Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([C:10]1[C:19]2[C:18](=[O:20])[CH:17]3[CH2:21][N:22](CC4C=CC=CC=4)[CH2:23][CH:16]3[CH2:15][CH2:14][C:13]=2[NH:12][CH:11]=1)=[O:9].C([O-])=O.[NH4+]>CCO.[OH-].[OH-].[Pd+2]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([C:10]1[C:19]2[C:18](=[O:20])[CH:17]3[CH2:21][NH:22][CH2:23][CH:16]3[CH2:15][CH2:14][C:13]=2[NH:12][CH:11]=1)=[O:9]
Reactant: O=C(Nc1ccccn1)c1c[nH]c2c1C(=O)C1CN(Cc3ccccc3)CC1CC2
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(Nc1ccccn1)c1c[nH]c2c1C(=O)C1CNCC1CC2
Temperature: 78 °C
Yield: 40.3 %

Procedure:
Pd(OH)2 (Pearlman's catalyst, 30 mg) is added to a solution of 6-benzyl-4-oxo-4,4a,5,6,7,7a,8,9-octahydro-1H-1,6-diaza-cyclopenta[f]azulene-3-carboxylic acid pyridin-2-ylamide (65 mg, 0.16 mmol) and HCOONH4 (204 mg, 3.24 mmol) in EtOH (10 ml). The reaction mixture is heated at 78° C. for 20 min. Pd catalyst is filtered off with celite. The solvent is removed by rotavapor. The residue is loaded on a column (0.5% TEA+19.5% MeOH+80% CH3CN) to provide the title compound (20 mg, 40%) as white solid. This compound may be salted as HCl salt. 1H NMR (400 MHz, CD3OD) δ 1.98 (1H, m), 2.01-2.16 (2H, m), 2.65 (1H, m), 3.02-3.25 (5H, m), 3.76 (1H, m), 7.09 (1H, m), 7.57 (1H, s), 7.78 (1H, m), 8.27 (2H, m). MS (ES+) 311 (M+1)
Reaction SMILES: [Mg+2].[Cl-].[Cl-].C(O)(=O)CC(O)=O.C([K])C.[C:14]([N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26]([OH:28])=O)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C1N=CN(C(N2C=NC=C2)=O)C=1.[C:44]([O:50][CH2:51][CH3:52])(=[O:49])[CH2:45]C([O-])=O.Cl>C1COCC1>[CH2:51]([O:50][C:44](=[O:49])[CH2:45][C:26]([C@@H:25]1[CH2:29][CH2:30][CH2:31][N:24]1[C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])=[O:28])[CH3:52]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CC[K]
Agent: Cl
Agent: O=C(O)CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 67.5 °C
Reaction time: 7 h
Yield: 90 %

Procedure:
MgCl2 (153 g, 1640 mmol) was added in one portion to a solution of ethyl potassium malonate (354.9 g, 2085 mmol) in THF (2500 mL). The reaction mixture was stirred for 7 h at 65-70° C. and then at 30° C. overnight. A solution of Cbz-L-Proline (400 g) in THF (1000 mL) was slowly added to a mixture of CDI (312.1 g, 1924.8 mmol) in THF (1500 mL) and stirred at 30° C. for 2 h. The solution was added to the ethyl malonate mixture over 20 min at 20-30° C. and stirred overnight at 30° C. The mixture was cooled to 20° C. and neutralized with diluted HCl (4 N, 1800 mL). The solution was concentrated and the product was dissolved in ethyl acetate and rinsed with 5% aqueous sodium bicarbonate. The organic layer was concentrated and the residue was purified by flash column chromatography (eluent: petroleum ether:ethyl acetate=20:1 to 3:1) to give pure (S)-benzyl 2-(3-ethoxy-3-oxopropanoyl)pyrrolidine-1-carboxylate (460 g, 90% yield). Method A4 Rt: 1.23 min. m/z: 341.9 (M+Na)+ Exact mass: 319.1
Reaction SMILES: [Br:1][C:2]1[S:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:24]=[O:25].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Mg]Br)=[CH:29][CH:28]=1>C1COCC1.O>[Br:1][C:2]1[S:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:24]([C:30]1[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=1)[OH:25]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C=O)c(Br)sc21
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Br)sc21
Reaction time: 0.08 h
Yield: 51.6 %

