Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[Cl:13][CH2:14][CH2:15][CH2:16]I.[Na+].[Cl-]>CN(C)C=O.O>[Cl:13][CH2:14][CH2:15][CH2:16][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: ClCCCI
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(OCCCCl)c1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
Under a nitrogen atmosphere, a solution of 3-nitrophenol (15.00 g, 108.0 mmol) in N,N-dimethylformamide (DMF) (10 mL) was added drop-wise over 5 min to a cold (0-5° C.), stirring slurry of sodium hydride (3.42 g of an 80% dispersion in mineral oil, 114.0 mmol) in DMF (40 mL). The mixture was allowed to stir and warm to ambient temperature over 1 h. The mixture was cooled to 0-5° C., and 1-chloro-3-iodopropane (26.37 g, 127.0 mmol) was added drop-wise over 5 min. The resulting dark-brown mixture was stirred at ambient temperature for 2 h. Water (25 mL) was added, followed by saturated NaCl solution (25 mL), and the mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 19.75 g (85.1%) of an oil.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][N+:14]([O-])=O)[CH2:9][C:8]2=[O:17])=[CH:4][CH:3]=1>C(O)C.[Ni].O>[NH2:14][CH2:13][CH:10]1[CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:19][CH:18]=2)[C:8](=[O:17])[CH2:9]1
Reactant: O=C1CC(C[N+](=O)[O-])CCN1Cc1ccc(F)cc1
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: NCC1CCN(Cc2ccc(F)cc2)C(=O)C1
Reaction time: 16 h

Procedure:
To a degassed solution of 1-(4-fluorobenzyl)-4-(nitromethyl)piperidin-2-one (1.4 g, 5.3 mmol) in absolute ethanol (80 mL) was added wet Raney nickel catalyst (1.4 g of a 50% weight slurry in water) which was washed to neutral pH with deionized water and absolute ethanol. The reaction mixture was shaken under an atmosphere of 55 psi of hydrogen for 16 hours. The product mixture was filtered through celite and the filtrate was concentrated under vacuum to afford the title compound as colorless viscous oil. 1H NMR (400 MHz, CDCl3) δ 7.24 (m, 2H), 7.01 (t, J=8.7 Hz, 2H), 4.64 (d, J=14.6 Hz, 1H), 4.44 (d, 1H), 3.23 (m, 2H), 2.65 (m, 2H), 2.16-1.28 (m).
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[CH2:8](O)[CH3:9]>>[NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([O:5][CH2:8][CH3:9])=[O:4]
Reactant: CC(C)(N)C(=O)O
Reactant: CCO
Product: CCOC(=O)C(C)(C)N
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 2-aminoisobutyric acid (3.3 g, 32 mmol) in absolute ethanol (100 mL) was cooled to -78° C. and HCl(g) bubbled in for 10 minutes. The flask was sealed with a septum and stirred at ambient temperature. After 14 hours the mixture was concentrated in vacuo to afford 5.3 g (99% yield) of ethyl 2-aminoisobutyrate as a white solid; NMR (CDCl3) 8.9 (br s, 3), 4.1 (q, 2), 1.7 (s, 6), 1.3 (t, 3) ppm.
Reaction SMILES: [C:1]([C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([Si](C)(C)C)=[CH:14][CH:13]=2)[CH2:10][C@H:9]2[N:22]([CH3:23])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2].[F:24]C1C=CC([Mg]Br)=CC=1>>[C:1]([C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([F:24])=[CH:14][CH:13]=2)[CH2:10][C@H:9]2[N:22]([CH3:23])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)[C@H]1[C@@H](c2ccc([Si](C)(C)C)cc2)C[C@@H]2CC[C@H]1N2C
Reactant: Fc1ccc([Mg]Br)cc1
Product: COC(=O)[C@H]1[C@@H](c2ccc(F)cc2)C[C@@H]2CC[C@H]1N2C

Procedure:
This compound was synthesized using a similar reaction as 2β-Carbomethoxy-3β-(4′-trimethylsilylphenyl)tropane starting with anhydroecognine methyl ester and 4-fluorophenylmagnesium bromide.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([CH3:13])[CH:9]([CH3:10])[CH2:8][CH2:7][CH:6]([CH3:11])[C:5]1=[O:12].[Cl-].[CH3:15][S+](C)C>CS(C)=O>[CH3:13][C:4]1([CH3:3])[CH:9]([CH3:10])[CH2:8][CH2:7][CH:6]([CH3:11])[C:5]21[O:12][CH2:15]2
Reactant: C[S+](C)C
Reactant: CC1CCC(C)C(C)(C)C1=O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC1CCC(C)C2(CO2)C1(C)C
Reaction time: 6 h

