Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[CH3:10][C:11]1[C:15](B(O)O)=[C:14]([CH3:19])[O:13][N:12]=1.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(O)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:10][C:11]1[C:15]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=2)=[C:14]([CH3:19])[O:13][N:12]=1
Reactant: CSc1nccc(I)n1
Reactant: Cc1noc(C)c1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Product: CSc1nccc(-c2c(C)noc2C)n1
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 97.7 %

Procedure:
To a solution of 4-iodo-2-methylsulfanyl-pyrimidine (745 mg, 2.95 mmol) in degassed nPrOH (55 ml), 3,5-dimethyl-isoxazole-4-boronic acid (500 mg, 3.54 mmol), Na2CO3 (375 mg, 3.54 mmol), triphenylphosphine (80 mg, 0.29 mmol) and Pd(OAc)2 (20 mg, 0.09 mmol) were added. The mixture was stirred at 100° C. for 4.5 hours. The solvent was evaporated under vacuum, and the crude was dissolved in DCM and washed with water. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography with petroleum ether-ethyl acetate (95-5 to 9-1) to give 638 mg of the title compound (97% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[H-].[Na+].[Br:15][C:16]1[CH:32]=[CH:31][C:19]([O:20][C:21]2[CH:28]=[CH:27][C:26]([CH2:29][OH:30])=[CH:25][C:22]=2[C:23]#[N:24])=[CH:18][C:17]=1[F:33]>CN(C=O)C>[Br:15][C:16]1[CH:32]=[CH:31][C:19]([O:20][C:21]2[CH:28]=[CH:27][C:26]([CH2:29][O:30][C:2]3[CH:3]=[C:4]4[N:11]([CH3:12])[CH2:10][CH2:9][N:5]4[C:6](=[O:8])[N:7]=3)=[CH:25][C:22]=2[C:23]#[N:24])=[CH:18][C:17]=1[F:33]
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(Br)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccc(Br)c(F)c3)c(C#N)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (200 mg, 1.078 mmol), sodium hydride (86 mg, 2.155 mmol) and 2-(4-bromo-3-fluorophenoxy)-5-(hydroxymethyl)benzonitrile (346 mg, 1.074 mmol) in DMF (5 mL).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[H-].[Na+].Br[CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C=O)C.C1COCC1.O.CCOCC>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:6]=[CH:5]2)[CH3:28]
Reactant: Oc1ccc2c(ccn2Cc2ccccc2)c1
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CCCOc1ccc2c(ccn2Cc2ccccc2)c1
Reaction time: 0.17 h
Yield: 40.4 %

Procedure:
A solution of 850 mg (4.0 mmol) of 5-hydroxy-1-(phenylmethyl)-1H-indole in 75 mL of DMF and 20 mL of THF was treated with 200 mg (5.0 mmol) of 60% NaH/mineral oil and after stirring for 0.17 hours, 0.7 mL (4.9 mmol) of ethyl 4-bromobutyrate was added. After 2.75 hours, the mixture was diluted with water and extracted with EtOAc. The EtOAc solution was washed with water, saturated NaCl solution, dried(Na2SO4) and concentrated at reduced pressure. The residue was chromatographed on silica gel and the 545 mg (40% yield) of 4-[[1-(phenylmethyl)-1H-indol-5-yl]oxy]butanoic acid ethyl ester by eluting with a gradient, 15% ether/hexaneØ50% ether/hexane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[N:16]1([C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35](O)=[O:36])=[CH:30][C:29]=2[O:38][CH3:39])=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[N:16]1([C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C@H:8]([CH3:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=3)=[O:36])=[CH:30][C:29]=2[O:38][CH3:39])=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)N1CCc2ccccc21
Reactant: CCOC(=O)C[C@@H](C)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H](C)c1ccc(NC(=O)Cc2ccc(NC(=O)N3CCc4ccccc43)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
A solution of ethyl (R) 3-(4-aminophenyl)butyrate (790 mg), 4-[(2,3-dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenyl-acetic acid (1.24 g, Reference Example 5) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.45 g) in dimethylformamide (20 mL) was treated in one portion with diisopropylethylamine (1.4 mL). The resulting mixture was stirred at room temperature for 2 hours then poured into water (100 mL) and then extracted three times with ethyl acetate (50 mL). The combined extracts were washed with hydrochloric acid (0.5M), then with sodium hydrogen carbonate solution, then dried and then evaporated. The residue was triturated with a mixture of ethyl acetate and petrol to give the title compound (1.7 g) as a pink/orange powder. HPLC: RT=18.9 minutes (86% by ELS).
Reaction SMILES: [CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[CH:21]=4)[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2].[CH3:29][C:30]([CH3:36])([CH3:35])[CH2:31][CH2:32]C=O>>[CH3:29][C:30]([CH3:36])([CH3:35])[CH2:31][CH2:32][C:21]1[C:20]2[CH:19]=[CH:18][C:17]([F:22])=[CH:16][C:15]=2[N:14]=[C:13]2[C:23]3[N:10]([CH2:11][C:12]=12)[C:9](=[O:26])[C:8]1[CH2:7][O:6][C:5](=[O:27])[CH2:4][C@@:3]([CH2:1][CH3:2])([OH:28])[C:25]=1[CH:24]=3
Reactant: CC(C)(C)CCC=O
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3ccc(F)cc3nc2-1
Product: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)ccc1c2CCC(C)(C)C

