Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5])=O.[NH2:12][C:13](N)=[O:14]>O>[OH:14][C:13]1[N:12]=[CH:1][C:3]2[C:4](=[CH:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=2)[N:5]=1
Reactant: COc1ccc(C=O)c(N)c1
Reactant: NC(N)=O
Solvent: O
Product: COc1ccc2cnc(O)nc2c1
Temperature: 175 °C
Reaction time: 1 h

Procedure:
2-Formyl-5-methoxyaniline (11.93 g, 79.5 mmol, 1.0 eq) and urea (38.0 g, 0.636 mol, 8.0 eq) were mixed, ground into a fine powder and placed into a 1 L 2-neck flask equipped with a mechanical stirrer and an air condenser. The flask was placed into a preheated (160° C.) oil bath. The reaction mixture melted and was stirred at 170-180° C. for 1 hour until it solidified forming yellowish-brown solid. The reaction mixture was cooled to RT, crushed, mixed with 70 mL of H2O and stirred for ˜1 hour at RT. The solid was filtered, washed with 150 mL of H2O and 20 mL of ice cold Et2O. The yellow solid thus obtained was dried over P4O10 under high vacuum for several hours and the crude material (12.57 g) was used for the next step without purification.
Reaction SMILES: Br[C:2]1[C:3]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C([Mg]Cl)(C)C.[CH2:20]([N:27]1[CH:32]2[CH2:33][CH2:34][CH:28]1[CH:29]=[C:30](OS(C(F)(F)F)(=O)=O)[CH2:31]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.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>[CH2:20]([N:27]1[CH:32]2[CH2:33][CH2:34][CH:28]1[CH:29]=[C:30]([C:2]1[C:3]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6])[CH2:31]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=S(=O)(OC1=CC2CCC(C1)N2Cc1ccccc1)C(F)(F)F
Reactant: CC(C)(C)Oc1c(Br)cccc1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)Oc1c(C#N)cccc1C1=CC2CCC(C1)N2Cc1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 104.2 %

Procedure:
To a solution of 3-bromo-2-tert-butoxy-benzonitrile (30.73 g, 0.121 mol) in THF (100 mL) at 0° C. was added 2 M isopropylmagnesium chloride in THF (60 mL) dropwise. The reaction mixture was stirred for 1 h and then tetrakis(triphenylphosphine)palladium(0) (2.33 g, 0.002 mol) was added followed by trifluoro-methanesulfonic acid 8-benzyl-8-aza-bicyclo[3.2.1]oct-2-en-3-yl ester (35.00 g, 0.101 mol) in THF (23 mL). The reaction mixture was refluxed at 80° C. for 1 h, cooled to RT, washed with brine, and extracted with EtOAc (2×). The organic layer was dried over sodium sulfate and the solvent was evaporated to provide the title compound (39.2 g) which was used without further purification. (m/z): [M+H]+ calcd for C25H28N2O 373.22. found 373.2.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@@H:9]1[CH2:21][N:22]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[S:23]([CH3:26])(=[O:25])=[O:24])C1C=CC=CC=1.CC(O)=O.CCO>[Pd].CCOC(C)=O>[C:27]1([N:22]([CH2:21][C@H:9]2[CH2:10][NH:11][CH2:12][CH2:13][NH:8]2)[S:23]([CH3:26])(=[O:25])=[O:24])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)N(C[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N(C[C@H]1CNCCN1)c1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 119.7 %

Procedure:
A 150-mL round-bottomed flask was charged with N-(((2R)-1,4-dibenzyl-2-piperazinyl)methyl)-N-phenylmethanesulfonamide (0.527 g, 1.172 mmol, step 2), AcOH (0.10 mL, 1.7 mmol), Pd (10 wt. % (dry basis) on activated carbon, wet, Degussa type, 0.528 g), EtOH (10 mL) and EtOAc (2 mL). The reaction mixture was evacuated under vacuum and refilled with hydrogen. The mixture was stirred under an atmosphere of hydrogen at room temperature for 4.5 h then at 50° C. for 12 h. The reaction mixture was filtered and the filtrate was concentrated and re-subjected to the reaction condition (Pd/C 0.683 g and EtOH 10 mL). The reaction mixture was evacuated under vacuum and refilled with hydrogen. The mixture was stirred under an atmosphere of hydrogen at 50° C. for 12 h. The reaction mixture was filtered through a pad of filter agent. The filtrate was concentrated to give N-phenyl-N-((2R)-2-piperazinylmethyl)methanesulfonamide (0.378 g) as a clear oil.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([C:6]2[C:7]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:8]=3[N:9]=[CH:10][N:11]=2)[CH:5]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1[N:2]=[CH:3][N:4]([C:6]2[C:7]3[CH2:15][CH2:14][NH:13][CH2:12][C:8]=3[N:9]=[CH:10][N:11]=2)[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(ncnc2-n2cnnc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1nc2c(c(-n3cnnc3)n1)CCNC2
Reaction time: 2 h
Yield: 90 %

