Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([CH3:4])[CH3:3].[Mg].[C:6]1([C:12]2[NH:13][C:14]([CH3:19])=[C:15]([CH:17]=[O:18])[N:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(OCC)C.C1COCC1>[C:6]1([C:12]2[NH:13][C:14]([CH3:19])=[C:15]([CH:17]([OH:18])[CH:2]([CH3:4])[CH3:3])[N:16]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cc1[nH]c(-c2ccccc2)nc1C=O
Reactant: CC(C)Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1[nH]c(-c2ccccc2)nc1C(O)C(C)C
Yield: 57.9 %

Procedure:
35 Grams (0.45 mol) of 2-chloropropane was added to 10.8 g (0.45 mol) of magnesium in 100 ml of diethyl ether. Then 55.8 g (0.3 mol) of 2-phenyl-4-formyl-5-methyl-1H-imidazole in 100 ml of THF were added. At the end of the addition, the mixture was refluxed for 30 minutes and then cooled and poured on ice water. The aqueous layer was extracted twice with 100 ml of diethyl ether. Evaporation of the solvent gave a residue which was recrystallized in ethanol to yield 40 grams of 2-phenyl- 4-(1-hydroxy-2-methylpropyl)-5-methyl-1H-imidazole, which melted at 214° C.
Reaction SMILES: C(OC([NH:11][C@:12]1([C:22]([OH:24])=[O:23])[C@@H:17]2[CH2:18][C@@:14]3([C:19]([OH:21])=[O:20])[C@@H:15]([CH2:16]2)[C@@H:13]13)=O)C1C=CC=CC=1.[H][H]>C(O)C.O.[Pd]>[NH2:11][C@:12]1([C:22]([OH:24])=[O:23])[C@@H:17]2[CH2:18][C@@:14]3([C:19]([OH:21])=[O:20])[C@@H:15]([CH2:16]2)[C@@H:13]13
Reactant: O=C(N[C@]1(C(=O)O)[C@H]2C[C@H]3[C@@H]1[C@@]3(C(=O)O)C2)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: N[C@]1(C(=O)O)[C@H]2C[C@H]3[C@@H]1[C@@]3(C(=O)O)C2
Yield: 27.7 %

Procedure:
To a solution of 1.1 g (3.3 mmole) of (+/−)-(1R*,2R*,3R*,4S*,6S*)-3-benzyloxycarbonylamino-tricyclo[2.2.1.02,6]heptane-1,3-dicarboxylic acid in 100 mL of 1:1 ethanol/water was added 0.25 g of 10% palladium on carbon. The mixture was treated with 60 psi of hydrogen on a Parr apparatus for 24 hours. The catalyst was removed by filtration through celite and the filtrate was concentrated in vacuum to give 0.18 g of the title compound as a gray solid sesquihydrate. Extraction of the catalyst and celite with boiling water, filtration of the extracts through a millipore filter and concentration in vacuum led to the isolation of an additional 0.32 g of white solid. This was recrystallized from water to give 0.21 g of the title compound as a white crystalline one-quarter hydrate, m.p.>250° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]([F:24])([F:23])[C:8]1[N:13]=[C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]([NH2:22])=O)[CH2:16][CH2:15]2)[CH:11]=[CH:10][N:9]=1>CN(C=O)C>[F:24][C:7]([F:6])([F:23])[C:8]1[N:13]=[C:12]([N:14]2[CH2:15][CH2:16][CH:17]([C:20]#[N:22])[CH2:18][CH2:19]2)[CH:11]=[CH:10][N:9]=1
Reactant: NC(=O)C1CCN(c2ccnc(C(F)(F)F)n2)CC1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: N#CC1CCN(c2ccnc(C(F)(F)F)n2)CC1
Reaction time: 20 h
Yield: 87.2 %

