Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]3[CH2:19][N:20]([C:23](=[O:25])[CH3:24])[CH2:21][CH2:22][C:17]=3[NH:16][N:15]=2)=[CH:10][CH:9]=1.[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>CN(C=O)C.CCOC(C)=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:18]3[CH2:19][N:20]([C:23](=[O:25])[CH3:24])[CH2:21][CH2:22][C:17]=3[N:16]([CH2:26][CH:28]3[CH2:29][O:30]3)[N:15]=2)=[CH:12][CH:13]=1
Reactant: ClCC1CO1
Reactant: CC(=O)N1CCc2[nH]nc(-c3ccc(Br)cc3)c2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2c(c(-c3ccc(Br)cc3)nn2CC2CO2)C1
Reaction time: 18 h
Yield: 55.8 %

Procedure:
Cs2CO3 (11.58 g, 35.5 mmol) was added to a solution of 1-[3-(4-bromo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (7.59 g, 23.7 mmol) and epichlorohydrin (20 mL, 234 mmol) in DMF (100 mL). The mixture was stirred for 18 h then diluted with EtOAc (800 mL) and washed with saturated aqueous NaHCO3 (2×100 mL), H2O (2×100 mL), and brine (100 mL). The NaHCO3 layer was extracted with EtOAc (2×150 mL). The combined washes were extracted with EtOAc (2×100 mL). The combined extracts were dried over Na2SO4 and concentrated. Column chromatography (silica, 10-20% acetone/CH2Cl2) afforded 4.98 g (56%) of the title compound. HPLC, tR=4.90 min. (Reverse phase conditions: HP 1100 LCMS, Phenomenex luna 2.1×150 mm column, 60% MeOH/H2O (0.5% AcOH) to 90% MeOH/H2O (0.5% AcOH), held at initial conditions for 2 min then ramped to final conditions over 5 min.) MS (electrospray): m/z calculated for C17H1979BrN3O2, [M+H]+, 376.07. found 376.0. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers): 7.47 (d with fine splittings, J=8.5, Hz, 2H), 7.44 (m, 4H), 7.38 (d with fine splittings, J=8.5, Hz, 2H), 4.71 and 4.64 (A and B of AB quartet, Jab=15.7 Hz, 2H), 4.51 (s, 2H), 4.39 (dd, J=15.1, 2.5 Hz, 1H), 4.34 (dd, J=15.0, 2.9 Hz, 1H), 4.02 (dd, J=5.2, 3.9 Hz, 1H), 3.98 (dd, J=5.3, 3.7 Hz, 1H), 3.83 (m, 2H), 3.64 (m, 2H), 3.25 (br m, 2H), 2.80-2.60 (m, 6H), 2.46 (dd, J=4.6, 2.6 Hz, 1H), 2.38 (dd, J=4.6, 2.6 Hz, 1H), 2.10 (s, 3H), 2.06 (s, 3H).
Reaction SMILES: [CH:1]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]2[C:2]=1[CH:3]1[O:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH:4]1[CH2:5][O:6]2.[H-].[Na+].[CH2:21](Br)[CH:22]=[CH2:23].Cl>CN(C=O)C.O>[CH2:23]([O:11][C:9]1[CH:8]=[C:7]2[C:2]([CH:3]3[O:14][C:13]4[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=4[CH:4]3[CH2:5][O:6]2)=[CH:1][CH:10]=1)[CH:22]=[CH2:21]
Reactant: Oc1ccc2c(c1)OCC1c3ccccc3OC21
Reactant: C=CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc2c(c1)OCC1c3ccccc3OC21
Yield: 49.3 %

