Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].Br[C:17](Br)([F:19])[F:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC(N(C)C)=O.O.[Zn]>[F:18][C:17]([F:19])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: FC(F)(Br)Br
Reactant: COC(=O)CCCCCCCCCC=O
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)CCCCCCCCCC=C(F)F
Temperature: 25 °C
Reaction time: 60 h
Yield: 49.5 %

Procedure:
A stirred mixture of 7.5 grams (0.035 mole) of methyl 11-oxoundecanoate and 14.7 grams (0.07 mole) of dibromodifluoromethane was cooled to 0°-10° C., and a solution of 18.4 grams (0.07 mole) of triphenylphosphine in 50 ml of dimethylacetamide was added dropwise. During the addition the temperature of the reaction mixture was maintained at 0°-10° C. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature, and 4.6 grams (0.07 mole) of zinc dust was added in two portions. The addition caused an exothermic reaction which raised the temperature of the reaction mixture to 90° C. The reaction mixture was allowed to cool to ambient temperature where it stood without stirring for 60 hours. The reaction mixture was diluted with water and was subjected to a steam distillation with pentane. The appropriate fractions were combined and concentrated under reduced pressure yielding 4.3 grams of methyl 12,12-difluoro-11-dodecenoate. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[N:6][CH:7]=1.[CH3:10][CH:11]([OH:15])[CH2:12][CH:13]=[CH2:14].C(N(CC)CC)C.C(#N)C>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:9][O:8][C:4]1[CH:3]=[C:2](/[CH:14]=[CH:13]/[CH2:12][CH:11]([OH:15])[CH3:10])[CH:7]=[N:6][CH:5]=1
Reactant: COc1cncc(Br)c1
Reactant: C=CCC(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cncc(/C=C/CC(C)O)c1
Temperature: 140 °C
Yield: 83.6 %

Procedure:
A mixture of 5-bromo-3-methoxypyridine (4.11 g, 21.86 mmol), 4-penten-2-ol (2.25 g, 26.23 mmol), palladium(II) acetate (49 mg, 0.22 mmol), tri-o-tolylphosphine (266 mg, 0.87 mmol), triethylamine (13.71 mL, 98.37 mmol), and acetonitrile (15 mL) was heated in a sealed glass tube at 140° C. for 14 h. The reaction mixture was cooled to ambient temperature, diluted with water, and extracted with chloroform (3×200 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation to give 3.53 g (70.3%) of a pale-yellow oil.
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27].S.[OH-].[Na+]>C(O)C.C1(C)C(C)=CC=CC=1>[C:1]1([C:7]2[S:27][C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[CH:9][C:8]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CC(C(=O)c1ccccc1)c1ccccc1)c1ccc(F)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: S
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: CCO
Product: Fc1ccc(-c2cc(-c3ccccc3)c(-c3ccccc3)s2)cc1
Temperature: 20 °C
Yield: 107.6 %

Procedure:
A mixture 49.8 g (0.15 mole) of 1,2-diphenyl-4-p-fluorophenylbutane-1,4-dione, 100 ml of xylene, 30 g (0.0675 mole) of phosphorus pentasulfide and 130 g (3.81 moles) of hydrogen sulfide was heated and stirred in a 1-liter stainless steel autoclave for 4 hours at 157°-185° C. (620-1145 psig). After cooling the vessel to 20° C. and venting the hydrogen sulfide into a sodium hydroxide solution, the residue was stirred with 150 ml of absolute ethanol. Filtration gave 31.5 g (63.6%) of crude product, m.p. 108°-110° C. Recrystallization from 30 ml of dioxane and 90 ml of ethanol gave 24 g of pure 2,3-diphenyl-5-p-fluorophenylthiophene, m.p. 111°-113° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[N:14]=[C:13](Cl)[C:12]([Cl:16])=[CH:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:8][C:9]1[N:14]=[C:13]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:12]([Cl:16])=[CH:11][N:10]=1
Reactant: Nc1ccccc1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Clc1ncc(Cl)c(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of Aniline (205 mg, 2.2 mmol) and 2,4,5-Trichloropyrimidine (500 mg, 2.7 mmol) in 5 mL of Ethanol, was added 500 mg of Potassium carbonate. The reaction mixture was stirred at room temperature for 2 hours. Solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography with 10% Ethyl Acetate in Heptane to yield the desired product as an oil (370 mg, 70% yield).
Reaction SMILES: [C:1]([C:3]1[C:4]([N:9]([CH3:14])[S:10]([CH3:13])(=[O:12])=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[H][H]>[Pd].N.CO>[NH2:2][CH2:1][C:3]1[C:4]([N:9]([CH3:14])[S:10]([CH3:13])(=[O:12])=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CN(c1ncccc1C#N)S(C)(=O)=O
Reactant: [H][H]
Agent: [Pd]
Agent: N
Solvent: CO
Product: CN(c1ncccc1CN)S(C)(=O)=O

