Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:17][CH2:18][CH2:19]Cl)[C:5]=2[CH:4]=1.C(N(CC)CC)C.[CH2:30]([C:33]1([O:39][CH2:40][CH2:41][OH:42])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[CH2:31][CH3:32]>C(C(C)=O)C.[I-].[Na+]>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:17][CH2:18][CH2:19][N:36]3[CH2:37][CH2:38][C:33]([O:39][CH2:40][CH2:41][OH:42])([CH2:30][CH2:31][CH3:32])[CH2:34][CH2:35]3)[C:5]=2[CH:4]=1
Reactant: CCCC1(OCCO)CCNCC1
Reactant: FC(F)(F)c1ccc2c(c1)N(CCCCl)c1ccccc1S2
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: CCCC1(OCCO)CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)CC1
Yield: 99.6 %

Procedure:
10 g of 2-trifluoromethyl-10-(3-chloropropyl)-phenothiazine were dissolved in 50 ml of methyl ethyl ketone and 4.36 g of sodium iodide, 2.9 g of triethylamine, then dropwise a solution of 5.4 g of 2-(4-propyl-4-piperidyloxy)-ethanol in 50 ml of methyl ethyl ketone were added successively thereto. The mixture was refluxed for 24 hours and after cooling, the precipitate formed was removed by vacuum filtration. The precipitate formed was removed by filtration and the filtrate was evaporated in vacuo and the residue was dissolved in methylene chloride. The organic solution was washed with an aqueous solution of sodium bicarbonate, then with water and the solution was dried and concentrated in vacuo to obtain 14.2 g of 2-trifluoromethyl-10-[3-(4-β-hydroxyethoxy-4-propylpiperidino)-propyl]-phenothiazine as a beige product which was dissolved in 50 ml of ethanol. The resulting solution was reacted with an ether solution of hydrogen chloride and the hydrochloride was precipitated by the addition of ether. The said precipitate was recovered by vacuum filtration and was washed with ether and crystallized from acetonitrile to obtain 7 g of 2-trifluoromethyl-10-[3-(4-β-hydroxyethoxy-4-propylpiperidino)-propyl]-phenothiazine hydrochloride as white crystals melting at 192° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][C:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN(C)[CH:31]=[O:32]>>[C:6]1([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:15]([CH:31]=[O:32])[C:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(-c2cc(-c3ccccc3)n(-c3ccccc3)n2)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(-c2ccccc2)nn(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
32 grams phosphorus oxychloride were added dropwise at 0°-5° C. to 75 grams dimethylformamide. The mixture was thereafter stirred for 1 hours at room temperature. Thereafter, 25 grams 1,3,5-triphenyl-pyrazol were added to the mixture, which was then stirred for 8 hours at 80° C. The reaction mixture, which was evaporated and water added to the residue. The pH of the aqueous mixture was adjusted to 8-10. The precipitate was separated and crystallized from ethanol. 22 grams 1,3,5-triphenyl-pyrazol-4-aldehyde, melting at 159°-160° C., were obtained, representing a yield of 80%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:12])[CH:9]([F:11])[F:10])=[N:6][CH:7]=1.[CH3:13][Mg+].[Br-].[NH4+].[Cl-]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:12])([CH3:13])[CH:9]([F:10])[F:11])=[N:6][CH:7]=1
Reactant: C[Mg+]
Reactant: O=C(c1ccc(Br)cn1)C(F)F
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)(c1ccc(Br)cn1)C(F)F
Reaction time: 0.17 h

Procedure:
To a solution of 1-(5-bromopyridin-2-yl)-2,2-difluoroethanone (1.5 g, 6.4 mmol) in tetrahydrofuran (15 mL) under nitrogen was added 3 N solution of MeMgBr in THF (3.2 mL, 9.6 mmol) dropwise at −15° C. The resulting solution was stirred at ambient temperature for 2 hours before the addition of saturated aqueous NH4Cl solution (10 mL) at 0° C. The resulting mixture was vigorously stirred for 10 minutes, and then extracted with ethyl acetate (3×20 mL). All the organic solution was dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography with 1-3% ethyl acetate in hexane to afford the title compound as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.83 (d, J=2.0 Hz, 1H), 7.92 (dd, J=8.4, 2.0 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 5.76 (t, J=56.4 Hz, 1H), 5.22 (br, 1H), 1.60 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7]C(=O)[C:5]2=[O:13].[OH:14]O>>[NH2:7][C:8]1[CH:9]=[C:10]([F:11])[C:2]([F:1])=[CH:3][C:4]=1[C:5]([OH:13])=[O:14]
Reactant: O=C1Nc2cc(F)c(F)cc2C1=O
Reactant: OO
Product: Nc1cc(F)c(F)cc1C(=O)O