Procedure:
According to a preferred embodiment of the invention, NaOH is added to a mixture consisting of 2,2,3,6-tetramethyl-1-cyclohexanone and trimethylsulfonium chloride in dimethylsulfoxide. The reaction is slightly exothermic, hence the necessity to maintain an external cooling of the reaction mixture so as to keep the temperature at about 25°-30° C. Good stirring is also applied for about 6 hr. 4,4,5,8-Tetramethyl-1-oxaspiro[2.5]octane is then obtained by extraction of the resulting mixture with petrol ether, concentration of the organic extracts and fractional distillation.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.[Li]CCCC.CCCCCC.[CH:25](N1CCOCC1)=[O:26]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:25]=[O:26])=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: O=CN1CCOCC1
Reactant: FC(F)(F)Oc1cc(Br)ccc1I
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(Br)cc1OC(F)(F)F
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
A solution of 4-bromo-1-iodo-2-trifluoromethoxy-benzene (1.00 g, 2.72 mmol) in THF (15 mL) was cooled to −78° C., and 2.66 M BuLi in hexane (2.05 mL, 5.44 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 1.5 h, and N-formylmorpholine (0.57 mL, 5.63 mmol) was added. The reaction mixture was stirred at −78° C. for 15 min and at ambient temperature for 80 min. The reaction was quenched with 0.25 M aqueous citric acid (10 mL), and the resulting mixture was extracted with EtOAc (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (silica gel, 2% to 5% EtOAc in hexane) to give 4-bromo-2-trifluoromethoxy-benzaldehyde (560 mg, 77%) as a pale brown solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([O:18][CH3:19])[CH:9]=2)[C:5]([CH3:20])=[CH:4][N:3]=1.[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>O1CCOCC1>[O:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:28]=[CH:29][C:30]([NH:31][C:2]3[N:7]=[C:6]([C:8]4[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([O:18][CH3:19])[CH:9]=4)[C:5]([CH3:20])=[CH:4][N:3]=3)=[CH:32][CH:33]=2)[CH2:25][CH2:26]1
Reactant: COC(=O)c1ccc(-c2nc(Cl)ncc2C)cc1OC
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(-c2nc(Nc3ccc(N4CCOCC4)cc3)ncc2C)cc1OC
Temperature: 25 °C
Yield: 32.8 %

Procedure:
To a solution of methyl 4-(2-chloro-5-methylpyrimidin-4-yl)-2-methoxybenzoate (165 mg, 0.56 mmol) in 1,4-dioxane (5 mL) was added 4-morpholinoaniline (96 mg, 0.54 mmol) and p-toluenesulfonic acid monohydrate (97 mg, 0.51 mmol). The reaction was heated at reflux for 40 h, cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted twice more with ethyl acetate and the combined organic fractions were washed twice with 5% aqueous citric acid, water, brine then dried (sodium sulfate) filtered and concentrated to afford the crude product. Trituration with methanol provided methyl 4-(2-(4-morpholinophenylamino)-5-methylpyrimidin-4-yl)-2-methoxybenzoate as a yellow solid (77 mg, 32%); 1H NMR (300 MHz, d6-DMSO) δ 9.36 (s, 1H), 8.38 (s, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.62 (d, J=9.0 Hz, 2H), 7.38 (s, 1H), 7.27 (d, J=8.1 Hz, 1H), 6.88 (d, J=9.0 Hz, 2H), 3.89 (s, 3H), 3.82 (s, 3H), 3.72 (m, 4H), 3.01 (m, 411), 2.12 (s, 3H); LC-ESI-MS (method B): rt 6.7 min.; m/z 435.3 [M+H]+.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][CH2:15][CH2:16][CH:17]([Br:19])[CH3:18].C1(=O)NC(=O)C2=CC=CC=C12>CC(C)=O>[Br:19][CH:17]([CH3:18])[CH2:16][CH2:15][CH2:14][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: CC(Br)CCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CC(C)=O
Product: CC(Br)CCCN1C(=O)c2ccccc2C1=O
Temperature: 15 °C
Yield: 97.6 %

