Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[C:6]([N:13]1[CH2:19][CH2:18][CH2:17][C@H:14]1[CH:15]=[O:16])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]>>[C:6]([N:13]1[CH2:19][CH2:18][CH2:17][C@H:14]1[C:15](=[O:16])[CH:1]([CH3:3])[CH3:2])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CC(C)[Mg]Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Product: CC(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
30.1 ml (60.2 mmol) 2 M isopropylmagnesium chloride (diethyl ether) and 4.0 g (20.1 mmol) BOC-L-prolinal were allowed to react at −80° C. for 30 min according to procedure F. Yield of the crude product 4.31 g. The product was purified with a silica column using 16% ethyl acetate in petroleum ether as eluent. Yield 1.84 g (7.6 mmol, 38%). The product was oxidized to the corresponding ketone according to procedure G. Yield of crude product 1.59 g. The product was purified with a silica column using 16% ethyl acetate in petroleum ether as eluent. Yield 1.15 g (4.8 mmol, 63%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:42])=[C:4]([C:8]([I:41])=[C:9]([C:12](=[O:40])[NH:13][CH2:14][CH:15]([O:36][C:37](=[O:39])[CH3:38])[CH:16]([O:32][C:33](=[O:35])[CH3:34])[CH:17]([O:28][C:29](=[O:31])[CH3:30])[CH:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:19][O:20][C:21](=[O:23])[CH3:22])[C:10]=1[I:11])[C:5](O)=[O:6].S(Cl)([Cl:45])=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[NH2:1][C:2]1[C:3]([I:42])=[C:4]([C:8]([I:41])=[C:9]([C:12](=[O:40])[NH:13][CH2:14][CH:15]([O:36][C:37](=[O:39])[CH3:38])[CH:16]([O:32][C:33](=[O:35])[CH3:34])[CH:17]([O:28][C:29](=[O:31])[CH3:30])[CH:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:19][O:20][C:21](=[O:23])[CH3:22])[C:10]=1[I:11])[C:5]([Cl:45])=[O:6]
Reactant: CC(=O)OCC(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(CNC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I)OC(C)=O
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OCC(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(CNC(=O)c1c(I)c(N)c(I)c(C(=O)Cl)c1I)OC(C)=O
Reaction time: 1.5 h

Procedure:
15.5 g (16.4 mmol) of 3-amino-5-(2,3,4,5,6-pentaacetoxyhexylcarbamoyl)-2,4,6-triiodobenzoic acid [Example 18a)] is suspended in 80 ml of ethyl acetate and refluxed with 1.9 ml (24.6 mmol) of thionyl chloride for 5 hours. The reaction mixture is added to 30 g of sodium bicarbonate in 300 ml of water and stirred vigorously for 1.5 hours. Then, the phases are separated and the organic phase is dried on sodium sulfate, filtered, and the solution is concentrated by evaporation. The oily reaction product is foamed up in a high vacuum.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=2)[NH2:11])[N:4]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:25]=[C:26]([CH2:29][CH2:30][C:31](O)=[O:32])[S:27][CH:28]=2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[N:25]=[C:26]([CH2:29][CH2:30][C:31]([NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:8]([C:5]4[N:4]=[C:3]([C:2]([F:15])([F:1])[F:16])[O:7][N:6]=4)[CH:9]=3)=[O:32])[S:27][CH:28]=2)=[CH:22][CH:23]=1
Reactant: Nc1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: O=C(O)CCc1nc(-c2ccc(F)cc2)cs1
Product: O=C(CCc1nc(-c2ccc(F)cc2)cs1)Nc1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 43 %

Procedure:
This compound was synthesized from 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)aniline and 3-(4-(4-fluorophenyl)thiazol-2-yl)propanoic acid as described in example 8 step 6 (80 mg, yield 43%). 1H NMR (400 MHz, CDCl3) δ 8.80 (br s, 1H), 8.11 (s, 1H), 7.88-7.83 (m, 4H), 7.48-7.44 (t, J=7.9 Hz, 1H), 7.33 (s, 1H), 7.14-7.10 (t, J=8.7 Hz, 2H), 3.52-3.48 (m, 2H), 3.04-3.01 (m, 2H). MS (ESI) m/z: Calculated for C21H14F4N4O2S: 462.08. found: 463.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([CH:14]([S:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25](Br)=[C:24]([CH3:30])[CH:23]=2)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:13]=1)=[O:8].[C:32]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([CH:14]([S:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25]([C:39]3[CH:40]=[CH:41][C:36]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:37][CH:38]=3)=[C:24]([CH3:30])[CH:23]=2)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:13]=1)=[O:8]
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCC(F)(F)F)Sc2cc(C)c(Br)c(C)c2)s1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: COC(=O)CCNC(=O)c1ccc(C(CCC(F)(F)F)Sc2cc(C)c(-c3ccc(C(C)(C)C)cc3)c(C)c2)s1

