Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[C:10]([CH3:23])=[C:11]([CH3:22])[C:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14](=O)[C:13]=2[C:20]=1[CH3:21].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:7][O:8][C:9]1[C:10]([CH3:23])=[C:11]([CH3:22])[C:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14](=[CH2:1])[C:13]=2[C:20]=1[CH3:21]
Reactant: COc1c(C)c(C)c2c(c1C)C(=O)C(C)(C)O2
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C1c2c(C)c(OC)c(C)c(C)c2OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
Potassium tert-butoxide (4 g, 35.5 mmol) is added portionwise at 0° C. and under nitrogen to a suspension of methyltriphenylphosphonium bromide (12.7 g, 35.5 mmol) in dry tetrahydrofuran (120 mL) and the reaction mixture is stirred for 1 hr at room temperature. The 5-methoxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-one (5.55 g, 23.7 mmol) in dry tetrahydrofuran (40 mL) is added dropwise at 0° C. to the yellow suspension and the reaction is stirred overnight at room temperature. Water (50 mL) is carefully added and most of the solvent is evaporated under reduced pressure. The residue is taken in ethyl acetate (200 mL), washed with brine, dried (magnesium sulfate) and evaporated to dryness. Purification through a small pad of silica gel using dichloromethane as a solvent gave 5.47 g 5-methoxy-3-methylene-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran (99%) as a yellow oil. Rf=0.48 (heptane/ethyl acetate 90:10).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[C:8]([NH2:13])=[N:9][CH:10]=[CH:11][CH:12]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[C:6]([C:7]1[C:8]([NH2:13])=[N:9][CH:10]=[CH:11][CH:12]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1cccnc1N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cccnc1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.8 %

Procedure:
To a solution of 3-trimethylsilanylethynyl-pyridin-2-ylamine (28.1 g, 148 mmol.) described in Manufacturing Example 1-2-2 in tetrahydrofuran (300 mL) was added tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 20 mL, 20 mmol), which was stirred for 15 minutes at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate 4 times. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel chromatography (heptane:ethyl acetate=1:1 then 1:2) to obtain the title compound (16.4 g, 93.7%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[N:9]=[CH:10][C:11]3[CH:16]=[C:15]([CH:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])O)[S:14][C:12]=3[N:13]=2)[CH2:3][CH2:2]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[O:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]2[N:9]=[CH:10][C:11]3[CH:16]=[C:15]([CH2:17][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[S:14][C:12]=3[N:13]=2)[CH2:5][CH2:6]1
Reactant: OC(c1cc2cnc(NC3CCOCC3)nc2s1)c1ccccc1F
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccccc1Cc1cc2cnc(NC3CCOCC3)nc2s1

