Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][CH2:6][NH:7][C:8](=O)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[K+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:4]=1[CH2:5][CH2:6][N:7]=[C:8]2[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1
Reactant: COc1ccccc1CCNC(=O)c1ccc(C(F)(F)F)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1cccc2c1CCN=C2c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
To a 100 mL round-bottomed flask was added N-(2-methoxyphenethyl)-4-(trifluoromethyl)benzamide (1.41 g, 4361 μmol, from step 1), toluene (30 mL), phosphorus pentoxide (1077 μL, 17445 μmol, Aldrich). The reaction mixture was stirred at reflux for overnight (ca 18 h). The mixture was cooled down to RT and poured it to ice (ca 100 g). The mixture was neutralized with KOH until pH 12. The mixture was extracted with EtOAc (2×100 mL). The organic extract was washed with saturated NaCl (50 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 20% EtOAc/hexanes to give 5-methoxy-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline. MS (ESI pos. ion) m/z: 306 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([O:10][C:11]([F:14])([F:13])[F:12])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:35])=[C:4]([O:10][C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccc(Br)cc1OC(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)Oc1cc(Br)ccc1CBr
Temperature: 0 °C
Yield: 87.3 %

Procedure:
Add (4-bromo-2-(trifluoromethoxy)phenyl)methanol (9.757 g, 36 mmol) and dichloromethane (180 mL) to a 500 mL flask equipped with a magnetic stir bar and N2 inlet. Cool the solution to 0° C. and then treat with triphenylphosphine (11.33 g, 43 mmol) and carbon tetrabromide (14.26 g, 43 mmol). Stir the reaction at 0° C. for 45 minutes, warm to room temperature and stir an additional 1 hour. Wash the reaction with water (2×180 mL) and saturated sodium chloride solution (1×180 mL), then dry over anhydrous magnesium sulfate. Filter through Celite® and concentrate under vacuum to dryness. Dissolve the residue in hexanes, filter to remove the triphenyl phosphine oxide, and concentrate to a colorless oil. Purify the crude product via silica gel chromatography eluting with hexanes to afford 10.5 g (88%) of the product as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.46-7.40 (m, 2H), 7.38-7.33 (m, 1H), 4.46 (s, 3H).
Reaction SMILES: Cl.[CH:2]([O:5][CH2:6][CH2:7][N:8]([C:13]1[CH:35]=[CH:34][C:16]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH2:21][CH2:20]2)=[O:18])=[CH:15][CH:14]=1)[C:9](=[O:12])[CH2:10]Cl)([CH3:4])[CH3:3].[SH:36][CH:37]([CH2:41][C:42]([OH:44])=[O:43])[C:38]([OH:40])=[O:39]>>[CH:2]([O:5][CH2:6][CH2:7][N:8]([C:13]1[CH:35]=[CH:34][C:16]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH2:21][CH2:20]2)=[O:18])=[CH:15][CH:14]=1)[C:9](=[O:12])[CH2:10][S:36][CH:37]([C:38]([OH:40])=[O:39])[CH2:41][C:42]([OH:44])=[O:43])([CH3:4])[CH3:3]
Reactant: O=C(O)CC(S)C(=O)O
Reactant: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Agent: Cl
Product: CC(C)OCCN(C(=O)CSC(CC(=O)O)C(=O)O)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1

Procedure:
Analogously to Example 1, 1-{4-[N-(2-isopropoxyethyl)-N-chloroacetylamino]-benzoyl}-4-[2-(4-chlorophenyl)-ethyl]-piperazine hydrochloride is reacted with DL-2-mercapto-succinic acid (=DL-thiomalic acid), yielding (±)-1-{4-[N-(2-isopropoxyethyl)-N-(1,2-dicarboxyethylmercapto-acetyl)-amino]-benzoyl}-4-[2-(4-chlorophenyl)-ethyl]-piperazine.
Reaction SMILES: Br[CH:2]1[CH2:4][CH2:3]1.[Mg].[O:6]=[C:7]1[C:16]2[CH:17]=[C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:20][C:15]=2[O:14][CH2:13][C:12]2[CH:11]=[CH:10][S:9][C:8]1=2.[Cl-].[NH4+]>C1COCC1>[CH:2]1([C:7]2([OH:6])[C:16]3[CH:17]=[C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:20][C:15]=3[O:14][CH2:13][C:12]3[CH:11]=[CH:10][S:9][C:8]2=3)[CH2:4][CH2:3]1
Reactant: BrC1CC1
Reactant: COC(=O)Cc1ccc2c(c1)C(=O)c1sccc1CO2
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc2c(c1)C(O)(C1CC1)c1sccc1CO2
Reaction time: 0.5 h
Yield: 79 %