Procedure:
Phosphorus oxychloride (22 mL) was added with stirring to DMF (220 mL). The exothermic reaction mixture turned deep red, and compound VI (23.20 g, 85 mmol) was added. The mixture was cooled in a water bath and stirred for 20 hr. The DMF was then removed under vacuum and the residue was dissolved in methylene chloride (300 mL). Saturated aqueous sodium carbonate (ca 200 mL) was added to the solution with ice bath cooling until no more bubbling was observed. The methylene chloride layer was separated and concentrated in vacuo. The residue was recrystallized from hexanes-ethyl acetate to give the crystalline product (19.0 g, 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].Br[CH2:13][C:14]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[CH:17]=1)=O.CN(C)C1C=CC=CC=1>CCOC(C)=O>[CH3:11][O:10][C:8]1[CH:9]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[C:7]=1[CH:13]=[C:14]([C:16]1[CH:17]=[C:18]([O:24][CH3:25])[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[NH:6]2
Reactant: COc1cc(N)cc(OC)c1
Reactant: COc1cc(OC)cc(C(=O)CBr)c1
Solvent: CCOC(C)=O
Solvent: CN(C)c1ccccc1
Product: COc1cc(OC)cc(-c2cc3c(OC)cc(OC)cc3[nH]2)c1
Reaction time: 0.17 h

Procedure:
0.32 g (2.1 mmoles) of 3,5-dimethoxyaniline, 0.26 g (1.0 mmol) of 2-bromo-1-(3,5-dimethoxyphenyl)ethanone and 0.42 ml (3.3 mmol) of N,N-dimethylaniline were placed in a vial. The vial was placed inside a monomode microwave reactor and was radiated at a power of 100 W, at a temperature of 150° C. for 10 minutes. After cooling the reaction vial, the mixture was dissolved in AcOEt, was washed with an aqueous HCl 2N solution, was dried on anhydrous Na2SO4 and was evaporated at low pressure. The crude portion was purified by means of pressure column chromatography (Eluent: AcOEt/hexanes) obtaining 4,6-dimethoxy-2-(3,5-dimethoxyphenyl)-1H-indole.
Reaction SMILES: [ClH:1].[NH:2]=[C:3]1[NH:9][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([NH:19]C(OCC2C=CC=CC=2)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:7][CH2:6][CH2:5][CH2:4]1>[H][H].[Pd]>[ClH:1].[ClH:1].[NH2:19][CH:13]([CH2:12][CH2:11][CH2:10][CH:8]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3](=[NH:2])[NH:9]1)[C:14]([O:16][CH2:17][CH3:18])=[O:15].[ClH:1]
Reactant: [H][H]
Reactant: CCOC(=O)C(CCCC1CCCCC(=N)N1)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Product: CCOC(=O)C(N)CCCC1CCCCC(=N)N1

Procedure:
The product of EXAMPLE 249 is reduced using hydrogen and Pd/C as catalyst to yield the title product after lyophilization from aqueous HCl.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[CH:16][C:17]4[C:22]([CH:23]=3)=[CH:21][C:20]([C:24]3[CH:25]=[N:26][N:27]([CH:29]5[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]5)[CH:28]=3)=[CH:19][CH:18]=4)=[C:9]([O:42][CH3:43])[CH:8]=2)=[CH:5][N:4]=[C:3]1[CH3:44].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[CH:16][C:17]4[C:22]([CH:23]=3)=[CH:21][C:20]([C:24]3[CH:25]=[N:26][N:27]([CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)[CH:28]=3)=[CH:19][CH:18]=4)=[C:9]([O:42][CH3:43])[CH:8]=2)=[CH:5][N:4]=[C:3]1[CH3:44]
Reactant: COc1cc(-c2cnc(C)n2C)ccc1Nc1cc2cc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)ccc2cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2cnc(C)n2C)ccc1Nc1cc2cc(-c3cnn(C4CCNCC4)c3)ccc2cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.5 %