Procedure:
The alcohol (140 mg) obtained in Example 2A was stirred with triethylsilane (1.0 mL) and trifluoroacetic acid (1.5 mL) in dichloromethane (5 mL) for 4 hours. The solvents were removed. The residue was diluted with toluene (5 mL) and then concentrated. This dilution-concentration process was repeated three times. Purification with preparative TLC (50% EtOAc/Hexanes) gave the final product. It was converted to the hydrochloride salt with 1N HCl in ether to yield 65 mg of the salt. MP: 217-219° C. MS: 344 (M+H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[CH:14]1([CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:17][CH2:16][CH2:15]1>>[CH:14]1([CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:5](=[O:7])[C:4]4[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=4[C:2]([F:1])([F:13])[F:12])[CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:17][CH2:16][CH2:15]1
Reactant: O=C(NCC1CCC1)c1ccc(N2CCNCC2)nn1
Reactant: O=C(O)c1ccccc1C(F)(F)F
Product: O=C(NCC1CCC1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 2-trifluoromethylbenzoic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid cyclobutylmethylamide, the title compound was obtained as a white powder (45.0% yield). 1H NMR (CDCl3) δ 8.04, 7.83, 7.72, 7.64-7.51, 7.32, 7.00, 4.10-4.01, 3.90-3.66, 3.49-3.27, 2.63-2.47, 2.11-1.67. 13C NMR (CDCl3) δ 167.7, 162.9, 159.8, 145.4, 134.2, 132.4, 129.6, 127.4, 126.9, 126.8, 125.4, 121.8, 112.8, 46.4, 44.6, 41.2, 35.1, 25.7, 18.3. MS (ES+) m/z 448 (M+1).
Reaction SMILES: [CH3:1][CH:2]([NH2:5])[C:3]#[CH:4].Cl.CCN(CC)CC.[Cl:14][C:15]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>C1COCC1>[CH3:1][CH:2]([NH:5][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[C:23]([C:24]([F:25])([F:26])[F:27])[C:15]=1[Cl:14])[C:3]#[CH:4]
Reactant: C#CC(C)N
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CC(C)NC(=O)c1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the suspension of but-3-yn-2-amine.HCl salt (10 g, 94.7 mmol, 1.0 equiv.) in THF (150 mL), Et3N (27.5 mL, 199 mmol, 2.1 equiv.) and (2-chloro-3-(trifluoromethyl)benzoyl chloride (23.1 g, 94.7 mmol, 1.0 equiv.) were added sequentially at 0° C. The reaction mixture was then stirred at room temperature for 16 hours. The precipitate was filtered off and washed with THF. The filtrate solution was concentrated and re-dissolved in EtOAc. The EtOAc solution was washed with saturated NaHCO3 and brine, dried over Na2SO4, concentrated. Trituration of the crude product from EtOAc/hexanes afforded Intermediate 233: (23 g, 83.8 mmol, 88%) as a white solid. 1H NMR (600 MHz, CDCl3) δ 7.82-7.75 (dd, J=7.9, 1.6 Hz, 1H), 7.73-7.66 (dd, J=7.7, 1.6 Hz, 1H), 7.48-7.41 (dd, J=8.2, 7.3 Hz, 1H), 6.35-6.02 (d, J=7.9 Hz, 1H), 5.09-4.90 (dqd, J=8.1, 6.9, 2.3 Hz, 1H), 2.47-2.20 (m, 1H), 1.58-1.54 (d, J=6.9 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 164.7, 137.9, 132.5, 129.4 (q, JC—F=31.5 Hz), 129.1, 129.0 (q, JC—F=5.2 Hz), 127.1, 122.5 (q, JC—F=273.4 Hz), 83.2, 71.2, 37.8, 22.1. HRMS-ESI (m/z): [M+H]+ calcd for C12H10ClF3NO, 276.0398. found, 276.0390.
Reaction SMILES: [CH3:1][S:2]([O-:4])=[O:3].[Na+].Br[CH2:7][C:8]1[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=1>C(O)C>[CH3:1][S:2]([CH2:7][C:8]1[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=1)(=[O:4])=[O:3]
Reactant: COC(=O)c1ccc(CBr)s1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccc(CS(C)(=O)=O)s1
Yield: 29.4 %

Procedure:
Methyl 5-(methylsulfonylmethyl)thien-2-ylcarboxylate may be obtained in the following manner: 31.7 g of sodium methyl sulfinate are added to a solution of 73 g of methyl 5-(bromomethyl)thien-2-ylcarboxylate in 150 cm3 of ethanol and the suspension obtained is heated under reflux for 7 hours. The reaction medium is then concentrated to dryness under reduced pressure (2.7 kPa). The residue is extracted with four times 500 cm3 of ethyl acetate, the combined organic phases are washed successively with 250 cm3 of distilled water and 250 cm3 of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and incompletely concentrated under reduced pressure. The solid which appears is isolated by filtration, rinsed with three times 25 cm3 of ice-cold ethyl acetate and provides 21.4 g of methyl 5-(methylsulfonylmethyl)thien-2-ylcarboxylate in the form of a cream-colored powder.
Reaction SMILES: [CH:1]1[C:14]2[S:13](=[O:16])(=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li:21])CCC>O1CCCC1.CCCCCC>[Li:21][C:1]1[C:14]2[S:13](=[O:15])(=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=S1(=O)c2ccccc2Oc2ccccc21
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: [Li]c1cccc2c1S(=O)(=O)c1ccccc1O2
Temperature: -40 °C