Procedure:
The product of Example 84 is treated with 4,4-dimethylpentanal according to a procedure similar to Stage 95e in order to produce the expected solid.
Reaction SMILES: [CH3:1][O:2][P:3]([C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])(=[O:6])[O:4][CH3:5].[Br:22]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[CH3:1][O:2][P:3]([C:7]1[CH:8]=[C:9]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][Br:22])=[CH:19][CH:20]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])(=[O:6])[O:4][CH3:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(-c2ccc(C)cc2)cc1P(=O)(OC)OC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(-c2ccc(CBr)cc2)cc1P(=O)(OC)OC
Temperature: 25 °C
Yield: 66.1 %

Procedure:
A mixture of 4-methoxy-4′-methylbiphenyl-3-yl-phosphonic acid dimethyl ester (300 mg, 1.1 mmol), N-bromosuccinimide (190 mg, 1.1 mmol) and a few crystal of benzoyl peroxide in CCl4 (15 mL) was refluxed and irradiated with a sun lamp for 1 h. More N-bromosuccinimde (30 mg, 0.17 mmol) was added and the mixture was refluxed for 30 min. After cooling to r.t., the mixture was diluted with CH2Cl2 and washed with H2O (3×), dried (MgSO4) and concentrated. The solid residue was swished with Et2O to give 280 mg (67%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([O:16][C:17](=O)[O:18]C(C)(C)C)([CH3:15])([CH3:14])[CH3:13]>C(O)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:17](=[O:18])[O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Yield: 87.4 %

Procedure:
A mixture of 4-fluoro-3-nitroaniline (30 g, 0.192 mol), di-t-butylcarbonate (84 g, 0.384 mol) was stirred in ethanol (300 mL) at r.t. for 1 week. The solvents were removed in vacuo and chromatographic purification (ethyl acetate-hexane) of the residue gave tert-butyl 4-fluoro-3-nitrophenylcarbamate (43 g, 88%) as a white solid.
Reaction SMILES: C(O[CH:4](OCC)[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[C:16]([C@@H:21]([C@H:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[OH:24])[OH:22])([O:18][CH2:19][CH3:20])=[O:17]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1(C)C=CC=CC=1>[C:7]1([CH:6]=[CH:5][CH:4]2[O:24][C@@H:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C@H:21]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:22]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Reactant: CCOC(C=Cc1ccccc1)OCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1OC(C=Cc2ccccc2)O[C@H]1C(=O)OCC
Temperature: 25 °C
Yield: 72.3 %