Procedure:
N-(3-Aminomethyl-pyridin-2-yl)-N-methyl-methanesulfonamide was prepared from N-(3-cyano-pyridin-2-yl)-N-methyl-methanesulfonamide (3.35 g, 15.8 mmol) (prepared as described in J. Heterocyclic Chemistry, 1979, 16, 1361-1363) via hydrogenation using a Paar apparatus with 10% palladium on carbon (50% Wet) (5:45:50, Palladium:carbon black:Water, 5.71 g, 2.68 mmol) and hydrogen (50 psi) in 7M ammonia in methanol (100 mL). The mixture was shaken on a Paar apparatus until adsorption of hydrogen ceased. The mixture was degassed, backflushed with nitrogen, filtered through a plug of diatomaceous earth and rinsed with dichloromethane. The filtrate was evaporated under reduced pressure. Product isolated as pale yellow oil (3.20, 93%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.37 (dd, J=4.6, 1.7 Hz, 1H), 7.92 (dd, J=7.7, 1.7 Hz, 1H), 7.32 (dd, J=7.7, 4.8 Hz, 1H), 4.04 (s, 2H), 3.26 (s, 3H), 3.08 (s, 3H). MS=216 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:34].[Na+].O.O.OP([O-])(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:34])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][C:20]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[O:21])=[CH:17][CH:18]=1
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(CC(=O)N4CCOCC4)cc3)cc12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CC(C)(C)O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(CC(=O)N4CCOCC4)cc3)cc12
Temperature: 0 °C
Reaction time: 18 h
Yield: 25.1 %