Procedure:
A mixture of phenoxathiin 10,10-dioxide (50.5 g) in dry tetrahydrofuran (500 mL) under nitrogen was cooled in an acetone/dry ice bath. To this slurry was added a 1.6 M solution of n-butyllithium in hexane (144 mL) at a rate which maintained the reaction temperature at -40° C., resulting after 30-45 min. in an orange solution of 1-lithiophenoxathiin 10,10-dioxide. To this solution was added ethyl iodide (35 mL), after which the reaction mixture was allowed to warm to room temperature. After about 3-4 hr the yellow solution was partially evaporated under reduced pressure and was then partitioned between methylene chloride and water. The methylene chloride phase was washed with dilute hydrochloric acid, dried over anhydrous magnesium sulfate and evaporated to a yellow residue which was purified by column chromatography on Silica Gel 60 (E. Merck, Darmstadt, Germany) eluting with toluene. The desired fractions were combined and evaporated, and the residue was crystallized from ethyl acetate/pentane to give 1-ethylphenoxathiin 10,10-dioxide, mp. 112°-114° C. (del. 102°-104° C.).
Reaction SMILES: C[CH:2]([C@H:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5](=[O:7])[CH3:6])C.[BH4-].[Na+].[CH3:18]O>>[OH:7][CH:5]([CH3:6])[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])([CH3:2])[CH3:18]
Reactant: CC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)C(C)(C)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of (S)-tert-butyl 2-methyl-4-oxopentan-3-ylcarbamate (2.65 g, 12.31 mmol) in MeOH (30 mL) at 0° C. was added portion wise NaBH4 (0.931 g, 24.62 mmol). Cold bath was removed and the reaction was stirred for 1 hour. HCl solution (1 M, 0.3 mL) was then added cautiously to quench the reaction. The reaction mixture was then concentrated and diluted with EtOAc (50 mL) and water (10 mL). The phases were separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organics were then dried (Na2SO4) and concentrated. The residue was purified via silica gel flash chromatography (10-50% EtOAc-Hexanes) to afford the desired product as a white solid (2.05 g). LCMS m/z 240.2 (M+Na)+, Rt 0.69 min.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=O)[CH2:2]1.[CH3:12][Mg]Cl.[BH4-].[Na+].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:12][CH:3]1[NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2]1
Reactant: O=C1COc2ccccc2N1
Reactant: C[Mg]Cl
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1COc2ccccc2N1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 46 %

Procedure:
To a solution of 2H-1,4-benzoxazin-3(4H)-one (2.00 g, 13.4 mmol) in tetrahydrofuran (20 ml) was added dropwise at 5° C. a THF solution of methylmagnesium chloride (17.9 ml, 3 M, 53.7 mmol) and the reaction mixture was then stirred at 50° C. for 90 min. The reaction mixture was then cooled to 5° C. and quenched by dropwise addition of 20 ml acetic acid. Sodium borohydride (1.27 g, 33.5 mmol) was then added portionwise and the mixture was stirred at room temperature overnight. The resulting suspension was then cooled to 0° C. and 3 N aq. sodium hydroxide solution was added dropwise until the mixture was pH 10. Ethyl acetate was then added, the phases separated, and the organic phase dried over sodium sulphate and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluant: heptane/ethyl acetate gradient) to yield the title compound as a colorless oil (0.92 g, 46%); MS (ISP): 150.3 ([M+H]+).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([S:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[C:21]1[N:33]([CH3:34])[C:24]2=[N:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=[C:23]2[N:22]=1)[CH3:13].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:12]([S:14]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[C:21]1[N:33]([CH3:34])[C:24]2=[N:25][CH:26]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:28]=[C:23]2[N:22]=1)=[O:6])[CH3:13]
Reactant: CCSc1ccncc1-c1nc2cc(C(F)(F)F)cnc2n1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)c1ccncc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
448 mg of 3-chloroperoxybenzoic acid (purity of 65% or more) was added to a mixture of 420 mg of 2-(4-ethylsulfanylpyridin-3-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine and 9 ml of chloroform under ice cooling. The mixture was stirred at 0° C. for 1 hour, then stirred at room temperature for 30 minutes. A saturated aqueous sodium bicarbonate solution was poured to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 215 mg of 2-(4-ethylsulfinylpyridin-3-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as Compound of Present Invention 10) and 211 mg of 2-(4-ethylsulfonylpyridin-3-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as Compound of Present Invention 11).
Reaction SMILES: [H-].[Na+].[CH:3](=[C:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[N:16][OH:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:18][CH:19]([CH2:22][N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1)[CH2:20]Cl>>[CH:3](=[C:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[N:16][O:17][CH2:18][CH:19]([CH3:20])[CH2:22][N:23]1[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(CCl)CN1CCN(C)CC1
Reactant: ON=C1CCCCC1=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CC(CON=C1CCCCC1=Cc1ccccc1)CN1CCN(C)CC1

