Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:14][CH2:15]Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[C:17]([NH:25][CH:26]([P:36]([CH2:39][C:40]([N:42]1[CH2:56][CH2:55][CH2:54][C@H:43]1[C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])=[O:41])([OH:38])=[O:37])[CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O.C(OCC)(=O)C>[C:17]([NH:25][CH:26]([P:36]([CH2:39][C:40]([N:42]1[CH2:56][CH2:55][CH2:54][C@H:43]1[C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])=[O:41])([O:38][CH2:15][O:14][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:37])[CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(NC(CCCc1ccccc1)P(=O)(O)CC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccccc1
Reactant: CC(C)(C)C(=O)OCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCOP(=O)(CC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C(CCCc1ccccc1)NC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A equimolar mixture of triethylamine and chloromethyl pivalate are added to a solution of (±)-1-[[[1-(benzoylamino)-4-phenylbutyl]hydroxyphosphinyl]acetyl]-L-proline, phenylmethyl ester, prepared for example as set forth in Example 20 (d), in dimethylformamide under an argon atmosphere. The mixture is stirred for several hours at room temperature, diluted with ethyl acetate, washed with water, brine, dried (MgSO4), and evaporated. The crude product is chromatographed to give (±)-1-[[[1-(benzoylamino)-4-phenylbutyl][(2,2-dimethyl-1-oxopropoxy)methoxy]phosphinyl]acetyl]-L-proline, phenylmethyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1.[CH3:8][CH2:9][CH2:10][CH:11]=[O:12].C1CCCCC1>O.C(Cl)(Cl)=O.[Rh]>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH:11]=[O:12].[CH3:8][CH2:9][CH2:10][CH:11]=[O:12]
Reactant: CC1=CCCCC1
Agent: [Rh]
Agent: O=C(Cl)Cl
Solvent: CCCC=O
Solvent: C1CCCCC1
Solvent: O
Product: CC1CCCCC1C=O
Temperature: 145 °C
Reaction time: 2 h

Procedure:
100 g of limonenemonoaldehyde (4-methylcyclohex-3-ene-β-methylpropanal), 300 ml of cyclohexane and 0.1 g of dimeric rhodium carbonyl-chloride were introduced into a stainless steel autoclave of 700 ml capacity and were heated to 145° C. under water gas (CO/H2), while stirring. The pressure was kept between 200 and 220 bar by regularly forcing in more water gas. After 2 hours, the pressure remained constant. The autoclave was cooled and let down and the reaction mixture was separated into its components by thin film distillation. 75 g of limonenedialdehyde (4-methyl-3-formylcyclohexane-β-methylpropanal) were obtained at 150° C. under 0.05 mbar, corresponding to a selectivity of 75%.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:18])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].B1C2CCCC1CCC2.[OH-:28].[Na+].OO>C1COCC1>[OH:28][CH2:3][CH2:2][CH2:1][O:4][C:5]1([CH3:18])[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]1
Reactant: C=CCOC1(C)CCN(C(=O)OC(C)(C)C)CC1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C)(OCCCO)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.2 %

Procedure:
To a solution of tert-butyl 4-(allyloxy)-4-methylpiperidine-1-carboxylate (8.4 g, 32.9 mmol) in THF (200 mL) at room temp was added 0.5 M solution of 9-BBN (132 mL, 65.8 mmol) and the resulting mixture was stirred at room temp for 16 h. Mixture was then cooled in an ice bath and 1N NaOH (164 mL, 164 mmol) followed by 30% H2O2 (30.2 mL, 296 mmol) were added and the mixture was stirred for 1 h. Mixture was then extracted with ethyl acetate (250 mL), washed with water (100 mL), brine (100 mL), dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage (5-80% EtOAc/Hexane) to afford tert-butyl 4-(3-hydroxypropoxy)-4-methylpiperidine-1-carboxylate (6.4 g, 23.41 mmol, 71.2% yield) as colorless oil. 1H NMR (500 MHz, CDCl3) δ 3.84-3.79 (m, 2H), 3.74 (dt, J=13.4, 3.7 Hz, 2H), 3.57 (t, J=5.6 Hz, 2H), 3.19-3.06 (m, 2H), 1.85 (quin, J=5.6 Hz, 2H), 1.75 (d, J=13.1 Hz, 2H), 1.48 (s, 9H), 1.47-1.41 (m, 2H), 1.21 (s, 3H). LCMS (M+Na)=296.7.
Reaction SMILES: C([O:5][C:6](=[O:45])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C@H:16]2[C@H:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=3[F:28])[C@:19]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])([C:29]#[N:30])[C@H:18]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[NH:17]2)=[O:15])=[CH:9][C:8]=1[F:44])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:27][C:23]1[C:22]([F:28])=[C:21]([C@@H:20]2[C@:19]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])([C:29]#[N:30])[C@H:18]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[NH:17][C@H:16]2[C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:45])=[O:5])=[C:8]([F:44])[CH:9]=2)=[O:15])[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)OC(C)(C)C)c(F)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)c(F)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F