Procedure:
Compound 6a,11a-Dihydro-6H-benzo[4,5]furo[3,2-c]chromen-3-ol (100 mg, 0.42 mmol) was dissolved in DMF (5 ml) and NaH (10 mg, 0.42 mmol) was added to the solution at room temperature, followed by allyl bromide (0.07 ml, 0.84 mmol). The reaction mixture was stirred at room temperature to 6 hours and poured into iced water and neutralized with 10% HCl to get the white precipitate. Precipitate were washed with water and purified by silica gel column chromatography using hexane-chloroform as the eluent to give 3-(allyloxy)-6a,11a-dihydro-6H-benzofuro[3,2-c]chromene (58 mg, 50%) as white solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.C(OC([O:15][C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[CH:18]=[CH:19][CH2:20]Cl)=O)C>CO>[OH:15][C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[CH:18]=[CH:19][CH2:20][N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1
Reactant: CCOC(=O)Oc1ccccc1C=CCCl
Reactant: c1ccc2c(c1)CNC2
Solvent: CO
Product: Oc1ccccc1C=CCN1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.8 %

Procedure:
The process for the preparation of this compound and its physical properties will be given below. A solution of 5.8 grams of isoindoline in 20 milliliters of methanol is added dropwise to a solution of 3.3 grams of o-ethoxycarbonyloxycinnamyl chloride in 30 milliliters of methanol, and the resulting mixture is stirred for 1 hour at room temperature. After completion of the reaction, the methanol is distilled off, and the residue is extracted with chloroform. The chloroform layer is then purified by silica gel column chromatography and recrystallized from ethanol to obtain 1.2 grams (yield 35%) of N-(o-hydroxycinnamyl)-isoindoline as crystals having a melting point of 161°-163° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=2[O:25][CH2:26][C:27]([OH:29])=[O:28])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9].B([C:33]1C=C(C(F)(F)F)C=CC=1O[C@@H](C)C(O)=O)(O)O>>[CH3:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:20]=[C:19]([C:21]([F:23])([F:24])[F:22])[CH:18]=[CH:17][C:16]=2[O:25][C@@H:26]([CH3:33])[C:27]([OH:29])=[O:28])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:11][CH2:12][CH2:13][CH2:14]1)=[O:9]
Reactant: C[C@H](Oc1ccc(C(F)(F)F)cc1B(O)O)C(=O)O
Reactant: Cc1cc(-c2cc(C(F)(F)F)ccc2OCC(=O)O)ccc1C(=O)N1CCCC1
Product: Cc1cc(-c2cc(C(F)(F)F)ccc2O[C@@H](C)C(=O)O)ccc1C(=O)N1CCCC1

Procedure:
The title compound was prepared using the product of example 27 step a) and (2S)-2-[2-borono-4-(trifluoromethyl)phenoxy]-propanoic acid [WO2004089885] by the method of example 32 step b).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[F:12][C:13]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:14]=1[C:15]([N:17]=[C:18]=[O:19])=[O:16]>C(#N)C>[F:12][C:13]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:14]=1[C:15]([NH:17][C:18]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:8][N:7]=1)=[O:19])=[O:16]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Nc1ccc(C(F)(F)F)cn1
Solvent: CC#N
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc(C(F)(F)F)cn1
Reaction time: 3 h

Procedure:
An 0.7 g. portion of 5-trifluoromethyl-2-aminopyridine was dissolved in 20 ml. of acetonitrile, and to the solution was added 0.85 g. of 2,6-difluorobenzoyl isocyanate under a nitrogen blanket at ambient temperature. A precipitate formed immediately. The mixture was stirred for 3 hours, and was then filtered and the solids were washed with acetonitrile. The solids were dried under vacuum to obtain 1.0 g. of the product named above, m.p. 215°-220° C. Elemental analysis gave the following results:
Reaction SMILES: [O:1]=[C:2]1[O:6][CH:5]([C:7]([OH:9])=[O:8])[CH:4]([C:10]([OH:12])=[O:11])[CH2:3]1.[CH2:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(C)=O>[CH2:13]([O:8][C:7]([CH:5]1[CH:4]([C:10]([OH:12])=[O:11])[CH2:3][C:2](=[O:1])[O:6]1)=[O:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CC(C(=O)O)C(C(=O)O)O1
Reactant: OCc1ccccc1
Solvent: CC(C)=O
Product: O=C1CC(C(=O)O)C(C(=O)OCc2ccccc2)O1
Reaction time: 12 h

