Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(=O)(O)(O)O.CO[CH:22](OC)[CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Br:31]>ClC1C=CC=CC=1>[Br:31][C:26]1[C:25]2[O:24][CH:23]=[CH:22][C:30]=2[CH:29]=[CH:28][CH:27]=1
Reactant: COC(COc1ccccc1Br)OC
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Clc1ccccc1
Product: Brc1cccc2ccoc12
Temperature: 0 °C
Yield: 57.7 %

Procedure:
A mixture of phosphorus pentoxide (19.3 g) and phosphoric acid (64 ml, 85%) was added carefully to a stirred solution of 2-(2-bromophenoxy)acetaldehyde dimethyl acetal (69.6 g) in chlorobenzene (450 ml) at ambient temperature under nitrogen. The mixture was then heated under reflux for 20 hours, cooled and poured into ice/water (500 ml). The aqueous layer was separated and washed with dichloromethane (2×250 ml). The combined organic extracts were washed with brine (400 ml), dried (MgSO4), and the solvent removed in vacuo. The residue was purified by flash column chromatography over silica using a 1:49 mixture of ether and petroleum ether (b.p. 60-80° C.) as the eluant, followed by distillation to give 7-bromobenzo[b]furan (30.3 g) as a clear oil, b.p. 66-68° C. at 0.93 mbar.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.O.[C:10]1([N:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:23]1([N:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:17]2[CH:22]=[CH:21][C:20]([Br:1])=[CH:19][CH:18]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Product: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reaction time: 12 h
Yield: 59 %

Procedure:
In addition, 15 g of triphenylamine dissolved in 50 ml of N,N-dimethylformide is prepared. 11.4 g of N-bromosuccinimide is added into the N,N-dimethylformide solution and the solution is stirred for 12 hours. After 20 ml of water is added, a white crystal is obtained. The white crystal is filtered and dried to obtain 11.70 g of N,N-diphenyl-4-bromoaniline (60%). Next, 8.26 g of N,N-diphenyl-4-bromoaniline is dissolved in 100 ml of tetrahydrofuran. After cooling the solution to −78° C., 24 ml of n-butyl lithium is dropt into the cold solution slowly, then the solution is stirred for 2 hours and the temperature of solution is raised to 0° C. Then, the reacting solution is cooled to −78° C. again, and 5.2 ml of boric acid trimethyl ester is added into the solution slowly. After stirring the reacting solution for 12 hours, 20 ml of 2N HCl is added to terminate the reaction. 100 ml of ethyl ether is used to extract the solution, and the extracted solution is dehydrated by MgSO4. Then, the extracted solution is concentrated, and hexane is added to obtain a white crystal. This white crystal is filtered and dried to obtain 4.3 g of compound (B)(60%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13](Cl)=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1.C(Cl)(Cl)Cl.[CH3:24][S:25]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH2:32])(=[O:27])=[O:26]>CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH3:24][S:25]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH:32][C:13]([C:12]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:9]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)=[O:14])(=[O:26])=[O:27]
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Reactant: CS(=O)(=O)c1cccc(CN)c1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cccc(CNC(=O)c2cc(C(F)(F)F)nn2-c2ccccc2Cl)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 21 %

Procedure:
To a round bottom flask was added 2-(2-chlorophenyl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl chloride (160 mg, 0.520 mmol) in a solution of anhydrous CHCl3 (10 mL). To the reaction solution was added 3-methylsulfonyl benzylamine (122 mg, 0.661 mmol), TEA (150 μL, 1.10 mmol), and DMAP (67 mg, 0.549 mmol). The reaction solution was allowed to stir at 60° C. for 5 hrs. The reaction solution was diluted with EtOAc (150 mL), poured into a separatory funnel and washed with aq. NH4Cl. The partitioned organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure on the rotavapor. The crude material was chromatographed through a silica gel column using a solvent gradient of 100% hexane to 30% EtOAc to afford 50 mg of title compound (20%). 1H NMR (CDCl3): δ 7.83 (m, 1H), 7.79 (s, 1H), 7.48-7.58 (m, 4H), 7.42-7.46 (m, 2H), 7.05 (s, 1H), 6.66 (t, J=6 Hz, 1H), 4.58 (d, J=6 Hz, 2H), 3.03 (s, 3H); MS (ES): 458.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(N(CC)CC)C.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86 %

