Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16](OS(C(F)(F)F)(=O)=O)[C:17]=1[C:18]([O:20]C(C)(C)C)=[O:19])=[O:11].[F:33][C:34]([F:46])([F:45])[O:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>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.O.C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:39]2[CH:38]=[CH:37][C:36]([O:35][C:34]([F:33])([F:45])[F:46])=[CH:41][CH:40]=2)[C:17]=1[C:18]([OH:20])=[O:19])=[O:11]
Reactant: CC(C)(C)OC(=O)c1c(OS(=O)(=O)C(F)(F)F)csc1NC(=O)c1cc2ccccc2o1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(Nc1scc(-c2ccc(OC(F)(F)F)cc2)c1C(=O)O)c1cc2ccccc2o1
Reaction time: 2 h
Yield: 24.3 %

Procedure:
tert-butyl 2-(benzofuran-2-carbonylamino)-4-(trifluoromethylsulfonyloxy)thiophene-3-carboxylate (85, 50 mg, 0.102 mmol), 4-(trifluoromethoxy)phenylboronic acid (32 mg, 0.153 mmol), Tetrakis(triphenylphosphine)palladium(0) (1.0 mg, 0.001 mmol), and sodium carbonate (42 mg, 0.407 mmol), were combined in 2:1:1 ethanol, toluene and water the biphasic mixture was stirred vigorously in sealed vial at 70 C. After 2 hours, the mixture was filtered through Celite and the Celite rinsed with methylene chloride. The organic fraction of the filtrate was washed with water, dried with sodium sulfate, filtered, concentrated, purified by preparative layer chromatography (10% ethyl acetate/Hexane) then treated with a 1:1 mixture of methylene chloride and trifluoroacetic acid. After 4 hours the mixture was concentrated in vacuo, and the residue triturated in methylene chloride, centrifuged, decanted and dried under high vacuum to give 87 as a white powder (11.1 mg, 25%). 1H NMR (500 MHz, DMSO d6) δ=13.35 (br, 1 H), 12.55 (br, 1 H), 7.87 (d, 1 H), 7.86 (s, 1 H), 7.76 (d, 1 H), 7.57 (t, 1 H), 7.49 (d, 2 H), 7.42 (t, 1 H), 7.36 (d 2 H), 7.08 (s, 1 H) ppm. ESI MS [M+H] 448.26.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]4[C:27](=[O:28])[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:20]4=[O:29])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[C:30]([Cl:38])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O)C>CCOCC>[ClH:38].[C:30]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=2)[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]3[C:27](=[O:28])[C:26]4=[CH:25][CH:24]=[CH:23][CH:22]=[C:21]4[C:20]3=[O:29])[CH2:13][CH2:12]2)=[N:7]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCN(c2n[nH]c3cc(F)ccc23)CC1
Solvent: CCOCC
Solvent: CCO
Product: Cl
Product: O=C1c2ccccc2C(=O)N1CCN1CCN(c2nn(C(=O)c3ccccc3)c3cc(F)ccc23)CC1
Reaction time: 2 h

