Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[OH:10])(=[O:3])[CH3:2].[CH3:16][O:17][CH2:18][CH2:19][O:20][C:21]([NH:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O)=[O:22].O>C(Cl)(Cl)Cl.N1CCCCC1>[OH:10][C:9]1[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[O:6][C:5](=[O:15])[C:4]=1[C:1](=[O:3])[CH:2]=[CH:27][C:26]1[CH:29]=[CH:30][CH:31]=[C:24]([NH:23][C:21]([O:20][CH2:19][CH2:18][O:17][CH3:16])=[O:22])[CH:25]=1
Reactant: CC(=O)c1c(O)c2ccccc2oc1=O
Reactant: COCCOC(=O)Nc1cccc(C=O)c1
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: COCCOC(=O)Nc1cccc(C=CC(=O)c2c(O)c3ccccc3oc2=O)c1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
In 10 ml of chloroform were dissolved 2.04 g of 3-acetyl-4-hydroxy-2H-1-benzopyran-2-one, 2.23 g of 3-[(2-methoxyethoxy)carbonylamino]benzaldehyde and 60 mg of piperidine, and the solution was heated under refluxing for 1 hour and 30 minutes while water was removed with a Soxhlet's extractor filled with a molecular sieve. After cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and fractions corresponding to Rf=0.3 were collected by thin layer chromatography (silica gel, hexane/acetone (1:1)), and concentrated to obtain 3.42 g of 4-hydroxy-3-[3-[3-[(2-methoxyethoxy)carbonylamino]phenyl]-1-oxo-2-propenyl]-2H-1-benzopyran-2-one [Compound No. (24d)].
Reaction SMILES: O[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:6][CH:7]=1.S(Br)([Br:20])=O>CN(C)C=O>[Br:20][CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=S(Br)Br
Reactant: OCc1ccc(-c2cccc(C(F)(F)F)c2)o1
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(-c2ccc(CBr)o2)c1

Procedure:
The hydroxymethyl compound (4.84 g; 0.02 mole) prepared in (a) above, was dissolved in dimethylformamide (30 ml) cooled to 0°-5° C. and thionyl bromide (1.7 ml; 0.02 mole) was added dropwise with stirring. After 2 hours the greenish-yellow solution was poured onto ice/water and extracted via diethyl ether. The ether extract was washed with NaCl (saturated solution) dried over molecular sieve 3A and evaporated to give a light brown oil which slowly crystallised (4.6 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH:17]([C:19]1[NH:23][C:22]([C:24]([OH:26])=[O:25])=[CH:21][C:20]=1[CH3:27])=O>>[CH3:27][C:20]1[CH:21]=[C:22]([C:24]([OH:26])=[O:25])[NH:23][C:19]=1[CH:17]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[CH:4]2[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]2)[NH:11][C:10]1=[O:16]
Reactant: Cc1cc(C(=O)O)[nH]c1C=O
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Product: Cc1cc(C(=O)O)[nH]c1C=C1C(=O)Nc2cccc(C3CCNCC3)c21

Procedure:
4-Piperidin-4-yl-1,3-dihydro-indol-2-one (45 mg, 0.2 mmol) was condensed with 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (34 mg, 0.23 mmol) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7](=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][NH:4][N:3]=1.CN(C)[CH:17]=[CH:18][C:19]([C:21]1[CH:22]=[C:23]([NH:27][C:28](=[O:30])[CH3:29])[CH:24]=[CH:25][CH:26]=1)=O>C(O)(=O)C>[CH2:7]([C:6]1[CH:5]=[N:4][N:3]2[C:19]([C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:30])[CH3:29])[CH:24]=[CH:25][CH:26]=3)=[CH:18][CH:17]=[N:1][C:2]=12)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1n[nH]cc1C(=O)c1ccccc1
Reactant: CC(=O)Nc1cccc(C(=O)C=CN(C)C)c1
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(-c2ccnc3c(Cc4ccccc4)cnn23)c1
Yield: 21.3 %