Procedure:
A mixture of cinnamaldehyde diethylacetal (223.0 g, 1.08 mol), diethyl L-tartrate (290 g, 1.41 mol), toluene (1100 g) and pyridinium p-toluenesulfonate (1.7 g) was heated at 92°-110° C. for a 6 hour period. During the heating period, volatiles (250-300 mL) were removed by distillation through an 8" Vigreaux column. The mixture was cooled (25° C.) and washed with aqueous sodium bicarbonate solution (350 mL) and brine (4×200 mL). Evaporation of solvents and crystallization of the residue gave 250 g (72.3% yield) of (4R,5R)-2-(2-phenyl-1-ethenyl)-4,5-dicarboethoxy-1-3-dioxolane, mp 55.5°-56° C., [α]D25 -5.2° (c,0.1,methanol) 1H-NMR (CDCl3)δ7.45-7.26 (5H,m), 6.86 (1H,d, J=16.1 Hz), 6.26 (1H,dd,J=6.8 Hz and 16.1 Hz), 5.82 (1H,d,J=6.8 Hz), 4.87 (1H,d,J=3.6 Hz), 4.78 (1H,d,J=3.6 Hz), 4.36-4.26 (4H,2 q, overlapping J=7.1 Hz), 1.38-1.31 (6H, 2 t, overlapping, J=7.1 Hz). IR(KBr) 2970,2890,1745,1720,1450,1410 cm.-1MS m/e (% abundance) 320(2), 247(6), 148 (38), 131(78), 115(100), 95(80), 91(8), 77(15), 55(14).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6]=[C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])=[CH:4][CH:3]=1.C1(OC2C=CC=CC=2)C=CC=CC=1.O>[C].[Pd].C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])=[CH:14][CH:15]=1
Reactant: Cc1ccc(C=C2CCCCC2=O)cc1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: O
Product: Cc1ccc(Cc2ccccc2O)cc1
Temperature: 170 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
In a 100-ml, four-necked flask equipped with a magnetic stirrer, a reflux condenser and a thermometer were placed 20.0 g (0.1 mole) of the 2-(4-methylbenzylidene)cyclohexanone produced in Example 4 and 40 ml of diphenyl ether in this order. The flask inside was purged with nitrogen. Thereto was added 2.0 g (10 wt. %, 0.47 mmole as palladium) of 5% palladium carbon (containing 50% of water, a product of N.E. CHEMCAT CORPORATION, a standard product). The system was made vacuum using an aspirator and then returned to ordinary pressure using nitrogen; this operation was repeated three times. Then, the system was stirred at 170° C. for 1 hour while the moisture was discharged out of the system, and further was stirred at 210° C. for 2 hours. The system was cooled to room temperature. 200 ml of toluene was added to the system. Filtration was conducted to remove the palladium carbon. The filtrate was extracted with 100 ml of a 10% aqueous sodium hydroxide solution, and this operation was repeated twice. The aqueous layer was washed with 50 ml of toluene. To the resulting aqueous layer was added 35% hydrochloric acid until the aqueous layer became acidic, after which the aqueous layer was extracted with 150 ml of ethyl acetate. The ethyl acetate layer was washed with water and a saturated aqueous sodium chloride solution in this order. The ethyl acetate layer was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove ethyl acetate, to obtain 11.6 g of brown crystals. Yield: 59% The purity of the intended product in the crystals was 91% as measured by gas chromatography.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN(C)CCCN=C=NCC.Cl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH2:52][C@H:53]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:54][CH:55]([CH3:57])[CH3:56]>C(Cl)Cl.CCOC(C)=O>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([NH:52][C@H:53]([C:58]([O:60][C:61]([CH3:63])([CH3:62])[CH3:64])=[O:59])[CH2:54][CH:55]([CH3:57])[CH3:56])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
500 mg (1.7 mmol) Z-Phe-OH was dissolved in 10 mL of CH2Cl2. Subsequently, 415 mg N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide.HCl (EDCl, 2.2 mmol, 1.3 eq), 250 mg 7-aza-N-hydroxybenzatriazole (HOAt, 1.8 mmol, 1.1 eq), 478 μL triethylamine (TEA, 1.8 mmol, 1.1 eq) and 344 mg H-Leu-OtBu (1.8 mmol, 1.1 eq) were added. The reaction mixture was stirred at ambient temperature for 20 h. Subsequently, 20 mL EtOAc was added and the organic mixture was washed with 15 mL saturated aqueous Na2CO3 (2×), 15 mL saturated aqueous NaHCO3 (2×), 15 mL brine, dried (Na2SO4), concentrated in vacuo and co-evaporated with 10 mL toluene
Reaction SMILES: [F:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][CH:7]=1.[CH2:9]([N:11](CC)CC)C.C[Si](C#N)(C)C>C(#N)C>[C:9]([C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:11]
Reactant: [O-][n+]1cccc(F)c1
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Product: N#Cc1ncccc1F
Temperature: 25 °C
Yield: 70.3 %