Procedure:
rac 4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-fluoro-benzoic acid tert-butyl ester (35 mg, 0.053 mmol) was treated with 50% TFA/methylene chloride (10 mL) overnight. Removal of solvent and treating the residue with acetonitrile and water gave a white solid after filtration and dying. 29 mg.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:9]([CH3:11])[CH:10]=2)[CH2:5][CH2:6][N:7]=1.[BH4-].[Na+].[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24]>CO.O.C(O)C>[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24].[CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]2[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:9]([CH3:11])[CH:10]=[C:3]12
Reactant: CC1=NCCn2c1cc(C)c2-c1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CO
Product: Cc1cc2n(c1-c1ccccc1)CCNC2C
Yield: 63 %

Procedure:
3,4-Dihydro-1,7-dimethyl-6-phenylpyrrolo[1,2-a]pyrazine (0.6 g) was dissolved in a mixture of 40 ml of methanol and 4 ml of water under argon. The solution was treated portionwise with 0.3 g of sodium borohydride while stirring and stirred at room temperature overnight. Thereafter, the methanol was removed in a vacuum, the residue was taken up in 50 ml of methylene chloride and washed with 50 ml of 10% ammonia solution. The phases were separated and the aqueous phase was extracted twice with 30 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The crude product, 0.6 g of yellow, amorphous solid, was dissolved in a 25-fold amount of ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There was obtained 0.5 g (63%) of 1,2,3,4-tetrahydro-1,7-dimethyl-6-phenylpyrrolo[1,2-a]pyrazine fumarate (2:1); m.pt.: 152°-154° C. (dec.).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[C:12](=[S:14])=[S:13].[OH-].[K+].[CH3:17]I>CS(C)=O>[CH3:17][S:13][C:12](=[S:14])[O:3][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([OH:11])=[O:10]
Reactant: O=C(O)C(O)c1ccccc1
Reactant: CI
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CSC(=S)OC(C(=O)O)c1ccccc1

Procedure:
4.56 g (30 mM) of DL-mandelic acid are dissolved in 100 ml. of carbon disulfide and 3.37 g. (60 mM) of pulverized potassium hydroxide are added all at once. Absolute dimethylsulfoxide is then added with stirring until a clear solution is obtained. The whole is stirred for 1 hour and then 4.26 g (30 mM) of methyl iodide are added. After 4 hours the carbon disulfide is removed in vacuum and the oily residue is dissolved in 200 ml. of water. The aqueous solution is extracted three times with 50 ml. of ether. After cooling the aqueous phase to 5°, it is acidified with 2N hydrochloric acid and extracted with ether. From the ether, 3.1 g. of crude DL-α-[(methylthio)thioxomethoxy]benzene acetic acid is obtained. Recrystallization from benzol/cyclohexane yields 2.7 g., m.p. 109°-110°.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:9]1[CH:18]=[C:17]([CH2:19][CH3:20])[CH:16]=[CH:15][C:10]=1[C:11](OC)=[O:12])[CH3:8]>C1COCC1>[CH2:7]([C:9]1[CH:18]=[C:17]([CH2:19][CH3:20])[CH:16]=[CH:15][C:10]=1[CH2:11][OH:12])[CH3:8]
Reactant: CCc1ccc(C(=O)OC)c(CC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1ccc(CO)c(CC)c1
Yield: 101.5 %