Procedure:
A solution of 1.87 g of 3-amino-4-benzoylpyrazole and 2.32 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]acetamide (Example 168) in 50 ml of glacial acetic acid was refluxed for 8 hours. The reaction mixture was evaporated to dryness and a saturated sodium bicarbonate solution was added along with 400 ml of methylene chloride. The solid that separated was recovered by filtration and was the desired compound (2.57 g, mp 205°-207° C.). The methylene chloride solution afforded more compound (0.73 g, mp 205°-207° C.).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([C:6]1[CH:24]=[CH:23][C:9]2[C:10]3(OCC[O:19]3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH:13]=[CH:14][C:8]=2[CH:7]=1)[CH3:5].S(=O)(=O)(O)O>O>[CH:7]1[C:8]2[CH:14]=[CH:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10](=[O:19])[C:9]=2[CH:23]=[CH:24][C:6]=1[CH:4]([CH3:5])[C:3]([OH:25])=[O:2]
Reactant: COC(=O)C(C)c1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Yield: 70 %

Procedure:
2.0 Gm. of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d] cyclohepten-2-yl)propionic acid methyl ester is stirred in 25 ml. of 1:1 concentrated sulfuric acid:water for 12 hours. The mixture is poured into water and extracted with ethyl acetate and the extract is washed, dried and evaporated to afford a 70% yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid, m.p. (chloroform-hexane) 138°-139°C.; m.p. (acetone-hexane) 113°-115°C. Use of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)acetic acid methyl ester gives a similar yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetic acid, m.p. (acetone-hexane) 148°-149.5°C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])[C:5]([NH2:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:27]2[CH:41]=[CH:40][C:30]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:29][CH:28]=2)O1>>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[CH2:10][O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:27]2[CH:41]=[CH:40][C:30]([O:31][CH2:32][CH2:33][N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:29][CH:28]=2)[CH:3]=1
Reactant: CC1(C)OB(c2ccc(OCCN3CCOCC3)cc2)OC1(C)C
Reactant: Nc1ncc(Br)cc1OCc1c(Cl)cccc1Cl
Product: Nc1ncc(-c2ccc(OCCN3CCOCC3)cc2)cc1OCc1c(Cl)cccc1Cl

Procedure:
3-(2,6-Dichloro-benzyloxy)-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine was prepared from 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (example I(a)) and 4{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-ethyl}-morpholine (prepared in part 1) following procedure 3 as a white solid.
Reaction SMILES: [CH2:1]1[C:4](=[O:5])[N:3]2[C@@H:6](C(O)=O)/[C:7](/[O:11][C@H:2]12)=[CH:8]/[CH2:9]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC([N+](=NC(OCC)=O)[O-])=O)C>O1CCCC1.CCOCC.CCCCC>[O:5]=[C:4]1[N:3]2[C@H:2]([O:11][C:7]([CH:8]=[CH2:9])=[CH:6]2)[CH2:1]1
Reactant: O=C(O)[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21
Agent: CCOC(=O)N=[N+]([O-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: CCOCC
Product: C=CC1=CN2C(=O)C[C@H]2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
Clavulanic acid (1.5 mmole) in dry tetrahydrofuran (5 ml) under a dry nitrogen atmosphere was treated with triphenylphosphine (1.5 mmole) and then, dropwise, diethylazoxicarboxylate (1.5 mmole) in dry tetrahydrofuran (2 ml). After addition was complete (2 minutes), the mixture was stirred for 30 minutes at room temperature and was then ice-cooled and diluted with a mixture of ether and n-pentane (1:2, 20 ml). The mixture was filtered and the filtrate was diluted with dry benzene (10 ml) and then concentrated to about 5 ml under reduced pressure to yield a solution of the title compound (1 mmole).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([P:12](=[O:15])([CH3:14])[CH3:13])[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>CCO.[Pd]>[CH3:14][P:12]([C:5]1[CH:6]=[CH:7][C:8]([NH2:9])=[C:3]([O:2][CH3:1])[CH:4]=1)([CH3:13])=[O:15]
Reactant: COc1cc(P(C)(C)=O)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(P(C)(C)=O)ccc1N
Reaction time: 2 h
Yield: 100.4 %