Procedure:
On starting from 2.4 g (0.1 moles) of sodium hydride, 20.1 g (0.1 moles) of 2-benzalcyclohexanone oxime and 20.76 g (0.11 moles) of 2-methyl-3-(4'-methylpiperazinyl)-propyl chloride, one proceeds in the way specified in Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[O:5][C:6]=1Br.Cl[Zn][CH3:14]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[O:5][C:6]=1[CH3:14]
Reactant: COC(=O)c1cc(Br)c(Br)o1
Reactant: C[Zn]Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)c(C)o1
Reaction time: 10 h
Yield: 72 %

Procedure:
To a solution of methyl 4,5-dibromo-2-furancarboxylate (4.5 g, 15.85 mmol) and BIS(TRIPHENYLPHOSPHINE)PALLADIUM(II) CHLORIDE (0.38 g, 0.541 mmol) in THF (100 mL) at RT was added chloro(methyl)zinc (15 mL, 30 mmol) dropwise. After stirring for 10 h, the reaction was quenched with NH4Cl (sat'd) (50 mL). The mixture was extracted with EtOAc (50 mL×3), and the collected organic layers were dried over MgSO4. Solvent was removed under vacuum and the resulting residue was purified via column chromatography (silica, EtOAc/Hex 10-20%) to give the title compound (2.5 g, 72%) as a white solid: LC-MS (ES) m/z 220 (M+H)+.
Reaction SMILES: [CH:1]([NH2:5])([CH2:3][CH3:4])[CH3:2].Br[CH:7]([CH2:9][CH2:10][CH3:11])[CH3:8].OS(O)(=O)=O.[OH-].[Na+]>C(O)C>[CH:1]([NH:5][CH:7]([CH2:9][CH2:10][CH3:11])[CH3:8])([CH2:3][CH3:4])[CH3:2]
Reactant: CCCC(C)Br
Reactant: CCC(C)N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCC(C)NC(C)CC
Yield: 55.3 %