Procedure:
An anhydrous THF (50 mL) solution of bromocyclopropane (8.3 mL) was added dropwise to a metal magnesium (2.5 g), while heating. After the termination of dropwise addition, an anhydrous THF (20 mL) was added thereto, and the mixture was refluxed under heating for an additional 2 hours. Thereafter, the reaction mixture was allowed to air-cool, and this solution was added dropwise to an anhydrous THF (30 mL) solution of methyl (4-oxo-4,10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl)acetate (10.0 g) previously chilled in an ice bath. After stirring the mixture for 30 minutes, an aqueous saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, and thereafter dried over anhydrous sodium sulfate. The solvents were distilled off under a reduced pressure, and the residue obtained was purified by silica gel column chromatography (hexane-ethyl acetate=5:1), to give 9.0 g (79%) of the captioned compound as an oily product.
Reaction SMILES: C1(N(CCO)C(C2C(OCC3C=CC=CC=3)=C(O)N=C(CC3(C4C=CC=CC=4)CCCC3)N=2)=O)CC1.[Si]([O:44][CH2:45][CH2:46][N:47]([CH2:77][C:78]1[CH:83]=[CH:82][C:81]([F:84])=[CH:80][CH:79]=1)[C:48]([C:50]1[C:55]([O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[C:54]([OH:64])[N:53]=[C:52]([CH2:65][C:66]2([C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)[CH2:70][CH2:69][CH2:68][CH2:67]2)[N:51]=1)=[O:49])(C(C)(C)C)(C)C>>[F:84][C:81]1[CH:82]=[CH:83][C:78]([CH2:77][N:47]([CH2:46][CH2:45][OH:44])[C:48]([C:50]2[C:55]([O:56][CH2:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[C:54]([OH:64])[N:53]=[C:52]([CH2:65][C:66]3([C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)[CH2:67][CH2:68][CH2:69][CH2:70]3)[N:51]=2)=[O:49])=[CH:79][CH:80]=1
Reactant: CC(C)(C)[Si](C)(C)OCCN(Cc1ccc(F)cc1)C(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: O=C(c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CC1
Product: O=C(c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)Cc1ccc(F)cc1
Yield: 94.9 %

Procedure:
This compound was prepared following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid cyclopropyl-(2-hydroxyethyl)-amide (285) from 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-(4-fluoro-benzyl)-amide (312) (146 mg, 0.22 mmol). The product was obtained as colourless sticky solid (116 mg, 95.66%).
Reaction SMILES: [Cl:1][C:2]1[S:21][C:5]2[NH:6][C:7](=O)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N+:17]([O-:19])=[O:18])[C:4]=2[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:23]>N1C=CC=CC=1>[Cl:1][C:2]1[S:21][C:5]2[NH:6][C:7](=[S:23])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N+:17]([O-:19])=[O:18])[C:4]=2[CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1CN=C(c2ccccc2[N+](=O)[O-])c2cc(Cl)sc2N1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1C1=NCC(=S)Nc2sc(Cl)cc21

Procedure:
1 g (0.00327 mol) of 7-chloro-1,3-dihydro-5-(o-nitrophenyl)-2H-thieno[2,3-e]-1,4-diazepin-2-one are heated to reflux with 0.8 g of phosphorus pentasulphide in 30 ml of absolute pyridine, nitrogen being conducted through the solution. The mixture is separated on a column (φ3 cm) filled with 50 g of Silica gel[(0.05 to 0.2 mm) (Merck)] (the product travelling on the front and the impurities travelling only slowly). After concentration of the pyridine solution under a vacuum, the residue is treated with methylene chloride and brought to crystallization. After completion of the crystallization in a refrigerator, the mixture is filtered under a vacuum and washed with a small amount of ice-cold methylene chloride. Recrystallization from absolute methanol yields 7-chloro-1,3-dihydro-5-(o-nitrophenyl)-2H-thieno[2,3-e]-1,4-diazepine-2-thione in the form of yellow crystals, melting point 213°-215° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]([O:8]C)=[O:7])#[N:2].CO.[Li+].[OH-]>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1ccc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1ccc(C(=O)O)cc1C#N)C(=O)OC(C)(C)C
Reaction time: 1.25 h
Yield: 43.9 %