Procedure:
To the product of Example 109 step a (574 mg, 1.9 mmol) in DCM (9.5 mL) was added TFA (3.8 mL). After stirring 2 h the reaction was concentrated in vacuo. The residue was redissolved in DCM and treated with Dowex 550A resin to neutralize the TFA salt. The resin was removed by filtration and concentration afforded a yellow solid (347 mg, 90%). This material was used without further purification. MS (ESI) mass calcd. C9H10N6, 202.2. m/z found 203.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]12[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[C:11](Cl)(=[O:13])[CH3:12]>N1C=CC=CC=1>[C:11]([NH:1][C:2]12[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3]2)(=[O:13])[CH3:12]
Reactant: CC(=O)Cl
Reactant: CC1(C)C2CCC1(N)CC2
Solvent: c1ccncc1
Product: CC(=O)NC12CCC(CC1)C2(C)C

Procedure:
A solution of 1-amino-7,7-dimethylnorbornane (1.022 g) in pyridine (10 ml) was cooled in an ice-bath and stirred whilst acetyl chloride (1 ml) was added dropwise. The ice-bath was removed and the mixture was kept at room temperature until the reaction was complete. Dilution with water, acidification with dilute hydrochloric acid and extraction with ether afforded the crude product which was purified by filtration through a small column of neutral alumina and crystallization from ether-petroleum ether to give 1-acetamido-7,7-dimethylnorbornane m.p. 133°-134° (Kofler) after previous softening.
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH3:19])=[CH:4][C:5]([F:17])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[O:9])[CH:7]=1.O.[CH3:21][N:22](C)C=O>[C-]#N.[Zn+2].[C-]#N.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)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:17][C:5]1[C:6]([C:8](=[O:9])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[CH:7][C:2]([C:21]#[N:22])=[C:3]([O:18][CH3:19])[CH:4]=1
Reactant: COc1cc(F)c(C(=O)c2cccc(F)c2)cc1Br
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: COc1cc(F)c(C(=O)c2cccc(F)c2)cc1C#N
Temperature: 120 °C
Reaction time: 7 h

Procedure:
A total of 856 mg of (5-bromo-2-fluoro-4-methoxy-phenyl)-(3-fluoro-phenyl)-methanone obtained in Production Example II-1-b was dissolved in 13.1 ml of N,N-dimethylformamide, 185 mg of zinc cyanide, 13.6 mg of tris(dibenzylideneacetone)dipalladium and 17.4 mg of 1,1′-bis(diphenylphosphino)ferrocene were added thereto, and the mixture was stirred at 120° C. in an atmosphere of nitrogen gas for 7 hours. After cooling to room temperature, water was added to the reaction mixture and the mixture was extracted with diethyl ether. The resulting organic layer was washed with brine, dried over magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:2), to give 203 mg of the title compound as pale yellow crystals.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[S:15][C:14]([C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[O:17])=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[NH2:24][CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:18]1([C:16]([C:14]2[S:15][C:11]([C:9]3[CH:8]=[CH:7][N:6]=[C:5]([NH:24][CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][NH:29][C:28]4=[O:32])[N:10]=3)=[CH:12][CH:13]=2)=[O:17])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: CS(=O)(=O)c1nccc(-c2ccc(C(=O)N3CCOCC3)s2)n1
Reactant: NCCN1CCNC1=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1NCCN1CCNc1nccc(-c2ccc(C(=O)N3CCOCC3)s2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of (5-(2-(methylsulfonyl)pyrimidin-4-yl)thiophen-2-yl)(morpholino)methanone (100 mg, 0.26 mmol), 1-(2-aminoethyl)imidazolidin-2-one (36 mg, 0.28 mmol) and triethylamine (56 mg, 0.52 mmol) in toluene (3 mL) was refluxed for 6 h. After cooling to rt, the solvent was evaporated in vacuo and then methanol (5 mL) was added. After stirring for 15 min the solid was filtered and dried to give title compound as a light yellow solid. MS (M+H)+ 403.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[C:7]([NH2:9])=[O:8])[CH3:2].Br[CH2:17][C:18](=O)[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:7]2[O:8][CH:17]=[C:18]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[N:9]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[CH3:2]
Reactant: COC(=O)CCC(=O)CBr
Reactant: CCOc1ccc(C(N)=O)cc1OCC
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2nc(CCC(=O)OC)co2)cc1OCC
Temperature: 130 °C
Reaction time: 16 h