Procedure:
To a solution of 6-bromo-1-methyl-2,4-dioxo-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carbaldehyde (See Compound 2, Step 4, 185 mg, 0.428 mmol) in THF (5 mL) was added (4-chlorophenyl)magnesium bromide (0.77 mL, 0.772 mmol). The reaction was stirred for 5 min, diluted with water (10 mL) and extracted with DCM (3×10 mL). The combined organic layers were dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (5:1 to 1:1) to give 6-bromo-5-((4-chlorophenyl) (hydroxy)methyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (120 mg, 51.4% yield) as a solid. LCMS: [M+-THP-OH] 441 and TR=2.021 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][N:6]([CH3:16])[C:7]=1[C:8]1[CH:9]=[C:10]([C:13]([OH:15])=O)[S:11][CH:12]=1)[CH3:2].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[O:29]=[C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:30])[N:20]1[CH2:19][C@@H:18]([NH:17][C:13]([C:10]1[S:11][CH:12]=[C:8]([C:7]2[N:6]([CH3:16])[N:5]=[CH:4][C:3]=2[CH2:1][CH3:2])[CH:9]=1)=[O:15])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:40])([F:39])[F:41]
Reactant: CCc1cnn(C)c1-c1csc(C(=O)O)c1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnn(C)c1-c1csc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (106 mg, 0.45 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (164 mg, 0.43 mmol) [prepared according to Preparation 6] and PyBrop (254 mg, 0.54 mmol) in Chloroform (6 mL). DIEA (400 μL, 2.29 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (182 mg, 0.32 mmol, 71%): LC-MS (ES) m/z=567 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][N:6]=1.[CH3:15][N:16](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:17].F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.CNC>CN(C)C=O>[CH3:15][N:16]([CH3:17])[C:9]([C:8]1[CH:12]=[CH:13][C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:14])=[N:6][CH:7]=1)=[O:10]
Reactant: COC(=O)Cc1ccc(C(=O)O)cn1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1ccc(C(=O)N(C)C)cn1
Reaction time: 8 h

Procedure:
A solution of 6-(2-methoxy-2-oxoethyl)nicotinic acid (37 mg, 0.19 mmol), HATU (72.6 mg, 0.19 mmol), and N-ethyl-N-isopropylpropan-2-amine (26.5 mg, 0.20 mmol) in N,N-dimethylformamide (2 ml) was stirred at room temperature for 15 min, then, dimethyl amine (0.05 mL, 1 mol solution in THF) was added and continued to stir overnight. The reaction is quenched with water, extracted with EtOAc and purified by a standard method to give the desired compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2C=CC(Br)=CC=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:21][C:22]1[CH:23]=[N:24]C(N2CCNCC2)=[N:26][CH:27]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:24]=[CH:23][C:22]([Br:21])=[CH:27][N:26]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Brc1cnc(N2CCNCC2)nc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Yield: 93 %

Procedure:
Prepared according to the method for the preparation of 4-(4-bromophenyl)-piperazine-1-carboxylic acid ter-butyl ester, from 5-bromo-2-piperazin-1-ylpyrimidine (5.00 g), to yield the title compound as a white solid (6.55 g, 93%)
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[F:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([O:21][CH3:22])=[C:16]([NH2:23])[C:15]=1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=1[F:32].C(OCC)(=O)C>C(Cl)Cl.CCCCCC>[F:20][C:19]1[CH:18]=[C:17]([O:21][CH3:22])[C:16]2[NH:23][C:1](=[O:2])[N:24]([C:25]3[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=3[F:32])[C:15]=2[C:14]=1[F:13]
Reactant: COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1cc(F)c(F)c2c1[nH]c(=O)n2-c1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.9 %