Procedure:
To a −25° C. solution of methyl 3-cyano-4-(N,N-bis-(t-butoxycarbonyl)aminomethyl)benzoate (1.81 g, 4.64 mmol) in THF (14 mL) was added a 1:1 mixture of MeOH (4.6 mL) and 1 M LiOH (4.6 mL). After 1.25 h, the reaction was quenched with 1 N HCl (4.6 mL), diluted with Et2O (150 mL) and washed with H2O (2×30 mL). The combined aqueous layers was extracted with EtOAc (150 mL). The combined organic layers was MgSO4 dried, filtered, and concentrated. The crude material was chromatographed (0.5% HOAc in 30% EtOAc/hexanes to 0.5% HOAc in 40% EtOAc/hexanes) to give the title compound (767 mg, 44%); IR(CHCl3): 1146, 1370, 1704, 2984, 3020 cm−1; NMR(300 MHz, DMSO-d6): 1.36 (s, 18H); 4.93 (s, 2H); 7.41 (d, 1H, J=8.4 Hz); 8.21 (d, 1H, J=8.4 Hz); 8.25 (s, 1H); MS(FD): 377.0.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[S:3][C:2]=1[SH:10].[C:11](=O)([O-])[O-].[K+].[K+].IC>C1COCC1.C(OCC)(=O)C>[CH3:11][S:10][C:2]1[S:3][C:4]2[C:9]([N:1]=1)=[CH:8][CH:7]=[CH:6][N:5]=2
Reactant: Sc1nc2cccnc2s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1nc2cccnc2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To the suspension of thiazolo[5,4-b]pyridine-2-thiol (168 mg, 1.0 mmol) in THF (3.3 ml) was added potassium carbonate (193 mg, 1.4 mmol), followed by iodomethane (68.2 μl, 1.1 mmol) dropwise. The reaction mixture was stirred at room temperature for 16 h. Additional iodomethane were mixed in (40 uL) and stirred at room temperature for another 3 h. LCMS showed reaction was complete. The crude reaction mixture was suspended in ethyl acetate and washed with water, then brine, dried over sodium sulfate, filtered, and concentrated to give 2-(methylthio)thiazolo[5,4-b]pyridine (182 mg, 1.0 mmol, 100% yield) as a tan solid.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([Cl:30])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:20]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[CH:29]=[C:28]([Cl:30])[S:27][C:17]=3[N:18]=2)[CH:22]=1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: Clc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Product: Clc1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18]C1C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([O:14][CH3:18])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(C(=O)c2ccccc2)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)c1cccc(C(=O)c2ccccc2)c1
Yield: 905.5 %

Procedure:
A stirred solution of 3-benzoylbenzoic acid (10.0 g, 44.4 mmol) and p-TSA (0.85 g, 4.39 mmol) in methanol (200 mL) was heated at 75° C. for 18 hours. The reaction mixture was allowed to cool, and the solvent evaporated at reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was evaporated at reduced pressure to afford the title compound (9.55 g, 90%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([O:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]=[CH2:21])=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>[C:8]([O:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1/[CH:20]=[CH:21]/[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: C=C[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: Brc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1/C=C/c1cccnc1
Yield: 119.9 %