Procedure:
To a suspension of lithium aluminum hydride (0.47 g, 11.8 mmol) in anhydrous THF (20 mL) at room temperature under nitrogen was added a solution of methyl 2,4-diethylbenzoate (1.5 g, 7.8 mmol) in THF (15 mL) with stirring over a period of −5 min. The resulting mixture was stirred at room temperature for 60 min and was then quenched by slow addition of ethyl acetate (until bubbling stopped). The mixture was partitioned between ethyl acetate and 1N HCl (aq). The aqueous layer was separated and extracted with ethyl acetate. Organic layers were combined, dried (MgSO4), and evaporated to dryness to give 1.3 g of the desired alcohol as a clear oil (yield of 100%). 1H NMR (300 MHz, CDCl3) δ1.13 (t, 3H), 1.17 (t, 3H), 2.58 (q, 2H), 2.61 (q, 2H), 4.43 (d, 2H), 5.02 (t, 1H), 7.05-7.11 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].S(Cl)([Cl:23])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][Cl:23])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18]
Reactant: OCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)c1cc(Oc2ccc(CCl)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
To the solution of (4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)methanol (3 g, 9.91 mmol) in DCM (90 mL), was added thionyl chloride (7.5 mL, 103 mmol) dropwise. The mixture was stirred at room temperature for 1.5 h. After removing the solvent, the residue was dissolved in DCM, then washed with water twice, dried over Na2SO4. Concentration in vacuo afforded the title compound (2.8 g, 88% yield) as light brown oil. LCMS: rt=4.14 min
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:13])#[N:2].[SH2:14]>N1C=CC=CC=1.C(N(CC)CC)C>[C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:13])(=[S:14])[NH2:2]
Reactant: N#Cc1cccc2c1CCCC2=O
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC(=S)c1cccc2c1CCCC2=O

Procedure:
Analogously to Example 29a), 10.6 g (62 mmol) of 5-cyano-l-tetralone in 200 ml of pyridine and 8.6 ml of triethylamine are treated with hydrogen sulfide and worked up. There is thus obtained the title compound in the form of yellow crystals, m.p. 200°-205°.
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([C:10]([OH:12])=[O:11])[NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:15])=O.[CH3:17]O>>[ClH:15].[CH3:17][O:11][C:10](=[O:12])[C@H:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[NH2:9]
Reactant: N[C@@H](CC1CCCCC1)C(=O)O
Reactant: O=S(Cl)Cl
Reactant: CO
Product: COC(=O)[C@@H](N)CC1CCCCC1
Product: Cl
Yield: 83.9 %

Procedure:
This was synthesised according to Standard Procedure 1, using 3-cyclohexyl-L-alanine (3.0 g, 17.5 mmol), methanol (30 ml), and thionyl chloride (2.56 ml, 35 mmol). The product was isolated as a white solid (3.23 g, 83.9%).
Reaction SMILES: C(O[C:4]([C:6]1[C:21](=[O:22])[N:20]([CH2:23][CH2:24][O:25][CH3:26])[C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:13][C:8]=2[C:7]=1[OH:27])=[O:5])C.[CH3:28][O:29][CH2:30][CH2:31][NH2:32]>C(O)C>[OH:27][C:7]1[C:8]2[CH:13]=[N:12][C:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[N:10][C:9]=2[N:32]([CH2:31][CH2:30][O:29][CH3:28])[C:4](=[O:5])[C:6]=1[C:21]([NH:20][CH2:23][CH2:24][O:25][CH3:26])=[O:22]
Reactant: CCOC(=O)c1c(O)c2cnc(-c3ccccc3)nc2n(CCOC)c1=O
Reactant: COCCN
Solvent: CCO
Product: COCCNC(=O)c1c(O)c2cnc(-c3ccccc3)nc2n(CCOC)c1=O

Procedure:
To 1.0 g. (0.0027 mole) of 7,8-dihydro-5-hydroxy-8-(2-methoxyethyl)-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (prepared as in Example 9) was added 0.4 g. (0.0054 mole) of 2-methoxyethylamine in 25 ml. of ethanol and this was heated at reflux for 4 hours. The reaction was then filtered and chilled and the filtrate gave up a solid that was collected on a suction filter and rinsed with petroleum ether. No further purification was necessary--m.p. 150°-154° C.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[OH:25]>O>[C:1]1([S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]3)=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCc2cc(OCCCCSc3ccccc3)ccc2N1
Reactant: CO
Solvent: O
Product: O=C1CCc2cc(OCCCCS(=O)c3ccccc3)ccc2N1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1.6 gm of 6-(4-phenylmercapto-butoxy)-3,4-dihydro-carbostyril were dissolved in 50 ml of methanol, and 0.9 gm of N-bromosuccininimide were added. After stirring for 15 hours at room temperature, the mixture was diluted with 500 ml of hot water (80° C.) and decanted from the initially oily precipitate which gradually crystallized. After recrystallization from xylene, white crystals with a melting point of 144° to 145° C. were obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH:11]3[CH3:23])=[CH:7][CH:8]=[CH:9][C:2]1=2.FC(F)(F)C(O)=O.C(Cl)[Cl:32]>>[ClH:32].[ClH:32].[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH:11]3[CH3:23])=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1c1cccc2sccc12
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CNCCN1c1cccc2sccc12
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.22 g (3.7 mmol) of tert-butyl 4-benzo[b]thiophen-4-yl-3-methylpiperazin-1-carboxylate in methylene chloride (12 ml) was added to trifluoroacetic acid (6 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, then an aqueous solution of 5% potassium carbonate was added to the residue and the resulting mixture was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. Concentrated hydrochloric acid (6 ml) and methanol (10 ml) were added to the residue and the resulting mixture was concentrated under reduced pressure. The residue was recrystallized from acetonitrile to obtain 1-benzo[b]thiophen-4-yl-2-methylpiperazine dihydrochloride (0.98 g) as light brown powder.
Reaction SMILES: CON(C)[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[CH2:13]([Mg]Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[C:14]1([CH2:13][C:4]([C:5]2[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=2)=[O:11])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CON(C)C(=O)c1ccncc1
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)c1ccncc1
Reaction time: 2 h
Yield: 10.1 %

