Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].[C:17]([O:20][C@H:21]([CH3:45])[CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[C:35](=[O:36])[C:34]2[N:33]([CH3:37])[CH:32]=[N:31][C:30]=2[N:29]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][NH2:44])[C:27]1=[O:28])(=[O:19])[CH3:18]>CN(C)C=O>[C:17]([O:20][CH:21]([CH3:45])[CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[C:35](=[O:36])[C:34]2[N:33]([CH3:37])[CH:32]=[N:31][C:30]=2[N:29]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:2](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:8]2[C@@H:16]3[C@@H:11]([NH:12][C:13]([NH:15]3)=[O:14])[CH2:10][S:9]2)[C:27]1=[O:28])(=[O:19])[CH3:18]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(ncn2C)n(CCCCCCN)c1=O
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Solvent: CN(C)C=O
Product: CC(=O)OC(C)CCCCn1c(=O)c2c(ncn2C)n(CCCCCCNC(=O)CCCC[C@H]2SC[C@@H]3NC(=O)N[C@@H]32)c1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 34.7 %

Procedure:
Disopropylcarbodiimide (113.5 mg, 0.55 mmol) was added to a solution of biotin (122 mg, 0.5 mmol), (R)-1-(5-acetoxyhexyl)-3-(6-aminohexyl)-7-methylxanthine(227 mg, 0.5 mmol) and 4-N,N-dimethylaminopyridine (73.3 mg, 0.6 mmol) in dimethylformamide. After stirring at room temperature for 6 hours, dimethylformamide was evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 20% methanol/ethyl acetate to provide (R)-1-(5-acetoxyhexyl)-3-(N-biotinyl-6-aminohexyl)-7-methylxanthine (110 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][C:9]2[CH:11]=[CH:12][S:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[N+:14]([C:17]1[CH:22]=[CH:21][C:20](O)=[C:19](I)[CH:18]=1)([O-:16])=[O:15].C([O-])(=O)C.[Na+].Cl>CC(N(C)C)=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:10][C:9]2[CH:11]=[C:12]([C:20]3[CH:21]=[CH:22][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=3)[S:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(O)c(I)c1
Reactant: CCOC(=O)c1cc2sccc2[nH]1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2sc(-c3ccc([N+](=O)[O-])cc3)cc2[nH]1
Temperature: 150 °C
Reaction time: 24 h
Yield: 31.2 %

Procedure:
The resulting fused thiophene-pyrrole product, 4H-thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (250 mg, 1.28 mmol) and 4-nitro-iodophenol (266 mg, 1.07 mmol) were dissolved in dimethylacetamide (10 ml). Sodium acetate (209.6 mg, 1.6 mmol) and tetrakis-(triphenylphosphine)palladium (61.8 mg, 0.005 mmol) were added thereafter and the reaction mixture was heated at 150° C. while stirring for 24 hours. A solution of HCl 0.1 M (50 ml) and ethyl acetate (20 ml) was then added, the organic and aqueous phases were separated, and the aqueous phase was extracted with ethyl acetate (3×20 ml). The combined organic phase was dried over Na2SO4 and the organic solvents were evaporated under reduced pressure. The crude product was purified by silica gel flash chromatography to give 105.5 mg of pure 2-(4-nitro-phenyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (yield 31.2%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].C(N(CC)CC)C.[N:21]1([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C1COCC1>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([N:30]2[CH2:31][CH2:32][CH:27]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:28][CH2:29]2)=[O:3])=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCC(N2CCCCC2)CC1
Reaction time: 2 h