Procedure:
5.2 g of (2RS,3SR)-5-oxotetrahydrofuran-2,3-dicarboxylic acid in 88 ml of acetone was stirred with 6.5 g of 1,1'-dicyclohexylcarboriimide at room temperature for 2 hours. After addition of 3.26 ml of benzyl alcohol, the reaction solution was stirred at the same temperature for 12 hours. The insolubles were filtered off, and the filtrated was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=4/1→chloroform/methanol=50/1] to give 7.93 g of the title compound as a yellow solid.
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([CH3:21])[N:12]=2)=[CH:6][CH:5]=1.[CH3:23]I>>[F:22][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([CH3:21])[N:12]=2)[CH3:23])=[CH:6][CH:5]=1
Reactant: Cc1nc(Nc2ccc(OC(F)F)cc2)c2ccccc2n1
Reactant: CI
Product: Cc1nc(N(C)c2ccc(OC(F)F)cc2)c2ccccc2n1

Procedure:
The title compound was prepared from (4-difluoromethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine (710 mg, 2.36 mmol) and methyl iodide (1.03 ml, 16.52 mmol), by a procedure similar to Example 36 (40.8% yield). 1H NMR (CDCl3): 7.77 (dd, J=8.4 Hz, J=0.9 Hz, 1H), 7.59-7.53 (m, 1H), 7.17-7.10 (m, 4H), 7.06-6.99 (m, 2H), 6.78 (d, J=0.6 Hz, 0.25H), 6.54 (d, J=0.9 Hz, 0.5H), 6.29 (d, J=0.9 Hz, 0.25H), 3.62 (s, 3H), 2.75 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][CH:14]([NH2:16])[CH3:15].[CH3:17][C:18]1[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][CH:14]([NH:16][CH2:23][C:21]1[O:22][C:18]([CH3:17])=[CH:19][CH:20]=1)[CH3:15]
Reactant: CC(N)COc1ccc2ccccc2c1Cl
Reactant: Cc1ccc(C=O)o1
Product: Cc1ccc(CNC(C)COc2ccc3ccccc3c2Cl)o1
Yield: 69 %

Procedure:
Prepared from 1-[(1-chloronaphthalen-2-yl)oxy]propan-2-amine and 5-methylfuran-2-carbaldehyde in 69% yield as a pale yellow oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[CH2:3][N:4]1[C:16]2[C:15]3[C:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=4)=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[CH:5]1.C(#[N:30])C>>[CH3:1][CH:2]([CH3:27])[CH2:3][N:4]1[C:16]2[C:15]3[C:14]([C:17]4[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][CH3:26])=[CH:21][CH:22]=4)=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:30])[C:7]=2[N:6]=[CH:5]1
Reactant: CCCOc1ccc(-c2cccc3ncc4ncn(CC(C)C)c4c23)cc1
Reactant: CC#N
Product: CCCOc1ccc(-c2cccc3nc(N)c4ncn(CC(C)C)c4c23)cc1
Reaction time: 36 h