Procedure:
To a solution of tert-butyl 4-(4-(3-((4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)-amino)isoquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Example 4, 27 mg, 0.045 mmol) in DCM (6 mL) at 0° C. was added TFA (0.6 mL) and the reaction was stirred at room temperature for 4 hours. The solvents were removed in vacuo and the residue was purified by SCX-2 column eluting with 2M NH3/MeOH to afford the title compound as a yellow oil (19 mg, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[OH:15].ClC1C=CC=C(C(OO)=[O:24])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([CH2:10][C:11]([F:12])([F:14])[F:13])=[O:24])=[CH:4][C:3]=1[OH:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Oc1cc(SCC(F)(F)F)c(Cl)cc1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=S(CC(F)(F)F)c1cc(O)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
In 80 ml of chloroform was dissolved 10.0 g (36.08 mmol) of 2,4-dichloro-5-(2,2,2-trifluoroethylthio)phenol. Thereto was added 9.80 g (39.75 mmol) of 3-chloroperbenzoic acid (purity: about 70%) under ice cooling, and the mixture was stirred for 30 minutes at room temperature. Then, saturated aqueous solution of sodium thiosulfate was added to the reaction mixture to decompose excess peroxide. Thereafter, the solvent was distilled off under reduced pressure, and extraction was conducted by adding ethyl acetate and water. The organic phase obtained was washed by aqueous potassium carbonate solution and saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, to obtain 9.30 g (yield: 88%) of an intended product.
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][NH:7][C:6]2=O.S(Cl)([Cl:18])=O>CN(C=O)C>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Cl)c2cc1OC

Procedure:
An analogous reaction to that described in Example 1, starting with 6,7-Dimethoxy-3H-quinazolin-4-one (31) reacted with thionylchloride in presence of DMF gave compound 32.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@H:14]([CH2:15][CH:16]=[CH:17][CH2:18]1)[CH2:13][CH2:12]3)=[O:4].ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)(Cl)Cl>[O:32]1[C@H:16]2[CH2:15][C@H:14]3[C@:19]([CH3:20])([CH2:18][C@@H:17]12)[C@@H:21]1[C@H:11]([C@H:8]2[C@@:6]([CH2:23][CH2:22]1)([CH3:7])[C@@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]2)[CH2:12][CH2:13]3
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A solution of 17β-methoxycarbonyl-5α-androst-2-ene (7.0 g.,) and 85% m-chloroperbenzoic acid (5.0 g.) in chloroform (125 ml.) was stirred for 1.5 hr. at room temperature and then diluted with chloroform (125 ml.). This solution was washed with aqueous 10% sodium bicarbonate and water prior to drying. Filtration and evaporation afforded a solid (8.075 g.) which was recrystallised from methylene chloride/cyclohexane to afford the pure title compound; [α]D + 67°, (c, 0.8).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]C)=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH:34]=[CH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:13]=2)[N:6]=1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: CCCCCCCCC=CCCCCCCCC(=O)NCCN=[N+]=[N-]
Product: CCCCCCCCC=CCCCCCCC(=O)NCCn1cc(CCCCCc2cn(C(=O)OC(C)(C)C)c(N)n2)nn1

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (g, mmol) was reacted with N-(2-azidoethyl)octadec-9-enamide (g, mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-heptadec-8-enamidoethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.26 (s, 1H), δ 6.81 (s, 1H), δ 6.42 (s, 2H), δ 5.88 (s, 1H), δ 5.27 (s, 2H), δ 4.38 (s, 2H), δ 3.65 (s, 2H), δ 2.60 (s, 2H), δ 2.09 (s, 2H), δ 1.53-1.01 (m, 35H), 0.79 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 174.2, 173.8, 148.3, 130.3, 130.1, 129.9, 129.8, 121.9, 85.1, 67.1, 49.5, 39.5, 39.1, 38.0, 37.7, 36.7, 36.6, 32.8, 32.3, 32.1, 31.7, 29.9, 29.8, 29.7, 29.5, 29.3, 29.2, 28.9, 28.7, 28.1, 28.0, 27.9, 27.4, 27.3, 27.3, 26.9, 25.9, 25.6, 25.3, 22.9, 22.8, 22.6, 14.3, 14.2 ppm; HRMS (ESI) calcd for C35H61N7O3(M+) 627.4836. Found 627.4823, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)heptadec-8-enamide hydrochloride (0.128 g, 66% yield). 1H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), δ 6.96 (s, 1H), δ 6.45 (s, 1H), δ 6.09 (s, 1H), δ 4.58 (s, 2H), δ 3.58 (s, 2H), δ 2.75 (s, 2H), δ 2.10 (s, 2H), δ 1.96 (s, 4H), δ 1.69 (s, 2H), δ 1.41 (m, 4H), 1.23 (s, 24H), δ 0.84 (s, 3H) ppm; 13C NMR (100 MHz, CD3OD) δ 175.5, 158.8, 155.7, 147.3, 129.7, 129.6, 127.6, 108.5, 94.6, 76.7, 51.3, 50.4, 48.6, 48.4, 48.2, 47.9, 47.8, 47.5, 47.3, 38.9, 37.5, 36.6, 45.9, 45.8, 33.9, 32.6, 31.9, 31.5, 29.8, 29.5, 29.4, 29.3, 29.2, 29.1, 28.2, 27.8, 27.0, 25.8, 24.9, 24.2, 23.8, 22.5, 13.5, 13.3 ppm; HRMS (ESI) calcd for C30H53N7O (M+) 527.4312. Found 527.4298.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]([CH3:24])([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH:16]2[CH2:20][NH:19][C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][C:8]=1[CH3:23])[CH3:5].Cl[CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=1>>[CH3:24][C:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)[C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][C:8]=1[CH3:23])([CH3:5])[C:3]([OH:25])=[O:2]
Reactant: ClCc1ccc2ccccc2n1
Reactant: COC(=O)C(C)(C)Oc1ccc(CCCC2CNC(=O)N2C)cc1C
Product: Cc1cc(CCCC2CN(Cc3ccc4ccccc4n3)C(=O)N2C)ccc1OC(C)(C)C(=O)O

