Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-:1].[K+].[CH3:3][C:4]([C:7]1[N:12]=[C:11](Cl)[C:10]([CH:14]([CH:20]([CH3:22])[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:8]=1)([CH3:6])[CH3:5].C1OCCOCCOCCOCCOCCOC1.O>S1(CCCC1)(=O)=O>[CH3:3][C:4]([C:7]1[N:12]=[C:11]([F:1])[C:10]([CH:14]([CH:20]([CH3:22])[CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:8]=1)([CH3:6])[CH3:5]
Reactant: CCOC(=O)C(c1cnc(C(C)(C)C)nc1Cl)C(C)C
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: CCOC(=O)C(c1cnc(C(C)(C)C)nc1F)C(C)C
Temperature: 150 °C
Yield: 45 %

Procedure:
A stirred suspension of dry potassium fluoride (1.41 g) and ethyl (RS)-2-[2-(2-methylprop-2-yl)-4-chloropyrimidin-5-yl]-3-methylbutyrate (1.88 g) in dry sulpholane (14 cm3) in the presence of 18-crown-6 (0.38 g) was heated to 150° C. for a period of 24 hours, under an atmosphere of dry nitrogen. After cooling to the ambient temperature (ca. 22° C.), the reaction mixture was poured into water, and extracted into ethyl acetate. The organic layer was washed with water and brine, dried and the solvent evaporated under reduced pressure. The residual brown liquid was purified by column chromatography on silica gel, using dichloromethame as eluent, to give ethyl (RS)-2-[2-(2-methylprop-2-yl)-4-fluoropyrimidin-5-yl]-3-methylbutyrate (0.8 g) as an orange liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:5][C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11]([CH3:13])=[N:12][C:8]=2[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:34][Si:35]([CH3:43])([CH3:42])[CH2:36][CH2:37][S:38](Cl)(=[O:40])=[O:39]>C(#N)C>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:5][C:6]1[CH:15]=[CH:14][C:9]2[N:10]([S:38]([CH2:37][CH2:36][Si:35]([CH3:43])([CH3:42])[CH3:34])(=[O:40])=[O:39])[C:11]([CH3:13])=[N:12][C:8]=2[CH:7]=1
Reactant: COC(=O)[C@@H](Cc1ccc2[nH]c(C)nc2c1)NC(=O)OCc1ccccc1
Reactant: C[Si](C)(C)CCS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)[C@@H](Cc1ccc2c(c1)nc(C)n2S(=O)(=O)CC[Si](C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of (R)-2-benzyloxycarbonylamino-3-(2-methyl-1H-benzoimidazol-5-yl)-propionic acid methyl ester (533 mg, 1.96 mmol), and sodium carbonate in acetonitrile (20 mL) was added neat 2-trimethylsilanylethanesulfonyl chloride all at once. The mixture was stirred at room temperature overnight. Solvents were removed and the residue was purified by chromatography on silica gel using ethyl acetate/hexanes (1:2) as eluent to afford the title compound as a waxy solid (1:1 mixture of N1 and N3 isomers, 66%). 1H-NMR (CDCl3, 500 MHz) δ 7.68 (d, J=8.5 Hz, 0.5H), 7.55 (d, J=8.5 Hz, 0.5H), 7.53 (s, 0.5H), 7.41 (s, 0.5H), 7.34-7.29 (m, 5H), 7.06-7.04 (m, 1H), 5.22 (d, J=8.0 Hz, 0.5H), 5.17 (d, J=7.5 Hz, 0.5H), 5.11-5.07 (m, 2H), 4.72-4.69 (m, 1H), 3.75 (s, 1.5H), 3.72 (s, 1.5H), 3.24-3.17 (m, 2H), 2.79 (s, 3H), 0.92-0.83 (m, 2H), −0.02 (s, 4.5H), −0.05 (s, 4.5H). Mass spec.: 532.26 (MH)+.
Reaction SMILES: C(O)(=O)C.[CH:5]([NH:8][C:9]1[N:14]=[CH:13][CH:12]=[CH:11][N:10]=1)([CH3:7])[CH3:6].[Br:15]N1C(=O)CCC1=O>O>[CH:5]([NH:8][C:9]1[N:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1)([CH3:7])[CH3:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)Nc1ncccn1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Nc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
75 ml of acetic acid, 13.7 g (0.1 mole) of 2-isopropylamino-pyrimidine and 17.8 g (0.1 mole) of N-bromosuccinimide are poured into a 1 liter reaction vessel. The reaction mixture is stirred for 1 hour at room temperature and then poured into iced water. The resultant precipitate is filtered off, washed with water and dried. 20 g (yield 92%) of the title compound was obtained as a white powder melting at 90° C. Elemental analysis showed that the compound had the expected empirical formula of C7H10N3Br.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:13]=2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)=[N:6][CH:7]=1.[C:39](Cl)(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]>>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([S:19]([NH:18][C:14]2[N:15]=[CH:16][N:17]=[C:12]([O:11][CH2:10][CH2:9][O:8][C:5]3[N:6]=[CH:7][C:2]([NH:1][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:3][CH:4]=3)[C:13]=2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:21])=[O:20])=[CH:23][CH:24]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(N)cn2)cc1
Reactant: CC(C)(C)C(=O)Cl
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(NC(=O)C(C)(C)C)cn2)cc1