Procedure:
To a solution of 6-chloro-5-{4-[2-(morpholin-4-yl)-2-oxoethyl]phenyl}-1H-indole-3-carbaldehyde (249 mg, 0.650 mmol) in acetonitrile (6 mL) and tert-butanol (6 mL) was added 2-methyl-2-butene (4 mL). The reaction mixture was cooled to 0° C. and treated with a solution of sodium chlorite (880 mg, 13.1 mmol) and sodium phosphate monobasic dihydrate (2030 mg, 13.01 mmol) in water (3 mL) via addition funnel. The icebath was removed and the mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with aqueous sodium sulfite, concentrated in vacuo and extracted with ethyl acetate (4×25 mL). The combined organic phases were washed with brine (20 mL), dried and concentrated in vacuo. The crude product was purified by prep-HPLC (Column: Phenomenex Synergi C18 150*30 mm*4 μm; Mobile phase: from 38% MeCN in water (0.225% FA) to 58% MeCN in water (0.225% FA); Wavelength: 220 nm) to afford the title compound (65 mg, 28% yield) as a white solid. MS (ES+) 399.0 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 8.03 (s, 1H), 8.01 (s, 1H), 7.59 (s, 1H), 7.43 (d, 2H), 7.34 (d, 2H), 3.87 (s, 2H), 3.65 (m, 4H), 3.52 (m, 2H), 3.55 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C@@H:3]([OH:21])[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH2:6]1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1.Cl>C(#N)C>[ClH:24].[F:23][C:2]([F:1])([F:22])[C@@H:3]([O:21][C:32](=[O:33])[NH:31][C:28]1[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=1)[CH2:4][N:5]1[CH2:10][CH2:9][O:8][C@H:7]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=2)[CH2:6]1
Reactant: O[C@@H](CN1CCOC(c2ccc(C(F)(F)F)cc2)C1)C(F)(F)F
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CC#N
Product: O=C(Nc1ccc(Cl)cc1)O[C@@H](CN1CCO[C@H](c2ccc(C(F)(F)F)cc2)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
(S)-1,1,1-Trifluoro-3-[2-(4-trifluoromethyl-phenyl)-morpholin-4-yl]-propan-2-ol (52 mg, 151 μmol) and 1-chloro-4-isocyanatobenzene (25.6 mg, 167 μmol) were combined in acetonitrile (2 mL). The mixture was stirred at room temperature overnight and evaporated. The residue was purified by flash chromatography (20% EtOAc/hexanes) to provide the front-running isomer, which was converted to the HCl salt to afford (4-chloro-phenyl)-carbamic acid (S)-2,2,2-trifluoro-1-[(R)-2-(4-trifluoromethyl-phenyl)-morpholin-4-ylmethyl]-ethyl ester hydrochloride as a white solid (30 mg). (M+H)+=497 m/e.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:9]=[N+:10]=[N-:11].[Na+].[Cl:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH2:23][C:24]#[CH:25])=[C:16]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:15]=1.C(N(CC)CC)C>CS(C)=O>[Cl:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH2:23][C:24]2[N:9]=[N:10][N:11]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:25]=2)=[C:16]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:15]=1
Reactant: BrCc1ccccc1
Reactant: C#CCn1cnc2c(NCc3ccccc3)nc(Cl)nc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Clc1nc(NCc2ccccc2)c2ncn(Cc3cn(Cc4ccccc4)nn3)c2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
Benzyl bromide (110 mg, 0.58 mmol) was added dropwise to a solution of sodium azide (42 mg, 0.64 mmol) in DMSO (5 mL, and stirred at room temperature for 15 min. Compound 5 (173 mg, 0.58 mmol), triethylamine (6 mg, 0.06 mmol) and CuBr (8 mg, 0.6 mmol) were added to the contents in that order, and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was poured into ice-cold water (20 mL), and the resulting off-white precipitate was filtered and washed with dilute NH4OH (20 mL) and water (50 mL) to give the compound 6 (200 mg 80%) essentially pure by NMR; mp 235° C. EI/MS (m/z (relative %)): 430 (32, M+.), 431 (11), 432 (13), 258 (54), (100); 1H NMR (400 MHz, DMSO) δ 8.23 (s, 1H), 8.15 (s, 1H), 7.40-7.17 (m, 10H), 5.56 (s, 2H), 5.40 (s, 2H), 4.62 (d, J=6 Hz, 2H); 13C NMR (100 MHz, DMSO) δ 155.6 (s), 153.9 (s), 150.3 (s), 143.1 (d, 1JC—H=199 Hz), 141.9 (s), 139.9 (s), 136.51 (s), 129.4 (d, 1JC—H=160 Hz), 128.9 (d, 1JC—H=159 Hz), 128.8 (d, 1JC—H=159 Hz), 128.5 (d, 1JC—H=158 Hz), 127.9 (overlapping doublets), 127.4 (overlapping doublets), 124.4 (d, 1JC—H=200 Hz) 118.6 (s), 53.4 (t, 1JC—H=145 Hz), 43.7 ((t, 1JC—H=135 Hz), 38.9 (t, 1JC—H=139 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH:4]=[CH:5][CH2:6]2.C([Li:16])CCC>O1CCCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH:4]=[CH:5][CH:6]2[Li:16]
Reactant: Cc1ccc(C)c2c1C=CC2
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: [Li]C1C=Cc2c(C)ccc(C)c21
Reaction time: 4 h