Procedure:
Dissolve 3-fluoropyridine-N-oxide (1.0 g, 8.687 mmol) in anhydrous acetonitrile (100 mL). Add triethylamine (1.319 g, 1.82 mL, 13.031 mmol), trimethylsilylcyanide (3.447 g, 4.63 mL, 34.749 mmol) and heat the mixture to reflux overnight. Cool to ambient temperature and concentrate in vacuo. Dissolve the residue in EtOAc and wash with saturated aqueous NaHCO3. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 17:3) to give the desired intermediate as a solid (746 mg, 70%). GC-MS m/z: 122 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][C@H:16]([O:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][C:21]=3[F:29])[C:15]2=[O:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31]([NH:34][NH2:35])(=[O:33])[CH3:32].C(N(C(C)C)C(C)C)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>C(Cl)Cl.O>[C:31]([NH:34][NH:35][C:24]([C:23]1[CH:27]=[CH:28][C:20]([O:19][C@H:16]2[CH2:17][CH2:18][N:14]([CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]3)[C:15]2=[O:30])=[C:21]([F:29])[CH:22]=1)=[O:26])(=[O:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@H](Oc3ccc(C(=O)O)cc3F)C2=O)CC1
Reactant: CC(=O)NN
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NNC(=O)c1ccc(O[C@H]2CCN(C3CCN(C(=O)OC(C)(C)C)CC3)C2=O)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102 %

Procedure:
(S)-4-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)-3-fluorobenzoic acid (834 mg, 1.97 mmol), acetohydrazide (219 mg, 2.96 mmol) and N-ethyl-N-isopropylpropan-2-amine (1375 μL, 7.90 mmol) were dissolved in CH2Cl2 (20 mL) and bis(2-oxooxazolidin-3-yl)phosphinic chloride (2010 mg, 7.90 mmol) was added and stirred at ambient temperature for 3 hours. The reaction was poured into water, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated to afford crude (S)-tert-butyl 4-(3-(4-(2-acetylhydrazinecarbonyl)-2-fluorophenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (960 mg, 2.01 mmol, 102% yield) which was taken forward without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:19][CH2:20][NH:21][C:22]2[C:31]3[C:26](=[C:27]([F:33])[CH:28]=[CH:29][C:30]=3[F:32])[N:25]=[CH:24][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=1.[C:34]([Cu])#[N:35]>CN(C=O)C>[F:32][C:30]1[CH:29]=[CH:28][C:27]([F:33])=[C:26]2[C:31]=1[C:22]([NH:21][CH2:20][CH2:19][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]3[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=3)=[C:2]([CH:3]=1)[C:34]#[N:35])=[N:23][CH:24]=[N:25]2
Reactant: N#C[Cu]
Reactant: Fc1ccc(F)c2c(NCCc3ccc(Oc4cc(C(F)(F)F)ccn4)c(Br)c3)ncnc12
Solvent: CN(C)C=O
Product: N#Cc1cc(CCNc2ncnc3c(F)ccc(F)c23)ccc1Oc1cc(C(F)(F)F)ccn1
Yield: 57 %