Procedure:
In accordance with the above reaction scheme, an aqueous solution of 3,4-difluoroaniline (I) and hydroxylamine hydrochloride containing hydrochloric acid is reacted with an aqueous solution of chloral hydrate and sodium sulfate at the reflux, then filtered while hot, giving N-(3,4-difluorophenyl)-2-(hydroxyimino)-acetamide (II). The compound (II) is reacted with concentrated sulfuric acid with heat, then added to cracked ice, giving 5,6-difluoro-1H-indole-2,3-dione (III). A basic aqueous solution of compound (III) is treated with hydrogen peroxide and heat, then cooled and acidified, giving 2-amino-4,5-difluorobenzoic acid (IV). The compound (IV) is added to a mixture of anhydrous copper(II) chloride, t-butyl nitrite and anhydrous acetonitrile at 0°-5° C., then added to a dilute mineral acid, giving 2-chloro-4,5-difluorobenzoic acid (V).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.O=S(Cl)Cl.[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14].O>C(Cl)(Cl)Cl>[CH2:13]([N:15]([CH2:16][CH3:17])[C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:8])[CH3:14]
Reactant: O=C(O)c1ccsc1
Reactant: CCNCC
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)c1ccsc1
Temperature: 25 °C
Yield: 88.7 %

Procedure:
A solution of 5.0 g (39 mmol) of 3-thiophenecarboxylic acid (Aldrich Chemical Co.), to which was added 10 mL (134 mmol) of SOCl2 in 20 mL of CHCl3 was stirred at reflux for 3 hours. After cooling to room temperature, the solution was concentrated in vacuo. The residue was dissolved in 15 mL of methylene chloride, and the solution was cooled in an ice bath. To this was added dropwise 13 mL (126 mmol) of diethyl amine, and the reaction was stirred at room temperature for 1 hour. Water was added, and the mixture was extracted with methylene chloride, which was washed with aqueous NaHCO3 solution, water, and bdne, and concentrated to give 9.3 g of crude product. This material was purified by flash chromatography on silica gel, eluting with 6:1 hexane:ethyl acetate, to afford 6.34 g of the title product after removal of the solvents. NMR (CDCl3) δ:7.48 (dd, 1H, J=1, J=3 Hz), 7.32 (dd, 1H, J=3, J=6 Hz), 7.20 (dd, 1H, J=1, J=6 Hz), 3.60-3.30 (bs, 4H), 1.20 (bm, 6H).
Reaction SMILES: [Mg:1].[Br:2]C(Br)C.[CH2:6]([C:8]1[CH:13]=[C:12]([CH2:14][CH3:15])[CH:11]=[C:10]([CH2:16][CH3:17])[C:9]=1Br)[CH3:7]>O1CCCC1>[CH2:14]([C:12]1([Mg:1][Br:2])[CH:13]=[C:8]([CH2:6][CH3:7])[CH:9]=[C:10]([CH2:16][CH3:17])[CH2:11]1)[CH3:15]
Reactant: CC(Br)Br
Reactant: [Mg]
Reactant: CCc1cc(CC)c(Br)c(CC)c1
Solvent: C1CCOC1
Product: CCC1=CC(CC)([Mg]Br)CC(CC)=C1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