Procedure:
N-{6-{2-(5-Aminopyridin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide and pivaloyl chloride are treated in the same manner as in Example 135 to give N-[6-[2-{6-(4-tert-butylphenylsulfonylamino)-5-(4-methylphenyl)pyrimidin-4-yloxy}ethoxy]pyridin-3-yl]pivalamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:12])[CH:6]=[C:7]([O:10][CH3:11])[C:8]=1[OH:9].Br[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1>>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH2:15][CH2:14][O:9][C:8]2[C:7]([O:10][CH3:11])=[CH:6][C:5]([CH3:12])=[CH:4][C:3]=2[O:2][CH3:1])=[CH:18][CH:19]=1
Reactant: COc1cc(C)cc(OC)c1O
Reactant: Fc1ccc(CCCBr)cc1
Product: COc1cc(C)cc(OC)c1OCCCc1ccc(F)cc1
Yield: 90.6 %

Procedure:
3,5-Dimethoxy-4-hydroxy-toluene (1.0 g, 5.95 mmol) and 1-(3-bromopropyl)-4-fluorobenzene (1.5 g, 6.15 mmol) were reacted as described under General Procedure A and the crude product was purified by flash chromatography (silica-gel, hexane/Et2O 19:1) to afford the title compound (1.64 g, 91%) as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 7.31-7.19 (m, 6H), 4.06 (t, J=6.4 Hz, 2H), 3.95 (s, 3H), 3.90 (s, 3H), 2.81 (t, J=7.7 Hz, 2H), 2.46 (s, 3H), 2.10-2.05 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2.[H-].[Na+].[C:27](Cl)(=[O:29])[CH3:28].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:27](=[O:29])[CH3:28])[CH:20]=[CH:19]2
Reactant: CC(=O)Cl
Reactant: COc1cc2nccc(Oc3ccc4[nH]ccc4c3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc4c(ccn4C(C)=O)c3)c2cc1OC
Reaction time: 0.5 h
Yield: 41 %

Procedure:
6,7-Dimethoxy-4-[(1H-5-indolyl)oxy]quinoline (50 mg) was dissolved in N,N-dimethylformamide (1 ml), and 60% sodium hydride (7 mg) was added to the solution, followed by stirring under ice cooling for 30 min. Acetyl chloride (16.6 μl) was added to the reaction solution, and the mixture was stirred under ice cooling for additional one hr. Further, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (23 mg, yield 41%).
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1.[CH3:23][C:24]1([NH2:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.Cl[C:32]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34][N:33]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN1C(=O)CCC1>[CH3:23][C:24]1([NH2:30])[CH2:29][CH2:28][N:27]([C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34][N:33]=2)[CH2:26][CH2:25]1
Reactant: Cc1cc(Cl)ncn1
Reactant: CC1(N)CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cc(N2CCC(C)(N)CC2)ncn1
Temperature: 80 °C
Reaction time: 18 h
Yield: 61.9 %

Procedure:
To a mixture of 4-methylpiperidin-4-amine bis(4-methylbenzenesulfonate) (3.91 g, 8.53 mmol) and 4-chloro-6-methylpyrimidine (1.10 g, 8.53 mmol) in NMP (35 mL) was added K3PO4 (3.12 g, 17.9 mmol) and the reaction mixture was stirred at 80° C. for 18 hours. After cooling to room temperature, 0.5 M aqueous K3PO4 was added and the mixture extracted twice with dichloromethane. The combined organic layers were extracted twice with HCl (1 N). The combined aqueous layers were made alkaline with NaOH (6 N), extracted twice with dichloromethane and the organic layers washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica gel, 70 g, 0 to 100% ethyl acetate in heptane; then 0 to 50% methanol in ethyl acetate, containing 10% triethylamine) afforded the title compound (1.09 g, 62%) as a light yellow semisolid.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([NH:16][CH2:17][CH2:18][N:19]1[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][C:21]([OH:29])=[N:20]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:29][C:21]1[CH:22]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:19]([CH2:18][CH2:17][NH:16][C:14]([O:13][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:15])[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc(O)nn1CCNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1cc(OCc2ccccc2)nn1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.5 %