Procedure:
A 40 g quantity of 3,4-diethoxybenzamide and 80 g of methyl 5-bromo-4-oxopentanoate (containing about 35% of methyl 3-bromo-4-oxopentanoate) were added to 400 ml of dimethylformamide, and the mixture was stirred at 130° C. for 16 hours. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. Ethyl acetate (500 ml) and saturated sodium bicarbonate solution (500 ml) were gradually added with stirring, and stirring was continued. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:8 to 1:4) to give 18 g of white powdery methyl 3-[2-(3,4-diethoxyphenyl)oxazol-4-yl]propionate.
Reaction SMILES: C([C:3]1[C:4]([Br:14])=[C:5]([CH:10]=[CH:11][C:12]=1[F:13])[O:6]C([O-])=O)C.FC1C=C(F)C([N+:23]([O-:25])=[O:24])=CC=1O>>[Br:14][C:4]1[C:3]([N+:23]([O-:25])=[O:24])=[C:12]([F:13])[CH:11]=[CH:10][C:5]=1[OH:6]
Reactant: O=[N+]([O-])c1cc(O)c(F)cc1F
Reactant: CCc1c(F)ccc(OC(=O)[O-])c1Br
Product: O=[N+]([O-])c1c(F)ccc(O)c1Br
Yield: 87.5 %

Procedure:
This compound was prepared from ethyl-2-bromo-4-fluorophenoxycarboxlate (4.0 g, 15.2 mmol) in the manner described for 2,4-difluoro-5-nitrophenol, affording 3.14 g (87.5%) of 2-bromo-4-fluoro-3-nitrophenol as a yellow solid. 1H-NMR (DMSO-d6) δ 11.19 (s, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.57 (d, J=5.1 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[CH3:11][C:12]([CH3:14])=O>>[CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[C:5](=[C:12]([CH3:14])[CH3:11])[C:4](=[O:9])[O:3]1
Reactant: CC(C)=O
Reactant: CC1(C)OC(=O)CC(=O)O1
Product: CC(C)=C1C(=O)OC(C)(C)OC1=O

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 120, Step 1 starting from acetone and 2,2-dimethyl-1,3-dioxane-4,6-dione.
Reaction SMILES: [N:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH:5]=[CH:4][N:3]=[CH:2]1.Br>C(O)(=O)C>[N:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]3[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=3)[CH2:10][CH2:11]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc(N2CCN(n3ccnc3)CC2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc(N2CCN(n3ccnc3)CC2)cc1
Yield: 95 %

Procedure:
A mixture of 3.1 parts of 1-(1H-imidazol-1-yl)-4-(4-methoxyphenyl)piperazine and 150 parts of a hydrobromic acid solution 48% in glacial acetic acid is stirred and refluxed overnight. The reaction mixture is evaporated and the residue is dissolved in water. Upon the addition of an excess of sodium hydrogen carbonate, the product is crystallized. It is filtered off and crystallized again from a mixture of N,N-dimethylformamide and water, yielding 2.8 parts (95%) of 4-[4-(1H-imidazol-1-yl)-1-piperazinyl]phenol; mp. 282.4° C.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]([C:42](=[O:49])[NH:43][C@H:44]([C:46](=[O:48])[NH2:47])[CH3:45])([CH3:41])[CH3:40])=[CH:33][CH:32]=2)=[C:28]([CH:50]([CH3:52])[CH3:51])[NH:27][N:26]=1)(=O)C.C[O-].[Na+]>CO>[C:46]([C@@H:44]([NH:43][C:42]([C:39]([CH3:41])([CH3:40])[CH2:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:50]([CH3:52])[CH3:51])=[CH:36][CH:35]=1)=[O:49])[CH3:45])(=[O:48])[NH2:47]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCC(C)(C)C(=O)N[C@@H](C)C(N)=O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(OCC(C)(C)C(=O)N[C@@H](C)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-[(4-{2-[(S)-1-(carbamoyl)ethylcarbamoyl]-2-methylpropoxy}phenyl)methyl]-5-isopropyl-1H-pyrazole (0.14 g) in methanol (4 mL) was added sodium methoxide (28% methanol solution, 0.04 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (94 mg).
Reaction SMILES: [OH:1][CH:2]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[CH3:26])[C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:6]=[CH:5][C:4]=1[CH3:14].N1C=CC=CC=1.[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH:43][C@@H:44]([CH3:48])[C:45](Cl)=[O:46])(=[O:42])=[O:41])=[CH:36][CH:35]=1>ClC(Cl)C>[N:9]1([C:7]2[CH:6]=[CH:5][C:4]([CH3:14])=[C:3]([CH:8]=2)[CH:2]([C:15]2[C:16]([CH3:26])=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][C:24]=2[CH3:25])[O:1][C:45](=[O:46])[C@@H:44]([NH:43][S:40]([C:37]2[CH:38]=[CH:39][C:34]([CH3:33])=[CH:35][CH:36]=2)(=[O:42])=[O:41])[CH3:48])[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)Cl)cc1
Reactant: COC(=O)c1cc(C)c(C(O)c2cc(-n3ccnc3)ccc2C)c(C)c1
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1cc(C)c(C(OC(=O)[C@H](C)NS(=O)(=O)c2ccc(C)cc2)c2cc(-n3ccnc3)ccc2C)c(C)c1
Yield: 100.9 %