Procedure:
A one liter, four necked round bottom flask equipped with a mechanical stirrer, thermowatch and condenser was charged with acetone (500 ml), potassium phthalimide (92.5 g, 0.5 moles) and 1,4-dibromopentane (153 g, 0.665 moles). The resulting mixture was refluxed for 24 hours (HPLC showed 2.5% unreacted phthalimide), then cooled to 15° C. Solid sodium bromide was removed by suction filtration and one wash of the cake with acetone (50 ml). The solvent was removed using a rotary evaporator to give 187.2 g of a crude viscous yellow oil. Excess 1,4-dibromopentane (34.5 g) was removed by vacuum distillation at 35-40° C./0.3 mm of pressure, leaving 144.6 g (97.7%) of a yellow viscous oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1N=C=O.[NH2:9][C@H:10]([C:12]([NH:14][CH:15]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]2[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=2[N:17]([CH3:32])[C:16]1=[O:33])=[O:13])[CH3:11]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:16][CH2:15][NH:14][C:12]([NH:9][C@H:10]([C:12]([NH:14][CH:15]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]2[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=2[N:17]([CH3:32])[C:16]1=[O:33])=[O:13])[CH3:11])=[O:13]
Reactant: O=C=Nc1cccs1
Reactant: C[C@H](N)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Product: C[C@H](NC(=O)NCCc1cccs1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure (5-A1) using 2-thiophene-yl isocyanate and 3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one, as described in Example 8-B above, the title compound was prepared. The molecular weight as determined by mass spectrometry (FD) was: (M+H).
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:4]=[C:5]([C:7]([O:9]C)=[O:8])[N:6]=1.O[Li].O>C1COCC1.CO.O>[Br:1][C:2]1[N:3]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1
Reactant: COC(=O)c1cn(COCC[Si](C)(C)C)c(Br)n1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(C(=O)O)nc1Br
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a stirred solution of methyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (2.85 g, 8.50 mmol) in mixed solvents (THF/MeOH/water; 2:2:1; 50 mL) was added LiOH H2O (1.07 g, 25.5 mmol) at 0° C. The cold bath was removed and stirring was continued for 2 h. The reaction mixture was concentrated in vacuo, diluted with water and washed with MTBE. The aqueous layer was neutralized with 1.5N HCl and extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to provide the title compound (2.4 g, 88%) as a white solid. 1H NMR (CDCl3) δ 12.54 (br s, 1H), 8.14 (s, 1H), 5.33 (s, 2H), 3.54 (t, J=8.0 Hz, 2H), 0.85 (t, J=8.0 Hz, 2H), 0.01 (s, 9H); MS(ESI+) m/z 323.0 (M+H)+.
Reaction SMILES: C(N=[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])C1C=CC=CC=1.[CH3:17][C:18]([CH3:22])([CH3:21])[CH:19]=[CH2:20].Cl.C1C[O:27]CC1>C1(C)C=CC=CC=1>[CH3:17][C:18]([CH3:22])([CH3:21])[CH2:19][CH2:20][C:16]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:9](=[O:27])[CH3:10]
Reactant: C1CCOC1
Reactant: C=CC(C)(C)C
Reactant: CC(=NCc1ccccc1)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1ccccc1CCC(C)(C)C
Temperature: 150 °C
Yield: 97 %