Procedure:
Into a 150 ml flask, provided with a reflux condenser, were placed 14.6 g of monosec.butylamine dissolved in 15.5 ml of C2H5OH. Added thereto was 30 g of 2-bromo-pentane. This mass was then boiled to reflux temperature for 10-12 hours and thereafter cooled down and neutralized with dilute H2SO4. The whole was then evaporated to dryness. The residue thus obtained was treated with an excess of a 15% NaOH solution and extracted with 3 successive portions of ethyl ether. The ether extracts were then combined and washed with H2O, dried or anhydrous Na2SO4, filtered and the ether removed by evaporation. The residue was distilled under atmospheric pressure and the fraction was gathered which passed over at 160° - 161°C. 15.75 g of N-sec.butyl,N-sec.amylamine were obtained thereby. The picrate shows a melting point of from 61°-63°C (crystals from petroleum ether). The analysis of the picrate gave: calculated C = 48.58%, found C = 48.22%; calculated H = 6.50%, found H = 6.4%.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])C=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].[Cl-].[CH3:23][NH3+:24].C(O)(=O)C>C(OCC)(=O)C>[CH3:23][N:24]1[C:12](=[O:20])[CH2:13][CH2:14][C@@:15]2([CH3:16])[C:10]1=[CH:9][CH2:8][C@@H:7]1[C@@H:17]2[CH2:18][CH2:19][C@@:2]2([CH3:1])[C@H:6]1[CH2:5][CH2:4][C:3]2=[O:21]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[NH3+]
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@@]2(C)C1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Androst-4-ene-3,17-dione is oxidized into 5-oxo-4-nor-3,5-seco-androstane-5,17-dione as in Example 16A (seco-acid). The seco-acid (9.000 g, 31.423 mmol) is slurried with methylammonium chloride (19.5000 g, 288.80 mmol) into acetic acid (75 mL) and heated to reflux under an inert atmosphere. After 3 days, the reaction mixture is allowed to cool to room temperature and diluted with ethyl acetate (EtOAc, 500 mL). The organic solution is washed with water (3×200 mL), saturated aqueous NaHCO3 (2×200 mL) and brine (200 mL), then dried over magnesium sulfate (MgSO4), filtered, concentrated and purified by flash chromatography (1:1:2 EtOAc/CH2Cl2) to afford 4-methyl-4-aza-androst-5-ene-3,17-dione (aza-dione).
Reaction SMILES: CC1(C)[CH2:7][CH2:6][CH2:5][C:4](C)(C)[NH:3]1.C([Li])CCC.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([OH:24])=[O:23].O=C1CCN(C(OC(C)(C)C)=O)C1>CCCCCC.C1COCC1>[NH:3]1[CH2:4][CH2:5][C:6]2([C:18]3[C:17](=[N:16][CH:21]=[CH:20][CH:19]=3)[C:22](=[O:24])[O:23]2)[CH2:7]1
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: O=C(O)c1ccccn1
Agent: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1OC2(CCNC2)c2cccnc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2,2,6,6-tetramethyl-piperidine (0.820 mL, 0.00486 mol) in tetrahydrofuran (5 mL, 0.06 mol) at −75 Celsius was added to 1.600 M of n-butyllithium in hexane (4.05 mL). After the mixture was stirred for 15 min, a solution of 2-pyridinecarboxylic acid (199 mg, 0.00162 mmol) was added. The resulting mixture was stirred at −75 Celsius for 10 minutes, then at −20 Celsius for 30 minutes. A solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (250 mg, 0.0013 mol) in THF (2 mL) was then added to the above mixture. The reaction mixture continued to be stirred at −20 Celsius for 20 minutes, then was warmed up to r.t. and then stirred for additional 1 hour. The reaction mixture was quenched with water, then concentrated to remove THF, and then acidified to pH ˜1 using 6M aqueous HCl solution, and then stirred at r.t. overnight. The resulting mixture was extracted with methylene chloride. The aqueous layer was concentrated and the residue was directly purified by flash chromatography on silica gel column with 10% methanol in methylene chloride to give the desired compound. MS (ESI): 190.9 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:16]1(C)C=CC=CC=1.CO.C[Si](C=[N+]=[N-])(C)C>CCOCC>[CH3:16][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([O:14][CH3:15])[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=1[F:1]
Reactant: Cc1ccccc1
Reactant: COc1cc(C(=O)O)c(F)cc1[N+](=O)[O-]
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1cc(OC)c([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a round bottom flask, 2-fluoro-5-methoxy-4-nitro-benzoic acid (2.84 g, 0.0132 mol;), toluene (25 mL, 0.23 mol), methanol (5 mL, 0.1 mol;) were added. 2.00 M of trimethylsilyldiazomethane in ether (7.92 mL) was added drop wise at 5° C. The reaction was stirred at room temperature for 2 hours. The solvent was removed under vacuum to afford a yellow solid. The solid was triturated with 10% Et2O and hexane to give 2-fluoro-5-methoxy-4-nitro-benzoic acid methyl ester as an off white solid (2.84, 93%). 1H-NMR (DMSO-D6, 400 MHz): δ 8.06 (d, 1H), 7.70 (d, 1H). 4.14 (s, 3H), 3.91 (s, 3H).
Reaction SMILES: C([O-])(=[O:3])C.[NH4+].Cl[C:7]1[C:16]([C:17]#[N:18])=[C:15]([Cl:19])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:20])[CH:13]=2)[N:8]=1>C(O)(=O)C>[Cl:19][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:20])[CH:13]=2)[NH:8][C:7](=[O:3])[C:16]=1[C:17]#[N:18]
Reactant: Cc1ccc2nc(Cl)c(C#N)c(Cl)c2c1
Reactant: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: Cc1ccc2[nH]c(=O)c(C#N)c(Cl)c2c1
Temperature: 140 °C
Yield: 69 %