Procedure:
To a solution of 4-chloro-3-nitro-pyridine (25.0 g, 157.69 mmol, 1.0 equiv; commercially available) and triethylamine (19.15 g, 189.23 mol, 1.2 equiv) in anhydrous DMF (100 mL) was added 4-amino-piperidine-1-carboxylic acid tert-butyl ester (31.58 g, 157.69 mmol, 1.0 equiv; commercially available), dissolved in anhydrous DMF (30 mL), and the reaction mixture stirred at rt for 15 h. The reaction mixture was poured into ice-cold water (1 L) and stirred for 2 h, allowed to settle for another 2 h and then filtered. The orange solid was washed with water and air-dried. The crude material was crystallized from ethyl acetate to obtain 43.7 g (86%) of the title compound. 1H NMR (400 MHz, DMSO): δ 1.41 (s, 9H), 1.48-1.56 (m, 2H), 1.88-1.90 (m, 2H), 2.93 (br s, 2H), 3.90-3.93 (m, 3H), 7.14 (d, J=6.3 HZ, 1H), 8.03 (d, J=7.9 Hz, 1H), 8.27 (s, J=6.2 Hz, 1H), 9.03 (s, 1H).
Reaction SMILES: C(OC)(=O)C(C)=C.[Na].S([CH:13]([CH2:25]C(OCCCCCCCC)=O)[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20]CCCC)=[O:15])(O)(=O)=O.[Al]>>[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:15])[CH:13]=[CH2:25]
Reactant: CCCCCCCCOC(=O)CC(C(=O)OCCCCCCCC)S(=O)(=O)O
Agent: C=C(C)C(=O)OC
Agent: [Al]
Agent: [Na]
Product: C=CC(=O)OCCCC

Procedure:
Using the emulsion polymerization process described above for the two stage copolymer, a two stage copolymer composed of methyl methacrylate: butyl acrylate ratio of 60:40 was synthesized to yield a polymer latex with 204 nm average particles (no clay). The emulsifier used in the polymerization process was 1.28% of a 75% solution of dioctyl sulfosuccinate sodium salt. The total solids content of the emulsion was 48.55 weight percent. A portion of the emulsion was coated onto a 0.002 cm thick aluminum sheet to yield a 0.069 cm thick film. The entire arrangement of film and substrate was dried overnight in a vacuum oven at 75° C. After drying a disk of surface area 2.7318 cm2 was cut from the laminate and evaluated, by dielectric relaxation spectroscopy, for assessment of the magnitude of the dielectric storage factor. The data listed in TABLE VI, reveal the value of the dielectric storage factor. A list of the mechanical properties are given in TABLE VII.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH3:6].II.[OH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14].Cl>CCOCC>[OH:9][C:10]1[CH:11]=[C:12]([CH:13]([OH:14])[CH2:3][CH2:4][CH2:5][CH3:6])[CH:15]=[CH:16][CH:17]=1
Reactant: CCCCBr
Reactant: O=Cc1cccc(O)c1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: CCCCC(O)c1cccc(O)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 221.9 %