Procedure:
This compound is made by the general method as exemplified in Preparation 77 using 3-({5-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-4,4,4-trifluoro-butyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester chiral Isomer 2 and 4-t-butyl-phenyl boronic acid as the starting materials. MS(ES): 592.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:19]#[N:20])=[C:10]([N+:16]([O-])=O)[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1.O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[NH2:16][C:10]1[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9]=1[C:19]#[N:20]
Reactant: COc1cc(-c2ccccc2Cl)c(C#N)c([N+](=O)[O-])c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(N)c(C#N)c(-c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
The product of step (a) (300 mg, 1.0 mmol) was dissolved in DMF (3 ml) and a solution of sodium dithionite hydrate added (500 mg, 2.9 mmol in 6 ml of H2O). The solution became warm and some solid precipitated out of solution. After stirring for 30 min at room temperature, 15 ml of H2O and 2N HCl were added. This mixture was extracted with EtOAc (2×30 ml), neutralised using 2N NaOH and re-extracted with EtOAc (2×30 ml). The combined EtOAc extracts were dried over MgSO4 and the solvent removed to give the crude product. This was purified on silica gel, eluting with CH2Cl2 /MeOH (98/2, v/v) to give the subtitle compound as colourless gum (190 mg, 74%). Rf 0.29 (hexane/ether 1/1, v/v). MS m/e 276 and 278 (MNH4+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[N:12]([CH3:13])[N:11]=[CH:10][C:9]=1[C:14]([NH:16][CH2:17][CH2:18][NH:19][C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O.[F-].[Na+]>O1CCCC1>[NH2:7][C:8]1[N:12]([CH3:13])[N:11]=[CH:10][C:9]=1[CH2:14][NH:16][CH2:17][CH2:18][NH:19][C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cn1ncc(C(=O)NCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)c1N
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: C1CCOC1
Product: Cn1ncc(CNCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)c1N
Yield: 31.1 %

Procedure:
To a suspension of lithium aluminium hydride (3.78 g) in tetrahydrofuran (150 ml) was added 5-amino-1-methyl-N-[2-(tritylamino)ethyl]-1H-pyrazole-4-carboxamide (10.64 g) at room temperature. The mixture was stirred under reflux for 18 hours. After cooling on an ice bath, to the reaction mixture were added sodium fluoride (20 g) and aqueous tetrahydrofuran solution (10 ml). The insoluble materials were removed by filtration. The resulting filtrate was concentrated in vacuo, and the residue was dissolved in chloroform. The solution was washed with 10% aqueous sodium hydroxide solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The oily residue was triturated with ethyl acetate and dried in vacuo to give N-[(5-amino-1-methyl-1H-pyrazol-4-yl)methyl]-N′-tritylethane-1,2-diamine (3.2 g) as a solid.
Reaction SMILES: [CH2:1]([CH:3]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:4][O:5][C:6](=[O:27])/[C:7](/[CH2:12][CH2:13][C:14]([F:26])([F:25])[C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])=[CH:8]\[C:9]([O-:11])=[O:10])[CH3:2].[S:32]([O-:35])([OH:34])=[O:33].[Na+:36].O.C(O)C>C(OCC)(=O)C>[CH2:1]([CH:3]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:4][O:5][C:6](=[O:27])[C:7]([CH2:12][CH2:13][C:14]([F:25])([F:26])[C:15]([F:23])([F:24])[C:16]([F:21])([F:22])[C:17]([F:19])([F:20])[F:18])([S:32]([OH:35])(=[O:34])=[O:33])[CH2:8][C:9]([O-:11])=[O:10])[CH3:2].[Na+:36]
Reactant: O=S([O-])O
Reactant: CCCCC(CC)COC(=O)/C(=C\C(=O)[O-])CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCC(CC)COC(=O)C(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(CC(=O)[O-])S(=O)(=O)O
Yield: 83.5 %