Procedure:
The method described in Part J of Example 365 was used to oxidize and aminate 1-(2-methylpropyl)-9-(4-propoxyphenyl)-1H-imidazo[4,5-c]quinoline (1.1 g, 3.1 mmol). The amination reaction was stirred for 36 hours. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 70:30) to provide an oil, which was stirred with acetonitrile to provide a solid. The solid was isolated by filtration and recrystallized from acetonitrile to provide 165 mg of 1-(2-methylpropyl)-9-(4-propoxyphenyl)-1H-imidazo[4,5-c]quinolin-4-amine as light tan needles, mp 181-182° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=O.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5][N:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]1
Reactant: CC(C)(O)C1CCNCC1
Reactant: O=Cc1ccc([N+](=O)[O-])c(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(O)C1CCN(Cc2ccc([N+](=O)[O-])c(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To a solution of 3-fluoro-4-nitrobenzaldehyde (0.5 g, 2.96 mmol) and 2-(piperidin-4-yl)propan-2-ol (0.466 g, 3.25 mmol) in DCM (25 mL) was added AcOH (0.017 mL, 0.296 mmol) and sodium triacetoxyborohydride (0.689 g, 3.25 mmol), and the reaction was stirred at RT for 1 hour. After 1 hour, the reaction was quenched by the addition of 1 N aqueous NaOH (15 mL), and the layers were separated. The aqueous layer was extracted with DCM, and the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residual product was adsorbed onto a plug of silica gel, and purified by column chromatography, eluting with 0-100% EtOAc in DCM, to provide 2-(1-(3-fluoro-4-nitrobenzyl)piperidin-4-yl)propan-2-ol as a yellow oil (0.75 g, 86% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[CH:3][CH:2]=1.Cl.[C:16]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)(=[NH:18])[NH2:17].C(=O)([O-])[O-].[K+].[K+].C(O)C>C(O)(=O)C>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:16]2[NH:18][C:9](=[O:11])[CH:8]=[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[N:17]=2)[CH:20]=1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: N=C(N)c1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Product: O=c1cc(-c2ccncc2)nc(-c2cccnc2)[nH]1
Temperature: 75 °C
Yield: 50.2 %

Procedure:
ethyl 3-(4-pyridyl)-3-oxopropionate (0.60 g), 3-amidinopyridine hydrochloride (0.54 g) and potassium carbonate (1.15 g) were added to 5 ml of ethanol, and the mixture was heated under reflux at 75° C. for 20 hours. Acetic acid was added to the reaction mixture, and the solvent was removed by distillation. The residue was added with water and then with acetic acid, and the resulting solid was separated by filtration, washed with water and ethyl acetate, and dried to obtain 0.39 g of the desired compound.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:12]=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:15][NH2:16]>CN(C)C=O>[CH3:15][NH:16][C:2]1[C:3]2[N:4]([CH:12]=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CN
Reactant: Clc1nc2ccccc2n2cnnc12
Solvent: CN(C)C=O
Product: CNc1nc2ccccc2n2cnnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
4-Chloro-[1,2,4]triazolo-[4,3-a]quinoxaline (2.0 g., 0.01 mole), the product of Example 2, in N,N-dimethyl formamide (30 ml.) was saturated with monomethylamine gas and stirred at room temperature for 3 hours. Monomethylamine gas was again bubbled into the solution and the solution was stirred at room temperature for an additional 2 hours. The precipitate was separated by filtration and washed with N,N-dimethylformamide. Recrystallization from N,N-dimethylformamide gave 1.37 g. (69% yield) of 4-methylamino-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. >300° C. Mass spectrum: m/e, 199 (P).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([NH:14][C@@H:15]([C:24](OC)=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>O1CCCC1>[OH:25][CH2:24][C@H:15]([NH:14][C:7](=[O:8])[O:9][C:10]([CH3:12])([CH3:11])[CH3:13])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1
Reactant: COC(=O)[C@@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CO)Cc1ccc(O)cc1
Temperature: 70 °C
Yield: 55.5 %