Procedure:
The titled compound was prepared using 2-Methyl-2-{2-methyl-4-[3-(3-methyl-2-oxo-imidazolidin-4-yl)-propyl]-phenoxy}-propionic acid methyl Ester (0.100 g, 0.287 mmole) and 2-chloromethyl-quinoline (0.092 g, 0.431 mmole) to produce an oil (0.023 g, 17%). Mass [EI+] 476 (M+H)+, [EI−] 474 (M−H)−.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:5]=1[CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([C:16]([O:18]CC)=[O:17])[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH3:21].Cl>C(O)C>[C:16]([C:13]1[CH:14]=[CH:15][C:10]2[N:9]=[C:8]([CH3:21])[N:7]([CH2:6][C:5]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:4]=3[Cl:3])[C:11]=2[CH:12]=1)([OH:18])=[O:17]
Reactant: CCOC(=O)c1ccc2nc(C)n(Cc3ccc(Cl)cc3Cl)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2ccc(C(=O)O)cc2n1Cc1ccc(Cl)cc1Cl
Yield: 78.4 %

Procedure:
10% sodium hydroxide aqueous solution (3.10 g) and ethanol (10 ml) are added to 1-(2,4-dichlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole (0.94 g) (example 70), and the solution is refluxed by heating for 1 hour. Its acidity is adjusted to pH 6 with 10% hydrochloric acid. The precipitated crystals are separated through filtration, dried, and thus, 6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (0.68 g) is obtained. 1H-NMR (DMSO-d6, δ): 2.52 (3H, s), 5.61 (2H, s), 6.54 (1H, d, J=8.4 Hz), 7.33 (1H, dd, J=8.4 and 2.1 Hz), 7.64 (1H, d, J=8.4 Hz), 7.74 (1H, d, J=2.1 Hz), 7.81 (1H, dd, J=8.4 and 1.5 Hz), 7.98 (1H, s), 12.72 (1H, s).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[CH:24]([OH:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:29](Cl)(=[O:33])[CH:30]([CH3:32])[CH3:31].[C:35]([OH:40])(=[O:39])[C:36]([OH:38])=[O:37]>CN(C)C=O.C(C(C)=O)C>[C:35]([OH:40])(=[O:39])[C:36]([OH:38])=[O:37].[C:29]([O:26][CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24](=[O:25])[N:16]1[CH2:15][CH2:14][CH2:13][N:10]1[CH2:9][CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)(=[O:33])[CH:30]([CH3:32])[CH3:31]
Reactant: O=C1c2ccccc2C(O)N1CCCN1CC=C(c2ccccc2)CC1
Reactant: CC(C)C(=O)Cl
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C(=O)OC1c2ccccc2C(=O)N1CCCN1CC=C(c2ccccc2)CC1
Reaction time: 2 h
Yield: 35.4 %