Procedure:
Mono(2-ethylhexyl)mono(3,3,4,4,5,5,6,6,6-nonafluorohexyl)maleate (137.5 g, 0.29 mol), sodium hydrogensulfite (33.2 g, 0.32 mol) and water/ethanol (140 mL, 1/1 (v/v)) were mixed and refluxed for 2 hours with heating. Thereafter, the reaction mixture was added with ethyl acetate (1000 mL), and the organic phase was washed with a saturated sodium chloride aqueous solution. The organic layer was collected, and the organic solvent was evaporated under reduced pressure. The residue was subjected to recrystallization from toluene (800 mL). Upon cooling on an ice bath, crystals deposited. The crystals were finally separated by filtration to obtain the target compound (140 g, yield: 84%), which was colorless and transparent.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O)[NH:7][C:8](=[O:21])[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([O-])=O.[O:28]1[CH2:33][CH2:32][N:31]([C:34]2[S:38][C:37]([CH:39]=O)=[CH:36][CH:35]=2)[CH2:30][CH2:29]1>>[O:28]1[CH2:33][CH2:32][N:31]([C:34]2[S:38][C:37]([C:39]3[NH:25][C:24]4[CH:23]=[CH:22][C:6]([NH:7][C:8](=[O:21])[C:9]5[CH:14]=[CH:13][C:12]([N:15]6[CH2:20][CH2:19][O:18][CH2:17][CH2:16]6)=[CH:11][CH:10]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:36][CH:35]=2)[CH2:30][CH2:29]1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCOCC2)cc1
Reactant: O=Cc1ccc(N2CCOCC2)s1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(N4CCOCC4)s3)nc2c1)c1ccc(N2CCOCC2)cc1

Procedure:
Compound 418 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-morpholinobenzoyl)aniline and 5-morpholinothiophene-2-carboxaldehyde. [M+H]+ calcd for C26H27N5O3S: 490.18; found: 489.95.
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C([N:14](CC)CC)C>C1(C)C=CC=CC=1>[C:4]1(=[O:5])[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1](=[O:6])[NH:14]1
Reactant: CCN(CC)CC
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: O=C1NC(=O)c2ccccc21
Temperature: 20 °C

Procedure:
0.8 g of phthalic anhydride and 2 ml of triethylamine were added to a solution of 3 g of the product of Stage B in 30 ml of toluene and then the mixture was heated for 16 hours at reflux. The reaction medium was cooled to 20° C. and washed with 20 ml of N hydrochloric acid. After decanting, washing with water and drying, the solvent was evaporated off to obtain 4.42 g of the expected product which was used as is for the following stage.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[F:15])=[CH:6][N:5]2[N:16]=[C:17]([CH3:19])[N:18]=[C:4]2[N:3]=1.[CH:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:15][C:9]1[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=1[C:7]1[C:2]([C:25]2[CH:26]=[CH:27][C:22]([CH:20]=[O:21])=[CH:23][CH:24]=2)=[N:3][C:4]2[N:5]([N:16]=[C:17]([CH3:19])[N:18]=2)[CH:6]=1
Reactant: Cc1nc2nc(Cl)c(-c3ccc(F)cc3F)cn2n1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccc(F)cc3F)cn2n1
Temperature: 90 °C
Yield: 81 %

Procedure:
To a mixture of 1 g (3.56 mmol) of the 5-chloro-6-(2,4-difluorophenyl)-2-methyl-[1,2,4]triazolo[1,5-a]pyrimidine described in step 3 and 587.6 mg (3.9 mmol) 4-formylphenylboronic acid in 12 mL 1,2-dimethoxyethane are added 131 mg (0.16 mmol) dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) and 6.9 mL of a sodium carbonate solution (10%). The resulting mixture is heated to 90° C. under an inert gas atmosphere for 2 h. The reaction mixture is diluted with water and extracted three times with dichloromethane. The combined organic layers are washed with brine and dried over sodium sulphate; the solvent is evaporated and the residue is purified by chromatography on silica gel (dichloromethane/methanol) to yield 1.01 g (77%) of the desired aldehyde.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([O:21]C)=O)[C:11](=[O:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:24][NH2:25]>COCCO>[CH3:24][N:25]1[C:11](=[O:23])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]2[C:19](=[O:21])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=[C:3]2[CH2:2]1
Reactant: CN
Reactant: COC(=O)c1ccccc1-n1c(CCl)nc2ccccc2c1=O
Solvent: COCCO
Product: CN1Cc2nc3ccccc3c(=O)n2-c2ccccc2C1=O
Yield: 82.5 %