To a 3 L volume four-necked flask, magnesium (cutting chip) (51.4 g) and tetrahydrofuran (anhydrous) (250 ml) were added under a nitrogen atmosphere. After the temperature of the mixture was raised to about 30° C., dibromoethane (17.3 g) was added dropwise. The resulting mixture was stirred for 30 minutes. To the mixture, 1,3,5-triethylbromobenzene (10-b) (443.5 g) dissolved in tetrahydrofuran (250 ml) was added dropwise over 2 hours. The mixture was stirred at 50° C. for 1 hour, and cooled to room temperature to give a solution of 1,3,5-triethylphenylmagnesium bromide in tetrahydrofuran.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[N+](=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N-]>CC(OC)(C)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C@H:6]2[CH2:7][C@@H:12]2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1ccc(Br)cc1
Solvent: COC(C)(C)C
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a 1-neck, 1-L round bottom flask equipped with a magnetic stirrer was added 265 mL methyl tert-butyl ether. The flask was evacuated and flushed with nitrogen three times. 2,2′-Isopropylidenebis[(4R)-4-tert-butyl-2-oxazolidine] (2.39 g, 8.03 mmol) was added, followed by copper(I) trifluoromethanesulfonate benzene complex (4.49 g, 8.03 mmol). The green suspension was stirred at room temperature for about 2 hours and was then filtered. The filtrate was added to a 4-neck, 5-L, round bottom flask equipped with a mechanical stirrer, thermocouple, nitrogen bubbler, and addition funnel. Then, 4-bromostyrene (150 g, 0.803 mol) was added to this solution and the reaction was cooled to 0° C. via an ice/water bath. Ethyl diazoacetate (167 mL, 1.606 mol) was dissolved in 1675 mL of MTBE and the solution was evacuated/flushed with nitrogen three times. This solution was then added to an addition funnel and added dropwise to the reaction mixture. A slight exotherm was observed. The ethyl diazoacetate was allowed to add slowly over the weekend and the reaction slowly warmed to room temperature. The reaction was poured into a large extractor and diluted with 4 L MTBE. The organics were washed with 2×1 L 3% aq. ammonium hydroxide and 2 L brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was dissolved in heptane and a small amount of dichloromethane, injected onto an ISCO 1500 g column prepacked in heptane. The column was eluted with 100% heptane over 1 column volume, 0-20% ethyl acetate/heptane over 6.5 column volumes, and held at 20% ethyl acetate/heptane over 8 column volumes. The product containing fractions were collected and concentrated to give 191 g (yield 88%) of the title compound. 1H NMR (500 MHz, (CDCl3): 7.42 (d, 2H), 7.01 (d, 2H), 4.21 (q, 2H), 2.49 (m, 1H), 1.88 (m, 1H), 1.62 (m, 2H), 1.25 (t, 3H).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([CH2:11][CH:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][CH3:16])=[C:9]3[CH:19]=[CH:20][S:21][C:8]3=[C:7]([O:22][CH2:23][CH:24]([CH2:29][CH3:30])[CH2:25][CH2:26][CH2:27][CH3:28])[C:5]=2[CH:6]=1.[Cu][C:32]#[N:33]>>[CH2:29]([CH:24]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:23][O:22][C:7]1[C:8]2[S:21][CH:20]=[CH:19][C:9]=2[C:10]([CH2:11][CH:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][CH3:16])=[C:4]2[S:3][C:2]([C:32]#[N:33])=[CH:6][C:5]=12)[CH3:30]
Reactant: N#C[Cu]
Reactant: CCCCC(CC)COc1c2cc(Br)sc2c(CC(CC)CCCC)c2ccsc12
Product: CCCCC(CC)COc1c2cc(C#N)sc2c(CC(CC)CCCC)c2ccsc12
Yield: 37.5 %