Procedure:
To a solution of 4-nitrophenyl chloroformate (31) (5.15 g, 25.6 mmol) in 150 mL of dry THF at −78° C. was added triethylamine (10.7 mL, 76.2 mmol), followed by a solution of 4-piperidinopiperidine (30) (4.51 g, 25.6 mmol) in 40 mL of THF. This solution was stirred for two hours, after which the solvent was removed, and the residue was taken up in AcOEt, filtered and evaporated. The crude yellow solid was passed through a pad of neutral alumina using AcOEt as an eluent to yield, after evaporation, 6.73 g (79%) of a white solid: IR (CHCl3, cm−1) 3046, 2937, 2859, 1704, 1620, 1513, 1466, 1242, 1197; 1H NMR (300 MHz, CDCl3) δ1.20-1.80 (m, 8H), 1.90 (d, J=12.7 Hz, 2H), 2.20-2.70 (m, 5H), 2.87 (t, J=12 Hz, 1H), 3.01 (t, J=12 Hz, 1H), 4.30 (br s, 2H), 7.29 (d, J=9 Hz, 2H), 8.26 (d, J=9 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 24.6, 26.3, 27.5, 28.2, 40.1, 44.4, 50.1, 62.0, 122.2, 124.9, 144.8, 151.9, 156.3; HRMS (EI) m/z calcd for C17H23N3O4 (M+) 333.1676, found 333.1688; LRMS (EI) m/z 333 (M+), 195, 167, 124, 110, 96, 55.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[C:22]3[CH2:32][CH2:31][NH:30][CH2:29][C:23]=3[N:24]=[C:25]([S:27][CH3:28])[N:26]=2)=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].Cl[C:34]1[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][N:35]=1>O1CCOCC1.C(N(CC)C(=O)C)C>[C:10]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[C:22]3[CH2:32][CH2:31][N:30]([C:34]4[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][N:35]=4)[CH2:29][C:23]=3[N:24]=[C:25]([S:27][CH3:28])[N:26]=2)=[CH:16][CH:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CSc1nc2c(c(Nc3ccc(C(C)(C)C)cc3)n1)CCNC2
Reactant: Clc1cccnc1Cl
Agent: CCN(CC)C(C)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc2c(c(Nc3ccc(C(C)(C)C)cc3)n1)CCN(c1ncccc1Cl)C2
Yield: 25 %

Procedure:
The solution of diisopropylethylamine (235 mg, 1.82 mmol), N-(4-tert-butylphenyl)-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-amine (300 mg, 0.91 mmol) and 2,3-dichloropyridine (270 mg, 1.82 mmol) in dioxane (5 mL) and N,N-diethylacetamide (0.5 mL) was irradiated in microwave at 180° C. for 10 hr. Solvent was removed in vacuo and residue was dissolved in ethyl acetate, washed by water, brine, dried over sodium sulfate and purified by column chromatography, product was obtained as a beige solid (100 mg, 25%).
Reaction SMILES: Cl.[CH2:2]([NH:9][C@@H:10]([C@@H:14]1[CH2:18][S:17][C:16](=[O:19])[N:15]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:11](=[O:13])N)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:20]([N:15]1[C@H:14]2[CH2:18][S:17][C:11](=[O:13])[C@H:10]2[N:9]([CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:16]1=[O:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NC(=O)[C@@H](NCc1ccccc1)[C@@H]1CSC(=O)N1Cc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1SC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 73.2 %

Procedure:
In 10 ml of N,N-dimethylformamide was dissolved 0.541 g of (4R)-4-[(1S)-1-(N-benzylamino)-1-carbamoylmethyl]-3-benzylthiazolidin-2-one hydrochloride, the solution was stirred under nitrogen atmosphere at 100° C. for 3 hours. Ethyl acetate was added to the reaction mixture, and the resulting mixture was washed with water, and saturated brine, dried and concentrated. The residue was crystallized from hexane to give 342 mg of (3aS,6aR)-1,3-dibenzyl-hexahydro-4H-thieno[3,4-d]imidazol-2,4-dione as colorless crystal.
Reaction SMILES: [C:1]([O:20]CC(CO)O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CC.[S:26]([O-])([O:29]CCCCCCCCCCCC)(=[O:28])=[O:27].[Na+:43]>>[S:26]([O-:29])([O:20][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:28])=[O:27].[Na+:43]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: [Na+]
Product: CCCCCCCCCCCCCCCCOS(=O)(=O)[O-]

Procedure:
Glyceryl monostearate containing sodium lauryl sulphate
Reaction SMILES: [F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]([O-])=O.[Na+].[NH2:15][C:16]1[CH:24]=[C:23]([Br:25])[CH:22]=[CH:21][C:17]=1[C:18]([NH2:20])=[O:19].C[Si](OP(=O)=O)(C)C.CCOC(C)=O>O>[Br:25][C:23]1[CH:24]=[C:16]2[C:17]([C:18]([OH:19])=[N:20][C:3]([C:2]([F:13])([F:1])[C:6]3[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=3)=[N:15]2)=[CH:21][CH:22]=1
Reactant: O=C([O-])C(F)(F)c1ccc(F)cn1
Reactant: NC(=O)c1ccc(Br)cc1N
Agent: C[Si](C)(C)OP(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Oc1nc(C(F)(F)c2ccc(F)cn2)nc2cc(Br)ccc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To a mixture of sodium 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetate from Example 2 Step B (2.05 g, 9.62 mmol) and 2-amino-4-bromobenzamide (1.89 g, 8.75 mmol) was added trimethylsilyl polyphosphate (˜15 mL) and the mixture was stirred overnight at 120° C. Equal volumes of EtOAc and water were added and the resulting solution was stirred for 1 h. The EtOAc layer was washed with brine, dried over Na2SO4 and then concentrated under reduced pressure. Et2O was added and evaporated. Trituration of the residue with hexanes, followed by collection of the solid by filtration afforded 7-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazolin-4-ol (2.49 g, 77%). 1H NMR (300 MHz, DMSO-d6) δ 11.37 (s, 1H), 8.76 (s, 1H), 7.97-8.07 (m, 2H), 7.88 (d, J=8.3 Hz, 1H), 7.69-7.81 (m, 2H);
Reaction SMILES: [CH:1]1([CH:6]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([NH:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[O:25])=[CH:20][CH:19]=2)[C:7]2[S:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:6]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([NH:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:25])=[CH:20][CH:19]=2)[C:7]2[S:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2sc3ccccc3c2C)C2CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCC2)sc2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.7 %

Procedure:
To a mixture of ethyl 3-{[(4-{[cyclopentyl(3-methyl-1-benzothiophen-2-yl)methyl]amino}phenyl)carbonyl]amino}propanoate (331 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 1.5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (276 mg, 89%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22].C1C(=O)N([I:30])C(=O)C1.FC(F)(F)C(O)=O.[NH4+].[Cl-]>CN(C=O)C>[F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:30])=[CH:18][C:17]=1[F:22]
Reactant: COC(=O)c1cc2scnc2c(F)c1Nc1ccccc1F
Reactant: O=C1CCC(=O)N1I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc2scnc2c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 4-fluoro-5-((2-fluorophenyl)amino)benzo[d]thiazole-6-carboxylate (1.963 g, 6.14 mmol) in DMF (10 mL) was added NIS (1.5 g, 6.5 mmol) followed by trifluoroacetic acid (0.5 mL). After stirring for 4 h at ambient temperature, the reaction was treated by saturated NH4Cl (aq.). The aqueous layer was extracted with ethyl acetate (150 mL×3). The combined organic layer was washed with water (100 mL×3) and brine (100 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo. After purification by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 10:1, v/v), the desired product was obtained as white solid (1.889 g, 69% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.03 (s, 1H), 8.10 (s, 1H), 7.93 (s, 1H), 7.18-6.72 (m, 3H), 3.91 (s, 3H).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[CH:52]=[C:53]([C:57]2[CH:58]=[C:59]([NH2:63])[CH:60]=[CH:61][CH:62]=2)[CH:54]=[N:55][CH:56]=1>CN(C=O)C>[CH3:49][O:50][C:51]1[CH:52]=[C:53]([C:57]2[CH:58]=[C:59]([NH:63][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:60]=[CH:61][CH:62]=2)[CH:54]=[N:55][CH:56]=1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: COc1cncc(-c2cccc(N)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cncc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)c1
Temperature: 25 °C
Yield: 55.5 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(5-methoxy-pyridin-3-yl)-phenylamine (0.013 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.014 g of product in 56% yield: LCMS (ESI) m/z 389 (MH+).
Reaction SMILES: [C:1]([C:3]1[C:7]2[CH2:8][CH2:9][CH:10]([NH:12][CH:13]([CH2:18][OH:19])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:11][C:6]=2[S:5][C:4]=1[NH:20][C:21](=[O:27])[CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])#[N:2].C(N(C(C)C)CC)(C)C.[CH:37]1([C:43](Cl)=[O:44])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>ClCCl>[C:1]([C:3]1[C:7]2[CH2:8][CH2:9][CH:10]([N:12]([CH:13]([CH2:18][OH:19])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:43]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[O:44])[CH2:11][C:6]=2[S:5][C:4]=1[NH:20][C:21](=[O:27])[CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])#[N:2]
Reactant: CCC(CC)C(=O)Nc1sc2c(c1C#N)CCC(NC(CO)C(C)(C)C)C2
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)C(=O)Nc1sc2c(c1C#N)CCC(N(C(=O)C1CCCCC1)C(CO)C(C)(C)C)C2
Reaction time: 16 h

Procedure:
To a solution of the intermediate isolated in Step A in 5.0 mL of dichloromethane was added 0.175 mL (1.00 mmol) of di-isopropylethylamine and 0.041 mL (0.280 mmol) of cyclohexanecarbonyl chloride. After stirring 16 h at ambient temperate, the reaction mixture was concentrated in vacuo, and purified by preparative reversed phase HPLC, affording the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>COCCOC.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([CH3:9])[CH:5]=[C:6]([C:21]2[CH:22]=[CH:23][C:18]([C:17]([F:28])([F:27])[F:16])=[CH:19][CH:20]=2)[N:7]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Temperature: 90 °C
Yield: 58.5 %

Procedure:
To a solution of 2,4-dichloro-6-methyl-pyrimidine (5 g, 30.67 mmol) in 1,2-dimethoxyethane (35 mL) and water (25 mL) was added sodium carbonate (9.75 g, 92.03 mmol), and 4-(trifluoromethyl)-phenylboronic acid (5.53 g, 29.14 mmol). This was degassed with nitrogen for 5 minutes. The bis(triphenylphosphine)palladium (II) dichloride (1.08 g, 1.53 mmol) was then added and the reaction was heated to 90° C. overnight. The solvent was evaporated and the residue was partitioned between water (300 mL) and EtOAc (300 mL). The organics were washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo to afford a yellow oil. The material was purified using a Biotage SP4, 0 to 50% i-hexane/EtOAc and the fractions containing the lower (major) spot were collected and the solvent evaporated to afford the 2-chloro-4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidine (D5) (4.65 g, 17.06 mmol, 55.6% yield) as a colourless solid.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([NH:26][C:27](=[O:30])[CH2:28]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([NH:26][C:27](=[O:30])[CH2:28][N:17]2[CH2:18][CH2:19][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:9][CH:10]=3)[CH2:15][CH2:16]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Reactant: O=C(CBr)Nc1ccccc1
Product: O=C(CN1CCC(c2ccc(Oc3ccccc3)cc2)CC1)Nc1ccccc1

Procedure:
The compound (4) synthesized in Reference Example 4 and the compound (23) synthesized in Reference Example 23 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9](=O)[CH3:10].[OH-:12].[K+].O.NN>C(O)CO>[OH:12][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH2:9][CH3:10]
Reactant: [OH-]
Reactant: CC(=O)c1cccn1CCBr
Agent: NN
Agent: [K+]
Solvent: O
Solvent: OCCO
Product: CCc1cccn1CCO
Temperature: 200 °C
Reaction time: 1.5 h

Procedure:
A mixture containing 2-bromoethyl-2-acetyl-1H-pyrrole (8.2 g), ethylene glycol (45 mL), 85% potassium hydroxide pellets (8.91 g) and 80% hydrazine hydrate (6.76 mL) was stirred at 200° C. for about 1.5 hr along with simultaneous distillation of volatile materials. The product obtained was extracted with ethyl acetate (2×100 mL). The ethyl acetate layer was washed with water (100 mL), dried over sodium sulfate, filtered and evaporated. The crude product obtained was purified by column chromatography (silica gel 100-200), using ethyl acetate:pet. ether (8:2) as an eluent to obtain 2.2 g of the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[C@H:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[NH2:6].C(Cl)(Cl)Cl.Cl[C:18]([O:20][C:21]1([CH3:25])[CH2:24][CH2:23][CH2:22]1)=[O:19]>C(N(CC)CC)C>[CH3:2][O:3][C:4](=[O:12])[C@H:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[NH:6][C:18]([O:20][C:21]1([CH3:25])[CH2:24][CH2:23][CH2:22]1)=[O:19]
Reactant: COC(=O)C[C@H](N)C(=O)OC
Reactant: CC1(OC(=O)Cl)CCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)C[C@H](NC(=O)OC1(C)CCC1)C(=O)OC
Reaction time: 8 h

Procedure:
A suspension of 0.05 moles of aspartic acid dimethyl ester hydrochloride in 50 ml. of chloroform is cooled to 0°C. and the pH adjusted to 8 by addition of triethylamine. 1-Methylcyclobutyl chloroformate 0.10 moles prepared according to the procedure of Example 1 is added portion-wise at 0°C. and the pH of the reaction is maintained at 8 by addition of triethylamine. Upon completion of the addition, the reaction is stirred overnight at 20°-25°C. The reaction solution is washed successively with 10 ml. portions of a saturated sodium bicarbonate solution, 50% saturated solution of sodium chloride, 0.2 N sulfuric acid saturated with sodium sulfate, 50% saturated solution of sodium chloride (twice), and the chloroform solution is dried over sodium acetate. Removal of the chloroform affords N-(1-methylcyclobutyloxycarbonyl)-aspartic acid dimethyl ester. Saponification is accomplished by dissolving the ester in 50 ml. of methanol, water 50 ml. is added, and the pH is adjusted to 12 by addition of 2 N sodium hydroxide. After stirring overnight at 25°C., the pH is adjusted to 7 with 2N sulfuric acid. The methanol is removed in vacuo and saturated sodium bicarbonate solution is added to the water solution. The aqueous bicarbonate solution is washed two times with ether and then the pH is adjusted to 3 by addition of concentrated hydrochloric acid. The acidified solution is extracted three times with ethyl acetate and the organic extracts combined, washed twice with sodium chloride solution and dried over sodium sulfate. The solvent is removed in vacuo to afford N-(1-methylcyclobutyloxycarbonyl) aspartic acid.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]3[C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=[CH:11][C:8]=3[C:9](=[O:10])[C:4]2=[CH:3][CH:2]=1.S(Cl)([Cl:20])=O>>[CH:11]1[C:8]2[C:9](=[O:10])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7]=2[C:14]([C:15]([Cl:20])=[O:17])=[CH:13][CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc2c1-c1ccccc1C2=O
Product: O=C(Cl)c1cccc2c1-c1ccccc1C2=O

Procedure:
The following steps are suitable for synthesizing some charge transport materials of this invention involving a linking reaction as described in the following. In the first step, diphenic acid or its derivative is dissolved in large access of concentrated sulfuric acid and the solution is heated at approximately 70° C. for about 10 minutes. The product, 9-fluorenone-4-carboxylic acid or its derivative, is isolated. In the second step, 9-fluorenone-4-carboxylic acid or its derivative is chlorinated with thionyl chloride to form 9-fluorenone-4-carbonyl chloride or its derivative. Then, 9-fluorenone-4-carbonyl chloride or its derivative reacts with a diol, a dithiol, a diamine, a hydroxylamine, a hydroxythiol, or a thioamine in the presence of triethylamine. Non-limiting examples of suitable dithiol are 4,4′-thiobisbenzenethiol, 1,4-benzenedithiol, 1,3-benzenedithiol, sulfonyl-bis(benzenethiol), 2,5-dimecapto-1,3,4-thiadiazole, 1,2-ethanedithiol, 1,3-propanedithiol, 1,4-butanedithiol, 1,5-pentanedithiol, and 1,6-hexanedithiol. Non-limiting examples of suitable diols are 2,2′-bi-7-naphtol, 1,4-dihydroxybenzene, 1,3-dihydroxybenzene, 10,10-bis(4-hydroxyphenyl)anthrone, 4,4′-sulfonyldiphenol, bisphenol, 4,4′-(9-fluorenylidene)diphenol, 1,10-decanediol, 1,5-pentanediol, diethylene glycol, 4.4′-(9-fluorenylidene)-bis(2-phenoxyethanol), bis(2-hydroxyethyl) terephthalate, bis[4-(2-hydroxyethoxy)phenyl] sulfone, hydroquinone-bis (2-hydroxyethyl)ether, and bis(2-hydroxyethyl) piperazine. Non-limiting examples of suitable diamine are diaminoarenes, and diaminoalkanes. Non-limiting examples of suitable hydroxylamine are p-aminophenol and fluoresceinamine. Non-limiting examples of suitable hydroxythiol are monothiohydroquinone and 4-mercapto-1-butanol. Non-limiting example of suitable thioamine is p-aminobenzenethiol. The intermediate product is isolated and dried. Then, the intermediate product is reacted with malononitrile in the presence of piperidine to form the dimeric electron transport material, which can be purified and dried.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[CH:18]=O.Cl.[NH2:21][OH:22].O>CN(C)C=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[CH:18]=[N:21][OH:22]
Reactant: O=CC1=C(Cl)c2ccccc2OC1c1ccccc1
Reactant: NO
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: ON=CC1=C(Cl)c2ccccc2OC1c1ccccc1

Procedure:
A solution of 27 g 4-chloro-3-formyl-flav-3-ene in 25 ml dimethylformamide is refluxed. To this solution one adds 7.7 g hydroxylamine hydrochloride dissolved in 60 ml dimethylformamide. After two hours reflux, the solution is cooled at room temperature before the addition of 400 ml water. The precipitate is formed, filtered, washed with water and dried. The solid is crystallized in diisopropylether. Pure 4-chloro-3-hydroxyiminomethyl-flav-3-ene is obtained as pale yellow crystals; m.p. 199°-200° C.