Procedure:
In a 500 ml pressure reactor, N-benzyl-(1-phenylethylidene)-amine 68 mg (0.32 mmol), tristriphenylphosphine rhodium (I) chloride 6 mg (0.0065 mmol), 3,3-dimethyl-1-butene 27 mg (0.32 mmol) were placed and dissolved in toluene 100 mg. While the reactor was stopped with a stopper, the reactants were heated at 150° C. for 2 hours with stirring. After completion of the reaction, the reactant mixture was dissolved in THF 3 ml and then combined with 1 N HCl soln. 10 ml, followed by hydrolysis with stirring for 12 hours at room temperature. After the mixture was three times extracted with Et2O and CH2Cl2, the organic layer was dried over MgSO4 and then filtered and the solvent was evaporated under reduced pressure. The reactant mixture of the organic layer was purified by column chromatography on silica gel (5:2 hexane:ethyl acetate) to obtain 2-(3,3-dimethylbutyl)phenyl-1-ethanone 64 mg (0.31 mmol). Yield: 97%. Under the same conditions, a variety of olefins were employed, and the results are given in Table 1, below.
Reaction SMILES: [O:1]=[C:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:24])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@@H:12]([CH:14]=[O:15])[CH3:13])=[CH:3]1.[BH4-].[Na+]>C(O)C>[OH:15][CH2:14][C@@H:12]([CH3:13])[C@@H:11]1[C@:16]2([CH3:24])[C@H:8]([C@H:7]3[C@H:19]([CH2:18][CH2:17]2)[C@:20]2([CH3:23])[C:4](=[CH:3][C:2](=[O:1])[CH2:22][CH2:21]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1
Reactant: C[C@H](C=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -10 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
i)—A solution of (20S)-3-oxopregn-4-ene-20-carboxaldehyde (125 g) in dry ethanol (1250 ml) was cooled to −10° C., whereupon a solution of sodium borohydride (4.4 g) in dry ethanol (80 ml) was added in 30 min. After stirring the mixture for 2 h at −10° C., the reaction was quenched by adding a 50% aqueous solution of acetic acid. The reaction mixture was concentrated under reduced pressure to 25% of its original volume and then poured into ice-water (5 l). The resulting suspension was stirred overnight and filtered. The residue was washed with water and dried to give (20S)-21-hydroxy-20-methylpregn-4-en-3-one (124 g) which was used in the following step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7]Br)[CH3:2].[Cl:10][C:11]1[CH:21]=[CH:20][C:14]([CH2:15][NH:16][C:17](=[S:19])[S-:18])=[CH:13][CH:12]=1.[NH4+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7][S:19][C:17](=[S:18])[NH:16][CH2:15][C:14]1[CH:20]=[CH:21][C:11]([Cl:10])=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)CCCBr
Reactant: S=C([S-])NCc1ccc(Cl)cc1
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCSC(=S)NCc1ccc(Cl)cc1

Procedure:
To a solution of 160 g. of 4-bromobutyric acid ethyl ester in 1125 ml. of absolute dimethylformamide were added gradually under an atmosphere of argon at 0° C. while stirring well and cooling, 172.3 g. of ammonium (N-4-chlorobenzyl)dithiocarbamate, the temperature was maintained constant. The slightly yellow solution was stirred overnight at room temperature, diluted with 1500 ml. of water and extracted four times with 500 ml. of ethyl acetate each time. The combined organic phases were washed three times with 200 ml of saturated sodium chloride solution each time and dried over 80 g. of magnesium sulfate with the addition of carbon, filtered and evaporated under reduced pressure. The resulting crystalline residue was recrystallized from 700 ml. of diisopropyl ether, and 218 g. of 4-{[(p-chlorobenzyl)thiocarbamoyl]thio}-butyric acid ethyl ester having a melting point of 61°-62° C. was obtained.
Reaction SMILES: [C:1]1([CH2:11][S:12][CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[F:24][Sb-:25]([F:30])([F:29])([F:28])([F:27])[F:26].[CH2:31]([O+](CC)CC)[CH3:32]>C(Cl)Cl>[F:24][Sb-:25]([F:30])([F:29])([F:28])([F:27])[F:26].[C:1]1([CH2:11][S+:12]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[CH2:31][CH3:32])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(CSCc3cccc4ccccc34)cccc2c1
Reactant: CC[O+](CC)CC
Agent: F[Sb-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC[S+](Cc1cccc2ccccc12)Cc1cccc2ccccc12
Yield: 98.5 %

Procedure:
5.0 g (15.9 mmol) of bis(1-naphthylmethyl) sulfide and 5.93 g (17.5 mmol) of triethyloxonium hexafluoroantimonate in 30 ml of methylene chloride are reacted according to Example 1a) to give 9.07 g (98% of theory) of bis(1-naphthylmethyl)ethylsulfonium hexafluoroantimonate in the form of white crystals of melting point 101°-105° C.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=2)[N:11]([S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])[N:10]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:35]1COCC1>>[OH:3][CH2:4][CH:6]1[CH2:8][CH:7]1[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=2)[N:11]([S:20]([C:23]2[CH:24]=[CH:25][C:26]([CH3:35])=[CH:27][CH:28]=2)(=[O:21])=[O:22])[N:10]=1
Reactant: CCOC(=O)C1CC1c1nn(S(=O)(=O)c2ccccc2)c2ccc(C#N)cc12
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1ccc(S(=O)(=O)n2nc(C3CC3CO)c3cc(C#N)ccc32)cc1
Temperature: -40 °C
Reaction time: 5 h
Yield: 58 %