Procedure:
1,1′-Carbonyldiimidazole (4.68 g, 288 mmol) was added portion wise to a solution of 3,4-difluoro-N2-(2-fluoro-4-iodo-phenyl)-6-methoxy-benzene-1,2-diamine (I-5a: 6.3 g, 144 mmol) in DCM (60 mL) and the resulting mixture was stirred at room temperature overnight. The reaction was monitored by TLC (50% ethyl acetate in hexane). The reaction mixture was filtered, the residue was washed with DCM and dried under reduced pressure to afford 6.0 g of the product (89.5% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH2:18])=[O:17])=[N:14][CH:15]=1.[H-].[Na+].[C:32](OC(=O)C)(=[O:34])[CH3:33].O>CN(C)C=O>[C:32]([NH:18][C:16]([C:13]1[CH:12]=[C:11]([CH3:19])[C:10]([CH:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[S:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:15][N:14]=1)=[O:17])(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C(N)=O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NC(=O)c1cc(C)c(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxamide (150 mg, 0.36 mmol) obtained in Example 15 in N,N-dimethylformamide (7 ml), sodium hydride (60%, 34 mg, 0.79 mmol) was added at 0° C., and the mixture was stirred for 1 hour at room temperature. Subsequently, acetic anhydride (40 μl) was added to the reaction solution at 0° C., and the mixture was stirred for 1 hour at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and was dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the resulting residue was subjected to silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=10:3 was concentrated under reduced pressure, and the resulting residue was washed with diethyl ether and n-hexane, and then was collected by filtration, to obtain the title compound (80 mg, 0.17 mmol, 48%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])=[N:16][C:15]3[C:10](=[CH:11][C:12]([O:28]C)=[C:13]([C:24]([O:26][CH3:27])=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])=[N:16][C:15]3[C:10](=[CH:11][C:12]([OH:28])=[C:13]([C:24]([O:26][CH3:27])=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2nc(N3CCC[C@@H]3C)c(-c3ccc(F)cc3)nc2cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1cc2nc(N3CCC[C@@H]3C)c(-c3ccc(F)cc3)nc2cc1O
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 77.1 %

Procedure:
To a solution of (S)-methyl 2-(4-fluorophenyl)-7-methoxy-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (200 mg, 0.51 mmol) in dichloromethane (80 ml) was added BBr3 (2.0 ml) dropwise with stirring at −78° C., and the reaction was allowed to proceed for 40 minutes. The reaction was then quenched by the addition of water/ice. The resulting solution was extracted with dichloromethane (3×80 ml), and the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the residue, which was purified via silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford (S)-methyl 2-(4-fluorophenyl)-7-hydroxy-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate as a yellow solid (150 mg, 78%).
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:8])[C:5]([OH:7])=O.[Br:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].N1C=CC=CC=1>C(Cl)Cl>[Br:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([NH:17][C:5](=[O:7])[C:4]([O:3][CH3:2])=[O:8])[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1cccc(OCCCBr)c1
Reactant: COC(=O)C(=O)O
Agent: [Cl-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(=O)Nc1cccc(OCCCBr)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1.5 ml of oxalic acid monomethyl ester chloride in 10 ml of methylene chloride is added dropwise to a solution of 3.5 g of 3-(3-bromopropoxy)-aniline and 1.3 ml of pyridine in 40 ml of methylene chloride in the course of 10 minutes. After stirring at room temperature for 2 hours, the mixture is poured onto water and extracted with methylene chloride. The combined extracts are evaporated and the residue is chromatographed on silica gel with methylene chloride/ethyl acetate (10:1). The eluate is evaporated and the residue is crystallised from ether/hexane. Methyl N-[3-(3-bromopropoxy)-phenyl]-oxamate of melting point 90°-91° is obtained.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)[CH3:2].[CH3:10][NH:11][CH3:12]>>[CH2:1]([N:3]1[CH2:8][CH2:7][C:6]([N:11]([CH3:12])[CH3:10])=[CH:5][CH2:4]1)[CH3:2]
Reactant: CNC
Reactant: CCN1CCC(=O)CC1
Product: CCN1CC=C(N(C)C)CC1
Yield: 73.5 %