Procedure:
Benzyl bromide (0.13 mL, 1.1 mmol) was added to a stirred suspension of ethyl 1-{2-[(tert-butoxycarbonyl)amino]ethyl}-3-hydroxy-1H-pyrazole-5-carboxylate (0.3 g, 1 mmol) and Cs2CO3 (0.65 g, 2 mmol) in ACN (5 mL). The mixture was stirred at room temperature for 16 hours and the solvents were evaporated in vacuo. The crude product was diluted with water and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in heptane 0/100 to 50/50). The desired fractions were collected and the solvents evaporated in vacuo to yield ethyl 3-(benzyloxy)-1-{2-[(tert-butoxycarbonyl)amino]ethyl}-1H-pyrazole-5-carboxylate (0.29 g, 73% yield) as a colourless oil.
Reaction SMILES: BrBr.[Br:3][C:4]1[C:9]([Br:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:11].S(=O)(=O)(O)[OH:13]>>[Br:3][C:4]1[C:9]([Br:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH:11]=[O:13]
Reactant: O=S(=O)(O)O
Reactant: Cc1cccc(Br)c1Br
Agent: BrBr
Product: O=Cc1cccc(Br)c1Br
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Bromine (168 g., 1.05 m.) is added over about one hour, with vigorous stirring, to 117.5 g. (0.47 m.) of 2,3-dibromotoluene at 190°C. After the addition is complete, the mixture is cooled to 100°C., then 120 cc. of concentrated sulfuric acid is added and the mixture is stirred for one hour at 100°C. Temperature is raised to 140°C. for 5 minutes, then the mixture is cooled and the reaction is quenched in ice water. The solid is extracted into ether, and the ether extract is washed with water, then dilute aqueous sodium bicarbonate until the acid is completely removed, and filtered. Removing the ether by evaporation gives 2,3-dibromobenzaldehyde as the residue.
Reaction SMILES: [Sn:1](I)([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH2:4][CH3:5].[F-:15].[K+]>>[Sn:1]([F:15])([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCC[Sn](I)(CCCC)CCCC
Reactant: [F-]
Agent: [K+]
Product: CCCC[Sn](F)(CCCC)CCCC

Procedure:
Bu3SnI will react on the column with KF to give Bu3SnF, which rapidly reacts with the silica. The purified product in ether is recovered and then dried on a vane pump. Bu3SnI+KFaq→Bu3SnF↓+Klaq
Reaction SMILES: O[C:2]1[C:3]2[S:11][CH:10]=[CH:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:2]1[C:3]2[S:11][CH:10]=[CH:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1nc(O)c2sccc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc(Cl)c2sccc2n1

Procedure:
A suspension of 4-hydroxy-2-methylthieno[3,2-d]pyrimidine (0.631 g, 3.8 mmol) in POCl3 (10 mL, 400 mmol) was refluxed for 4 h, concentrated in vacuo, treated with saturated NaHCO3 (20 mL), extracted with EtOAc (2×20 mL) and the combined extracts dried (MgSO4) and concentrated in vacuo to give the title compound (0.645 g, 92% as a pale yellow solid: mp 82-84° C.; IR νmax (Nujol)/cm−1 3073, 2925, 2855, 1566, 1515, 1460, 1378, 1344, 1307, 894 and 795; NMR δH (400 MHz, DMSO-d6) 3.41 (3H, s), 7.72 (1H, d, J 5.0 Hz) and 8.61 (1H, d, J 5.0 Hz).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[C:18]([NH2:19])=[C:17]([OH:20])[C:16]([Cl:21])=[CH:15][C:14]=2[F:22])[C:3]1=[O:23].[C:24](Cl)(=O)[CH:25]([CH3:27])[CH3:26].C(N(CC)CC)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[C:18]3[N:19]=[C:24]([CH:25]([CH3:27])[CH3:26])[O:20][C:17]=3[C:16]([Cl:21])=[CH:15][C:14]=2[F:22])[C:3]1=[O:23]
Reactant: CC(C)C(=O)Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(O)c2N)c1=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: CC(C)c1nc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c2o1
Yield: 36.1 %