Procedure:
Methyl (±)-4-[α-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoate (35 g) was suspended in dichloroethane (350 ml) and pyridine (12 ml) and a solution of (S)-2-(4-methylbenzenesulfonylamino)propionyl chloride (31.4 g) in dichloroethane (70 ml) was added dropwise to the suspension over 10 minutes with stirring under ice-cooling. The mixture was stirred at room temperature for 4 hours, and the reaction mixture was washed successively with water, 5% citric acid, 5% potassium carbonate and water. The organic layer was separated and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 58 g of methyl (±)-4-[5-(1-imidazolyl)-2-methyl-α-{(S)-2-(4-methylbenzenesulfonylamino)propionyloxy}benzyl]-3,5-dimethylbenzoate as a pale-yellow oil. This was crystallized from ethyl acetate (120 ml) and isopropyl ether (480 ml), and the obtained crystals were recrystallized from ethyl acetate (50 ml) and isopropyl ether (100 ml) to give 20 g of methyl (S)-4-[5-(1-imidazolyl)-2-methyl-α-{(S)-2-(4-methylbenzenesulfonylamino)propionyloxy}benzyl]-3,5-dimethylbenzoate as white crystals, melting point 103-105° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:6]([O:8]C)=[O:7])#[N:2].[I-].[Li+]>N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:12]=1)[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1cc(C#N)cc(C(F)(F)F)c1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: N#Cc1cc(C(=O)O)cc(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
A mixture of methyl 3-cyano-5-(trifluoromethyl)benzoate (2.67 g, 0.0105 mol) and lithium iodide (13 g, 0.070 mol) in pyridine (70 mL) was subjected to MWI for 30 min at 100° C. The mixture was concentrated and residue was extracted with EtOAc. The organic solutions were combined, washed with 1N HCl(, water and brine, dried over Na2SO4, filtered, and concentrated. The residue was redissolved in EtOAc, washed by 0.2N HCl and brine, dried and concentrated to give 3-cyano-5-(trifluoromethyl)benzoic acid (2.09 g. 92%). 1H NMR (400 MHz, d6-DMSO) δ: 8.58 (s, 1H), 8.55 (s, 1H), and 8.39 (s, 1H). LCMS: ES− 214.2.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7](I)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][CH:16]=1.O>CN(C=O)C.C(NCC)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]2[O:11][C:21]([C:18]3[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=3)=[CH:22][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccc(OC)cc1
Reactant: CC(C)(C)c1ccc(O)c(I)c1
Solvent: CCNCC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2cc3cc(C(C)(C)C)ccc3o2)cc1
Reaction time: 1 h