Procedure:
The respective starting substance is prepared from 90 g of 1-ethyl-4-piperidone with dimethylamine gas introduced into the reaction mixture on three subsequent days for a total 20 hours introduction time as described in Example 1, 1-ethyl-4-dimethylamino-1,2,5,6-tetrahydropyridine is obtained with a yield of 73.5%, bp.: 90°-93° C./1.47 kPa; nD20 =1.4931.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH:3]2[CH2:7][CH:8]3[C:13]([CH:12]=[CH:11][CH:10]=[CH:9]3)=[C:2]12.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.[Cu-]=O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:1]2[C:5](=[O:6])[CH2:4][CH:3]3[CH2:7][C:8]4[C:13]([CH:2]23)=[CH:12][CH:11]=[CH:10][CH:9]=4)=[CH:17][CH:16]=1
Reactant: Clc1ccc(I)cc1
Reactant: O=C1CC2CC3C=CC=CC3=C2N1
Agent: O=[Cu-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: O=C1CC2Cc3ccccc3C2N1c1ccc(Cl)cc1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
To a solution of tetrahydro-1H-indeno[1,2-b]pyrrol-2-one (1.00 g, 5.77 mmol) in water (3 mL) was added copper (I) oxide (167 mg), p-chloroiodobenzene (1.38 g, 5.77 mmol), tetrabutylammonium bromide (0.372 g, 1.15 mmol) and potassium phosphate (2.45 g, 11.5 mmol). The suspension was vigorously stirred at 130° C. overnight. The mixture was cooled down and diluted with dichloromethane. The solid were filtered off and the organic layer was dried and concentrated. The residue was purified by flash chromatography with a gradient of ethyl acetate in cyclohexane of 1 to 60%, to give the desired product F16 (600 mg, 39%). LCMS (method A) 1.72 min; ES+: 284 (M+H+).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:14]([O:18][C:19](=[O:22])[NH:20][NH2:21])([CH3:17])([CH3:16])[CH3:15].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[Cu]I.O>[C:14]([O:18][C:19]([N:20]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:3]=1)[NH2:21])=[O:22])([CH3:17])([CH3:16])[CH3:15]
Reactant: Ic1cccc(N2CCOCC2)c1
Reactant: CC(C)(C)OC(=O)NN
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(N)c1cccc(N2CCOCC2)c1
Temperature: 80 °C
Yield: 62.1 %

Procedure:
To a solution of 4-(3-iodo-phenyl)-morpholine (1.81 g, 6.26 mmol) in DMF (6.5 mL) under nitrogen was added tert-butylcarbazate (993 mg, 7.52 mmol), copper (I) iodide (59.5 mg, 0.313 mmol), 1,10-phenanthroline (113 mg, 0.626 mmol) and cesium carbonate (2.85 g, 8.77 mmol). The mixture was heated at 80° C. for 18 h and then cooled to room temperature. Water (100 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated. The residue was purified by silica gel column chromatograghy eluted with EtOAc:hexanes (25 to 50% EtOAc) to give N-(3-morpholin-4-yl-phenyl)-hydrazinecarboxylic acid tert-butyl ester (1.14 g, 62%) as a yellowi oil. MS (ES+): m/z=294.2. 1H NMR (DMSO-d6, 500 MHz): δ 1.44 (s, 9H), 3.06 (t, 4H), 3.73 (t, 4H), 4.97 (s, 2H), 6.66 (dd, 1H), 6.91 (d, 1H), 7.01-7.05 (m, 1H), 7.09-7.14 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](Cl)=[O:5].[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:4](=[O:5])[CH:3]=[C:2]([CH3:7])[CH3:1])=[CH:11][CH:10]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(C)=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)=CC(=O)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100.1 %