Procedure:
A mixture of 2-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperazinyl]ethyl]-1H-isoindol-1,3-(2H)-dione (6.0 g, 15 mmol) and benzoyl chloride (25 ml) was stirred at 175 C. under N2 for 2.0 hours. The reaction was cooled and diluted with anhydrous Et2O and the resultant hydrochloride salt was collected to yield 7.2 g. The compound was stirred in boiling absolute ethanol (300 ml) for 1 hour and then at ambient temperature overnight. The solid was collected and dried to afford 6.9 g. Recrystallization from MeOH gave 3.9 g of a light grey solid, m.p. 257°-260° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C@@H:14]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH2:37](I)[CH3:38]>CN(C=O)C.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C@@H:14]([NH:22][C:23](=[O:30])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]([CH2:37][CH3:38])[CH:13]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCI
Reactant: N#Cc1ccc(-c2c[nH]c([C@H](Cc3ccccc3)NC(=O)c3ccccc3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1cc(-c2ccc(C#N)cc2)nc1[C@H](Cc1ccccc1)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
The compound of Example 182 Part A (60 mg, 0.15 mmol) was dissolved in DMF (2.5 mL) and potassium carbonate (32 mg, 0.23 mmol) was added followed by ethyl iodide (0.015 mL, 0.19 mmol), and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with EtOAc (3×). The combined extracts were washed with water and brine, then dried over Na2SO4, filtered and evaporated. The residue was chromatographed on silica gel to provide the product (48 mg, 76%). 1H NMR (400 MHz, DMSO-D6) δ 1.17 (t, J=7.25 Hz, 3H) 3.34-3.48 (m, 2H) 3.89-4.05 (m, 2H) 5.46 (d, J=7.03 Hz, 1H) 7.14 (d, J=7.03 Hz, 1H) 7.21 (t, J=7.47 Hz, 2H) 7.31 (d, J=7.47 Hz, 2H) 7.41 (t, J=7.25 Hz, 2H) 7.48 (d, J=7.03 Hz, 1H) 7.76-7.84 (m, 3H) 7.88 (s, 1H) 7.94 (d, J=8.79 Hz, 2H) 9.08 (d, J=8.35 Hz, 1H). m/z 421.2 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.Cl[CH:9]1[S:13][C:12]2[C:14]([C:19]#[N:20])=[CH:15][CH:16]=[C:17]([F:18])[C:11]=2[CH:10]1[Cl:21]>ClCCl>[Cl:21][C:10]1[C:11]2[C:17]([F:18])=[CH:16][CH:15]=[C:14]([C:19]#[N:20])[C:12]=2[S:13][CH:9]=1
Reactant: N#Cc1ccc(F)c2c1SC(Cl)C2Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(F)c2c(Cl)csc12
Temperature: 25 °C
Reaction time: 168 h

Procedure:
Triethylamine (1.70 mL, 12.2 mmol) was added to a solution of 2,3-dichloro-4-fluoro-2,3-dihydrobenzo[b]thiophene-7-carbonitrile (1.57 g, 5.93 mmol) in dichloromethane (50 mL). The mixture was stirred at room temperature for 7 days, then the solvent was removed and the residue extracted with EtOAc. The organic extracts were then washed with water, brine and dried over Na2SO4. After removal of the solvent, the residue was purified by silica gel column chromatography to give 3-chloro-4-fluorobenzo[b]thiophene-7-carbonitrile as a white solid (1.19 g, 95% for two steps). 1H NMR (400 MHz, CDCl3, δ in ppm) 7.73 (dd, J=4.1, 8.2 Hz, 1H), 7.42 (s, 1H), 7.17 (dd, J=8.2, 10.5 Hz, 1H).
Reaction SMILES: [CH:1]1([CH:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([N:33]([CH3:41])[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])=[O:32])=[CH:27][CH:26]=2)[C:8]2[O:9][C:10]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:11]=3[C:12]=2[CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([N:33]([CH3:41])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:32])=[CH:29][CH:30]=2)[C:8]2[O:9][C:10]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:11]=3[C:12]=2[CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(F)cc3c2COCCOC)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COCCOCc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a mixture of ethyl 3-[({4-[(cyclohexyl{5-fluoro-3-[(2-methoxyethoxy)methyl]-1-benzofuran-2-yl}methyl)amino]phenyl}carbonyl)(methyl)amino]propanoate (175 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), 1N hydrochloric acid (1.00 mL) was added at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (143 mg, 82%) as a yellow solid.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH2:49][CH3:50])[N:20]([C:40]2[CH:41]=[CH:42][C:43]3[O:47][CH2:46][CH2:45][C:44]=3[CH:48]=2)[C:21](=[O:39])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][C:25]=1[F:38])[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH2:49][CH3:50])[N:20]([C:40]2[CH:41]=[CH:42][C:43]3[O:47][CH2:46][CH2:45][C:44]=3[CH:48]=2)[C:21](=[O:39])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][C:25]=1[F:38])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(CC)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(CC)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1F
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
A mixture of hydroxylammonium chloride (1.0 g), sodium hydrogen carbonate (1.5 g) and dimethyl sulfoxide (6 mL) was stirred at 50° C. for 30 min, 4′-{[4-butyl-1-(2,3-dihydro-1-benzofuran-5-yl)-2-ethyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (0.60 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (6 mL), N,N′-carbonyldiimidazole (0.37 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.34 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography and recrystallized from dichloromethane and diisopropyl ether to give the title compound (0.62 g, 92%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C@@:8]2([CH3:15])[NH:13][C:12](=S)[CH2:11][O:10][CH2:9]2)[CH:7]=1.[NH3:17].C(OO)(C)(C)C>CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C@:8]2([CH3:15])[CH2:9][O:10][CH2:11][C:12]([NH2:17])=[N:13]2)[CH:7]=1
Reactant: C[C@@]1(c2cc(Br)ccc2F)COCC(=S)N1
Reactant: N
Agent: CC(C)(C)OO
Solvent: CO
Solvent: O
Product: C[C@@]1(c2cc(Br)ccc2F)COCC(N)=N1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A pressure tube was charged with a solution of (R)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-morpholine-3-thione (1.93 g, 6.3 mmol) in methanol (195 ml). A solution of ammonia in methanol (7M, 54 ml, 381 mmol) and an aqueous solution of tert-butyl hydroperoxide (70%, 8.17 g, 63.4 mmol) were added. The tube was sealed and the reaction mixture was stirred overnight at room temperature for 21 hours. For the workup, the reaction mixture was diluted with water and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulphate and evaporated. The crude product was purified by chromatography on an Isolute flash NH2 column using dichloromethane as the eluent. The (R)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine was obtained as an off-white gum (1.42 g, 62% of theory). MS (ISP): m/z=287.1 [M+H]+, 289.0 [M+2+H]+.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[H][H].Cl.[CH3:19][N:20]([CH3:25])[CH2:21][CH2:22][CH2:23]Cl>CN(C=O)C.O>[CH3:19][N:20]([CH3:25])[CH2:21][CH2:22][CH2:23][N:14]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]2[C:15]1=[CH:3][CH:4]=[CH:5][CH:6]=2
Reactant: CN(C)CCCCl
Reactant: [H][H]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCCn1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82.6 %