Procedure:
To a solution of N-methoxy-N-methylisonicotinamide (500 mg, 3.0 mmol) in anhydrous THF (10 mL) was added benzylmagnesium chloride (2 M in THF, 1.8 mL, 3.6 mmol) drop wise at −78° C. After being stirred at the temperature for 2 h, the reaction was quenched with NH4Cl aqueous solution, and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (PE:EtOAc=5:1) to give Intermediate 35 (60 mg, yield 10%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.BrC1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1.C(N(C(C)C)CC)(C)C.Cl>CN1CCCC1=O.O>[Br:21][C:18]1[CH:19]=[CH:20][C:6]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[N:16][CH:17]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Brc1ccc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.2 %

Procedure:
A mixture of 5.0 g of 1-t-butoxycarbonyl piperazine, 6.36 gm of 2,5-dibromopyridine and 10.4 gm diisopropylethylamine in 50 ml of 1-methyl-2-pyrolidinone is kept for 12 hours at 150° C. Upon cooling to ambient temperature and addition of 10 ml water, the mixture is acidified with concentrated hydrochloric acid heated for 15 minutes and upon cooling extracted 2×5 ml ethyl ether. The aqueous layer is then neutralized with aqueous ammonium hydroxide solution and extracted with ethyl acetate. The ethyl acetate extract is collected, washed with 20 ml water and dried over Na2SO4. The crude product (4.3 gm) obtained after removing the solvents solidifies upon standing. This material is used without further purification.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:12]#[N:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>O1CCCC1>[CH3:24][S:21]([O:1][N:2]=[C:3]([C:12]#[N:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)(=[O:23])=[O:22]
Reactant: COc1ccc(C(C#N)=NO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C(C#N)=NOS(C)(=O)=O)cc1
Temperature: -5 °C
Reaction time: 3 h

Procedure:
α-(Methylsulfonyloxyimino)-4-methoxybenzyl cyanide was prepared in the following manner. Thus, 51.0 g (0.29 mole) of α-hydroxyimino-4-methoxybenzyl cyanide and a solution prepared by dissolving 44.0 g (0.43 mole) of triethylamine in 400 ml of tetrahydrofuran were introduced into a reaction vessel to form a uniform solution which was chilled to and kept at -5° C. Into the solution in the reaction vessel were added dropwise 36.5 g (0.32 mole) of mesyl chloride over a period of 2 hours under agitation. The reaction mixture in the vessel was agitated at -5° C. for 3 hours and then at about 10° C. for additional 2 hours. The reaction mixture was freed from tetrahydrofuran as the solvent by distillation under reduced pressure at 30° C. to give 73.6 g of a solid residue as a crude product which was purified by repeating recrystallization from acetonitrile to give 47.5 g of a white crystalline product having a melting point of 116° C., which could be identified to be the target compound from the results of the analysis described below. The above mentioned yield of the product corresponds to 64.9% of the theoretical value.
Reaction SMILES: [CH:1]1([O:4][CH:5]2[CH2:10][CH2:9][C@H:8]3[C@H:11]4[C@H:21]([CH2:22][CH2:23][C@:6]23[CH3:7])[C@:19]2([CH3:20])[C:14](=[C:15]([N+:25]([O-])=O)[C:16](=[O:24])[CH2:17][CH2:18]2)[CH2:13][CH2:12]4)[CH2:3][CH2:2]1>C(O)(=O)C.[Zn]>[NH2:25][C:15]1[C:16](=[O:24])[CH2:17][CH2:18][C@@:19]2([CH3:20])[C:14]=1[CH2:13][CH2:12][C@@H:11]1[C@@H:21]2[CH2:22][CH2:23][C@@:6]2([CH3:7])[C@H:8]1[CH2:9][CH2:10][CH:5]2[O:4][CH:1]1[CH2:2][CH2:3]1
Reactant: C[C@]12CCC(=O)C([N+](=O)[O-])=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(OC3CC3)CC[C@@H]12
Agent: [Zn]
Solvent: CC(=O)O
Product: C[C@]12CCC(=O)C(N)=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(OC3CC3)CC[C@@H]12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.1 %