Procedure:
To a solution of (3-methoxy-4-nitrophenyl)(dimethyl)phosphane oxide (0.1 g, 0.44 mmol) in 5 mL of EtOH was added 10% weight of palladium on carbon (0.2 g). The mixture was purged with argon, and hydrogenated under 30 psi for 2 h. The mixture was passed through Celite to a flask containing HCl in ethanol. Concentration of the filtrate gave the final product (0.088 g, 86% yield). MS/ES+: m/z=199.
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:3].[NH2:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[CH:16][N:17]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[O:27])=[CH:13][CH:12]=1>>[CH:5]1([O:4][C:2]([NH:10][C:11]2[CH:19]=[C:18]3[C:14]([CH:15]=[CH:16][N:17]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:28][S:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:31])=[O:30])=[O:27])=[CH:13][CH:12]=2)=[O:3])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: Nc1ccc2ccn(CCCCCCC(=O)NS(=O)(=O)c3ccccc3)c2c1
Reactant: O=C(Cl)OC1CCCC1
Product: O=C(CCCCCCn1ccc2ccc(NC(=O)OC3CCCC3)cc21)NS(=O)(=O)c1ccccc1
Yield: 51 %

Procedure:
Using similar procedure to that described in Example 157, but using cyclopentyl chloroformate and N-(7-[6-aminoindol-1-yl]heptanoyl)benzenesulphonamide, N-(7-[6-(cyclopentyloxycarbonyl)aminoindol-1-yl]heptanoyl)benzenesulphonamide was obtained in 51% yield as a solid, m.p. 74°-76° C.; microanalysis, found, C,62.74; H,6.54; N,7.84%; C27H33N3O5S, 1/4H2O requires: C, 62.83; H,6.54; N,8.14%.
Reaction SMILES: Cl.Br[C:3]1[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:12][CH:11]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.C1(N(C)C2CCCCC2)CCCCC1.[O:37]1[CH2:41][CH:40]=[CH:39][CH2:38]1>[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.O1CCOCC1>[O:37]1[CH:38]=[CH:39][CH2:40][CH:41]1[C:3]1[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:12][CH:11]=2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: Brc1cccnc1Oc1ccc(Nc2ccccn2)cc1
Reactant: C1=CCOC1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: C1=COC(c2cccnc2Oc2ccc(Nc3ccccn3)cc2)C1
Temperature: 80 °C

Procedure:
To a 25 mL microwave vial was added Bis(tri-tert-butylphosphine) palladium (0) (121 mg, 0.238 mmol) and N-(4-(3-bromopyridin-2-yloxy)phenyl)pyridin-2-amine hydrochloride (900 mg, 2.377 mmol) before sealing and evacuating and backfilling with nitrogen (2×). After addition of dioxane (11.900 ml), N-cyclohexyl-N-methylcyclohexanamine (1.008 ml, 4.75 mmol), and 2,5-dihydrofuran (0.701 ml, 9.51 mmol), the black suspension was heated to 80° C. for 5 h. The reaction mixture was cooled to room temperature, transferred to a 100 mL round bottom flask, and concentrated under reduced pressure. The material was taken up in DCM and adsorbed onto silica before purifying by flash chromatography (0 to 75% ethyl acetate/hexanes), affording a mixture of 2- and 3-dihydrofuranyl products that was used in subsequent reactions.
Reaction SMILES: [CH3:1][N:2]([OH:24])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[Cl:20])[CH:6]=[CH:5][C:4]=1[N+:21]([O-:23])=[O:22].[CH3:25][N:26]=[C:27]=[O:28]>C1COCC1>[CH3:1][N:2]([O:24][C:27](=[O:28])[NH:26][CH3:25])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:19])[F:18])=[CH:12][C:11]=2[Cl:20])[CH:6]=[CH:5][C:4]=1[N+:21]([O-:23])=[O:22]
Reactant: CN(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: CN=C=O
Solvent: C1CCOC1
Product: CNC(=O)ON(C)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N-methyl-N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl]hydroxyamine (700 mg, 1.93 mmol) in anhydrous THF (10 ml) is added methylisocyanate (220 mg, 2 eq.). The mixture is stirred at RT for 4 hours. The solvent and excess methlisocyanate are removed to yield N-methyl-N[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl](N-methyl)carbamoyloxyamine.
Reaction SMILES: [CH:1]1([C:4]2[CH:27]=[CH:26][C:7]([C:8]([N:10]([C@@H:12]3[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]3[C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH3:11])=[O:9])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH:28]1([C:31]([N:33]2[CH2:38][CH2:37][CH:36]([C:39](O)=[O:40])[CH2:35][CH2:34]2)=[O:32])[CH2:30][CH2:29]1>>[CH:1]1([C:4]2[CH:27]=[CH:26][C:7]([C:8]([N:10]([C@@H:12]3[CH2:17][CH2:16][N:15]([C:39]([CH:36]4[CH2:35][CH2:34][N:33]([C:31]([CH:28]5[CH2:30][CH2:29]5)=[O:32])[CH2:38][CH2:37]4)=[O:40])[CH2:14][C@H:13]3[C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH3:11])=[O:9])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)C1CCN(C(=O)C2CC2)CC1
Reactant: CN(C(=O)c1ccc(C2CC2)cc1)[C@@H]1CCNC[C@H]1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)c1ccc(C2CC2)cc1)[C@@H]1CCN(C(=O)C2CCN(C(=O)C3CC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
Using the compound obtained in Example 649, step 1 and 1-(cyclopropylcarbonyl)piperidine-4-carboxylic acid, and by the reaction and purification in the same manner as in Example 97, the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][Si](C)(C)C)[CH:10]=2)[NH:5][CH2:4][CH2:3]1.[OH-].[K+]>C(O)(C)C>[CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[CH:13])[CH:10]=2)[NH:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCNc2ccc(C#C[Si](C)(C)C)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: C#Cc1ccc2c(c1)C(C)(C)CCN2
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of 569 mg (2.21 mmol) of 4,4-dimethyl-6-trimethylsilylethynyl-1,2,3,4-tetrahydroquinoline in 3 ml of isopropanol was added, under argon, 1 ml of 1N aqueous KOH solution. The reaction mixture was stirred at room temperature for 36 hours and the isopropanol was removed under vacuum. The residue was extracted with ether and the ether extract was washed successively with water and saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue was purified by flash chromatography (silica; 10% ethyl acetate in hexanes) to give the title compound as a brown oil.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:14][CH2:13][NH:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C.Cl[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=1>C1COCC1.C([O-])(O)=O.[Na+]>[CH3:1][N:2]([CH:10]1[CH2:14][CH2:13][N:12]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=2)[CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc([N+](=O)[O-])cn2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.4 %