Procedure:
15 A solution of 2-[3-(4-phenyl-1,2,3,6-tetrahydro-1pyridyl)propyl]-3-hydroxy-1-isoindolinone (7 g) in anhydrous dimethylformamide (75 cc) is added to a suspension of sodium hydride (as a 50% suspension in oil) (1 g) in anhydrous dimethylformamide (25 cc) at a temperature close to 20° C. in the course of 10 minutes and agitation is continued for 2 hours. Then, 2.3 g of isobutyryl chloride is added in the course of 5 minutes, and agitation is continued for a further 20 hours. The suspension obtained is poured into distilled water (100 cc) and extracted with methylene chloride (4×50 cc). The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in methyl ethyl ketone (45 cc). A solution of oxalic acid (1.5 g) in methyl ethyl ketone (35 cc) is added and agitation continued for 1 hour at a temperature close to 20° C. The precipitate formed is separated by filtration and recrystallized from boiling methanol (200 cc). 3 g of 3-isobutyryloxy-2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone oxalate are thus obtained, melting at 164° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([NH:13][C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)=[N:10][C:9]=2[CH3:20])[CH:5]=[CH:4][N:3]=1.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[N:21]1([C:2]2[CH:7]=[C:6]([C:8]3[S:12][C:11]([NH:13][C:14]4[CH:19]=[N:18][CH:17]=[CH:16][N:15]=4)=[N:10][C:9]=3[CH3:20])[CH:5]=[CH:4][N:3]=2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: c1c[nH]cn1
Reactant: Cc1nc(Nc2cnccn2)sc1-c1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc(Nc2cnccn2)sc1-c1ccnc(-n2ccnc2)c1
Temperature: 140 °C

Procedure:
A stirred solution of [5-(2-Chloro-pyridin-4-yl)-4-methyl-thiazol-2-yl]-pyrazin-2-yl-amine (Ex. 2b, 0.4 g, 1.32 mmol) in DMSO (10 ml) is treated with imidazole (0.18 g, 2.64 mmol) followed by caesium carbonate (0.86 g, 2.64 mmol). The reaction mixture is heated to 140° C. for 48 hours and then allowed to cool to room temperature. The mixture is diluted with water (100 ml) and extracted with ethyl acetate (4×100 ml). The organics are combined, dried over MgSO4 and the solvent removed in vacuo to yield the crude product as a yellow oil. Purification by chromatography on silica, eluting with ethyl acetate-methanol (9:1) affords the titled compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]4[C:16]([CH3:23])=[N:17][N:18]([CH2:20][CH2:21][OH:22])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][N:29]=1>>[OH:22][CH2:21][CH2:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:31]5[CH:30]=[N:29][C:28]([O:27][CH3:26])=[CH:33][CH:32]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:25])[C:13]2=[O:24])[C:16]([CH3:23])=[N:17]1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cc1nn(CCO)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: COc1ccc(-c2ccc3ncc4c(c3c2)n(-c2cn(CCO)nc2C)c(=O)n4C)cn1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-[1-(2-hydroxy-ethyl)-3-methyl-1H-pyrazol-4-yl]-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage 103.1.1, 37.4 mg, 0.093 mmol) and 2-methoxypyridine-5-boronic acid (Aldrich, Buchs, Switzerland, 20 mg, 0.131 mmol) to give the title compound as a white solid. (HPLC: tR 2.42 min (Method A); M+H=431 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.95 (s, 1H), 8.35 (s, 1H), 8.13 (s, 1H), 8.10-8.05 (m, 1H), 7.95-7.88 (m, 1H), 7.81-7.75 (m, 1H), 7.51-7.46 (m, 1H), 6.93-6.86 (m, 1H), 5.00-4.94 (m, 1H), 4.24-4.17 (m, 2H), 3.88 (s, 3H), 3.86-3.74 (m, 2H), 3.57 (s, 3H), 1.94 (s, 3H))
Reaction SMILES: [CH2:1]([C:4]1[C:9]([OH:10])=[C:8]([Br:11])[CH:7]=[C:6]([F:12])[C:5]=1[N:13]1[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]1=[O:25])[CH:2]=[CH2:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Br:11][C:8]1[C:9]2[O:10][CH:2]([CH3:3])[CH2:1][C:4]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:22])([F:21])[F:23])[N:15]([CH3:24])[C:14]2=[O:25])=[C:6]([F:12])[CH:7]=1
Reactant: C=CCc1c(O)c(Br)cc(F)c1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CC1Cc2c(c(Br)cc(F)c2-n2c(=O)cc(C(F)(F)F)n(C)c2=O)O1
Yield: 97.3 %