Procedure:
In a sealed pressure tube under a nitrogen atmosphere, 3-bromopyridine (264.67 mg, 1.675 mmol), (2S)-N-tert-butoxycarbonyl-2-vinylpyrrolidine (300 mg, 1.52 mmol), tri-o-tolylphosphine (46.82 mg, 0.153 mmol), palladium(II) acetate (34.53 mg, 0.15 mmol), triethylamine (2 mL) and acetonitrile (20 mL) were stirred at 90° C. for 14 h. The tube was cooled and the contents were slowly poured into a stirred saturated aqueous NaHCO3 solution (20 mL) and extracted with chloroform (4×20 mL). The combined chloroform extracts were dried (K2CO3), filtered and concentrated under vacuum to give 500 mg of a viscous dark oil, which was chromatographed with an ethyl acetate:hexane gradient (1:4 to 1:1, v/v) as eluant. Selected fractions containing the product were combined and concentrated on a rotary evaporator to give 310 mg (84.0% yield) of pale-yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH2:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(OCC)(=O)C.CCCCCC>C(OCC)(=O)C>[CH:18]1([NH:17][C:13]2[N:12]=[C:11]([C:10]3[C:9]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)=[N:8][N:7]4[C:2]([NH:31][CH2:32][CH2:33][N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)=[CH:3][CH:4]=[CH:5][C:6]=34)[CH:16]=[CH:15][N:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COc1ccc(-c2nn3c(Cl)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Reactant: NCCN1CCOCC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nn3c(NCCN4CCOCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 140 °C
Yield: 73 %

Procedure:
A mixture of 4-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (150 mg, 0.36 mmol) and 4-(2-aminoethyl)morpholine (3 mL, 21.2 mmol) was heated at 140° C. for 4 hours. Concentration of the reaction mixture followed by flash chromatography (3:1 ethyl acetate-hexane to ethyl acetate) provided 3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)-N-[2-(4-morpholinyl)ethyl]pyrazolo[1,5-a]pyridin-7-amine (135 mg, 74%) as a pale yellow foam. 1H NMR (CDCl3): δ 8.01 (d, 1 H), 7.78 (d, 1 H), 7.61 (d, 2 H), 7.30 (t, 1 H), 6.99 (d, 2 H), 6.52 (t, 1 H), 6.36 (d, 1 H), 5.98 (d, 1 H), 5.08 (d, 1 H), 4.37 (m, 1 H), 3.88 (s, 3 H), 3.76 (m, 4 H), 3.46 (q, 2 H), 2.76 (t, 2 H), 2.54 (m, 4 H), 2.12–1.52 (m, 8 H); MS m/z 514 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]#[C:20][Si](C)(C)C)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.[Cl-].[NH4+]>CO.O1CCCC1>[C:19]([C:12]1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[N:14][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[N:10][CH:11]=1)#[CH:20]
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1cnc(Nc2cccc(F)c2)nc1NCCC
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
To a solution of N2-(3-fluorophenyl)-N4-propyl-5-((trimethylsilyl)ethynyl)pyrimidine-2,4-diamine (S1, 509 mg) in methanol (10 mL) and tetrahydrofuran (10 mL), potassium carbonate (246 mg) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, ethyl acetate and saturated aqueous ammonium chloride were added. The organic layer was separated, washed successively with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 94 to 60% hexane in ethyl acetate) to obtain 5-ethynyl-N2-(3-fluorophenyl)-N4-propylpyrimidine-2,4-diamine (S2, 226 mg).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[OH:8].ClCCl.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(N(CC)CC)C>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[O:8][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: OC1CC2C=CC1C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC1CC2C=CC1C2
Reaction time: 3 h

Procedure:
To a solution of bicyclo[2.2.1]hept-5-en-2-ol (25 g) in 200 mL of anhydrous, dichloromethane is added triethylamine (30 mL) and 4-N,N-dimethylaminopyridine (30 mg). With stirring at room temperature and under an inert atmosphere, of acetic anhydride (35 mL) was added neat and dropwise to the above reaction mixture while maintaining the reaction at room temperature over 1.5 h. Upon complete addition of the anhydride the reaction is left for 3 h, the solvents were stripped and the crude mixture was purified by silica gel chromatography eluting with 25% ethyl acetate/hexanes to afford the title compound in a quantitative yield. 1H NMR (CDCl3, 400 MHz) δ 6.21 (m, 1H), 5.83 (m, 1H), 5.18 (m, 1H), 3.12 (d, 1H), 2.72 (d, 1H), 2.16 (s, 3H), 2.00 (m, 1H), 1.35 (m, 1H), 1.21 (m, 1H), 0.83 (m, 1H), APCl MS m/z 153.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:14][CH:15]3[CH2:17][CH2:16]3)[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:8][C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[SH:29][CH2:30][C:31]([O:33][CH3:34])=[O:32]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH:15]1([CH2:14][N:6]2[C:5]3[CH:18]=[CH:19][C:2]([S:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:3][C:4]=3[N:8]=[C:7]2[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:17][CH2:16]1
Reactant: COC(=O)CS
Reactant: CC(C)(C)Cc1nc2cc(Br)ccc2n1CC1CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)CSc1ccc2c(c1)nc(CC(C)(C)C)n2CC1CC1
Temperature: 25 °C
Yield: 109.7 %