Procedure:
A dried 1 L 3-neck flask equipped with a N2 inlet, reflux condenser, mechanical stirrer and a 500 ml drppping funnel was charged with 24.3 g (1.0 mol) of magnesium and 50 ml of anhydrous ether. To this was added 15 g (0.11 mol) of 1-bromobutane (Aldrich 23,988-7) and one crystal of iodine. The dropping funnel was charged with 122 g (0.89 mol) of 1-bromobutane and 100 ml. of anhydrous ether. After the contents of the reaction flask began to reflux, the flask was cooled with a water/ice bath and the 1-bromobutane solution was added at such a rate as to maintain a gentle reflux. After the addition was complete the reaction mixture was refluxed for one-half hour, then cooled to 0° C. in an ice/water bath. The dropping funnel was then charged with 38.0 g (0.311 mol) of 3-hydroxybenzaldehyde (Aldrich H 1,980-8) and 250 ml of anhydrous ether. This slurry was added over a 1 hour period. After the addition the reaction mixture was allowed to warm up to room temperature and was stirred overnight. The reaction mixture was neutralized with 900 ml of 5% aqueous HCl. The reaction mixture was extracted with 2×500 ml of ethyl acetate, the organic extracts combined, washed with 1L of water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was recrystallized from ethyl acetate to yield 44.0 g (79%) of 1-(3-hydroxyphenyl)-1-pentanol, m.p. 120°-122° C.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:4]=1[C:5](OC)=[O:6])#[N:2]>C(O)C>[F:13][C:11]1[CH:12]=[C:3]2[C:4](=[CH:9][CH:10]=1)[C:5](=[O:6])[NH:2][CH2:1]2
Reactant: COC(=O)c1ccc(F)cc1C#N
Solvent: CCO
Product: O=C1NCc2cc(F)ccc21
Reaction time: 16 h
Yield: 76.2 %

Procedure:
A 250-mL Parr reactor bottle was purged with nitrogen and charged with Raney nickel (4.00 g) and a solution of 123a (2.00 g, 11.2 mmol) in ethanol (20 mL). The bottle was attached to a Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 16 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (5.00 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2×75 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford a 76% yield of 123b (1.29 g) as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.85 (dd, 1H, J=8.5, 5.5 Hz), 7.21-7.16 (m, 2H), 7.05 (br s, 1H), 4.56 (s, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[Na+].[Na+].C(COC)OC>O>[Cl:13][C:14]1[N:19]=[C:18]([C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:12])[CH3:1])=[CH:4][CH:5]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CN(C)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN(C)c1ccc(-c2ccnc(Cl)n2)cc1
Temperature: 80 °C
Yield: 78.6 %

Procedure:
A mixture of 4-dimethylaminophenyl boronic acid (10 g, 60.6 mM), 2,4-dichloropyrimidine (9 g, 60.4 mM), Na2CO3 (12 g, 114.2 mM), tetrakistriphenylphosphine palladium (2.5 g, 2.1 mM), dimethoxyethane (120 ml) and water (35 ml) was heated at 80° C. under a nitrogen atmosphere for 16 hr. The reaction was cooled in an ice bath and the resulting yellow suspension was filtered and the solid washed with water (3×50 ml) then ethyl acetate (2×50 ml). The solid was dried in vaccuo to afford [4-(2-Chloro-pyrimidin-4-yl)-phenyl]-dimethyl-amine (11.1 g, 78% yield) as an orange solid. ES-MS MH+234, 236, 1H NMR (300 MHz, ppm, DMSO-d6): 8.57 (d, 1H), 8.05 (d, 2H), 7.92 (d, 1H), 6.80 (d, 1H), 3.03 (s, 6H)
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=O)[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:11]>N1C=CC=CC=1>[OH:8][C:6]1[N:5]=[C:4]([SH:11])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1cc(=O)[nH]c(=O)[nH]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: Cc1cc(S)nc(O)n1
Temperature: 50 °C
Yield: 136.5 %

Procedure:
6-Methyluracil (25.0 g) was suspended in 1 liter of distilled pyridine with stirring and heated at 50° C. into solution. Phosphorus pentasulfide (12.6 g) was then added, and the mixture was refluxed for 20 hours. The solution was concentrated under reduced pressure, then the residue was refluxed with 500 ml of ethanol for one hour. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethanol, affording 5.5 g of the objective compound as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19].[BH4-].[Na+]>CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][OH:19]
Reactant: Cc1ccc(-c2nc(Cc3cccc(C=O)c3)c(C)o2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(-c2nc(Cc3cccc(CO)c3)c(C)o2)cc1
Yield: 99.3 %