Procedure:
3,3-Dimethylacryloyl chloride (Intermediate 1, 4.16 g, 35.1 mmol) was slowly added to a solution of 4-bromoaniline (Intermediate 2, 5.00 g, 29.2 mmol) in 25 mL of methylene chloride. After stirring at room temperature for 20 min, triethylamine (2.5 mL) was added dropwise to the mixture. The resulting solution was stirred at room temperature for 3 h and then poured on 100 mL of ice-water mixture. The organic layer was separated, washed with brine (2×20 mL), dried (MgSO4) and concentrated at reduced pressure to give a yellow residue. Purification by flash chromatography (90:10 hexane/ethyl acetate) afforded the title compound as a yellow solid (7.43 g, 100% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[C:12](=[O:14])[CH3:13].Br[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C([O-])(O)=O.[Na+]>C(N(CC)CC)C>[C:18]([CH2:17][CH2:16][NH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[C:12](=[O:14])[CH3:13])([O:20][CH2:21][CH3:22])=[O:19]
Reactant: COc1ccc(OC)c(C(C)=O)c1N
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNc1c(OC)ccc(OC)c1C(C)=O
Temperature: 10 °C
Reaction time: 2 h

Procedure:
Triethylamine (19.4 g, 192 mM) was added to a mixture of 2'-amino-3',6'-dimethoxyacetophenone (2.5 g, 128 mM) and ethyl 3-bromopropionate (139 g, 770 mM) in a 250 mL flask. The pale solid complex so formed was stirred at 135° for 2 hours with a large and heavy stirring bar. During this time the complex became a homogeneous brown oil. This oil was cooled to 10° C. and 200 mL of 2% NaHCO3 was added to the reaction mixture. The solution was then extracted with CHCl3 (3×100 mL) and the organic layer washed with H2O (100 mL) and then dried over MgSO4. After filtration, the CHCl3 and most of the bromopropionate were removed under reduced pressure. The oily residue was put on a 10×60 cm, SilicAR CC-7 column (500 g) and eluted with 5-20% ethyl acetate/hexane, collecting 1 L fractions. Evaporation of fractions 5 and 6 gave purified 2'-(N-2-carbethoxyethylamino)-3',6'-dimethoxyacetophenone (9.97 g, 26%); IR (neat) μ: 3.3, 5.78, 5.8, 6.25.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[F:10].[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])[CH3:12]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:4][C:3]=1[F:10]
Reactant: O=Cc1ccc(Cl)c(F)c1
Reactant: CC(=O)c1ccccc1
Product: O=C(C=Cc1ccc(Cl)c(F)c1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 4-chloro-3-fluorobenzaldehyde and acetophenone, 3-(4-chloro-3-fluorophenyl)-1-phenylprop-2-en-1-one was obtained as yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:16]2[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[N:17]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])#[N:2].[OH-].[Na+].O.C(O)(=O)C>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([N:16]2[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[N:17]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])#[N:2]
Reactant: CCCCCCOc1ccc(-n2cc(C(=O)OCC)cn2)cc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCCCOc1ccc(-n2cc(C(=O)O)cn2)cc1C#N
Temperature: 50 °C
Yield: 72.6 %

