Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[C:20](I)[C:21]=1[OH:22])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[CH2:9]1)=[O:7])#[N:2].N1C=CC=C[C:25]=1C1C=CC=CN=1.[CH3:36][S:37]SC>CN(C)C=O.[Zn].[Ni](Br)Br>[C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([S:37][CH3:36])[C:21]=1[O:22][CH3:25])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[CH2:9]1)=[O:7])#[N:2]
Reactant: c1ccc(-c2ccccn2)nc1
Reactant: N#Cc1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(I)c1O
Reactant: CSSC
Agent: Br[Ni]Br
Agent: [Zn]
Solvent: CN(C)C=O
Product: COc1c(C#N)cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc1SC
Temperature: 80 °C
Reaction time: 1 h

Procedure:
3-(3-cyano-4-hydroxy-5-iodobenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (334 mg) was dissolved in N,N-dimethylformamide (3.5 mL), and 2,2′-bipyridine (11 mg), zinc powder (95 mg), nickel bromide (16 mg) and dimethyl disulfide (0.04 mL) were added to the solution, and then the mixture was stirred at 80° C. for 1 hour. After the reaction solution was filtered, 1N hydrochloric acid was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was dissolved in N,N-dimethylformamide (3 mL). Potassium carbonate (298 mg) and dimethylsulfuric acid (0.13 mL) was added to the solution, and then the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to obtain the title compound (142 mg) as a pale yellow oily substance.
Reaction SMILES: [OH:1][C@H:2]1[CH2:24][C@@:23]2([CH3:25])[C@@H:13]([CH2:14][CH2:15][C@:16]2([OH:26])[C@@H:17]([OH:22])[C:18]([O:20]C)=[O:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:28])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:27])[CH:6]=[CH:5]1.[OH-].[Na+].Cl.O>CO>[OH:1][C@H:2]1[CH2:24][C@@:23]2([CH3:25])[C@@H:13]([CH2:14][CH2:15][C@:16]2([OH:26])[C@@H:17]([OH:22])[C:18]([OH:20])=[O:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:28])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:27])[CH:6]=[CH:5]1
Reactant: COC(=O)[C@H](O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)[C@@H](O)C(=O)O
Reaction time: 0.33 h

Procedure:
To a solution of the product of Example 9 (Product 9A), 500 mg, in methanol (50 ml), 1N NaOH (1 ml) was added. After 20 min in ice bath, the mixture was neutrlized with 0.1N HCl and 300 ml of distilled water was added. After extracting with ethyl acetate (300 ml), the organics was evaporated and recrystallization from methanol gave 360 mg of (20R)-11β,17,20-trihydroxy-3-oxo-1,4-pregnadien-21-oic acid as white prism, m.p.=213°-214° C. 1H-NMR (Me2SO-6) δ1.03(s,3H,13-CH3), 1.39(s,3H,10-CH3), 3.94(s,1H,20-H), 4.19(m,1N,11-H), 5.90(s,1H,4-H), 6.13(dd,1H,J=10 and 2 Hz,2-H), 7.31(d,1H,J=10 Hz,2-H), 8.30(s,1H,20-COOH).
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4]1[CH:11]=[CH:10]C(C#N)=[CH:6][C:5]=1[C:12]([F:15])([F:14])[F:13])[CH3:2].Cl.[C:19]([OH:22])(=[O:21])[CH3:20]>>[CH2:16]([N:3]([CH2:1][CH3:2])[C:4]1[CH:11]=[CH:10][C:20]([C:19]([OH:22])=[O:21])=[CH:6][C:5]=1[C:12]([F:13])([F:14])[F:15])[CH3:17]
Reactant: CCN(CC)c1ccc(C#N)cc1C(F)(F)F
Reactant: CC(=O)O
Agent: Cl
Product: CCN(CC)c1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 95 °C
Reaction time: 20 h

Procedure:
A mixture of 4-diethylamino-3-(trifluoromethyl)-benzonitrile (1.21 g, 5 mmol), 12 mL of acetic acid and 8 mL of fuming hydrochloric acid (37%) is shaken for 20 hours at 95° C. After cooling, the reaction mixture is evaporated to dryness under reduced pressure. The solid residue is dissolved in a warm half-saturated aqueous sodium carbonate solution and the pH is adjusted to ˜5-6 by dropwise addition of 2M hydrochloric acid. The formed precipitate is filtered off, washed with water and dried in vacuo to yield a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14]O)=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[C:10]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[P:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[OH2:41]>C1(C)C(C)=CC=CC=1>[C:29]1([P:28]([CH2:14][C:13]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][C:10]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[N:11][C:12]=2[CH:16]([CH3:18])[CH3:17])([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:41])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CO
Reactant: O
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CP(=O)(c1ccccc1)c1ccccc1
Temperature: 135 °C
Reaction time: 0.58 h
Yield: 53.5 %