Procedure:
This compound was prepared in the manner of Step C of Example 1, using 0.52 gram (0.0015 mole) of 1-methyl-6-trifluoromethyl-3-(6-amino4-chloro-2-fluoro-5-hydroxyphenyl)-2,4(1H,3H)-pyrimidinedione, 0.18 gram (0.0017 mole) of isobutyryl chloride, 0.24 gram (0.0017 mole) of triethylamine, and 0.09 gram (0.0004 mole) of pyridinium p-toluenesulfonate in 50 mL of xylene, yielding 0.22 gram of Compound 28. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH:1]([CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:2]([CH3:4])=[O:3].[Br:16][C:17]([CH2:19]Br)=[CH2:18].[H-].[Na+]>O1CCCC1>[Br:16][C:17](=[CH2:18])[CH2:19][CH2:4][C:2]([NH:1][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:3]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: C=C(Br)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(Br)CCC(=O)NC(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
To a stirred mixture of diethyl acetaminomalonate (217 g, 1.0 mol) and 2,3-dibromopropene (240 g, 1.2 mol) in dry tetrahydrofuran (2.50 L), under nitrogen, was added sodium hydride (26.4 g, 1.1 mol) in several portions. The reaction mixture was stirred at room temperature for 30 min, then heated to reflux. After heating for 18 h, the resultant slurry was cooled to room temperature and suction filtered through a short pad of silica gel. The solid rescue as washed with tetrahydrofuran (2×50 mL), and the filtrates were combined and concentrated. The residue was dissolved in ethyl acetate (2.0 L), washed with water and brine, and then was dried over MgSO4. Filtration and concentration gave a yellow oil which solidified upon drying. The resultant solid was recrystallized from a mixture of hot ethyl acetate/hexane to give 301 g (89%) of the desired product: m.p. 85-87° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([O:17]C(C)C)[N:14]([CH3:21])[C:13](=O)[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:24]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][C:15](=[O:17])[N:14]([CH3:21])[C:13](=[S:24])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COc1ccc(-c2cc(=O)n(C)c(OC(C)C)n2)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(-c2cc(=S)n(C)c(=O)[nH]2)cc1OC
Yield: 12.3 %

Procedure:
A mixture of 6-(3,4-dimethoxyphenyl)-2-isopropoxy-3-methyl-4(3H)-pyrimidinone (2.5 g) and phosphorus pentasulfide (3.5 g) in pyridine (50 ml) was refluxed for 13 hours with stirring. The reaction mixture was evaporated under reduced pressure. The residue was washed with 1N-hydrochloric acid and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated in ethanol and the resulting precipitate was triturated again in chloroform and collected by filtration to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)- 3-methyl-4-thioxo-2(1H)-pyrimidinone (0.27 g)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH:10]=O)=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([CH3:23])([CH3:22])[NH2:21])=[CH:15][CH:14]=1>>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([NH:21][CH2:10][CH:8]([OH:9])[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)([CH3:22])[CH3:23])=[CH:15][CH:14]=1
Reactant: Cc1ccc(CC(C)(C)N)cc1
Reactant: O=CC(=O)c1cccc(Cl)c1
Product: Cc1ccc(CC(C)(C)NCC(O)c2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared in the manner described in Example 9 using 3-chlorophenylglyoxal and 2-(4-Methylphenyl)-1,1-dimethyl ethanamine. The chromatographed material was recrystallized from cyclohexane to give the title compound m.p. 104-105. τ(CDCL3), 8.9 (6H, s), 7.7 (3H, s), 7.4 (2H, s), 7.1 (2H, dd,), 5.45 (1H, dd), 3.0 (4H, s), 2.5-2.8 (4H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:23](OC)(OC)(OC)[CH2:24][CH2:25][CH3:26]>C1(C)C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH2:24]([C:23]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:25][CH3:26]
Reactant: CCOC(=O)CCCCCNc1c(N)cnc2ccccc12
Reactant: CCCC(OC)(OC)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)OCC
Yield: 89.3 %

