω -mesitylenesulfonyl-L-arginine [Boc-Arg(Mts)-OH] was dissolved in 31 ml of dry dioxane and 31 ml of 4N HCl-dioxane was added thereto. The obtained mixture was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure to dryness and then crystallized by adding dry ether. The target product was collected by centrifugation, washed with dry ether several times and dried in a desiccator. Thus 1.1 g of HCl.H-Arg(Mts)-OH from which Boc groups had been removed was obtained. This product was next added to a solution, which had been prepared by slowly adding 2.9 ml of SOCl2 to 10.6 ml of methanol and stirring at -10° C. for 10 minutes, and the obtained mixture was stirred for 15 hours, concentrated to dryness, crystallized from dry ether, centrifuged, washed with dry ether several times and dried. Thus 0.94 g of HCl.H-Arg(Mts)-OMe was obtained.
Reaction SMILES: [CH3:1][C@@:2]1([C:18]([F:21])([F:20])[F:19])[CH2:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:9]=[C:4]2[NH:3]1.[CH3:22][C:23]1([O:26][CH2:25]1)[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][N:3]1[C:4]2=[N:9][C:8]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)=[CH:7][C:6](=[O:16])[N:5]2[CH2:17][C@@:2]1([CH3:1])[C:18]([F:21])([F:19])[F:20]
Reactant: CC1(C)CO1
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(O)CN1c2nc(N3CCOCC3)cc(=O)n2C[C@@]1(C)C(F)(F)F
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
To 0.500 g (1.643 mmol) of (S)-2-methyl-7-(morpholin-4-yl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one, in solution in 15 cm3 of acetonitrile, are added at a temperature close to 20° C., 1.185 g (16.43 mmol) of isobutylene oxide and 0.535 g (16.43 mmol) of cesium carbonate. After 1 hour of stirring at 120° C. and 1 hour 30 mins at 130° C. in a microwave appliance, the reaction medium is dry concentrated under reduced pressure (2.7 kPa) and then diluted in 30 cm3 of ethyl acetate and then washed with twice 20 cm3 of distilled water and 30 cm3 of solution saturated with sodium chloride. The organic phase is dried on anhydrous magnesium sulfate, filtered and dry concentrated under reduced pressure (2.7 kPa) in order to obtain a pale yellow oil which is purified by flash chromatography on silica [eluent: dichloromethane/methanol/acetonitrile (94/3/3 by volume)]. After concentration of the fractions under reduced pressure (2.7 kPa), 500 mg of (S)-1-(2-hydroxy-2-methyl-propyl)-2-methyl-7-(morpholin-4-yl)-2-(trifluoro-methyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one are obtained as a white solid melting at 72° C. and including the following characteristics: