Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[O-][CH2:21]C.[Na+].[Na].CI>C(O)C>[F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)([OH:10])[C:7]([O:9][CH3:21])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CI
Product: COC(=O)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 3 h

Procedure:
25.0 g (0.095 mol) of 4,4′-difluorobenzilic acid are added to freshly prepared sodium ethoxide solution containing 2.17 g (0.095 mol) of sodium and 200 mL of ethanol at 20° C. and stirred for 3 h. The solution is evaporated to dryness, the residue is dissolved in DMF, 22.57 g (0.16 mol) of methyl iodide are added dropwise at 20° C. and the mixture is stirred for 24 h. It is worked up and purified analogously to compound 3b. Yield: 21.06 g of 11 (80% of theory).
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[CH3:27])[C:14]([C:28]([NH2:30])=[O:29])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[NH2:31][C@@H:32]1[CH2:37][CH2:36][CH2:35][CH2:34][C@@H:33]1[NH:38]C(=O)OC(C)(C)C.CCN(C(C)C)C(C)C>>[NH2:31][C@H:32]1[CH2:37][CH2:36][CH2:35][CH2:34][C@H:33]1[NH:38][C:11]1[N:16]=[C:15]([NH:17][C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH:20]=[CH:21][N:22]3[CH3:27])[C:14]([C:28]([NH2:30])=[O:29])=[CH:13][N:12]=1
Reactant: Cn1ccc2c(Nc3nc(On4nnc5ccccc54)ncc3C(N)=O)cccc21
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc2c(Nc3nc(N[C@@H]4CCCC[C@@H]4N)ncc3C(N)=O)cccc21
Temperature: 80 °C
Yield: 22.1 %

Procedure:
To a solid of 2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-4-(1-methyl-1H-indol-4-ylamino)pyrimidine-5-carboxamide (100 mg, 0.25 mmol) in vial was added tert butyl (1S,2R)-2-aminocyclohexylcarbamate (0.3 M solution in NMP, 1.25 mL, 0.375 mmol) and DIPEA (0.09 mL, 0.5 mmol). It was heated at 80° C. for 2 h, cooled and purified by preparative HPLC to give 2-((1R,2S)-2-aminocyclohexylamino)-4-(1-methyl-1H-indol-4-ylamino)pyrimidine-5-carboxamide (21 mg). MS found for C20H25N7O as (M+H)+ 380.4. UV: λ=219.2, 241.6, 336.7.
Reaction SMILES: CO[NH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1C[O:15][CH2:14]C1.CCN(CC)CC.Cl[C:25]([O:27][CH3:28])=[O:26]>C(OCC)(=O)C.O>[CH3:28][O:27][C:25](=[O:26])[NH:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([O:15][CH3:14])[CH:11]=1
Reactant: CONCCc1ccccc1
Reactant: COC(=O)Cl
Reactant: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)NCCc1cccc(OC)c1
Reaction time: 18 h
Yield: 98.3 %

Procedure:
Combine Methoxyphenylethylamine (9.6 ml, 66.1 mmol), THF (300 mmol), Et3N (11.0 ml, 78.9 mmol), and methyl chloroformate (26.0 ml, 339 mmol) at 0° C. under nitrogen atmosphere. After the reaction stirs at room temperature for 18 hours, add the mixture into water, wash with brine, and dry the organic layer over Na2SO4 followed by concentrating under reduced pressure. Flash chromatograph using 2:1 Hexanes:Ethyl acetate to afford 13.6 g, 65.0 mmol (98% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 2.8 (2H, t, J=6.7, 7.0 Hz), 3.41-3.46 (2H, m), 3.7 (3H, s), 3.8 (3H, s), 4.6-4.8 (1H, b s), 6.7-6.8 (3H, m), 7.2-7.3 (1H, m); MS m/z 210 (M+1).
Reaction SMILES: Br[CH:2]([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].[CH2:9]([O:11][P:12]([O:16]CC)[O:13][CH2:14][CH3:15])[CH3:10]>>[CH3:6][O:5][C:3](=[O:4])[CH:2]([P:12]([O:13][CH2:14][CH3:15])([O:11][CH2:9][CH3:10])=[O:16])[CH2:7][CH3:8]
Reactant: CCC(Br)C(=O)OC
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(OCC)C(CC)C(=O)OC
Temperature: 110 °C
Reaction time: 72 h

Procedure:
Methyl 2-bromobutanoate (92 g, 0.508 mol) and triethylphosphite (95 g, 0.57 mol) were mixed, and the mixture was stirred at 110° C. for 3 days. The reaction mixture was dried under reduced pressure to give the title compound.
Reaction SMILES: C(OC(N[C@H](C([NH:13][C@H:14]([C:22]([OH:24])=[O:23])[CH2:15]C1ON=C(Br)C1)=O)C)=O)(C)(C)C.[C:25]([C:29]([OH:31])=[O:30])([F:28])([F:27])[F:26].C(Cl)Cl>>[F:26][C:25]([F:28])([F:27])[C:29]([OH:31])=[O:30].[NH2:13][C@H:14]([C:22]([OH:24])=[O:23])[CH3:15]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC1CC(Br)=NO1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)C(=O)O

Procedure:
N-tert-butoxycarbonyl-L-alanyl-beta-(3-bromo-4,5-dihydroisoxazol-5-yl) alanine, 0.8 gm, was taken in 50 ml of 20% CF3CO2H/CH2Cl2 at room temperature for 2 hours. Concentration gave a residue which was purified by HPLC, (reverse phase, eluting with water), to give two isomers as fluffy white material after lyophilization. 1H NMR (80 MHz, D2O): delta 1.55 (d, 3H, J=7.5 Hz, CH3), 2.0-2.4 (m, 2H, CH2), 2.9-3.7 (ABX, 2H, CH2CHO), 4.1 (q, 2H, J=7.3 Hz, OCH2), 4.4-5.0 ppm (m, CHN, CHO, plus HOD solvent peak). Most polar set of isomers from the HPLC: 13C NMR (20 MHz, D20): delta 173.2, 173.1 (CO), 143.5 143.4 (BrC=N), 82.7, 81.8 (CHO), 51.8, 50.5 (broad, CHN), 49.0, 48.9 (CH2), 38.6 (CH2), 19.2 ppm (CH3). Least polar isomer: 13C NMR (20 MHz, D20): delta 180.2, 173.0 (CO), 143.5, 143.4 (BrCN), 83.6, 82.4 (CHO), 55.9, 54.9 (broad, CHN), 52.0 (CHN), 49.1, 48.7 (CH2), 39.3, 38.9 (CH2), 19.4 (CH3).
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]3[O:11][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[CH:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[S:19][C:17]=2[N:18]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(Cl)nc2s1
Reactant: NCc1ccc2c(c1)OCO2
Product: FC(F)(F)c1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxybenzylamine with 2,4-dichloro-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine gives 2-chloro-6-trifluoromethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:5]([CH3:16])=[C:6]([CH3:15])[C:7]2[N:8]([C:10]([CH2:13][NH2:14])=[N:11][N:12]=2)[N:9]=1.O.ClCCl.[CH3:21][CH2:22][CH:23]([OH:26])[CH2:24][CH3:25]>CN(C=O)C>[CH2:22]([CH:23]([O:26][C:4]1[C:5]([CH3:16])=[C:6]([CH3:15])[C:7]2[N:8]([C:10]([CH2:13][NH2:14])=[N:11][N:12]=2)[N:9]=1)[CH2:24][CH3:25])[CH3:21]
Reactant: CCC(O)CC
Reactant: Cc1c(Cl)nn2c(CN)nnc2c1C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)Oc1nn2c(CN)nnc2c(C)c1C
Reaction time: 8 h

Procedure:
3-Pentanol (1.2 ml) was initially charged at RT with stirring. Thereafter, sodium hydride (77 mg) was added while cooling with ice. After stirring at 55° C. for 3 h, (6-chloro-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamine (W2.169; 50 mg), dissolved in 3-pentanol (1 ml) and DMF (2 ml), was added dropwise. After stirring for 2 h, the reaction mixture was left to stand at RT overnight, admixed with water and dichloromethane and then extracted three times more with dichloromethane. The combined organic phases were dried over magnesium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 44 mg of the title compound were obtained. LC-MS rt: 0.86 min [M+H]+: 264.2 (met. b)
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11](O)=O)[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1CCCCC1.C=O>CCO>[CH:1]1([CH2:6][C:7](=[CH2:11])[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)C(=O)O
Agent: C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: C=C(CC1CCCC1)C(=O)O
Yield: 85.6 %

Procedure:
A mixture of 2-cyclopentylmethyl-malonic acid (24.90 g, 133.7 mmol), piperidine (15.9 mL, 160.8 mmol), 37% aqueous formaldehyde (51.0 mL, 647.2 mmol), and EtOH (250 mL) is stirred at reflux for 16 hours. The reaction is quenched with 1N HCl to a pH=1, and the mixture is extracted with EtOAc. The EtOAc layers are combined, dried over Na2SO4, and concentrated. The crude product is purified by flash chromatography (SiO2, 10% acetone in DCM), which gives 2-cyclopentylmethyl-acrylic acid (17.65 g, 86% yield) as an oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH3:14])[CH:5]=1)=[O:3].[Se](=O)=[O:16]>>[CH3:14][O:13][C:6]1[CH:5]=[C:4]([C:2]([CH:1]=[O:16])=[O:3])[CH:9]=[CH:8][C:7]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1cc(C(C)=O)ccc1[N+](=O)[O-]
Reactant: O=[Se]=O
Product: COc1cc(C(=O)C=O)ccc1[N+](=O)[O-]

Procedure:
3-Methoxy-4-nitrophenylglyoxal was prepared according to the method described in Patent Application FR 2,351,108, but starting with 3-methoxy-4-nitroacetophenone (33.6 g) and selenium dioxide (22 g). The expected product (35 g) is obtained in the form of a brown oil, which was used without further purification for the subsequent steps.
Reaction SMILES: O1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]=[CH:7][CH:8]=[CH2:9]>C1CCCCC1>[CH2:2]=[CH:3][CH:4]=[CH2:5].[CH2:6]=[CH:7][CH:8]=[CH2:9].[CH:3]([CH:4]=[CH:5][CH:6]=[CH2:7])=[CH2:2]
Reactant: C1CCOC1
Agent: C=CC=C
Solvent: C1CCCCC1
Product: C=CC=CC=C

Procedure:
Butadiene was polymerized in a cyclohexane solvent with a polymerization catalyst of lithium n-butyl. Then, tetrahydrofuran was added as a vinylization agent, to polymerize butadiene, to obtain a butadiene-vinyl butadiene copolymer. The copolymer had a degree of vinylization of vinyl butadiene part of 60%. The polymer was hydrogenated to give a hydrogenatedblock copolymer having a hydrogenation ratio of 98%. This polymer was namedR-5.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[NH:21][CH:22]=[C:23]([C:25]#[N:26])[N:24]=3)=[O:19])=[C:13]([C:27]3[CH2:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH2:29][CH:28]=3)[CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[OH-].[Na+].O>C1COCC1.CO>[C:25]([C:23]1[N:24]=[C:20]([C:18]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([C:5]3([C:3]([OH:4])=[O:2])[CH2:6][CH2:7][O:8][CH2:9][CH2:10]3)=[CH:12][C:13]=2[C:27]2[CH2:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH2:29][CH:28]=2)=[O:19])[NH:21][CH:22]=1)#[N:26]
Reactant: COC(=O)C1(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCC(C)(C)CC3)c2)CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C)CC=C(c2cc(C3(C(=O)O)CCOCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.1 %

Procedure:
To a solution of 4-[4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-tetrahydro-pyran-4-carboxylic acid methyl ester (as prepared in Example 16, step (f), 129 mg, 0.279 mmol) in 2 mL of 1:1 THF/MeOH was added 6 N NaOH (400 μL, 2.40 mmol). After stirring at RT for 2 d, the mixture was treated with 10 mL of H2O and washed with EtOAc (3×10 mL). The aqueous layer was acidified to pH=5 with 15% citric acid and extracted with 10:1 EtOAc-MeOH (3×10 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford 119 mg (95%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.20 (d, 1H, J=8.8 Hz), 8.00 (s, 1H), 7.37 (dd, 1H, J=8.8, 2.3 Hz), 7.24 (d, 1H, J=2.3 Hz), 5.75 (m, 1H), 3.91 (m, 2H), 3.61 (t, 2H, J=11.5 Hz), 2.49 (m, 2H), 2.30 (m, 2H), 2.08 (m, 2H), 1.95 (m, 2H), 1.60 (t, 2H, J=6.1 Hz), 1.09 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C25H28N4O4, 449.2 (M+H). found 449.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([I:11])[CH:5]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:13](=[O:15])[CH3:14])=[C:6]([I:11])[CH:5]=1
Reactant: COC(=O)c1ccc(N)c(I)c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(NC(C)=O)c(I)c1
Temperature: 60 °C

Procedure:
To a solution of the crude 4-amino-3-iodo-benzoic acid methyl ester in 20 mL of acetic acid was added acetic anhydride (1.25 mL). The reaction was heated at 60° C. for 1 h. The reaction mixture was quenched with water, extracted with ethyl acetate, dried over Na2SO4, and concentrated in vacuo. Purification by flash chromatography (SiO2, 1:3 EtOAc/Hexane) afforded 4-acetylamino-3-iodo-benzoic acid methyl ester: MS (m/z) 320.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1.[CH3:26][O:27]C(Cl)Cl.[Sn](Cl)(Cl)(Cl)Cl.Cl>ClCCl>[Cl:1][C:2]1[C:7]2[C:8]([CH:26]=[O:27])=[C:9]([CH3:11])[O:10][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1
Reactant: COC(Cl)Cl
Reactant: Cc1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1oc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c2c1C=O
Reaction time: 2 h
Yield: 90.9 %

Procedure:
2.0 g (53 mmol) of 3-(4-chloro-6-fluoro-2-methylbenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil and 36.5 g (0.32 mol) of dichloromethyl methyl ether were dissolved in 100 ml of dichloromethane, and 200 ml (0.20 mol) of tin tetrachloride (1M dichloromethane solution) was dropwise added thereto at 0° C. After completion of the dropwise addition, stirring was carried out at room temperature for 2 hours. After completion of the reaction, the reaction solution was poured into a mixture of dilute hydrochloric acid and ice and extracted with dichloromethane. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 19.5 g (yield: 90.7%) of the desired product as white crystals. Melting point: 148-150° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:12])[CH:10]=[CH:9][CH2:8][CH2:7]1.C(N(CC)CC)C>ClCCl>[C:1]([NH:5][C:6]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:12])[CH:10]=[CH:9][CH2:8][CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: NC1(c2ccccc2Cl)CCC=CC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC1(c2ccccc2Cl)CCC=CC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (142 μl, 1.8 mmol) was added to a solution of 6-amino-6-(2-chlorophenyl)-2-cyclohexene-1-one (R. F. Parcell and J. P. Sanchez, J. Org. Chem., 46: 5055 [1981]), (200 mg, 0.9 mmol) and triethylamine (1.0 ml) in dichloromethane (10 ml), and the reaction stirred at room temperature for 1 h. Analysis by TLC indicated complete reaction, and the mixture was partitioned between ethyl acetate and 1N HCl. The organic phase was washed with brine, dried (MgSO4), and the solvent removed by evaporation. Flash chromatography on silica gel eluted with 1:1 ethyl acetate/hexane afforded 6-acetylamino-6-(2-chlorophenyl)-2-cyclohexen-1-one which crystallized on standing, m.p. 144°-145° C.
Reaction SMILES: FC(F)OC1C=CC(C=O)=CC=1OC.[F:15][C:16]([F:30])([F:29])[CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][C:20]=1[O:27]C>>[F:15][C:16]([F:29])([F:30])[CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][C:20]=1[OH:27]
Reactant: COc1cc(C=O)ccc1OCC(F)(F)F
Agent: COc1cc(C=O)ccc1OC(F)F
Product: O=Cc1ccc(OCC(F)(F)F)c(O)c1
Yield: 81 %

Procedure:
Repeating Example 3, except that 4-difluoromethoxy-3-methoxybenzaldehyde was replaced with 70 grams (0.3 mol) of 4-trifluoroethoxy-3-methoxybenzaldehyde to give 4-trifluoroethoxy-3-hydroxybenzaldehyde (m.p. 133˜135° C.) in a yield of 81%. 1H-NMR (ppm) δ: 9.81 (1H, s; —CHO); 7.26 (1H, m; 6-ArH); 7.17 (1H, m; 2-ArH); 6.79 (1H, m; 5-ArH); 4.88 (1H, s; —OH); 4.45 (2H, q; J3H-F=7.2 Hz; —CH2CF3). 13C-NMR (ppm)) δ: 191.0 (CHO), 157.2 (4-ArC), 146.2 (3-ArC), 130.6 (1-ArC), 126 (q, CF3), 123.5 (6-ArC), 116.7 (2-ArC), 116.2 (5-ArC), 87 (m, CH2).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[N:15]1([CH2:20][CH2:21][CH2:22]O)[CH2:19][CH2:18][CH2:17][CH2:16]1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([O:12][CH2:22][CH2:21][CH2:20][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: OCCCN1CCCC1
Reactant: COc1cc2ncnc(Cl)c2cc1O
Product: COc1cc2ncnc(Cl)c2cc1OCCCN1CCCC1

Procedure:
The compound was synthesised according to GP 4 from 4-chloro-6-hydroxy-7-methoxy-quinazoline and 3-Pyrrolidin-1-yl-propan-1-ol. LC/ESI-MS: m/z=322 [M+H].
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=O)[CH2:3]CC(=O)O.N[C@H](C(O)=O)C[C:14](=O)[OH:15].[OH2:20].[B:21]([O-:24])([O-:23])[O-:22]>>[B:21]([O-:24])([O-:23])[O-:22].[CH2:14]([OH:15])[C:2]([NH2:1])([CH2:3][OH:20])[CH2:8][OH:10]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: O
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: [O-]B([O-])[O-]
Product: NC(CO)(CO)CO

Procedure:
Poly(D/L Glu-DET)/DNA transfection complexes were prepared by initially adding equal volumes of Poly(D/L Glu-DET) solution (100 μL dissolved in either dH2O or 5% BSA-50 mM Borate pH 8.3) and plasmid DNA solution (20 μg dissolved in 100 μL in either dH2O or 5% BSA-50 mM Borate pH 8.3) at N:P ratio 10. Polymer was added to DNA solution, for a final volume of 200 μL, and incubated at room temperature for at least 15 min to allow polyplex formation. Transfection polyplexes were formed by incubating 200 μL of Poly(D/L Asp-DET)/DNA N:P 10 polyplexes with 300 μL of either H2O, 5% BSA-50 mM Borate pH 8.3, or 5% BSA-10 mM Tris pH 8 for 15 min at room temperature to give a final volume of 500 μL for all samples. (See FIG. 1 for schematic).
Reaction SMILES: [NH2:1][C:2]([CH3:14])=[CH:3][C:4]([O:6][CH2:7][CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:5].[N+:15]([C:18]1[CH:19]=[C:20]([CH:31]=[CH:32][CH:33]=1)[CH:21]=[C:22]([C:27](OC)=[O:28])[C:23]([O:25][CH3:26])=[O:24])([O-:17])=[O:16].C(N(CC)CC)C>CC(O)C>[OH:28][C:27]1[NH:1][C:2]([CH3:14])=[C:3]([C:4]([O:6][CH2:7][CH2:8][C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[O:5])[CH:21]([C:20]2[CH:31]=[CH:32][CH:33]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=2)[C:22]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: CC(N)=CC(=O)OCCc1cccs1
Reactant: COC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OC
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: COC(=O)C1=C(O)NC(C)=C(C(=O)OCCc2cccs2)C1c1cccc([N+](=O)[O-])c1
Yield: 26.5 %

Procedure:
A mixture of 2-(2-thienyl)ethyl 3-amino-2-butenoate (1.8 g) and dimethyl 3-nitrobenzylidenemalonate (2.25 g) was dissolved in anhydrous 2-propanol (80 ml) and, after addition of triethylamine (27 ml), the mixture was refluxed for 21 hours. After the solvent was distilled off under reduced pressure, the residue was purified by thin-layer silica gel chromatography (developing solvent: chloroform/methanol=19/1; elution solvent: chloroform/acetone=2/1) so as to obtain 1.0 g (26%) of the desired compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]1[N:16]=[CH:15][C:14]([CH3:18])([CH3:17])[CH2:13][S:12]1)([CH3:3])[CH3:2].[CH2:19](N(CC)CC)[CH3:20].ClCCl.[C:29](Cl)(=[S:33])OCC>O>[CH2:19]([C:29]([N:16]1[CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][S:12][C:11]1=[N:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2])=[S:33])[CH3:20]
Reactant: CC(C)c1ccccc1N=C1N=CC(C)(C)CS1
Reactant: CCN(CC)CC
Reactant: CCOC(=S)Cl
Solvent: ClCCl
Solvent: O
Product: CCC(=S)N1CC(C)(C)CSC1=Nc1ccccc1C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
To a mixture of 2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (1.00 g), triethylamine (0.58 g) and dichloromethane (5 ml) was added dropwise for 5 minutes ethyl chlorothiocarbonate (0.56 g). The mixture was stirred at room temperature for 1 hour. To the solution was added water (30 ml). The mixture was extracted with diethylether (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 3-(ethylthiocarbonyl)-2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (0.74 g, yield: 56%) as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][C@@H:8]([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:4][CH:3]=1.IC1C=CC=CC=1C(O)=O>C1COCC1.CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C@@H:8]([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[O:14])=[CH:16][CH:17]=1
Reactant: OCCCCC[C@H](O)COc1ccc(F)cc1
Agent: O=C(O)c1ccccc1I
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: O=CCCCC[C@H](O)COc1ccc(F)cc1
Reaction time: 0.25 h
Yield: 61.9 %

Procedure:
To a solution of (6S)-7-(4-fluorophenoxy)-heptane-1,6-diol (3.6 g, 14.8 mmol) in dry THF (60 ml) was added dropwise a solution of 2-iodobenzoic acid (5 g, 17.8 mmol) in dry DMSO (4 ml) over a period of 25 minutes at room temperature. After 15 minutes the reaction mixture was decomposed with crushed ice, filtered through celite and concentrated. The residue was extracted with ethylether, washed with brine, dried over Na2SO4 and the organic solvent was removed under reduced pressure. The residue was purified by silica gel chromatography using EtOAc-hexane (1:9) to give (6S)-7-(4-fluorophenoxy)-6-hydroxy-heptanal (2.2 g, 61.6%); [α]D+12 (c 3.8, CHCl3), 1H-NMR (CDCl3, 200 Hz): δ 1.4-1.8 (m, 6H), 2.49 (dt, 2H), 3.71-4.05 (m, 4H), 6.782-4H), 9.8 (s, 1H); HRMS (FAB): calcd. for C13H17O3F (M+) 240.116173 found 240.116465.
Reaction SMILES: [NH2:1][C:2]1[N:3]([N:14]=CC2C=CC=CC=2)[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:6]=1.O.NN.C(#N)C>C(O)COCCO>[NH2:14][N:3]1[CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:6]=[C:2]1[NH2:1]
Reactant: Nc1nc(-c2ccc(F)cc2)cn1N=Cc1ccccc1
Agent: NN
Solvent: OCCOCCO
Solvent: O
Solvent: CC#N
Product: Nc1nc(-c2ccc(F)cc2)cn1N
Temperature: 80 °C

Procedure:
A solution of 5.3 g (0.0189 mol) of 2-amino-1-benzylideneamino-4-(4-fluorophenyl)-imidazole and 12.5 ml of hydrazine hydrate in 18.8 ml of diethylene glycol is stirred at 140° C. for 15 hours. After cooling to 80° C., 70 ml of acetonitrile are added to the reaction mixture, which is then cooled further to 0° C. The product that has separated out is filtered off and washed with acetonitrile and diethyl ether. In that manner there is obtained the title compound, m.p. 227°-230° C., 1H-NMR (DMSO): δ=7.57-7.68 (m, 2H); 7.06-7.15 (m, 2H); 7.01 (s, 1H); 5.52 (s, 2H); 5.36 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[N:22]=[C:21]([N:23]3[C:27]([C:28]([F:31])([F:30])[F:29])=[C:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:25]=[N:24]3)[CH:20]=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.[H][H]>CCOC(C)=O.CCO.[Pt](=O)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[N:22]=[C:21]([N:23]3[C:27]([C:28]([F:31])([F:29])[F:30])=[C:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:25]=[N:24]3)[CH:20]=[CH:19][CH:18]=2)=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3C#Cc3ccc(OC)cc3)n2)c1C(F)(F)F
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3CCc3ccc(OC)cc3)n2)c1C(F)(F)F
Reaction time: 2 h

Procedure:
To a degassed solution of the title compound from Example 236 Step A (255 mg, 0.519 mmol) in EtOAc (3 mL) and EtOH (3 mL) was added platinum(IV) oxide (175 mg). The reaction mixture was fitted with a hydrogen balloon attached to a 3-way adapter. The reaction flask was then evacuated and back-filled with hydrogen. After this process was repeated three times, the reaction mixture was placed under a hydrogen atmosphere, and was stirred vigorously. After 2 h, the reaction mixture was filtered through Celite, rinsing with EtOAc. The mixture was then concentrated in vacuo, and used without further purification: LCMS m/z 496.2 [M+H]+.