Procedure:
38.2 g (265 mmol) of 4,7-dimethylindene were dissolved in 350 ml of tetrahydrofuran, and the temperature of the solution was taken to 0° C. 165 ml of n-butyllithium (1.6 M in hexane, 264 mmol) were then added dropwise drop over 2.5 hours. After returning to room temperature and continued stirring for 4 hours, a red-purple solution of 4,7-dimethylindenyllithium was obtained. This solution was cooled to -70° C. and treated dropwise in the course of 35 minutes with 25.3 g of 1,2-dibromoethane (135 mmol) in 15 ml of tetrahydrofuran. After returning to room temperature, this gave a clear yellow solution, to which water was added. The organic phase was collected and dried over Na2SO4. The solvent was then evaporated in vacuum, 20 g of product (48% yield) being obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:11]3[C:12](=[O:17])[C:13](I)=[CH:14][CH:15]=[C:10]3[N:9]2[S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])(=[O:28])=[O:27])=[CH:4][CH:3]=1.[CH3:36][S:37]([C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1)(=[O:39])=[O:38]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:11]3[C:12](=[O:17])[C:13]([C:44]4[CH:43]=[CH:42][CH:41]=[C:40]([S:37]([CH3:36])(=[O:39])=[O:38])[CH:45]=4)=[CH:14][CH:15]=[C:10]3[N:9]2[S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])(=[O:28])=[O:27])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: O=c1c(I)ccc2n1[C@H](c1ccc(Cl)cc1)[C@H](c1ccc(Cl)cc1)N2S(=O)(=O)c1ccccc1F
Product: CS(=O)(=O)c1cccc(-c2ccc3n(c2=O)[C@H](c2ccc(Cl)cc2)[C@H](c2ccc(Cl)cc2)N3S(=O)(=O)c2ccccc2F)c1

Procedure:
rac-cis-2,3-Bis-(4-chloro-phenyl)-1-(2-fluoro-benzenesulfonyl)-6-(3-methanesulfonyl-phenyl)-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one was prepared according to general method D by reaction of rac-cis-2,3-bis-(4-chloro-phenyl)-1-(2-fluoro-benzenesulfonyl)-2,3-dihydro-6-iodo-1H-imidazo[1,2-a]pyridin-5-one with 3-(methylsulfonyl)phenylboronic acid. The compound was isolated by preparative HPLC. The expected product was characterized by LC/MS (M+H) where the mass was observed as 669.0; the expected mass is 668. LC/MS indicated a purity of 100% as measured by UV 214 nM.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]([OH:19])=O)[C:12]2[C:7](=[CH:8][C:9]([CH3:20])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].FC1C(O)=C(F)C(F)=C(F)C=1F.Cl.[C:34]([C@@H:36]1[CH2:40][CH2:39][CH2:38][NH:37]1)#[N:35].C(N1CCOCC1)C>CN(C=O)C.C(Cl)Cl.C(Cl)CCl>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]([N:37]2[CH2:38][CH2:39][CH2:40][C@H:36]2[C:34]#[N:35])=[O:19])[C:12]2[C:7](=[CH:8][C:9]([CH3:20])=[CH:10][CH:11]=2)[N:6]=1)=[O:4]
Reactant: N#C[C@@H]1CCCN1
Reactant: COC(=O)c1cc(OCC(=O)O)c2ccc(C)cc2n1
Agent: CCN1CCOCC1
Agent: Cl
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)c1cc(OCC(=O)N2CCC[C@H]2C#N)c2ccc(C)cc2n1

Procedure:
To a solution of 1000 mg 4-Carboxymethoxy-7-methyl-quinoline-2-carboxylic acid methyl ester in 5 ml DMF were added 956 mg pentafluorophenol and 994 mg EDC. The mixture was stirred under exclusion of moisture until LCMS indicated complete conversion to the corresponding pentafluorophenolester. (S)-2-Cyano-pyrrolidine hydrochloride (437 mg) was mixed with 1.3 ml N-ethylmorpholine and 10 ml DMF and this mixture added dropwise to the solution of the pentafluorophenolester. After 12 h the reaction mixture was diluted with DCM and washed with aqueous LiCl (4%) and saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica eluting with ethyl acetate/heptane gradient. Yield: 772 mg.
Reaction SMILES: [C:1](OCC=C)(=O)[C:2]1C(=CC=C[CH:13]=1)C(OCC=C)=O.[CH2:19](Cl)[CH:20]=[CH2:21].C(O)(=O)C1C(=CC=CC=1)C(O)=O.[Cl:35][C:36]1[C:37]([Cl:50])=[C:38]([Cl:49])[C:39]([Cl:48])=[C:40]([C:45]([O-:47])=[O:46])[C:41]=1[C:42]([O-:44])=[O:43].[Na+].[Na+]>>[Cl:35][C:36]1[C:37]([Cl:50])=[C:38]([Cl:49])[C:39]([Cl:48])=[C:40]([C:45]([O:47][CH2:21][CH:20]=[CH2:19])=[O:46])[C:41]=1[C:42]([O:44][CH2:13][CH:2]=[CH2:1])=[O:43]
Reactant: C=CCCl
Reactant: C=CCOC(=O)c1ccccc1C(=O)OCC=C
Reactant: O=C([O-])c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(=O)[O-]
Agent: O=C(O)c1ccccc1C(=O)O
Agent: [Na+]
Product: C=CCOC(=O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(=O)OCC=C