Procedure:
To a solution of 5-bromo-1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazole (Step D, 4.0 g, 12.5 mmol) in 1,4-dioxane (25 mL) were added N,N′-diisopropylethylamine (4.4 mL, 25 mmol), methyl mercaptoacetate (1.1 ml, 12.5 mmol), tris(dibenzylideneacetone)dipalladium(0) (284 mg, 0.31 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (362 mg, 0.63 mmol). The mixture was stirred at reflux temperature for 24 h under nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1 as eluent) to afford the title compound (4.75 g, quant.) as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[NH:18][C:17]1=[O:27].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:10])([CH3:14])[C:11]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[NH:18][C:17]1=[O:27])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N[C@@H]1CCc2ccccc2NC1=O
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@@H]1CCc2ccccc2NC1=O

Procedure:
Prepared from N-t-butoxycarbonyl-2-methylalanine and 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1, Step E) substituting benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate for benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate according to the procedure described in Example 1, Step I. 1H NMR (200 MHz, CDCl3): δ 1.47 (s, 3H), 1.52 (s, 3H), 1.82 (m, 1H), 2.50-3.00 (m, 3H), 4.45 (m, 1H), 5.05 (s, 2H), 5.37 (s, 1H), 6.80-7.40 (m, 10H) and 8.65 (s, 1H). FAB-MS: calculated for C22H25N3O4 395; found 396 (M+H, 100%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=2)[O:10][CH:11]([CH2:15][CH2:16][CH3:17])[C:12](O)=[O:13])[N:3]=1.S(Cl)([Cl:23])=O>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=2)[O:10][CH:11]([CH2:15][CH2:16][CH3:17])[C:12]([Cl:23])=[O:13])[N:3]=1
Reactant: CCCC(Oc1cccc(-c2noc(C)n2)c1)C(=O)O
Reactant: O=S(Cl)Cl
Product: CCCC(Oc1cccc(-c2noc(C)n2)c1)C(=O)Cl

Procedure:
3.50 g (12.7 mmol) of 2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]pentanoic acid are dissolved in 10 ml of thionyl chloride, and the mixture is heated at the boil for 2 hours. The reaction mixture is evaporated, the residue is taken up in toluene, and the solution is reevaporated, giving 2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]-pentanoyl chloride as a yellowish solid.
Reaction SMILES: [CH2:1]([P:3]([O-:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2].[O-]CC.[Na+].[CH2:14](Cl)[CH:15]=[CH2:16]>C(O)C.Cl[Ni](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([P:3]([CH:14]=[CH:15][CH3:16])(=[O:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCCCOP([O-])CC
Reactant: C=CCCl
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC=CP(=O)(CC)OCCCC
Yield: 66 %

Procedure:
At room temperature, a three-neck flask equipped with stirrer and high-performance condenser is initially charged with 400 g of ethanol and this initial charge is devolatilized by stirring and passing nitrogen through it. Then, under nitrogen, 3.27 g (5 mmol) of bis(triphenylphosphine)nickel dichloride and 30 g (0.2 mol) of butyl ethylphosphonite (produced as in Example 2) are added followed by the dropwise addition of initially 14.5 g (0.25 mol) of sodium ethoxide in ethanol and thereafter 19.1 g (0.25 mol) of allyl chloride. Following a reaction time of 5 hours, the reaction solution is passed for purification through a column charged with Deloxan® THP II and the solvent is removed in vacuo. The product is purified by column chromatography to obtain 25.1 g (66% of theory) of butyl ethylpropenylphosphinate as colorless oil.