Procedure:
282.8 mg (0.80 mmol) of [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulphonylamino)pyrimidin-5-yl]methanol was initially charged in 4.5 ml of xylene (isomer mixture) and admixed with 55 mg (1.30 mmol) of sodium hydride (55 percent dispersion in mineral oil). After 35 min, 185 mg (0.84 mmol) of chlorodiphenylphosphine in 1.5 ml of xylene was added at room temperature with vigorous stirring over a period of 5 min, and the mixture was subsequently heated at 135° C. for 20 h. After cooling to room temperature, the mixture was admixed with 15 ml of water and extracted with 10 ml of ethyl acetate. The organic phase was separated off and the aqueous phase was extracted with 2×10 ml of ethyl acetate. The combined organic phases were subsequently dried (MgSO4) and concentrated under reduced pressure. This gave 510 mg of crude product which was purified by silica gel chromatography (mobile phase: n-hexane/ethyl acetate 1:2, then ethyl acetate), and 230 mg (53.5 percent) of N-[5-(diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulphonamide was isolated in the form of a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[N:22]=[C:12]3[CH:13]([C:17]([O:19]CC)=[O:18])[CH2:14][CH2:15][CH2:16][N:11]3[N:10]=2)[CH:6]=[CH:5][C:4]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1.Cl>C1COCC1.CO.[OH-].[Na+]>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[N:22]=[C:12]3[CH:13]([C:17]([OH:19])=[O:18])[CH2:14][CH2:15][CH2:16][N:11]3[N:10]=2)[CH:6]=[CH:5][C:4]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1
Reactant: CCOC(=O)C1CCCn2nc(-c3ccc(-n4cnc(C)c4)c(OC)n3)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1nc(-c2nc3n(n2)CCCC3C(=O)O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Ethyl 2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate (331 mg) was dissolved in a mixed solvent of THF (5 mL) and methanol (5 mL) A 5 N sodium hydroxide aqueous solution (693 μL) was added and the mixture was stirred at room temperature for two days. The reaction solution was neutralized with 5 N hydrochloric acid (693 μl), and then concentrated under reduced pressure to remove the organic solvent. Methanol (2 mL) was added to the residue, and the precipitated salt was separated by filtration. Thereafter, the filtrate was concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:21]=[C:20]2[C:13]([NH:14][CH:15]=[C:16]2[CH2:17][CH2:18][NH2:19])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:22]1(=O)[O:27][C:25](=[O:26])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.C(N(CC)C(C)C)(C)C.C(Cl)(Cl)Cl>N1C=CC=CC=1>[CH2:2]([O:9][C:10]1[CH:21]=[C:20]2[C:13](=[CH:12][CH:11]=1)[NH:14][CH:15]=[C:16]2[CH2:17][CH2:18][N:19]1[C:25](=[O:26])[C:24]2[C:23](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:22]1=[O:27])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCc1c[nH]c2ccc(OCc3ccccc3)cc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Combine 5-benzyloxytryptamine hydrochloride (1 g, 3.3 mmol), phthalic anhydride (.56 g, 4.0 mmol) and N,N-diisopropylethylamine (0.86 g, 6.6 mmol) in 25 mL anhydrous pyridine and reflux for 1 hour, cool to room temperature and treat with 4 g 3 Å molecular sieves. Refluxing was continued for 60 hours then the mixture was filtered. Concentrate under vacuum to give a residue which is mixed with 25 mL CHCl3 and filtered to give a solid. Purification of the filtrate by chromatography on silica gel eluting with 1% MeOH in CHCl3 to give an additional amount of title compound: ISMS 397 (M+1); Analysis for C25H20N2O3 0.3H2O C7H8: calcd: C, 75.09; H, 5.25; N, 6.82; found: C, 75.00; H, 5.22; N, 6.96.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[C:7]1([C:13](=[O:24])[CH2:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CI>C1(C)C=CC=CC=1.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:7]1([C:13](=[O:24])[CH:14]([CH3:1])[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([CH3:22])[CH3:23])=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)CCCCC(=O)CC(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CI
Solvent: O
Product: CC(C)CCCCC(=O)C(C)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
A mixture of 55.2 g anhydrous potassium carbonate, 1.6 g tetrabutylammonium fluoride, 24.8 g 1-phenyl-3-isoheptyl-1,3-propanedione and 150 ml. toluene were stirred and heated to reflux for 2 hours with a Dean-Stark trap under a nitrogen atmosphere. The mixture was cooled to room temperature, 7.0 ml methyl iodide was added and the mixture was heated with stirring to 50 degrees Centigrade overnight. The product was diluted with toluene and water, and the organic phase washed with water, and stripped under reduced pressure. The residue was distilled in a Kugelrohr apparatus at 100-110 degrees Centigrade at 0.3 mm Hg to give 25.6 g distillate. The distillate was purified on a silica gel column and redistilled in a Kugelrohr apparatus to give 16.4 g of 1-phenyl-2-methyl-3-isoheptyl-1,3-propanedione. Employing the same procedure using benzyl iodide will provide the corresponding 1-phenyl-2-benzyl-3-isoheptyl-1,3-propanedione.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].CN(C)C=O.[H-].[Na+].[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29]OC1C(Cl)=CC(C=O)=C(F)C=1>O>[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][O:10][C:8]1[C:7]([O:11][CH3:12])=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([F:1])[CH:9]=1
Reactant: O=Cc1cc(Cl)c(OCc2nc3ccccc3[nH]2)cc1F
Reactant: COc1cc(C=O)c(F)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(F)cc1OCc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.6 %