Procedure:
3-{[5-Methyl-2-(p-tolyl)oxazol-4-yl]methyl}-benzaldehyde (3.54 g) was suspended into 35 ml of methanol, and 230 mg of sodium borohydride was added thereto with stirring under ice-cooling, and stirred for 1.5 hours at room temperature. The reaction solution was poured into ice-cold water, extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduce pressure to provide 3.54 g of the objective compound as colorless crystals. M.p. 97–99° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:19]=1[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1.C(N(CC)C(C)C)(C)C>[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:21]=[CH:20][C:19]=1[CH:32]1[CH2:37][CH2:36][N:35]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH2:34][CH2:33]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccc(COc2ccc(C3CCNCC3)c(OCc3ccccc3)c2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccccc1)N1CCC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
In a 25 ml round-bottomed flask, 0.5 g of 4-(2,4-bis(benzyloxy)phenyl)piperidine in 10 ml of tetrahydrofuran is dissolved in the presence of 0.26 ml of N,N-diisopropylethylamine. 0.17 ml of benzoyl chloride is added and the mixture is then stirred for 24 hours at ambient temperature. The reaction mixture is extracted with ethyl acetate and then the organic phases are combined and dried over magnesium sulphate. The residue is chromatographed on silica gel (8/2 heptane/ethyl acetate). 0.5 g of [4-(2,4-bis(benzyloxy)phenyl)piperidin-1-yl]phenylmethanone is obtained. Yield=80%.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:4]1([CH:1]=[CH:2][C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:3])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(C=Cc1ccccc1)c1ccccc1

Procedure:
To a solution of acetophenone (0.05 mol) and aldehyde (0.05 mol) in 150 ml of MeOH was added 2.5 eq of NaOH as pellets. The reaction bottle was placed on a shaker (slightly exothermic reaction) for 24-48 hrs. Then the reaction container was placed in an acetone-ice bath (−5 to 0° C.) and the reaction mixture was quenched with 10.3 ml of 37% aqueous HCl (2.5 eq). Solvent was removed in vacuo and the residue was partitioned between EtOAc and water. The aqueous layer was discarded and the organic layer was washed with water, brine and dried over Na2SO4. Solvent was removed in vacuo and the crude chalcone (compound 1) was recrystallized from methanol (MeOH) or a mixture of hexane and ethyl acetate (Hex:EtOAc) 3:1 or purified by silica gel chromatography using a mixture of Hex:EtOAc=5:1 as an eluent.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3](=O)[CH:4]=[CH:5][NH:6][CH:7]=[CH:8][C:9]#[N:10].C(=O)([O-])[O-].[K+].[K+].CCCCCC.C(OCC)(=O)C>CO>[C:9]([C:8]1[CH:7]=[N:6][CH:5]=[CH:4][C:3]=1[C:2]([F:13])([F:12])[F:1])#[N:10]
Reactant: N#CC=CNC=CC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#Cc1cnccc1C(F)(F)F
Yield: 32.7 %

Procedure:
3-[(4,4,4-Trifluoro-3-oxo-1-butenyl)amino]-2-propenenitrile (a mixture of IIa and IIb; 1.90 g, 10 mmol) was dissolved in methanol (20 ml), and potassium carbonate (2.10 g, 15 mmol) was added. The mixture was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (a eluting solvent: hexane/ethyl acetate=3/1) to obtain 653 mg (yield 32.7%) of the title compound.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=3)=[O:17])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].[CH2:27]([NH2:31])[CH:28]([CH3:30])[CH3:29]>>[CH2:1]([NH:3][C:4]1[C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](=[O:24])[NH:31][CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:20][N:19]=3)=[O:17])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC(C)CN
Reactant: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Product: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCC(C)C)cn2)CC1
Yield: 77 %