Procedure:
A solution of 29.6 cm3 of lithium aluminium hydride at 1M in tetrahydrofuran is added, with stirring and under an inert atmosphere, at a temperature in the region of 20° C., to a solution of 4.38 g of methyl BOC-D-tyrosinate in 25 cm3 of tetrahydrofuran. After addition of 60 cm3 of tetrahydrofuran, the reaction mixture is heated at a temperature in the region of 70° C. for 3 hours. The reaction mixture is cooled and then concentrated under reduced pressure (1 kPa) at a temperature in the region of 60° C. The evaporation residue is dried in a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 40° C. and is then chromatographed under an argon pressure of 60 kPa on a column of silica gel (particle size 40-63μ; diameter 7 cm; height 24 cm), eluting with 10 dm3 of a dichloromethane/methanol mixture (98/2 by volume), 2 dm3 of a dichloromethane/methanol mixture (95/5 by volume) and 2 dm3 of a dichloromethane/methanol mixture (90/10 by volume). The fractions containing the expected product are combined and then concentrated under the above conditions. 2.2 g of tert-butyl N-[(1R)-1-hydroxymethyl-2-(4-hydroxyphenyl)ethyl]-carbamate are obtained in the form of a white foam [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 1.35 (s: 9H); 2.46 (dd, J=14 and 8 Hz: 1H); 2.68 (dd, J=14 and 6 Hz: 1H); from 3.15 to 3.40 (mt: 2H); 3.50 (mt: 1H); 4.61 (mt: 1H); 6.48 (d, J=8.5 Hz: 1H); 6.65 (d, J=8 Hz: 2H); 6.97 (d, J=8 Hz: 2H); 9.11 (broad s: 1H)].
Reaction SMILES: [CH2:1]([OH:6])[C:2]([F:5])([F:4])[F:3].[CH3:7][C:8]1([CH3:26])[C@@H:10](/[CH:11]=[CH:12]\[C:13](=O)[OH:14])[C@H:9]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>>[CH3:7][C:8]1([CH3:26])[C@@H:10](/[CH:11]=[CH:12]\[C:13](=[O:14])[O:6][CH2:1][C:2]([F:5])([F:4])[F:3])[C@H:9]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: OCC(F)(F)F
Reactant: CC1(C)[C@H](C(=O)OCc2ccccc2)[C@@H]1/C=C\C(=O)O
Product: CC1(C)[C@H](C(=O)OCc2ccccc2)[C@@H]1/C=C\C(=O)OCC(F)(F)F

Procedure:
Using the procedure of Example 53, trifluoroethanol and the product of Step B of Example 57 were reacted to obtain benzyl (1R,cis,Z) 2,2-dimethyl-3-[3-oxo-3-(2,2,2-trifluoroethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D° =+45° (c=0.6% in chloroform).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:10].[NH2:19][OH:20].[OH-].[K+].CO>C1COCC1>[OH:20][NH:19][C:3](=[O:2])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:10]
Reactant: NO
Reactant: COC(=O)C=CC=CCS(=O)c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(C=CC=CCS(=O)c1ccc(Cl)cc1)NO
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
To a solution of the 6-(4-chlorobenzenesulfinyl)-hexa-2,4-dienoic acid methyl ester (0.80 g, 2.79 mmol) in distilled THF (15 mL) containing an aqueous solution of hydroxylamine (50%/o, 1.7 ml, 25.8 mmol) was added at 0° C. a solution of potassium hydroxide in methanol (1M, 4.5 ml, 4.5 mmol) over a period of 30 minutes. After stirring at 0° C. for 1 hour, distilled water (15 mL) was added and the mixture was made neutral by dropwise addition of concentrated hydrochloric acid (10 M) at 0° C. The aqueous solution was extracted with ethyl acetate (3×50 mL) and the combined extracts were dried over anhydrous MgSO4, and evaporated to dryness. The residue was recrystallised from acetone to give the title compound (0.45 g, 56%) as a pale brown powder, mp 159° C. (decomp).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[CH3:12].[CH3:13]OC(N(C)C)OC>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]2[C:3]=1[CH:12]=[CH:13][NH:9]2
Reactant: Cc1c(Br)cc(F)cc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Fc1cc(Br)c2cc[nH]c2c1
Yield: 36.1 %

Procedure:
1-Bromo-5-fluoro-2-methyl-3-nitrobenzene (2.00 g, 8.55 mmol) and (dimethoxymethyl)dimethylamine (5.66 mL, 42.7 mmol) in dry DMF (20 mL) was refluxed under N2 for 8 h, then rt. over night. The mixture was diluted with DCM and extracted 5 times with water. The organic layer was dried, filtered and concentrated under reduced pressure. The residue was dissolved in AcOH (10 mL) and added drop wise to a boiling mixture of Fe(s, fine powder) in AcOH (10 mL). The mixture was refluxed for 40 min., partitioned between DCM and saturated aq. Na2CO3/brine (the mixture was filtered through celite before phase separation). The water layer was extracted once more with DCM. The organic layers were combined, dried and concentrated. Purification was performed by flash column chromatography (DCM/hexane 1:3) and afforded the title compound (660 mg, 39%) as a yellow oil. MS (ESI+) for C8H5BrFN m/z 214 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[NH:19][C:18](=[O:28])[N:17]([CH2:29][O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:44][CH2:45][O:46][CH2:47][CH3:48]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[N:19]([CH2:44][CH2:45][O:46][CH2:47][CH3:48])[C:18](=[O:28])[N:17]([CH2:29][O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)[nH]c(=O)n2COC(=O)C(C)(C)C
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(CCOCC)c(=O)n2COC(=O)C(C)(C)C
Temperature: 60 °C
Reaction time: 5 h