Procedure:
A solution of 17-cyclopropyloxy-4-nitroandrost-4-en-3-one (1.0 g, 2.71 mM) in acetic acid (10 mL) is treated with zinc dust (1.0 g). The combination is vigorously stirred for 1.5 hours at room temperature. The zinc salts are removed by filtration and washed with ethyl acetate. The combined filtrate and wash are combined and concentrated to a yellow solid which is then redissolved in ethyl acetate and extracted three times with 1M hydrochloric acid (150 ml). The combined acid extracts are neutralized with sodium hydroxide (pH 14) and further extracted with ether. The combined organic layers are then dried over sodium sulfate and concentrated to give 4-amino-17-cyclopropyloxyandrost-4-en-3-one (0.59 g), m.p. 100°-102° C. (aqueous methanol).
Reaction SMILES: [C-:1]#[N:2].[Na+].[F:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[CH:7](Cl)[CH3:8]>CS(C)=O>[F:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[CH:7]([C:1]#[N:2])[CH3:8]
Reactant: [C-]#N
Reactant: CC(Cl)c1ccccc1F
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C#N)c1ccccc1F
Temperature: 90 °C
Reaction time: 4 h
Yield: 85.1 %

Procedure:
In 300 ml of dimethyl sulfoxide was dissolved 35 g of sodium cyanide by heating at 90° C., and 45 g of 2-fluoro-α-methylbenzyl chloride was added. The mixture was stirred at 90° C. for 4 hours, and then cooled. Ice-water was added and the mixture was extracted with n-hexane. The n-hexane layer was washed with water and dried over anhydrous magnesium sulfate and the solvent was evaporated off. The residue obtained was purified by distillation under reduced pressure to afford 36 g of 2-fluoro-α-methylbenzyl cyanide, b.p.0.5 55° C.
Reaction SMILES: [OH:1][C:2]1[C:7](C(O)=O)=[CH:6][N:5]=[C:4]([OH:11])[CH:3]=1.P(=O)(O)(O)O.C(O)(=O)C.[N+:21]([O-])([OH:23])=[O:22].O>>[OH:11][C:4]1[C:3]([N+:21]([O-:23])=[O:22])=[C:2]([OH:1])[CH:7]=[CH:6][N:5]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cnc(O)cc1O
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1c(O)ccnc1O
Temperature: 90 °C
Reaction time: 4.5 h
Yield: 55.5 %

Procedure:
A 3-neck 22 L flask equipped with a temperature probe with a chart recorder, mechanical stirrer, a Dean-Stark apparatus and a reflux condenser is charged with 4,6-dihydroxy nicotinic acid (88 %, 2.0 Kg, 12.81 mol), phosphoric acid (85%. 6 L, 103.15 mol). The off gases from the condenser are scrubbed by bubbling into 50% aqueous NaOH. The suspension is heated until a sufficient amount of water has been removed (about 1.2 L), i.e., dehydration of the phosphoric acid. Without the dehydration of the phosphoric acid, the carboxylation does not occur. For the internal temperature to reach 210° C.±5° C., a mantle temperature of 290° C. is applied over an elapsed time of 3.5 hours. After being stirred for 4-5 hours at that temperature, the disappearance of the starting material is confirmed by HPLC. The reaction mixture is then allowed to cool down to a temperature of less than 100° C., at which point acetic acid (6 L, 104.81 mol) is added and the temperature is maintained at 90° C. To this mixture is added nitric acid (485 mL, 12.11 mol) at a constant rate (5-6 mL/minute) until HPLC shows no more 4,6-dihydroxy nicotinic acid present. Water (6 L, 333.3 mol) is then added to the reaction and heating is stopped. A yellow solid starts appearing at a temperature of less than 80° C. and is allowed to precipitate with stirring overnight. Filtration in a scintered glass funnel (course porosity) yields a yellow solid which is then washed with 2.5 L of isopropyl alcohol. The resulting cake is air-dried for 48 hours and then put in a drying oven under vacuum (20 in. Hg with a air bleed) at 50° C. for 3 days. 2,4-dihydroxy-3-nitropyridine (1.050 Kg) is obtained in 60% yield.