Procedure:
A solution of 4-t-butyl-2-iodophenol [38941-98-9] (1.09 g, 3.6 mmol), 4-Methoxyphenylacetylene (0.53 g, 4.0 mmol), PdCl2P(PH3)2 (70 mg), and Cul (50 mg) in DMF/Diethylamine (10 ml) was heated to 60° C. After 1 hr, the reaction was cooled and poured into water which was extracted with EtOAc. The organic layer was dried, concentrated to give a solid which was triturated with MeOH, filtered to give 84 as a solid.
Reaction SMILES: [C:1]([CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1)(=[O:3])[CH3:2].[BH4-].[Na+]>C1COCC1.CCO>[OH:3][CH:1]([CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1)[CH3:2]
Reactant: CC(=O)C1CN(C(=O)OCc2ccccc2)CCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(O)C1CN(C(=O)OCc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.38 of 2-acetyl-4-benzyloxycarbonylmorpholine in 50 mL of 1:1 THF-EtOH was added 400 mg of sodium borohydride, in several portions. The mixture was stirred at room temperature for 2 h, then quenched by addition of 25 mL of saturated NaHCO3. The mixture was diluted with 75 mL of water and 25 mL of EtOAc. The phases were separated and the aqueous phase was extracted with 2×25 mL of EtOAc. The combined organics were washed with 25 mL of brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography, eluting with 2:1 hexanes-EtOAc, to yield 383 mg of diastereomer 1, 341 mg of diastereomer 2, and 436 mg of a mixture of the two isomers. Data for diastereomer 1. Rf 0.35 (1:1 hexanes-EtOAc) 1H NMR (500 MHz, CDCl3): δ7.30-7.43 (m, 4H), 5.12-5.23 (m, 2H), 3.80-4.18 (m, 4H), 3.57 (br t, J=11.0Hz, 1H), 3.32 (br s, 1H), 2.84-3.11 (m, 2H), 2.05 (br s, 1H),1.22 (d, J=6.5 Hz, 3H). Data for diastereomer 2. Rf 0.28 (1:1 hexanes-EtOAc).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][C:7]=1[CH2:18]Br)=[O:5])[CH3:2].[CH2:20]([O:22][C:23](=[O:37])[CH2:24][NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1[O:35][CH3:36])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][C:7]=1[CH2:18][N:25]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1[O:35][CH3:36])[CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:37])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(Oc2ccccc2)nc1CBr
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Oc2ccccc2)sc1C(=O)OCC
Temperature: 25 °C
Reaction time: 17 h
Yield: 62.1 %

Procedure:
A mixture of 4-bromomethyl-2-phenoxy-thiazole-5-carboxylic acid ethyl ester (1.71 g, 5.01 mmol), (2,4-dimethoxy-benzylamino)-acetic acid ethyl ester (1.33 g, 5.24 mmol) and potassium carbonate (1.04 g, 7.52 mmol) in anhydrous dimethylformamide (15 mL) was stirred at room temperature for 17 h before it was quenched with water, extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (1.60 g): MS: (+) m/z 514.93 (M+1).
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH:18]([CH3:20])[CH3:19])=[C:12]([O:21][CH3:22])[CH:11]=1)(=O)OCC)C.[H-].[Na+].[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=O.O>C1COCC1>[CH3:17][O:16][C:14]1[CH:15]=[C:10]([CH:9]=[CH:28][C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[F:25])[CH:11]=[C:12]([O:21][CH3:22])[C:13]=1[CH:18]([CH3:19])[CH3:20]
Reactant: CCOP(=O)(Cc1cc(OC)c(C(C)C)c(OC)c1)OCC
Reactant: O=Cc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C=Cc2ccccc2F)cc(OC)c1C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of diethyl(3,5-dimethoxy-4-i-propylbenzyl)phosphonate (0.50 g, 1.5 mmol) in THF (10 mL) at 0° C. was added NaH (60% in mineral oil) (0.14 g, 3.5 mmol) under N2. After the addition was completed, the suspension was stirred at 0° C. for 1 h and then 2-fluorobenzaldehyde (0.2 mL, 1.9 mmol) in THF (10 mL) was added. The reaction was kept at 0° C. for 1 h and then at 50° C. for 5 h. The reaction was cooled to 0° C. Water (5 mL) was added slowly to quench the reaction followed by addition of 2N HCl (8 mL). The mixture was extracted with ether (3×20 mL). The extract was dried over anhydrous Na2SO4. Evaporation of ether followed by flash chromatography using 5% ethyl acetate in hexane as eluent afforded 2-(3,5-dimethoxy-4-i-propylphenyl)-1-(2-fluorophenyl)ethene (1). (0.31 g, 68%) as a yellow crystal. 1HNMR (CDCl3, ppm): δ 1.34 (d, J=7.1 Hz, 6H), 3.60 (qint. J=7.1 Hz, 1H), 3.89 (s, 6H), 6.74 (s, 2H), 7.0-7.2 (m, 5H), 7.4-7.6 (m, 1H).