Procedure:
16.4 g (0.05 mol) of 2-chloromethyl-3-(2-methoxycarbonyl-phenyl)-4H-quinazolin-4-one and 10 ml of liquid methylamine in 100 ml of ethylene glycol monomethyl ether are heated to 40° C. for 2 hours in an autoclave. After cooling the mixture, the colourless crystals are filtered off and washed several times with ethanol. 12 g (82.5% of theory) of 6-methyl-6,7-dihydro-5H,13H-quinazolino[3,2-a][1,4]benzodiazepine-5,13-dione are obtained.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCCC1>N1C=CC=CC=1>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:12][C:13]([OH:15])=[O:14]
Reactant: O=Cc1ccc(F)cc1F
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc(F)cc1F
Temperature: 100 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
2,4-Difluoro-benzaldehyde (10.0 g, 70.4 mmol), malonic acid (16.5 g, 158.3 mmol), and piperidine (5.8 mL, 58.4 mmol) were added to pyridine (42.7 mL). The reaction mixture was stirred at 100° C. for 2 hours, concentrated under reduced pressure, and then distilled water was added thereto. The mixture was filtered and then the resulting solid was dried under reduced pressure to give 9.5 g of the titled compound as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH:8]2[CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7]2>[Pd]>[CH3:1][N:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[C:9]2[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: CN1C2CCCCC2C2CCCCC21
Agent: [Pd]
Product: Cn1c2ccccc2c2ccccc21

Procedure:
Perhydro-N-methylcarbazole is catalytically dehydrogenated over a supported Pd or Pt catalyst to provide H2 and N-methylcarbazole (FIG. 6). Sequentially, the N-methyl group is oxidized with air using a copper halide catalyst to yield the N-formyl compound Ill. Because of the very high heat of this oxidative transformation, only an approximately 20% conversion of (II) to (III) should be necessary to provide for the heat of dehydrogenation.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=1>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:25]2[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][C:17]3[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=3)[CH2:27][CH2:26]2)=[O:10])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Solvent: CN(C)C=O
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCN(CCc2ccc(Cl)cc2)CC1

Procedure:
The 1-(4-nitrobenzoyl)-4-[2-(4-chlorophenyl)ethyl]piperazine is prepared from 4-nitrobenzoic acid and 1-[(4-chlorophenyl)ethyl]piperazine in N,N-dimethylformamide in the presence of N,N-carbonylimidazole. It melts at 109°-110°.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:15]2[CH2:17][CH2:16]2)=[C:6]([CH:8]2[C:12](=[O:13])[CH2:11][CH2:10][C:9]2=[O:14])[CH:7]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.[F-].[Cs+]>[O-]S(C(F)(F)F)(=O)=O.[Cu+2].[O-]S(C(F)(F)F)(=O)=O.C1(C)C=CC=CC=1>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:2]2[CH:3]=[CH:4][C:5]([CH:15]3[CH2:17][CH2:16]3)=[C:6]([CH:8]3[C:12](=[O:13])[CH2:11][CH2:10][C:9]3=[O:14])[CH:7]=2)=[CH:21][CH:20]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C1CCC(=O)C1c1cc(Br)ccc1C1CC1
Agent: [Cu+2]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: O=C1CCC(=O)C1c1cc(Oc2ccc(Cl)cc2)ccc1C1CC1
Temperature: 160 °C

Procedure:
To a mixture of 2-(5-bromo-2-cyclopropylphenyl)cyclopentane-1,3-dione (0.254 g, 0.062 mmol), 4-chlorophenol (0.400 g, 3.11 mmol), cesium fluoride (0.440 g, 1.25 mmol) and copper (II) triflate (11 mg, 0.03 mmol) is added 4 Å powdered molecular sieves (0.40 g) and anhydrous toluene (3.5 ml). This mixture is then heated at 160° C. for 1 hour under microwave irradiation, allowed to cool to room temperature then quenched with 2M hydrochloric acid. The reaction mixture is extracted with dichloromethane (×3), then the combined organics are washed with brine, dried over magnesium sulfate and concentrated in vacuo. The crude product is purified by preparative reverse phase HPLC to afford 2-[5-(4-chlorophenoxy)-2-cyclopropylphenyl]cyclopentane-1,3-dione as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1.[OH-].[K+].[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl>CO.ClCCl>[O:24]1[CH2:23][CH:22]1[CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][N:11]3[CH:17]=2)=[CH:6][CH:7]=1
Reactant: ClCC1CO1
Reactant: Cc1cccn2cc(-c3ccc(O)cc3)nc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Cc1cccn2cc(-c3ccc(OCC4CO4)cc3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of Step B (27 g) in methanol (500 mL) was treated with potassium hydroxide (14 g) and stirred at ambient temperature for 2 hours. To this solution was then added epichlorohydrin (9.4 mL) and the mixture stirred for an additional 48 hours. The reaction mixture was diluted with dichloromethane, filtered and the filtrate washed with water, dried, sodium sulfate filtered and evaporated to afford the title compound (18.2 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][NH:8][N:7]=1)[CH3:4].Cl[CH2:19][C:20]1[O:24][N:23]=[C:22]([O:25][CH2:26][C:27]2[N:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:30][C:31]=2[CH3:32])[CH:21]=1.O>CN(C)C=O>[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:19][C:20]2[O:24][N:23]=[C:22]([O:25][CH2:26][C:27]3[N:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:30][C:31]=3[CH3:32])[CH:21]=2)[N:7]=1)[CH3:4]
Reactant: Cc1oc(-c2ccccc2)nc1COc1cc(CCl)on1
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2cc(OCc3nc(-c4ccccc4)oc3C)no2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl)propionate (318 mg) and 5-chloromethyl-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)isoxazole (457 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethyl]-1H-pyrazol-4-yl]propionate (653 mg, yield: 91%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 82–83° C.
Reaction SMILES: O1[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.Cl.[F:9][C:10]([F:14])([F:13])[CH2:11][NH2:12]>N1C=CC=CC=1>[F:9][C:10]([F:14])([F:13])[CH2:11][N:12]1[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1
Reactant: NCC(F)(F)F
Reactant: O=c1ccocc1
Agent: Cl
Solvent: c1ccncc1
Product: O=c1ccn(CC(F)(F)F)cc1
Yield: 92.3 %