Procedure:
To a solution of tert-butyl methyl(pyrrolidin-3-yl)carbamate (1.00 g, 5.0 mmol) in THF (25 mL) was added triethylamine (0.70 mL, 5.0 mmol) and 2-chloro-5-nitropyridine (500 mg, 3.15 mmol). The reaction mixture was then stirred at room temperature for 16 h, diluted with a saturated NaHCO3 solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica, ethyl acetate/hexanes) afforded the desired product (1.02 g, 100%) as a yellow solid. ESI MS m/z 323 [C15H22N4O4+H]+
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=O)[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([O:26][C:27](=[O:31])[CH2:28][CH2:29][NH2:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27](=[O:31])[CH2:28][CH2:29][NH:30][C:16]([C:12]1[CH:11]=[C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:15]=[CH:14][CH:13]=1)=[O:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)O)c1
Reactant: NCCC(=O)OCc1ccccc1
Product: CC(C)(C)OC(=O)NCc1cccc(C(=O)NCCC(=O)OCc2ccccc2)c1

Procedure:
α-(1-t-Butoxyformamido)-m-toluic acid and β-alanine benzyl ester are coupled to give N-[α-(1-t-butoxyformamido)-m-toluoyl]-β-alanine benzyl ester, MS: 413 (4, M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7](Br)=[CH:8][CH:9]=1)=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[CH2:17]([C:19]([C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[C:40]([CH3:45])[CH:39]=1)([C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[C:24]([CH3:37])[CH:23]=1)[CH2:20][CH3:21])[CH3:18].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:25]2[CH:26]=[CH:27][C:22]([C:19]([CH2:20][CH3:21])([C:38]3[CH:43]=[CH:42][C:41]([OH:44])=[C:40]([CH3:45])[CH:39]=3)[CH2:17][CH3:18])=[CH:23][C:24]=2[CH3:37])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(Br)o1
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(-c2ccc(C(=O)OC)o2)c(C)c1
Temperature: 85 °C
Reaction time: 17 h
Yield: 73.8 %