Procedure:
NaH (14.4 g of 60%, 360 mmol) was added portion-wise under argon to a suspension of carbazole 1 (20 g, 119.8 mmol) in dry DMF (200 mL). The mixture was stirred at room temperature for about 1 h until the evolution of the hydrogen ceased. 3-Dimethylaminopropylchloride hydrochloride (28 g, 180 mmol) was added portion-wise at room temperature. The reaction mixture was stirred for 20 min at room temperature, then at 60° C. for 3 hrs, and poured into cold water (500 mL). The product was extracted with EtOAc (2×500 mL). The organic layer was back extracted with 10% HCl (200 mL) and the acidic layer was extracted with EtOAc to remove the unreacted carbazole. Saturated ammonia (200 mL) was added and the product extracted again with EtOAc. Evaporation of the solvent afforded 25 g (99 mmol, 83%) of 9-(2-dimethylaminopropyl)carbazole 2b as a brown oil.
Reaction SMILES: Cl.Cl.[N:3]1([NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:16][CH:17]=2)=[O:11])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:24](Cl)(=[O:26])[CH3:25].CCN(CC)CC>CN(C=O)C>[C:24]([N:6]1[CH2:5][CH2:4][N:3]([NH:9][C:10]([C:12]2[CH:17]=[N:16][C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][CH:13]=2)=[O:11])[CH2:8][CH2:7]1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: O=C(NN1CCNCC1)c1cnc(-c2ccccc2)nc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(NC(=O)c2cnc(-c3ccccc3)nc2)CC1
Yield: 70 %

Procedure:
A solution of 2-phenyl-pyrimidine-5-carboxylic acid piperazin-1-ylamide dihydrochloride (0.43 mmol), acetyl chloride (1.28 mmol) and Et3N (1.72 mmol) in DMF (8 mL) is stirred at rt overnight. mixture is concentrated in vacuo. The residue is dissolved in EtOAc (15 mL), washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue is triturated with ether to afford 2-phenyl-pyrimidine-5-carboxylic acid (4-acetyl-piperazin-1-yl)-amide (98 mg, 71%) as a solid. MS: 326 (M+H); 1H NMR (300 MHz, CDCl3): δ 2.12 (s, 3H), 2.92-3.10 (m, 4H), 3.40-4.10 (m, 4H), 7.43-7.60 (m, 3H), 7.75 (br, N—H), 8.52 (m, 2H), 9.11-9.38 (br, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:17]=[C:18]([F:20])[F:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-:21].[K+]>CS(C)=O.O.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C=C(F)F)cc2C1
Reactant: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1Cc2ccc(CC(F)(F)F)cc2C1
Temperature: 120 °C
Yield: 48 %