Procedure:
A solution of ethyl 6-(3-aminoquinolin-4-ylamino)hexanoate (34.3 g, 114 mmol), trimethyl orthobutyrate (19.5 g, 131 mmol), and pyridinium p-toluenesulfonate (1.0 g, 4.0 mmol) in toluene (250 mL) was heated at reflux under a Dean-Stark trap for 5 hours, periodically draining off the distillate and adding fresh toluene to the reaction mixture. The solution was concentrated under reduced pressure, and the residue was taken up in dichloromethane (150 mL), washed successively with a saturated aqueous sodium bicarbonate solution and water (100 mL each), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide ethyl 6-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanoate (36.0 g) as a dark oil that was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[N-]=C=O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[CH:16]1[C:17]([NH:20][C:21]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=2)=[O:22])=[CH:18][CH:19]=[C:14]([Cl:13])[CH:15]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: [N-]=C=O
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(Cl)cc1)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A cold solution of 3,4-dichloroaniline (13.2 parts) in chloroform 75 parts was added to the isocyanate solution from A (120 parts containing 7.5 parts of 4-chlorophenyl isocyanate). The mixture was stirred at room temperature for 16 hours, then the solid filtered off, washed with chloroform and dried.
Reaction SMILES: [CH:1]1([C:4]2[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][C:5]=2[C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1.[H][H]>CO.[Pt]>[NH2:13][C:12]1[C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C1CC1
Agent: [Pt]
Solvent: CO
Product: Nc1cccc(C(=O)O)c1C1CC1
Reaction time: 3 h
Yield: 94.7 %

Procedure:
A solution of 2-cyclopropyl-3-nitrobenzoic acid (0.63 g, 3.04 mmol) and 5% Pt/C (0.59 g, 0.152 mmol) in methanol (10 mL) was charged with 40 psi of hydrogen and shaken for 3 hours. The catalyst was removed by filtration and washed with methanol (10 mL). The filtrate was concentrated under reduced pressure to give 3-amino-2-cyclopropylbenzoic acid (0.51 g, 94.1%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.[F:11][C:12]([F:26])([F:25])[O:13][CH2:14][CH2:15][CH2:16]OS(C(F)(F)F)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([O:8][CH2:16][CH2:15][CH2:14][O:13][C:12]([F:26])([F:25])[F:11])[CH:7]=1
Reactant: COc1ccc(Br)cc1O
Reactant: O=S(=O)(OCCCOC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(Br)cc1OCCCOC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-2-methoxy-phenol (1.20 g, 5.62 mmol), crude trifluoro-methanesulfonic acid 3-trifluoromethoxy-propyl ester (2.52 g, 6.74 mmol; purity of 74%) and anhydrous K2CO3 (1.18 g, 8.42 mmol) in MeCN (8 mL) is stirred in a sealed flask at room temperature overnight and then filtered. The combined filtrates are concentrated and the crude product is chromatographed over silica gel (eluent: toluene) to give the title compound as oil. TLC, Rf (toluene/AcOEt 10:1)=0.63. 1H-NMR (CDCl3): δ 2.25 (m, 2H), 3.87 (s, 3H), 4.13 (m, 2H), 4.23 (m, 2H), 6.79 (dd, 1H), 7.04 (d,1H), 7.09 (dd, 1H) ppm. 19F-NMR (CDCl3): zδ −60.7 ppm.
Reaction SMILES: [OH:1][CH:2]([CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:23]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=O.[CH3:34][NH2:35]>>[OH:1][CH:2]([C:3]([NH:35][CH3:34])=[O:5])[CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:23]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccccc2)n1
Reactant: CN
Product: CNC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 2-hydroxy-4-phenyl-3-(2-(3-phenyl-1H-pyrazol-1-yl)nicotinamido)butanoic acid with methylamine; ESI-MS [M+H]+: 456.2
Reaction SMILES: C([O:5][C:6](=[O:37])[C@H:7]([CH3:36])[NH:8][C:9](=[O:35])[C@H:10]([CH2:19][CH2:20][CH:21]([F:34])[CH:22]([C:31]([OH:33])=[O:32])[NH:23]C(OC(C)(C)C)=O)[NH:11]C(OC(C)(C)C)=O)(C)(C)C.O>CCOCC.Cl>[F:34][CH:21]([CH:22]([C:31]([OH:33])=[O:32])[NH2:23])[CH2:20][CH2:19][C@@H:10]([C:9]([NH:8][C@H:7]([C:6]([OH:37])=[O:5])[CH3:36])=[O:35])[NH2:11]
Reactant: C[C@H](NC(=O)[C@H](CCC(F)C(NC(=O)OC(C)(C)C)C(=O)O)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: C[C@H](NC(=O)[C@@H](N)CCC(F)C(N)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
The Nα,Nε -di-t-butoxycarbonyl-δ-fluoro-ε-carboxylysyl-L-alanine t-butyl ester prepared above (511 mg) is dissolved in ether saturated with HCl gas, and the mixture is stirred at room temperature for 4 days. The precipitate is collected and dissolved in 1N HCl. Evaporation gives a white foam which is dried carefully and is dissolved in ethanol. Upon addition of excess propylene oxide, the title compound crystallizes with 0.75 mmoles of HCl and 0.75 mmoles of water.