Procedure:
By the same procedure as described example 24, the synthesis was carried out starting with 6-[1-[3-(ethylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid and using isobutylamine. And then, the product was recrystallized with ethanol and hexane to give a desired compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:10](=O)[C:11]([O:13]CC)=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[NH2:17][C:18]([NH2:20])=[O:19].Cl.CC(O)=O>>[CH2:8]([O:7][C:5](=[O:6])[C:4](=[C:10]1[C:11](=[O:13])[NH:20][C:18](=[O:19])[NH:17]1)[O:3][CH2:1][CH3:2])[CH3:9]
Reactant: CCOC(=O)C(=O)C(OCC)C(=O)OCC
Reactant: NC(N)=O
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)C(OCC)=C1NC(=O)NC1=O

Procedure:
A mixture of diethyl 2-ethoxy-3-oxo-succinate (55.86 g, 1 eq) and urea (14.41 g, 1 eq.) was refluxed for 2.5 h in 1 M HCl—AcOH (1200 ml, 5 eq.) and allowed to become cool. The cooled mixture was evaporated to dryness. The residues were dissolved in MeOH, heated aside for crystallization. After crystallization, the precipitates were filtered to give a product which was an off-white solid (15.11 g, 27.5%).
Reaction SMILES: C(N(CC)CC)C.[C:8]([OH:16])(=O)[C:9]1[CH:14]=[CH:13][CH:12]=[N:11][CH:10]=1.Cl.[CH3:18][NH:19][O:20][CH3:21].ON1C2C=CC=CC=2N=N1.Cl.CNC(N=C=NCC)CCNC>C(#N)C>[CH3:21][O:20][N:19]([CH3:18])[C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[N:11][CH:10]=1
Reactant: CNOC
Reactant: O=C(O)c1cccnc1
Agent: CCN=C=NC(CCNC)NC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cccnc1
Reaction time: 2 h
Yield: 97.8 %

Procedure:
Add triethylamine (11.9 mL, 84.5 mmol) dropwise to a suspension of nicotinic acid (10 g, 81.2 mmol), N,O-dimethylhydroxylamine hydrochloride (8.3 g, 85.3 mmol, 1.05 eq), 1-hydroxybenzotriazole (3.29 g, 24.36 mmol, 0.3 eq) and 1,3-dimethylamino propyl-3-ethylcarbodiimide hydrochloride (18.68 g, 97.44 mmol, 1.2 eq) in acetonitrile (100 mL) at room temperature under nitrogen. After 2 h a white precipitate forms. Add water (100 mL) and acetonitrile and evaporate under vacuum. Extract with ethyl acetate (3×100 mL), dry the organic phase over anhydrous sodium sulfate and concentrate to afford 13.19 g (98%) of the title compound.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[C:6]([CH2:9][S:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](O)=O)(O)=[O:7].[CH3:20][N+:21]([CH3:24])=[CH:22][Cl:23].[Cl-:25]>CN(C=O)C>[CH3:20][N+:21]([CH3:24])=[CH:22][Cl:23].[Cl-:3].[Cl:25][C:13]1[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[S:10][C:9]=1[CH:6]=[O:7]
Reactant: O=C(O)CSc1ccccc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Agent: C[N+](C)=CCl
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=Cc1sc2ccccc2c1Cl
Temperature: 25 °C
Yield: 68 %