Procedure:
To a solution (20 ml) of ethyl 1-(3-cyano-4-hexyloxyphenyl)pyrazole-4-carboxylate (1.8 g) in ethanol was added 1 N aqueous sodium hydroxide solution (6 ml) with stirring, and the mixture was heated at 50° C. for 1 hour. After the completion of the reaction, the reaction mixture was poured into water and the mixture was neutralized with acetic acid. The precipitated crystals were recrystallized from a mixed solution of dioxane and water to give 1.2 g of 1-(3-cyano-4-hexyloxyphenyl)pyrazole-4-carboxylic acid, melting point 164-165° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[F:10][CH:11]([F:43])[CH2:12][CH2:13][C:14]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:29](=[O:41])[C:28]2=[O:42])([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:15][CH2:16][CH:17]([F:19])[F:18]>O1CCCC1>[C:37]([O:36][C:34]([NH:30][C:31]1[CH:32]=[CH:33][C:25]([C:14]([CH2:15][CH2:16][CH:17]([F:19])[F:18])([CH2:13][CH2:12][CH:11]([F:43])[F:10])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:26][C:27]=1[C:28](=[O:42])[C:29]([N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)=[O:41])=[O:35])([CH3:39])([CH3:38])[CH3:40]
Reactant: CCOC(=O)C(CCC(F)F)(CCC(F)F)c1ccc2c(c1)C(=O)C(=O)N2C(=O)OC(C)(C)C
Reactant: c1ccc2c(c1)CNC2
Solvent: C1CCOC1
Product: CCOC(=O)C(CCC(F)F)(CCC(F)F)c1ccc(NC(=O)OC(C)(C)C)c(C(=O)C(=O)N2Cc3ccccc3C2)c1
Temperature: 23 °C
Reaction time: 1 h
Yield: 23.5 %

Procedure:
584 mg of isoindoline are added to 2.4 g of 5-[1-(3,3-difluoropropyl)-1-ethoxycarbonyl-4,4-difluorobutyl]-1-tert-butoxycarbonyl-2,3-dioxoindoline in 30 ml of tetrahydrofuran, and the mixture is subsequently stirred at 23° C. for 1 h. The mixture is evaporated to dryness in vacuo and purified by column chromatography, giving 700 mg (24%) of ethyl 2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]-2-(3,3-difluoropropyl)-5,5-difluoropentanoate;
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.[K]>CN(C=O)C>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:14]2[C:13](=[O:15])[C:12]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]3[C:10]2=[O:20])=[CH:4][CH:3]=1
Reactant: ClCc1ccc(I)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(I)cc1
Temperature: 55 °C
Yield: 75.6 %

Procedure:
(Brown, Stephen; Grigg, Ronald; Hinsley, Joanne; Korn, Stewart; Sridharan, Visuvanathar; Uttley, Michael; Tetrahedron (2001), 57(52), 10347-10355.) A mixture of 4-iodobenzylchloride (40.0 g, 134.7 mmol), potassium phthalimide (26.20 g, 141.5 mmol) and dry DMF (150 mL) was heated overnight at 55° C. under Ar, and then the solvent was removed at reduced pressure. The solid residue was triturated with CHCl3 (200 mL), filtered, and washed with CHCl3 (3×200 mL). The combined organic extracts were successively washed with aqueous 0.2 M NaOH (200 mL) and H2O (400 mL), and then dried (MgSO4). The solvent was removed at reduced pressure to afford a crude solid, which was triturated with Et2O to obtain a white solid (37.00 g, 75%): Rf=0.75 (1/1 EtOAc/hexanes); mp 138-139° C.; 1H NMR (CDCl3) □4.77 (s, CH2), 7.17 (d, J=8.6 Hz, 2 ArH), 7.63 (d, J=8.6 Hz, 2 ArH), 7.78 (dd, J=3.0, 5.7 Hz, 2 PhtH), 7.83 (dd, J=3.0, 5.7 Hz, 2 PhtH); 13C NMR (CDCl3) δ 41.0 (CH2), 93.5 (Cl), 123.4, 130.6, 131.9, 134.1, 135.9, 137.7 (6 Ar), 167.2 (2 C(O)); HRMS (ESI) 363.9831 [M+H+] (calcd for C17H13NO2H+ 363.9835).