Procedure:
5-Bromo-furan-2-carboxylic acid methyl ester (J. Org. Chem., 1988, 53(9), 2099.; 156 mg, 0.761 mmol), tetrakistriphenylphosphine palladium (15 mg, 0.013 mmol) and a 2 M sodium carbonate aqueous solution (0.3 mL, 0.6 mmol) were added to a solution of 4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenol (Example 15-(2); 100 mg, 0.254 mmol) in toluene (0.5 mL) at room temperature, and the mixture was stirred at 85° C. for 17 hours. Ethyl acetate was added to the reaction solution. The organic layer was filtered through celite, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=3/1) to give the title compound (73.6 mg, 73.9%).
Reaction SMILES: [C:1]([CH2:3][C:4]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)=[O:5])#[N:2].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[C:1]([CH:3]=[C:4]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)[O:5][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23])#[N:2]
Reactant: COC(=O)c1ccc(C(=O)CC#N)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=CC#N)OS(=O)(=O)c2ccc(C)cc2)cc1
Yield: 97.2 %

Procedure:
To a mixture of methyl 4-(cyanoacetyl)benzoate (10.29 g), p-toluenesulfonyl chloride (11.58 g) and dichloromethane (110 mL) was added dropwise triethylamine (7.68 g) under ice-cooling. After stirring under ice-cooling for 2.5 hrs, the mixture was diluted with dichloromethane (100 mL), washed with water (150 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:methyl acetate=9:1→1:1) to give the title compound (17.60 g) as a mixture of (E)-form and (Z)-form (6:5).
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]([F:25])([F:24])[O:7][C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=2)=[CH:10][CH:9]=1>C(Cl)Cl>[Br:2][CH2:22][C:19]1[CH:20]=[CH:21][C:16](/[CH:15]=[CH:14]/[C:11]2[CH:12]=[CH:13][C:8]([O:7][C:6]([F:25])([F:24])[F:5])=[CH:9][CH:10]=2)=[CH:17][CH:18]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc(/C=C/c2ccc(OC(F)(F)F)cc2)cc1
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(/C=C/c2ccc(CBr)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
PBr3 (56 μL, 0.60 mmol) was added to a solution of alcohol 127 (0.177 g, 0.601 mmol) in anhydrous CH2Cl2 (10 mL) at 0° C. The mixture was stirred at room temperature for 1 h, and then cooled to 0° C., quenched with ice, and extracted with CH2Cl2. The organic fraction was dried, and evaporated, and then column chromatography of the residue, eluting with CH2Cl2, gave 1-{(E)-2-[4-(bromomethyl)phenyl]ethenyl}-4-(trifluoromethoxy)benzene (128) (0.125 g, 58%) as a white solid: mp 100-102° C.; 1H NMR (CDCl3) δ 7.52 (d, J=8.6 Hz, 2H), 7.48 (d, J=8.3 Hz, 2H), 7.39 (d, J=8.3 Hz, 2H), 7.20 (br d, J=8.1 Hz, 2H), 7.10 (d, J=16.3 Hz, 1H), 7.05 (d, J=16.3 Hz, 1H), 4.51 (s, 2H). APCI MS m/z 277 [M+H−HBr]+.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([CH2:12][C:13]([N:15]3[CH2:41][CH2:40][N:18]4[CH2:19][C@H:20]([C:30]5[CH:35]=[CH:34][C:33]([F:36])=[C:32]([C:37]#[N:38])[C:31]=5[CH3:39])[N:21](C(OC(C)(C)C)=O)[CH2:22][C@@H:17]4[CH2:16]3)=[O:14])=[CH:8][N:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.C1(SC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[N:1]1([C:6]2[N:11]=[CH:10][C:9]([CH2:12][C:13]([N:15]3[CH2:41][CH2:40][N:18]4[CH2:19][C@H:20]([C:30]5[C:31]([CH3:39])=[C:32]([C:33]([F:36])=[CH:34][CH:35]=5)[C:37]#[N:38])[NH:21][CH2:22][C@@H:17]4[CH2:16]3)=[O:14])=[CH:8][N:7]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: Cc1c([C@H]2CN3CCN(C(=O)Cc4cnc(-n5cnnn5)nc4)C[C@H]3CN2C(=O)OC(C)(C)C)ccc(F)c1C#N
Solvent: ClCCl
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1c([C@H]2CN3CCN(C(=O)Cc4cnc(-n5cnnn5)nc4)C[C@H]3CN2)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of (3S,9aS)-tert-butyl 8-(2-(2-(1H-tetrazol-1-yl)pyrimidin-5-yl)acetyl)-3-(3-cyano-4-fluoro-2-methylphenyl)hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate (60 mg, 0.107 mmol) in methylene chloride (2 mL) was added thioanisole (50.5 μl, 0.427 mmol) and trifluoroacetic acid (3287 μl, 42.7 mmol), the resulting solution was stirred at rt for 1 h. After removing the volatile, the residue was participated between methylene chloride (100 mL) and 1N sodium hydroxide (50 mL), the alkaline phase was extracted with methylene chloride, the combined methylene chloride phase was dried over sodium sulphate, concentrated and the residue was purified on TLC using 10% methanol/methylene chloride to give title compound. 1H NMR (500 MHz, CDCl3) δ 9.60 (s, 1H), 8.81-8.80 (two singlets, 2H), 8.43-8.40 (m, 1H), 7.06-7.02 (m, 1H), 5.33 (s, 2H), 4.574-4.40 (m, 1H), 4.23-4.22 (m, 1H), 3.89-3.80 (m, 2H), 3.70-3.54 (m, 1H), 3.26-3.14 (m, 2H), 3.03-2.90 (m, 2H), 2.80-2.67 (m, 2H), 2.64-2.63 (two singlets, 3H), 2.59-2.38 (m, 2H); LC/MS: [(M+23)]+=485.13; [(M+1-28)]+=435.20.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][Cl:28]>CO>[Cl:28][CH2:27][CH2:26][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=c1[nH]c(-c2ccccc2)c(O)c2ccccc12
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=c1[nH]c(-c2ccccc2)c(OCCCl)c2ccccc12
Reaction time: 0.17 h
Yield: 43.9 %