Procedure:
4-[7-(2-Butynyl)-3-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (40 mg) and potassium carbonate (17 mg) were dissolved in N,N-dimethylformamide (1.5 ml), and 2-bromoethylethyl ether (14 μl) was added to the solution. The mixture was stirred at 60° C. for 5 hours, diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. After removing the solvent by distillation, the residue was purified by silica gel column chromatography to give 4-[7-(2-butynyl)-3-(2,2-dimethylpropionyloxymethyl)-1-(2-ethoxyethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester from the elution fraction of hexane-ethyl acetate (1:1). The obtained 4-[7-(2-butynyl)-3-(2,2-dimethylpropionyloxymethyl)-1-(2-ethoxyethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester was dissolved in a solvent mixture of tetrahydrofuran (1.0 ml) and methanol (0.5 ml), sodium hydride (5 mg) was added to the solution, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with 2 N hydrochloric acid, and extracted with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate and the solvent was removed by distillation. The obtained residue was dissolved in N,N-dimethylformamide (1 ml), and potassium carbonate (10 mg) and methyl bromoacetate (10 μl) were added to the solution. The mixture was stirred at room temperature for 2 hours, diluted with ethyl acetate, and washed with water. After the organic layer was concentrated by distillation, the residue was dissolved in trifluoroacetic acid (0.5 ml), and the solution was stirred at room temperature for 30 minutes. After removing the solvent by distillation, a half of the residue was purified by HPLC with a reversed phase column using water-acetonitrile-trifluoroacetic acid system as elution solvent to give 6.2 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([OH:29])=O)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.Cl.[NH:32]1[CH2:36][CH2:35][N:34]=[C:33]1[C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][NH2:45])=[CH:39][CH:38]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([NH:45][CH2:44][CH2:43][C:40]3[CH:41]=[CH:42][C:37]([C:33]4[NH:34][CH2:35][CH2:36][N:32]=4)=[CH:38][CH:39]=3)=[O:29])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NCCc1ccc(C2=NCCN2)cc1
Reactant: O=C(O)CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Product: O=C(CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1)NCCc1ccc(C2=NCCN2)cc1

Procedure:
The title compound was prepared from [5-(3,4-dichloro-benzenesulfonyl)-5,6-dihydro-phenanthridin-6-yl]-acetic acid and 2-[4-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-ethylamine dihydrochloride (Reference Example 2) according to the method described in Example 1e. MS (EI) 620.5 (MH+).
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].[C:6]1([S:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:6]1([S:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[S:1][CH2:2][C:3]([OH:5])=[O:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O[C@@H]1CCCC[C@H]1Sc1ccccc1
Reactant: O=C(O)CS
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CS[C@@H]1CCCC[C@H]1Sc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Mercaptoacetic acid (0.44 g, 0.0048 mole) was added to a cold solution of the compound of Example 6 (1.0 g, 0.0048 mole) in methylene chloride (5 ml) containing trifluoracetic acid (3.5 ml). The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated to an oil with a rotary evaporator. The residue was dissolved in diethyl ether (50 ml), washed three times with 20 ml of 5% sodium bicarbonate, followed by in hydrochloric acid (10 ml) and water (20 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to a colorless oil with a rotary evaporator. The product was purified by silica gel chromatography. The structure was supported by NMR, infrared spectroscopy and elemental analysis.