Procedure:
A suspension of {2-[3-bromo-4-(4-trifluoromethylpyridin-2-yloxy)-phenyl]-ethyl}-(5,8-difluoroquinazolin-4-yl)-amine) (137 mg, 0.26 mmol), CuCN (164 mg, 1.83 mmol) and DMF (10 mL) was heated at 126° for 3 h, then heated at reflux overnight. After addition of more CuCN (100 mg), the reaction was heated at reflux 2 h, then concentrated in vacuo. The residue was partitioned between water (10 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc (2×10 mL) and the pooled organic fractions were dried (Na2SO4), filtered through a silica gel/Celite plug and concentrated in vacuo to provide 5-[2-(5,8-difluoroquinazolin-4-ylamino)-ethyl]-2-(4-trifluoromethylpyridin-2-yloxy)-benzonitrile (70 mg) as an off-white powder (94% purity by LC), 57% yield, M.P. 157-159°. 1H NMR (CDCl3): δ 8.7 (bs, 1H), 8.29 (d, 1H), 7.62 (d, 1H), 7.57 (dd, 1H), 7.38 (m, 1H), 7.29 (s, 1H), 7.27 (s, 1H), 7.26 (m, 1H), 7.04 (m, 1H), 6.76 (bm, 1H), 3.96 (m, 2H), 3.10 (t, 2H). MS: m/z 471.
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:8]=[C:7](C)[CH:6]=[CH:5][C:4]=1[NH:10][NH2:11].Br[C:13]1C(C)=CC=CC=1N>>[ClH:1].[Br:2][C:3]1[C:8]([CH3:13])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:10][NH2:11]
Reactant: Cc1cccc(N)c1Br
Reactant: Cc1ccc(NN)c(Br)c1
Agent: Cl
Product: Cc1cccc(NN)c1Br

Procedure:
2-Bromo-3-methylphenylhydrazine hydrochloride (23 g) was prepared as described for 2-bromo-4-methylphenylhydrazine hydrochloride in Example 4, except using 2-bromo-3-methylaniline as starting material. ##STR34##
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:10][OH:11]>>[OH:11][C:10]1[CH:2]=[CH:1][CH:4]=[CH:5][C:6]=1[CH:7]=[CH:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccccc1
Reactant: CO
Product: O=C(C=Cc1ccccc1O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The previous product was mixed with acetophenone (2 g) suspended in methanol at −10° C. and stirred for 5 hr at room temperature. After neutralization with 5% hydrochloric acid solution, the product was extracted with 200 Ml of ethylacetate. The extracted organic phase was dried with anhydrous magnesium sulfate, and resulting 1-phenyl-3-(2-methoxymethyloxyphenyl)-prophenone was hydrolyzed with dilute alkaline solution. The reaction mixture was extracted with 200 Ml of ethylacetate. Extracted organic phase is dried with anhydrous magnesium sulfate and evaporated under vacuum. About 0.9 g of white solid (1-phenyl-3-(2-hydroxyphenyl)prophenone was obtained and subjected to silica gel column chromatography (5×3 cm, Merk). After being eluted with n-hexane:ethylacetate (v/v, 1:7), 0.7 g of purified compound was recovered and identified as follows:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH:10]([F:12])[F:11])[NH2:5].[CH3:13][C:14]1([C:17](Cl)=[O:18])[CH2:16][CH2:15]1.N1C=CC=CC=1.Cl>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:17]([C:14]2([CH3:13])[CH2:16][CH2:15]2)=[O:18])[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([F:11])[F:12]
Reactant: CC1(C(=O)Cl)CC1
Reactant: Nc1ccc(OC(F)F)c(Br)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC1(C(=O)Nc2ccc(OC(F)F)c(Br)c2)CC1
Yield: 96 %

Procedure:
In the same manner as in Example 3 but using 3-bromo-4-difluoromethoxyaniline (2.4 g) and 1-methylcyclopropanecarbonyl chloride (1.2 g) with pyridine (0.8 g) as the hydrogen chloride-eliminating agent and ethyl acetate as the solvent, the operations were effected to give N-(3-bromo-4-difluoromethoxyphenyl)-1-methylcyclopropanecarboxamide (3.1 g). M.P., 71°-71.5° C.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]([CH:18]([O:24][CH2:25][CH2:26][C:27]3[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=3)[C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:14][C:9]=2[C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]([CH:18]([O:24][CH2:25][CH2:26][C:27]3[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=3)[C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:14][C:9]=2[C:10]([OH:12])=[O:11])=[CH:33][CH:34]=1
Reactant: COC(=O)c1cc(C(OCCc2cncn2C)c2nccs2)ccc1CCc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1cncc1CCOC(c1ccc(CCc2ccc(F)cc2)c(C(=O)O)c1)c1nccs1
Temperature: 25 °C