Procedure:
Using a method similar to the known preparation of diallyl phthalate by reacting allyl chloride with metal salts of phthalic acid, Matsumoto et al prepared DATCP by reacting disodium tetrachlorophthalate with 2 moles of allyl chloride in an aqueous solution containing cuprous ions. Diallyl tetrachlorophthalate was also produced by Guseinov et al who reacted the anhydride with 3 moles of allyl alcohol plus 1 mole of hydrochloric acid in a benzene solution (Azerbaizhan Chemical Journal, No. 6, (1964), 21-23). Nordlander et al also produced DATCP by reacting the tetrachlorophthalic anhydride with 2 moles of allyl alcohol using sulfuric acid as a catalyst and driving off the water of reaction by distillation as an azeotrope with benzene (Journal of the American Chemical Society, 69, Nov., (1947), 2679-2682). However, only a 10% to 15% yield of the DATCP was obtained because of dehydration and polymerization reactions of the allyl alcohol.
Reaction SMILES: [H-].[Na+].[CH:3]12[CH2:8][CH:7]1[C:6](=[O:9])[NH:5][C:4]2=[O:10].Br[CH2:12][CH:13]([CH2:18][CH3:19])[CH2:14][CH2:15][CH2:16][CH3:17]>CN(C)C=O.O>[CH2:18]([CH:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][N:5]1[C:6](=[O:9])[CH:7]2[CH:3]([CH2:8]2)[C:4]1=[O:10])[CH3:19]
Reactant: O=C1NC(=O)C2CC12
Reactant: CCCCC(CC)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(CC)CN1C(=O)C2CC2C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydride (0.11 g) was added to a solution of 3-azabicyclo[3.1.0]hexane-2,4-dione (0.3 g) and 1-bromo-2-ethylhexane (0.52 g) in dimethylformamide (5 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was diluted with water (15 ml) and then extracted with toluene (20 ml). The organic extract was washed with water (15 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by Kugelrohr distillation (boiling point 140-160° C. @ 0.1 mmHg) to give the title compound as a colourless oil.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:14][O:15][C:16]([NH:18][C@H:19]([C:24]([OH:26])=[O:25])[CH2:20][C:21]([OH:23])=O)=[O:17]>C(OCC)(=O)C>[CH3:14][O:15][C:16]([NH:18][C@@H:19]1[C:24](=[O:25])[O:26][C:21](=[O:23])[CH2:20]1)=[O:17]
Reactant: COC(=O)N[C@@H](CC(=O)O)C(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H]1CC(=O)OC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
110.52 g of trifluoroacetic anhydride are added dropwise to a solution of 76.29 g of DL-N-(methoxycarbonyl)aspartic acid in ethyl acetate under cooling. After the mixturte is stirred at room temperature for 2 hours, a part of solvent is distilled off. n-hexane is added to the solution slowly under cooling, and the precipitated crystals are collected by filteration to give 65.54 g of DL-N-(methoxycarbonyl)aspartic anhydride as colorless prism.
Reaction SMILES: ClC(OCC)=O.C1C=CC=CC=1.C1(C[N:17]2[CH2:35][CH2:34][C@H:20]3[N:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[C@@H:19]3[CH2:18]2)CC1.[OH-].[K+]>C(O)CCC>[C:28]1([N:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C@@H:19]3[CH2:18][NH:17][CH2:35][CH2:34][C@@H:20]23)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: c1ccc(N2c3ccccc3[C@@H]3CN(CC4CC4)CC[C@H]32)cc1
Agent: CCOC(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CCCCO
Product: c1ccc(N2c3ccccc3[C@@H]3CNCC[C@H]32)cc1
Reaction time: 1 h