Procedure:
To a stirred solution of 0.71 mmol 5-(2,2-difluoro-vinyl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester in 5 ml DMSO and 0.25 ml water was added 4.98 mmol potassium fluoride and the mixture was heated at 120° C. for 2 h. The mixture was cooled to room temperature and then taken up in THF and washed sequentially with water and with brine. The organic phase was then dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a white solid (48% yield). MS (m/e): 246.3 ([M+H-Me2C═CH2]+, 100%).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:10]=3[N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[C:28]#[C:29][C:30](O)=[O:31]>ClCCl.CO>[N:1]1([CH2:6][C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([NH:16][C:30](=[O:31])[C:29]#[C:28][C:19]4[CH:20]=[CH:21][C:22]([C:24]([F:26])([F:25])[F:27])=[CH:23][C:18]=4[Cl:17])=[CH:12][C:10]=3[N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc2oc(CN3CCCC3)nc2c1
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(C#Cc1ccc(C(F)(F)F)cc1Cl)Nc1ccc2oc(CN3CCCC3)nc2c1

Procedure:
Prepared analogously to Example 2.3.f. from 0.2 g (0.92 mmol) of 2-pyrrolidin-1-ylmethylbenzoxazol-5-ylamine and 0.2 g (0.8 mmol) of (2-chloro-4-trifluoromethylphenyl)propynoic acid. Yield: 290 mg (81% of theory); C22H17ClF3N3O2 (M=447.84); melting point: 218° C.-223° C.; calc.: molecular ion peak (M+H)+: 448/450 (Cl); found: molecular ion peak (M+H)+: 448/450 (Cl); Rf value: 0.33 (silica gel, dichloromethane/methanol (19:1)).
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[C:10]([O:14][C:15]([NH:17][C@@H:18]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:19](=[O:27])[CH2:20]P(=O)(OC)OC)=[O:16])([CH3:13])([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+]>C(O)C>[C:10]([O:14][C:15]([NH:17][C@@H:18]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:19](=[O:27])/[CH:20]=[CH:2]/[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])=[O:16])([CH3:11])([CH3:12])[CH3:13]
Reactant: COC(=O)CCCC=O
Reactant: COP(=O)(CC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COC(=O)CCC/C=C/C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.4 %

Procedure:
A solution of aldehyde (methyl 5-oxopentanoate) (1) (3.0 g, 23.1 mmol), in absolute ethanol (100 mL) is added, under stirring, to a solution of dimethyl (3S)-3-[(tert-butoxycarbonyl)amino]-2-oxo-4-phenylbutyl-phosphonate (2) (8.58 g, 23.1 mmol) and K2CO3 (3.2 g, 23.1 mmol), dried at 75° C. for 12 hours, in absolute ethanol (200 mL). The mixture is then stirred at room temperature for 16 hours, the solid residue is filtered off and the solution neutralised with glacial acetic acid. The solvent is removed under reduced pressure and the residue partitioned between ethyl acetate and a saturated solution of NaHCO3. The aqueous phase is extracted with ethyl acetate (2×50 mL) and the pooled organic phases are washed with a saturated NaCl solution and dried over anhydrous Na2SO4. The solvent is removed by distilling under reduced pressure and the product purified by means of flash chromatography on a silica gel column by using a 1:1 mixture of ethyl ether and petroleum ether as eluant. 6.8 g (79%) of a colourless oil are obtained.
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:15].[K+].[CH3:17][CH2:18][OH:19]>O.C(OCC)(=O)CC(OCC)=O.[Na]>[C:1]1([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][CH2:17][C:18]([OH:15])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: BrCc1ccccc1-c1ccccc1
Reactant: [OH-]
Agent: [K+]
Agent: [Na]
Solvent: CCOC(=O)CC(=O)OCC
Solvent: O
Product: O=C(O)CCc1ccccc1-c1ccccc1
Temperature: 130 °C
Yield: 81 %