Procedure:
1 g (10.4 mmol) of 4H-pyran-4-on was dissolved in 10 ml of pyridine, 3.38 g (25 mmol) of 2,2,2-trifluoroethylamine hydrochloride was added, and reacted at 70° C. for an hour. The solvent was removed, and the residue was purified by chloroform-methanol (10:1) silica gel chromatograph to obtain 1.7 g of the title compound.
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:25])=O>C(O)C>[Cl:25][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1
Reactant: COCCCOc1ccnc(CO)c1C
Reactant: O=S(Cl)Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: COCCCOc1ccnc(CCl)c1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixed solution of 2-hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine (12.02 g (56.9 mmol)) and toluene (96.0 ml) was added dropwise thionyl chloride (8.11 g (68.2 mmol)), so that the internal temperature did not exceed 25° C., which was stirred for about 90 minutes at room temperature. Ethanol (24.0 ml) was added to this mixed solution to obtain a 2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine solution.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:9][C:10]([CH3:12])=O.C(O)(=O)C>>[NH:1]([C:10]([CH3:12])=[CH:9][C:8]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C=C(C)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound is commercially available. A mixture of aniline (9.785 mL, 107.4 mmol), ethyl acetoacetate (13.69 mL, 107.4 mmol), and acetic acid (0.6 mL, 10 mmol) was stirred at ambient temperature overnight. It was partitioned between heptane (50 mL) and sat. aq. NaHCO3 solution (50 mL). The organic layer was dried and evaporated to give the title compound of >90% purity that was used in the next steps without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].Cl[CH2:33][CH2:34][CH2:35][N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]([CH3:45])[C:37]1=[O:46].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:45][CH:38]1[C:39]2[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:36]([CH2:35][CH2:34][CH2:33][N:9]2[CH2:10][CH2:11][C:6]3([N:5]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:4][N:3]([CH2:18][C:19]4[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=4)[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:2]3=[O:1])[CH2:7][CH2:8]2)[C:37]1=[O:46]
Reactant: CC1C(=O)N(CCCCl)c2ccccc21
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC1C(=O)N(CCCN2CCC3(CC2)C(=O)N(Cc2cccc(C(=O)OC(C)(C)C)c2)CN3c2ccccc2)c2ccccc21
Temperature: 81 °C
Reaction time: 16 h
Yield: 34.6 %

Procedure:
A mixture of tert-butyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (200 mg, 0.475 mmol, 1 equiv), 1-(3-chloropropyl)-3-methylindolin-2-one (155 mg, 0.665 mmol, 1.4 equiv), sodium iodide (28.5 mg, 0.19 mmol, 0.4 equiv) and potassium carbonate (71.4 mg, 0.7125 mmol, 1.5 equiv) in 2-butanone was stirred at 81° C. for 16 h. After cooling the reaction mixture, the crude mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered, concentrated, and the crude residue was purified using preparative thin layer chromatography in 7% methanol in dichloromethane to afford the title compound (100 mg, ˜30%); MS for C37H44N4O4 m/z 609.3 (M+H)+.