Procedure:
2-(1-Benzenesulfonyl-5-cyano-1H-indazol-3-yl)-cyclopropanecarboxylic acid ethyl ester (1.12 g, 2.74 mmol) was dissolved in 30 mL anhydrous THF under N2 and cooled to −40° C. LAH (0.83 g, 22 mmol) was added portionwise over a 15 min. period. The reaction was stirred for 5 h at −40° C., then quenched with 50 mL ethyl acetate, followed by 10 mL water. After stirring at room temperature for 30 min, 50 mL saturated tartrate solution was added and stirred for 30 min. The precipitate was removed by filtration and washed with ethyl acetate. The precipitate was washed with more ethyl acetate, and the organic layer was washed with brine and dried over Na2SO4. Flash chromatography on silica gel using ethyl acetate/hexane (25-50%) as the eluent gave 3-(2-hydroxymethyl-cyclopropyl)-1-(toluene-4-sulfonyl)-1H-indazole-5-carbonitrile (580 mg, 58%). 1H NMR (500 MHz, CDCl3) 8.26 (1H, d, J=8.85 Hz), 8.08 (1H, s), 7.83 (2H, d, J=8.24 Hz), 7.74 (1H, dd, J=8.85, 1.22 Hz), 7.27 (2H, d, J=8.24 Hz), 3.78 (1H, dd, J=11.29, 6.10 Hz), 3.61 (1H, dd, 11.29, 6.71 Hz), 2.38 (3H, s), 2.10 (1H, p, J=4.88 Hz), 1.82 (1H, m), 1.39 (1H, dt, J=8.55, 4.88 Hz), 1.11 (1H, dt, J=8.55, 4.88 Hz). MS m/e 366.15 (M−H)−. Anal. calcd. for C19H17N3O3S: C, 62.11; H, 4.66; N, 11.43. Found: C, 62.16; H, 4.76; N, 11.19.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][C:11]2[CH:12]=[C:13]([NH:17][C:18]3[C:23]([Cl:24])=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][CH:7]=1.Cl>COCCO.C(O)C>[Cl:24][C:23]1[CH:22]=[N:21][C:20]2[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH:3]=3)[CH2:8][CH2:9][CH2:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]=1[N:19]=2)[CH:14]=[CH:15][CH:16]=3
Reactant: Nc1cccc(CCCc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Agent: Cl
Solvent: CCO
Solvent: COCCO
Product: Clc1cnc2nc1Nc1cccc(c1)CCCc1cccc(c1)N2
Temperature: 150 °C
Yield: 38.6 %

Procedure:
N-{3-[3-(3-Aminophenyl)propyl]phenyl}-2,5-dichloropyrimidin-4-amine (20 mg, 0.05 mmol) was stirred in 2-methoxyethanol (1.0 mL) and a solution of hydrogen chloride in ethanol (0.75 mL, 3.5 M). The mixture was heated to 150° C. for 30 minutes in a microwave. Purification by preparative LCMS gave the desired product (6.5 mg, 37%). LCMS for C19H18ClN4 (M+H)+: m/z=337.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[C:10](=[O:13])([O-])[OH:11].[Cs+].[CH3:15][N:16]1[C:20](=[O:21])[CH2:19]CC1>>[CH3:9][O:8][C:1](/[CH:2]=[CH:3]/[C:4]([O:6][CH2:19][C:20]([NH:16][CH2:15][C:10]([OH:11])=[O:13])=[O:21])=[O:5])=[O:7]
Reactant: CN1CCCC1=O
Reactant: COC(=O)/C=C/C(=O)O
Reactant: O=C([O-])O
Agent: [Cs+]
Product: COC(=O)/C=C/C(=O)OCC(=O)NCC(=O)O
Yield: 12 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (MHF) (0.68 g, 5.26 mmol) dissolved in NMP was reacted at ca. 55° C. with tert-butyl 2-(2-chloroacetylamino) acetate (0.91 g, 4.38 mmol) in the presence of CsHCO3 (1.19 g, 6.13 mmol) of the tert-butyl-protected intermediate and then purified by silica gel column chromatography (Biotage) using a mixture of ethyl acetate (EtOAc) and hexanes (1:2 to 2:3 to 1:1) as eluent. The purified product was treated with 50% trifluoroacetic acid (TFA) in dichloromethane (DCM). Removal of solvents afforded 0.13 g (12% yield) of the title compound (6). 1H NMR (CD3OD, 400 MHz): δ 6.96-6.93 (m, 2H), 4.74 (s, 2H), 3.98-3.95 (m, 2H), 3.81 (s, 3H). MS (ESI): m/z 246.00 (M+H)+, 244.02 (M−H)−.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([CH3:16])=[CH2:15])=O)(C)(C)C.O1CCOCC1.[ClH:23]>C(Cl)Cl>[ClH:23].[NH2:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([CH3:16])=[CH2:15]
Reactant: C=C(C)c1sccc1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C=C(C)c1sccc1N
Temperature: 0 °C