Procedure:
Ammonium acetate was added to a suspension of Compound 105 (7.1 g, 29.95 mmol) in glacial acetic acid and heated at 140° C. for 4 h. The solution was cooled and poured into ice water. The solids formed were filtered, washed by water, and dried under vacuum to yield 4.5 g (69%) of white solids. M.P. 264° C. 1H NMR (DMSO-d6): δ 2.32 (s, 3H), 7.34 (d, J=8.4 Hz, 1H), 7.63 (dd, J=1.5, 8.4 Hz, 1H), 7.75 (s, 1H). EIMS m/z 219 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[CH:4][N:3]=1.[CH3:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH2:17][NH2:18]>C(O)C.C(OCC)(=O)C>[CH3:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH2:17][NH:18][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cc(F)cnc1Cl
Reactant: CC(C)(C)CCN
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(F)cnc1NCCC(C)(C)C
Temperature: 150 °C

Procedure:
A solution of ethyl 2-chloro-5-fluoro-3-pyridinecarboxylate (0.300 g, 1.47 mmol) in ethanol (3.0 mL) was treated with (3,3-dimethylbutyl)amine (0.210 mL, 1.58 mmol). The mixture was heated to 150° C. for 0.5 h in a Biotage Initiator microwave synthesizer. The solution was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic portion was dried over magnesium sulfate, filtered, and concentrated in vacuo. The title compound was obtained as an amber oil (0.347 g, 88%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 6.61 (d, J=3.0 Hz, 1H), 6.30 (dd, J=8.8, 3.0 Hz, 1H), 6.24 (br. s., 1H), 2.80 (q, J=7.1 Hz, 2H), 1.88-1.99 (m, 2H), −0.02-0.09 (m, 2H), −0.14 (t, J=7.2 Hz, 3H), −0.53 (s, 9H). MS(ES+) m/e 269 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:15])=[CH:9][C:8]=2[CH:16]=1)([O-:3])=[O:2].[Br:17]N1C(=O)CCC1=O.O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH2:15][Br:17])=[CH:9][C:8]=2[CH:16]=1)([O-:3])=[O:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1=Cc2cc([N+](=O)[O-])ccc2OC1(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2C=C1CBr
Yield: 90.5 %

Procedure:
A solution of 6-nitro-2,2,3-trimethyl-2H-1-benzopyran (33.0 g, 0.151 mol) and benzoyl peroxide (0.020 g) in carbon tetrachloride (330 ml) were heated to 50° C. and N-bromo succinimide (26.8 g, 0.15 mol) was added. The mixture was heated at reflux for eighteen hours and then water and aqueous ferrous sulfate were added. The organic phase was separated and evaporated under reduced pressure, and the residue washed with pentane to give 40.45 g of 6-nitro-2,2-dimethyl-3-bromomethyl-2H-1-benzopyran, m.p. 107° C.