Procedure:
To a suspension of 180 mg (0.76 mmol) of 4-hydroxy-3-phenyl-2H-isoquinolin-1-one in methanol (6 mL), 315 mg (2.28 mmol) of potassium carbonate and 190 L (2.28 mmol) of 1-bromo-2-chloroethane were added and the mixture was submitted to microwaves at 120° C. for 10 min. The solvent was concentrated under reduced pressure and the resulting crude was purified by flash chromatography (eluant: ethyl acetate/hexane 1/2) affording 100 mg of the title compound (44%).
Reaction SMILES: [CH2:1]([N:4]([CH2:11][CH2:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1I)[C:5](=[O:10])[C:6]([F:9])([F:8])[F:7])[CH:2]=[CH2:3].CC([O-])=O.[K+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C)C=O.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].CC([O-])=O.CC([O-])=O.[Pd+2]>[F:7][C:6]([F:9])([F:8])[C:5]([N:4]1[CH2:1][C:2](=[CH2:3])[C:14]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:13]=2[CH2:12][CH2:11]1)=[O:10]
Reactant: C=CCN(CCc1cc(OC)ccc1I)C(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: C=C1CN(C(=O)C(F)(F)F)CCc2cc(OC)ccc21
Reaction time: 8 h
Yield: 46.3 %

Procedure:
A solution of N-allyl,N-trifluoroacetyl-2-iodo-5-methoxyphenethylamine (20.5 g, 50 mmol) in dimethylformamide (250 mL) is treated with KOAc (14.6 g, 149 mmol), n-Bu4NBr (16.0 g, 50 mmol), PPh3 (1.3 g, 5.0 mmol), Pd(OAc)2 (0.56 g, 2.5 mmol) and stirred overnight at 90 C. The product mixture was cooled to 20 C, filtered, diluted with water (500 mL) and extracted with ether (3×500 mL). The combined organic phases were washed with water (100 mL), brine (100 mL), dried with Na2SO4 and concentrated. Flash chromatography (10% EtOAc in hexane, silica) resulted in 6.6 g of a yellow oil. 1H NMR (400 MHz, CDCl3) d 7.26 (d, J=8 Hz, 1H), 6.77 (d, J=8 Hz, 1H), 6.66 (s, 1H), 5.34-5.19 (m, 2H), 4.40 (m, 2H), 3.83 (m, 2H), 3.80 (s, 3H), 3.00 (m, 2H). MS calculated for C14H14F3NO2+H: 285, observed: 285.