Procedure:
A dry 100-mL three-neck flask, equipped with a condenser, charged with 6-bromo-8-(2-ethylhexoxy)-4-(2-ethylhexyl)thieno[2,3-f]benzothiophene (4.2 g, 8.2 mmol) and flushed with N2. Deoxygenated pyridine (15 mL, 0.5 M) was then added via syringe. Copper (I) cyanide (2.2 g, 25 mmol) was added to the reaction flask and the mixture was evacuated and refilled with nitrogen three times. The reaction flask was heated to reflux for 48 hours. As the reaction was completed, the reaction mixture was poured into 50 mL of water and extracted with MTBE (50 mL) three times. The combined organic layer was washed with water two times and dried over anhydrous magnesium sulfate (MgSO4). After the product was filtered, the solvent was removed by rotary evaporation. The product was purified using column chromatography on silica gel with hexanes/ethyl acetate (gradient) to yield oil (1.4 g, 38%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9]2=O)=[CH:4][CH:3]=1.[C:15]([Mg]Cl)([CH3:18])([CH3:17])[CH3:16].CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]=[C:9]2[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Reactant: CC(C)(C)[Mg]Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C1=CCC(C)(C)c2ccc(Br)cc21
Temperature: -20 °C
Reaction time: 1 h

Procedure:
In a flame dried round bottom flask 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G, 2.0 g, 7.93 mmol) 16 was dissolved in anhydrous THF (50 ml) and 3,4,5,6,-tetrahydro-2(H)-pyrimidinone (DMPU) (11.5 ml, 95.16 mmol) was added, under argon atmosphere. The reaction was then cooled to -20° C. and a solution of t-butyl magnesium chloride (16 ml, 31.7 mmol) (2 M in Et2O) was added dropwise and stirred at -20° C. for 2 h and at ambient temperature for 1 h, under argon atmosphere. The reaction was quenched at 0° C. with saturated ammonium chloride solution (20 ml) and extracted with EtOAc (2×50 ml). The combined extract was washed with water (20 ml), brine (20 ml) and dried over MgSO4. The solvent was evaporated under reduced pressure to afford a yellow oil. To this yellow oil were added MeOH (50 ml) and p-tolylsulfonic acid (100 mg). The resultant reaction solution was heated in an oil bath (60° C.) for 3 h. The reaction was cooled and quenched with water (20 ml), extracted with EtOAc (2×50 ml). The combined extract was washed with saturated NaHCO3 (20 ml), water (20 ml), brine (20 ml), and dried over MgSO4. The solvent was concentrated in vacuo and the title compound was obtained as a colorless oil after purification by flash chromatography (silica, hexane).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=[CH:8][C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]1>>[OH:33][CH:30]1[CH2:31][CH2:32][N:27]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[C:10]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=[CH:8][C:7]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:28][CH2:29]1
Reactant: OC1CCNCC1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2ccccc2)c(OCCCCl)c1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2ccccc2)c(OCCCN2CCC(O)CC2)c1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 139 using tert-butyl N-[2-(3-chloropropoxy)biphenyl-4-ylmethyl]carbamate instead of 3-(3-chloropropoxy)-4-phenylbenzonitrile and piperidine-4-ol instead of pyrrolidine.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][CH2:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:11])=[O:7].C1CCNCC1.[F:31][C:32]([F:43])([F:42])[O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Br.C1(N=C=O)C=CC=CC=1>CC#N>[F:31][C:32]([F:42])([F:43])[O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][N:17]1[CH2:18][CH2:19][CH:14]([CH2:13][NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:20]=[CH:21][CH:22]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:4]=2)[CH2:15][CH2:16]1
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCNCC1
Solvent: C1CCNCC1
Solvent: O=C=Nc1ccccc1
Solvent: CC#N
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCN(Cc2cccc(OC(F)(F)F)c2)CC1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
A solution of 4-[{N-(3(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (19.9 mg, 0.058 mmol) in CH3CN (1.0 mL) and (piperidinomethyl)polystyrene (55 mg, 2.7 mmol base/g resin) were added to a solution of 3-(trifluoromethoxy)benzyl bromide (12.3 mg, 0.048 mmol) in CH3CN (1.0 mL). The reaction mixture was stirred at 60° C. for 2.5 h. Phenyl isocyanate (6.9 mg, 0.048 mmol) was added to the cooled reaction mixture and the mixture was stirred at 25° C. for 1 h. The reaction mixture was loaded onto Varian™ SCX column and washed with CH3OH (20 mL). Product was eluted off using 2 N NH3 in CH3OH (6 mL) and concentrated to afford 1-{3-(trifluoromethoxy)benzyl}-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (compound No. 927) (22.8 mg, 91%) as a pale yellow oil: The purity was determined by RPLC/MS (99%); ESI/MS m/e 518.1 (M++H, C24H26F6N3O3)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](C(=O)C)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[S].[OH2:18].N1[CH2:24][CH2:23][O:22]CC1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:24][C:23]([OH:22])=[O:18])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O
Reactant: C1COCCN1
Reactant: CC(=O)c1ccc(-c2ccc(Br)cc2)cc1
Agent: [S]
Product: O=C(O)Cc1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 5 h

Procedure:
The compound (3 g) obtained in the above (1) is suspended in morpholine (20 ml), and thereto is added sulfur (0.71 g), and the mixture is refluxed with stirring for five hours. After cooling, the reaction mixture is poured into water, and extracted with ethyl acetate. The organic layer is washed with 1N hydrochloric acid (twice) and a saturated brine (twice), and dried over anhydrous sodium sulfate. The desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is suspended in ethanol, and the precipitates are collected by filtration.
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8](O)=[C:5]([O:6][CH3:7])[CH:4]=1.[C:12](=O)([O-])[O-].[K+].[K+].[CH3:18][OH:19]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[C:5]1([O:6][CH3:7])[C:18](=[CH:12][CH:2]=[C:3]([CH:4]=1)[CH:11]=[CH:10][CH3:8])[OH:19]
Reactant: CO
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C=O)ccc1O
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Product: CC=Cc1ccc(O)c(OC)c1