Procedure:
A solution containing 0.3 g of 3-(t-butoxycarbonylamino)-2-isopropenylthiophene in 7 ml of methylene chloride was cooled to 0° C., and 3 ml of a 4N-hydrogen chloride dioxane solution was added. The mixture obtained was used as intact for the next reaction.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]1([CH3:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH:18]([OH:21])(C)C.O.C[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[C:11]1([C:17]2[CH:24]=[CH:25][C:26]([CH2:18][OH:21])=[CH:27][CH:28]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)O
Reactant: Cc1ccccc1
Reactant: CCCCCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Product: OCc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
At -60° C., 20 ml. of a 20% solution of diisobutyl-aluminum hydride in hexane was added to a solution of 2 g. of 2-[3α-p-biphenyl-carbonyloxy-5α-hydroxy-2β-(3,3-ethylenedioxy-octan-1-yl)-cyclopent-1α-yl]-acetic acid γ-lactone in 60 ml. of toluene. After 20 minutes, 3 ml. of isopropyl alcohol was added dropwise to the reaction mixture, the latter was heated to room temperature, mixed with 10 ml. of water, and agitated for 10 minutes. The mixture was thereafter extracted with ethyl acetate and the ethyl acetate solution was shaken with NaCl solution, dried over magnesium sulfate, and evaporated to dryness under vacuum. The residue was filtered with ether over 45 g. of silica gel, the elution yielding first p-phenylbenzyl alcohol. With ether/dioxane (9 + 1), 1.05 g. of 2-[3α,5α-dihydroxy-2β-(3,3-ethylenedioxy-octan-1-yl)-cyclopent-1α-yl]-acetaldehyde γ-hemiacetal was obtained as a colorless oil. The thin-layer chromatogram (ether/dioxane 2 + 1) showed a uniform spot having an Rf value of 0.23.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([C:11]1[N:15]2[C:16]3[C:21]([NH:22][C:23](=[O:24])[C:14]2=[N:13][N:12]=1)=[CH:20][C:19]([C:25]([F:28])([F:27])[F:26])=[CH:18][CH:17]=3)[CH3:10])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[Br:29]Br>S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[Ag+2]>[Br:29][C:18]1[CH:17]=[C:16]2[C:21]([NH:22][C:23](=[O:24])[C:14]3[N:15]2[C:11]([CH:9]([P:4]([O:3][CH2:1][CH3:2])([O:6][CH2:7][CH3:8])=[O:5])[CH3:10])=[N:12][N:13]=3)=[CH:20][C:19]=1[C:25]([F:27])([F:26])[F:28]
Reactant: CCOP(=O)(OCC)C(C)c1nnc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n12
Reactant: BrBr
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Product: CCOP(=O)(OCC)C(C)c1nnc2c(=O)[nH]c3cc(C(F)(F)F)c(Br)cc3n12
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
A mixture of 1-[1-(diethoxyphosphoryl)ethyl]-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one (811 mg, 1.94 mmol), silver sulfate (605 mg, 1.94 mmol) and bromine (100 μl, 1.94 mmol) in 5 ml of conc. sulfuric acid was stirred overnight at room temperature. The mixture was filtered and the filtrate was added dropwise to 100 ml of ice/water. The resulting precipitate was isolated by filtration, washed with water and dried to give 514 mg (53%) of the title compound; m.p.>200° C., decomp. 1H-NMR (DMSO-d6): δ 1.12 (t, 3H), 1.18 (t, 3H), 1.74 (dd, 3H), 3.95 (quint, 2H), 4.07 (quint, 2H), 4.78 (dq, 1H), 7.81 (s, 1H), 8.59 (s, 1H), 12.35 (s, 1H).