Procedure:
A mixture of methyl 2-(4-fluorophenethyl)-5-[1-(thiazol-2-yl)-2-(1-methylimidazol-5-yl)ethoxymethyl]benzoate (3.32 g, 6.92 mmol), sodium hydroxide (1.38 g, 34.61 mmol) in methanol (150 ml) and water (15 ml) was stirred under a nitrogen atmosphere at reflux for 18 hours, cooled to ambient temperature and the methanol evaporated off. The residue was treated with aqueous citric acid (1M, 40 ml) and extracted with dichloromethane. The organic extracts were dried and evaporated to dryness to give 2-(4-fluorophenethyl)-5-[1-(thiazol-2-yl)-2-(1-methylimidazol-5-yl)ethoxymethyl]benzoic acid as a yellow foam (2.85, 88%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[C:15]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16]1.C1(C)C(S(O)(=O)=O)=CC=CC=1>CCOCC.C1(C)C=CC=CC=1>[C:15]1([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[CH2:19][CH2:18][CH2:17][CH:16]=1
Reactant: c1ccc2occc2c1
Reactant: O=C1CCCC1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C1=C(c2cc3ccccc3o2)CCC1

Procedure:
Benzofuran was treated with butyllithium in ether followed by cyclopentanone. The resulting alcohol was dehydrated with toluenesulfonic acid in toluene to afford 2-cyclopenten-1-ylbenzofuran. Treatment with maleimide gave a cycloadduct which was aromatized by treatment with tetrachloroquinone. 1H NMR (DMSO-d6) δ 11.29 (s, 1H), 8.60 (d, 1H), 7.82 (d, 1H), 7.66 (t, 1H), 7.52 (t, 1H), 3.23 (m, 4H), 2.30 (quintet, 2H). MS m/e 276 (M−H)−.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[N:11]=[C:10]2[NH:12][CH:13]=[CH:14][C:9]2=[CH:8][CH:7]=1>[Ni].CCO>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[N:11]=[C:10]2[NH:12][CH2:13][CH2:14][C:9]2=[CH:8][CH:7]=1
Reactant: c1cc2ccc(C3OCCO3)nc2[nH]1
Agent: [Ni]
Solvent: CCO
Product: c1cc2c(nc1C1OCCO1)NCC2
Temperature: 95 °C
Reaction time: 27 h

Procedure:
A mixture of 6-(1,3-dioxolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (intermediate 292, 0.283 g, 1.443 mmol), and Raney nickel (0.140 g) in EtOH (30 ml) was stirred under a hydrogen atmosphere (5 bar) at 95° C. in an autoclave reactor. Additional Raney nickel (0.140 g) was added after 22 h. After 27 h, the reaction mixture was cooled to room temperature, poured onto a glass fiber filter, washed through with additional EtOH and concentrated to give the crude title compound as a brown oil. This was used withoug purification in the next step. (UPLC-MS 6) tR 0.38; ESI-MS 193.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([CH3:19])([CH3:18])[C:8]([O:10]CC2C=CC=CC=2)=[O:9])=[CH:4][C:3]=1[CH3:20].[OH-].[Na+]>CO.O>[Br:1][C:2]1[S:6][C:5]([C:7]([CH3:18])([CH3:19])[C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[CH3:20]
Reactant: Cc1cc(C(C)(C)C(=O)OCc2ccccc2)sc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C(C)(C)C(=O)O)sc1Br

Procedure:
A mixture of the benzyl 2-(5-bromo-4-methyl-2-thienyl)-2-methylpropanoate and sodium hydroxide (0.33 g, 8.3 mmol) in methanol (10 ml) and water (2.5 ml) was heated under reflux for 1 hour. The solvent was evaporated and the residue triturated with 1N hydrochloric acid and then extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate and then evaporated to leave 2-(5-bromo-4-methyl-2-thienyl)-2-methylpropanoic acid as a yellow gum which was used in the next step without purification.