Procedure:
A solution of ethyl chloroformate (22 g., 0.2 mole) in 100 ml. dry benzene was added to a solution of (±)-trans-2-cyclopropylmethyl-2,3,4,4a,5,9b-hexahydro-5-phenyl-1H-pyrido[4,3-b]indole (16 g. crude material, prepared as described above, 0.047 moles in theory) in 400 ml. anhydrous benzene with stirring. The resulting mixture was refluxed for three hours. As the mixture was refluxing, a whitish solid precipitated. After refluxing, the mixture was cooled and filtered to remove the precipitate, then the filtrate was evaporated to dryness under vacuum, yielding a yellow oil. This oil was dissolved in 400 ml. n-butanol, 40 g. of KOH pellets were added, and the resulting mixture was refluxed with stirring for one hour. After refluxing, the mixture was cooled, and concentrated under vacuum. Water and toluene were added and the mixture was placed in a separatory funnel. The toluene layer was removed and washed with water until the waste water was neutral to litmus. The toluene layer was then extracted four times with 125 ml. of 1 molar tartaric acid. The combined extracts were then washed once with ether, made basic by addition of 50% aqueous NaOH, cooled, and extracted two times with 75 ml. CHCl3. The CHCl3 extract was washed with water until the wash water was neutral to litmus, dried with K2CO3, filtered, and evaporated to dryness under vacuum, yielding 9.7 g. of an oil. This was left in a refrigerator overnight, then was triturated with hexane, yielding a solid. Recrystallization from hexane yielded 4.9 g. of the title compound, m.p. 94°-94.7° C.
Reaction SMILES: [CH:1]1([O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:34]=[CH:33][C:27]([C:28]([O:30]CC)=[O:29])=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+].[ClH:42]>O.C(O)C>[ClH:42].[ClH:42].[CH:1]1([O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH2:19][CH2:20][N:21]([C:24]4[CH:34]=[CH:33][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=4)[CH2:22][CH2:23]3)=[CH:16][CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1ccc(N2CCN(c3ccc(OCCCOC4CCCCC4)cc3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(N2CCN(c3ccc(OCCCOC4CCCCC4)cc3)CC2)cc1

Procedure:
A mixture of ethyl 4-[4-[4-(3-cyclohexyloxypropyloxy)phenyl]piperazin-1-yl]benzoate (290 mg) in the mixed solvent of tetrahydrofuran (15 ml) and ethanol (3 ml) was treated with 10% sodium hydroxide aqueous solution (0.50 ml), and the mixture was refluxed for 8 hours. After cooling, water was added to the reaction mixture, and the acidity of the mixture was adjusted to pH 1 with 1N-hydrochloric acid. The resulting precipitate was filtered, washed with water and dried under reduced pressure to give 4-[4-[4-(3-cyclohexyloxypropyloxy)phenyl]piperazin-1-yl]benzoic acid dihydrochloride (96 mg) as a pale brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](B(O)O)=[CH:8][C:7]=2[CH:14]=1.Br[C:16]1[N:21]=[N:20][C:19]([NH2:22])=[CH:18][CH:17]=1.CCN(CC)CC>CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:16]3[N:21]=[N:20][C:19]([NH2:22])=[CH:18][CH:17]=3)=[CH:8][C:7]=2[CH:14]=1
Reactant: COc1ccc2oc(B(O)O)cc2c1
Reactant: Nc1ccc(Br)nn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc2oc(-c3ccc(N)nn3)cc2c1
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 21.1 %

Procedure:
5-methoxybenzofuran boronic acid 1.2 mmol), 6-bromo-3-pyridazinamine (1.0 mmol), Pd(PPh3)2Cl2 (0.024 mmol) and NEt3 (317 μL) were mixed in EtOH (10 mL) in a 20 mL microwave vial. The mixture was stirred at 140° C. for 10 min in a microwave reactor. The solvent was removed under vacuum, water was added and the solution was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and the solvent removed under vacuum. The crude substance was purified by preparative HPLC to afford the title compound as a white solid (51 mg). 1H NMR δ ppm 7.77 (d, 1 H) 7.52 (d, 1 H) 7.35 (s, 1H) 7.19 (d, 1 H) 6.79-6.98 (m, 2 H) 6.72 (s, 2 H) 3.80 (s, 3 H); MS m/z 242 (M+H).