Procedure:
Vilsmeier reagent was prepared via the dropwise addition of POCl3 (7.9 mL, 84 mmol) into ice-cold DMF (14 mL). A solution of 2-carboxymethylsulfanyl-benzoic acid (3.0 g, 14 mmol) in DMF (15 mL) was added dropwise to the Vilsmeier reagent. The resulting mixture was warmed to room temperature and then heated to 80° C. for 3.5 h. The reaction mixture was cooled to ambient temperature. Crushed ice was added until a bright yellow precipitate appeared. The solid was isolated by filtration. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate 3:2) gave the title compound (1.87 g, 68%) as a yellow powder: 1H NMR (300 MHz, CDCl3) δ 10.36 (s, 1H), 8.03 (m, 1H), 7.86 (m, 1H), 7.59-7.53 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([C:18]2[NH:19][N:20]=[CH:21][CH:22]=2)[O:12]1.C(N(CC)C(C)C)(C)C.Cl.[O:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1>C(O)(C)C>[N:20]1[NH:19][C:18]([C@@H:13]2[C@H:14]([OH:17])[C@H:15]([OH:16])[C@H:11]([N:6]3[CH:5]=[N:4][C:3]4[C:7]3=[N:8][CH:9]=[N:10][C:2]=4[NH:39][CH:36]3[CH2:37][CH2:38][O:33][CH2:34][CH2:35]3)[O:12]2)=[CH:22][CH:21]=1
Reactant: NC1CCOCC1
Reactant: O[C@@H]1[C@H](O)[C@@H](c2ccn[nH]2)O[C@H]1n1cnc2c(Cl)ncnc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O[C@@H]1[C@H](O)[C@H](n2cnc3c(NC4CCOCC4)ncnc32)O[C@@H]1c1ccn[nH]1
Yield: 12.4 %

Procedure:
(2R,3R,4S,5R)-2-(6-Chloro-purin-9-yl)-5-(2H-pyrazol-3-yl)-tetrahydro-furan-3,4-diol (35 mg) was dissolved in isopropanol (3 ml), N,N-di-isopropylethylamine (0.12 ml) and tetrahydro-pyran-4-ylamine hydrochloride (46 mg) were added, and the resulting solution was heated under reflux under nitrogen for 17 h. The solvent was removed in vacuo, the residue dissolved in methanol (10 ml), and 8% sodium bicarbonate (3 ml) added, followed by silica gel (3 g). The solvents were removed in vacuo and the residue added to a flash column of silica gel packed in dichloromethane. Elution with dichloromethane-methanol (4:1) afforded the title compound as a clear viscous gum (5.2 mg).
Reaction SMILES: [BH4-].[Na+].O.[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C@H:28]3[CH2:33][CH2:32][C@H:31]([CH2:34][CH2:35][CH:36]=[O:37])[CH2:30][CH2:29]3)=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)(=[O:7])[CH:5]=[CH2:6]>O1CCOCC1>[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C@H:28]3[CH2:33][CH2:32][C@H:31]([CH2:34][CH2:35][CH2:36][OH:37])[CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[CH:20][CH:21]=1)(=[O:7])[CH:5]=[CH2:6]
Reactant: C=CC(=O)OCCCCCCOc1ccc(-c2ccc([C@H]3CC[C@H](CCC=O)CC3)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C=CC(=O)OCCCCCCOc1ccc(-c2ccc([C@H]3CC[C@H](CCCO)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.123 g of sodium borohydride and 10 ml of water was treated dropwise at 20° C. with a solution of 5.00 g of 6-[4'-[trans-4-(3-oxo-propyl)-cyclohexyl]-biphenyl-4-yloxy]-hexyl acrylate in 50 ml of dioxan. The mixture was subsequently stirred at room temperature for 1 hour. The reaction mixture was poured into 50 ml of water, the phases were separated and the aqueous phase was extracted twice with 25 ml of ethyl acetate each time. The combined organic phases were washed twice with 50 ml of water each time, dried over magnesium sulphate, filtered and concentrated. Chromatographic purification of the residue on silica gel with cyclohexane/ethyl acetate (vol. 8:2) gave 4.77 g of 6-[4'-[trans-4-(3-hydroxy-propyl)-cyclohexyl]-biphenyl-4-yloxy]-hexyl acrylate.