Procedure:
93 cm3 (0.61 mmol) of diethyl malonate dissolved in 50 cm3 of H2P-free EtOH were added dropwise at room temperature to 14 g (0.61 mmol) of sodium in 400 cm3 of H2O-free EtOR. 150 g (0.61 mmol) of 2-phenylbenzyl bromide in 200 cm3 of H2O-free EtOH were subsequently added dropwise, and the mixture was refluxed for 3 hours. 102 g (1.83 mol) of KOH dissolved in 150 cm3 of H2O were added at room temperature, and the mixture was refluxed for a further 4 hours. The solvent was removed in vacuo, H2O was added to the residue until the latter dissolved completely, and the mixture was acidified to pH 1 by means of concentrated aqueous HCl. The precipitate which formed was filtered off with suction, dried and heated at 130° C. for 1 hour, giving 112 g (81%) of 8 as a viscous oil.
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]#[N:8].[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=1)[C:20](OCC)=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([C:20](=[O:21])[CH2:6][C:7]#[N:8])[CH:25]=[CH:26][CH:27]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1cccc(OCc2ccccc2)c1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCC(=O)c1cccc(OCc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
n-BuLi (1.6 M in hexanes, 146 mL, 234 mmol) was added dropwise at −78° C. to a solution of CH3CN (10.39 mL, 199 mmol) in THF (600 mL) and the reaction mixture was stirred for 30 min. A solution of ester (2) (30.0 g, 117 mmol) in THF (50 mL) was added and the mixture was further stirred for 30 min at −78° C. The reaction mixture was quenched at −78° C. by addition of aqueous NH4Cl (200 mL), diluted with EtOAc (500 mL), the organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 3-(3-(benzyloxy)phenyl)-3-oxopropanenitrile (3) as a pale yellow solid. Yield (25.0 g, 85%); 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.48-7.36 (m, 6H), 7.35-7.33 (m, 1H), 7.27-7.26 (m, 1H), 5.12 (s, 2H), 4.05 (s, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1)#[CH:2].C#CCCCCCC.[C:26]([O:30][C:31](=[O:50])[NH:32][C:33]1([C:41]#[C:42][C:43]2[CH:48]=[CH:47][C:46](I)=[CH:45][CH:44]=2)[CH2:38][O:37][C:36]([CH3:40])([CH3:39])[O:35][CH2:34]1)([CH3:29])([CH3:28])[CH3:27].IC1C=C2C(=CC=1)CN(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C2>>[C:26]([O:30][C:31](=[O:50])[NH:32][C:33]1([C:41]#[C:42][C:43]2[CH:48]=[CH:47][C:46]([C:2]#[C:1][C:3]3[CH:4]=[CH:5][C:6]([C:9](=[O:10])[C:11]4[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=4)=[CH:7][CH:8]=3)=[CH:45][CH:44]=2)[CH2:34][O:35][C:36]([CH3:40])([CH3:39])[O:37][CH2:38]1)([CH3:27])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)NC1(C#Cc2ccc(I)cc2)COC(C)(C)OC1
Reactant: C#Cc1ccc(C(=O)c2ccc(F)cc2)cc1
Agent: C#CCCCCCC
Agent: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Product: CC(C)(C)OC(=O)NC1(C#Cc2ccc(C#Cc3ccc(C(=O)c4ccc(F)cc4)cc3)cc2)COC(C)(C)OC1
Yield: 42 %

Procedure:
When the product of Step D was substituted for 1-octyne and tert-butyl-5-((4-iodophenyl)ethynyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate was substituted for 5-iodo-2-tritylisoindoline in Example 2, Step D, the similar process afforded the title compound in 42% yield, as creamy paste. 1H-NMR (CDCl3) 1.44 (s, 3H); 1.47 (s, 9H); 1.5 (s, 3H); 4.02 (d, 2H, J=11.37 Hz); 4.1 (d, 2H, J=11.31 Hz); 5.2 (s, 1H); 7.16 (tr, 2H, J=8.64 Hz); 7.40 (d, 2H, J=8.49 Hz); 7.46 (tr, 2H, J=8.46 Hz); 7.60 (d, 2H, J=8.43 Hz); 7.74 (d, 2H, J=8.39 Hz); 7.80-7.83 (m, 2H).
Reaction SMILES: S(O[CH:6]1[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(C)(=O)=O.C1(=O)[NH:27]C(=O)C2=CC=CC=C12.[K]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC.C1(C)C=CC=CC=1>[NH2:27][CH:6]1[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K]
Solvent: Cc1ccccc1
Product: NC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Mesyloxy-1-benzhydrylazetidine (30.32 g, 95.5 mmol), potassium phthalimide (21.59 g, 116.53 mmol) and hexadecyl tributylphosphonium bromide (5.92 g, 11.7 mmol) were added to toluene (600 mL) and the mixture stirred at room temperature overnight. The reaction was then heated at reflux for 3 h. The solid was removed by filtration, washed with EtOAc and the combined organics then washed with H2O. After drying over Na2SO4, the organics were treated with charcoal and then concentrated to an oil. Addition of isopropyl ether induced crystallization of the product (16.37 g, 46%).