Procedure:
Isoeugenol is synthesized from vanillin in the presence of potassium carbonate and ethyl triphenyl phosphonium bromide in commercial methanol.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[N:15]3[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:5][CH2:4]1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C>C1COCC1>[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:14]1[N:15]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[C:16]2[C:12]([N:13]=1)=[C:11]([NH:10][CH2:9][CH:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][S:35]([CH3:34])(=[O:37])=[O:36])[CH2:4][CH2:5]1)[N:19]=[CH:18][N:17]=2
Reactant: NCC1CCC(CNc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)NCC1CCC(CNc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
To a solution of N-{[4-(aminomethyl)cyclohexyl]methyl}-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-amine (6 mg, 0.013 mmol, 1 eq.) in 5 mL of THF was added methanesulfonyl chloride (0.02 mL) and triethylamine (0.05 mL) The reaction was stirred at room temperature 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 5 mg (71%) of N-{[4-({[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}methyl)cyclohexyl]methyl}methanesulfonamide. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.82-1.16 (m, 2 H) 1.33-1.75 (m, 6 H) 1.77-2.02 (m, 2 H) 2.84-3.00 (m, 4 H) 3.00-3.16 (m, 1 μl) 3.43-3.80 (m, 2 H) 4.40-4.63 (m, 1 H) 5.89-6.18 (m, 1 H) 7.08-7.60 (m, 8 H) 8.44 (s, 1H), [M+H]+ 559.6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:14]([NH:15][CH2:16][CH2:17][NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13][CH2:12][N:11]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[C:39](=O)(OC(Cl)(Cl)Cl)[O:40]C(Cl)(Cl)Cl.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:14]([N:15]3[CH2:16][CH2:17][N:18]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:39]3=[O:40])[CH2:13][CH2:12][N:11]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NCCNc2ccccc2)[C@H](c2ccc(Cl)c(Cl)c2)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](N2CCN(c3ccccc3)C2=O)[C@H](c2ccc(Cl)c(Cl)c2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 18.6 %

Procedure:
To a solution of the compound (0.21 g) obtained in step 3 and triethylamine (0.19 mL) in THF (10 mL) was added bis(trichloromethyl) carbonate (0.13 g) at 5° C. The reaction mixture was stirred at 0° C. for 30 min and at room temperature for 1 hr, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous ammonium chloride solution and saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 10→33% ethyl acetate/hexane) to give the title compound (0.04 g, 18%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:20][CH2:21][CH3:22])[CH2:5][CH2:6][CH:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:8]#[N:9])[CH3:2].[I-].I[CH:25]([CH3:27])[CH3:26].[Na+].[I-]>>[CH2:1]([O:3][CH:4]([O:20][CH2:21][CH3:22])[CH2:5][CH2:6][C:7]([CH:25]([CH3:27])[CH3:26])([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:8]#[N:9])[CH3:2]
Reactant: CCOC(CCC(C#N)c1ccc(OC)c(OC)c1)OCC
Reactant: CC(C)I
Agent: [I-]
Agent: [Na+]
Product: CCOC(CCC(C#N)(c1ccc(OC)c(OC)c1)C(C)C)OCC
Temperature: 0 °C

Procedure:
The resulting acetal derivative of formula 5 is then alkylated with about 1 eq of an alkylhalide using a strong metallic base and a catalytic amount of an iodide source, e.g., 2-iodopropane or NaI, in a polar aprotic solvent at about 10°-40° C. for 2-18 hours, followed by treatment with sufficient ice water to decompose excess base, to yield a dialkylated derivative of formula 6. For example, 2-(3,3-diethoxypropyl)-2-(3,4-dimethoxyphenyl)acetonitrile (5) in DMF is treated with a slight molar excess of 2-chloropropane (and 0.1-5 mol% 2-iodopropane) at 20° C., stirred for 10 minutes, then treated with 1 eq NaH in mineral oil and slowly heated to 40° C. After adding 200 mL ice water and purifying the product, 2-(3,3-diethoxypropyl)-2-(prop-2-yl)-2-(3,4-dimethoxyphenyl)acetonitrile (6) is obtained.
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][CH:12]=[C:13]([C:24](O)=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[CH3:27][C:28]([NH2:31])([CH3:30])[CH3:29].C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>ClCCl>[C:28]([NH:31][C:24]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:17]([N:18]1[CH2:22][CH2:21][CH2:20][C@@H:19]1[CH3:23])=[N:16]2)=[O:25])([CH3:30])([CH3:29])[CH3:27]
Reactant: CC(C)(C)N
Reactant: C[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CCCN1c1nc2cc(C(=O)NC(C)(C)C)ccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-2-(4-fluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylic acid (200 mg, 0.57 mmol) in dichloromethane (30 mL) was added 2-methylpropan-2-amine (46 mg, 0.63 mmol), triethylamine (115 mg, 1.14 mmol) and T3P (217 mg, 0.68 mmol) dropwise with stifling. The resulting solution was stirred for 3 h at room temperature and then concentrated in vacuo to afford (S)—N-tert-butyl-2-(4-fluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxamide as a yellow oil (160 mg, crude).