Procedure:
3-(2-Allyl-4-bromo-6-fluoro-3-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidine-dione (1.50 g) was dissolved in xylene (15 ml). After p-toluenesulfonic acid monohydrate (0.54 g) was added thereto, it was allowed to react under the refluxing condition for 12 hours. After the completion of the reaction, it was extracted with ethyl acetate, washed with an aqueous sodium hydrogen-carbonate solution and water, and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off, and the resulting oily substance was purified by chromatography on silica gel (ethyl acetate:n-hexane=1:3) to obtain the objective 3-(7-bromo-5-fluoro-2-methyl-2,3-dihydro-benzo[b]furan-4-yl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (1.46 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]([CH3:21])[C:17]([O:19]C)=O)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([NH2:26])[CH2:23][CH2:24][NH2:25]>>[NH2:25][CH2:24][CH2:23][CH2:22][NH:26][C:17](=[O:19])[CH:16]([C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]([OH:11])=[C:9]([C:12]([CH3:14])([CH3:15])[CH3:13])[CH:8]=1)[CH3:21]
Reactant: NCCCN
Reactant: COC(=O)C(C)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Product: CC(C(=O)NCCCN)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
146 g of methyl 3,5-di-tert-butyl-4-hydroxyphenylpropionate and 370 g of 1,3-propanediamine are heated together at 130° C. for 11 hours, after which the mixture is evaporated down under reduced pressure. The residue melts at 75°-80° C.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C@@H:6]([CH3:20])[C@@H:7](O)[O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C@@:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C:6]([CH3:20])=[CH:7][O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1
Reactant: C[C@H]1[C@@H](O)O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC1=CO[C@@H]2O[C@@]3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.3 %

Procedure:
To a solution of dihydroartemisinin (500 mg, 1.86 mmol) in dichloromethane (28 ml) at 0° C. under nitrogen was added 4-(N,N-dimethylamino)pyridine (37 mg) and trifluoroacetic anhydride (0.79 ml, 5.58 mmol). The mixture was allowed to warm to room temperature and stirred overnight. The solution was then concentrated in vacuo. The residue was purified by flash chromatography (SiO2; ether:hexane from 0.5:9.5 to 1.5:8.5) to give 9,10-anhydro-10-deoxoartemisinin (9,10-anhydroartemisinin) (180 mg, 25%) as a white solid. M.p. 100° C.; [α]D20.5 +155.74° (c. 0.0101 in CHCl3); νmax (film): 2948, 2922, 2862, 2850, 1684, 1432, 1372, 1334, 1198, 1178, 1158, 1142, 1114, 1078; 1028, 1016, 992, 954, 944, 904, 880, 828, 812; δH: 6.18 (1H, s, H-10), 5.54 (1H, s, H-12), 2.40 (1H, ddd, J=17.1, 13.2, 4.14 Hz, H-9), 2.00-2.09 (2H, m), 1.88-1.95 (1H, m), 1.07-1.73 (8H, m), 1.58 (3H, d, J=1.37 Hz, H-16) 1.42 (3H, s, H-14), 0.98 (3H, d, J=5.98 Hz, H-15); m/z (EI): 380 (M+); Anal. Calc. for C15H22O4: C, 67.67; H, 8.27. Found: C, 67.63; H, 8.51.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2[CH3:21])[CH:7]=1)[CH3:2].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:14]2[CH:19]=[CH:18][C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:16][C:15]=2[CH3:21])=[O:22])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(NC(=O)c2ccc(Br)cc2C)c1
Reactant: OB(O)c1ccccc1
Product: CCOC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccccc3)cc2C)c1
Temperature: 80 °C

Procedure:
[3-(4-Bromo-2-methyl-benzoylamino)-phenyl]-acetic acid ethyl ester (188 mg, 0.50 mmol) was coupled to phenylboronic acid using Method E, except that the reaction mixture was heated at 80° C. The crude residue was purified by column chromatography using 20% EtOAc in heptane to give the title compound.