Procedure:
2-Fluoro-4-hydroxy-5-methoxy-benzaldehyde (39, 0.290 g, 1.7 mmol, prepared as described in Scheme 12 of Example 15) was dissolved in N,N-dimethylformamide (20 mL, 200 mmol). Sodium hydride (60% dispersion in oil, 0.852 g, 2.13 mmol) was added to the solution and after the mixture was stirred for 20 minutes at room temperature, 2-chloromethyl-1H-benzoimidazole (106, 0.28 g, 1.7 mmol) was added to the reaction. The obtained mixture was heated to 80° C. and stirred overnight. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate. The organic portion was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with a gradient of ethyl acetate (40 to 100%) in hexane to give the desired compound (142, 0.233 g, 45%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20].C([O-])([O-])=O.[K+].[K+].O1CCOCC1>O>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([C:2]2[N:3]=[C:4]3[CH:10]=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:14]=[C:13]([O:12][CH3:11])[C:18]=1[O:19][CH3:20]
Reactant: Brc1cnc2[nH]ccc2n1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2cnc3[nH]ccc3n2)cc(OC)c1OC
Temperature: 110 °C
Yield: 88.5 %

Procedure:
A flask was charged with 2-bromo-5H-pyrrolo[2,3-b]pyrazine (9.5 g, 48 mmol), 3,4,5-trimethoxyphenylboronic acid (13.22, 62 mmol), and K2CO3 (19.9, 144 mmol). Dioxane (213 ml) and water (71 ml) were added, and the solution was vacuum degassed under argon. [1,1′-bis(Diphenylphosphino)ferrocene]dichloro-palladium(ll) (3.92 g, 4.8 mmol) was added, and the reaction mixture was refluxed (110° C.) overnight. The reaction mixture was filtered through a plug of celite using dichloromethane, and the filtrate was concentrated giving a black oil. The oil was purified by silica gel chromatography using 5%-60% EtOAc in hexanes as eluant to provide 12.12 g (89%) of 2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[F:17][C:18]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][C:19]=1[CH2:20][OH:21].[CH2:33]([O:37][CH:38]1[CH:40]([C:41](O)=[O:42])[C:39]1([CH3:45])[CH3:44])[CH:34]([CH3:36])[CH3:35]>>[CH2:33]([O:37][CH:38]1[CH:40]([C:41]([O:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[C:3]([O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:4]=2)=[O:42])[C:39]1([CH3:45])[CH3:44])[CH:34]([CH3:36])[CH3:35].[CH2:33]([O:37][CH:38]1[CH:40]([C:41]([O:21][CH2:20][C:19]2[CH:22]=[C:23]([O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:24]=[CH:25][C:18]=2[F:17])=[O:42])[C:39]1([CH3:45])[CH3:44])[CH:34]([CH3:36])[CH3:35]
Reactant: OCc1cc(Oc2ccccc2)ccc1F
Reactant: CC(C)COC1C(C(=O)O)C1(C)C
Reactant: OCc1ccc(F)c(Oc2ccccc2)c1
Product: CC(C)COC1C(C(=O)OCc2cc(Oc3ccccc3)ccc2F)C1(C)C
Product: CC(C)COC1C(C(=O)OCc2ccc(F)c(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Example 14, each of 4-fluoro-3-phenoxybenzyl alcohol and 2-fluoro-5-phenoxybenzyl alcohol is reacted with 3-(i-butoxy)-2,2-dimethylcyclopropanecarboxylic acid to yield 4-fluoro-3-phenoxybenzyl 3-(i-butoxy)-2,2-dimethylcyclopropanecarboxylate and 2-fluoro-5-phenoxybenzyl 3-(i-butoxy)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([OH:9])=[O:8])[CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH2:16](O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl.CN(C)C=O>[CH2:16]([O:8][C:7]([CH:3]1[CH2:4][CH2:5][CH2:6][O:1][CH2:2]1)=[O:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)C1CCCOC1
Reactant: OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(OCc1ccccc1)C1CCCOC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
A cooled (0° C.) solution of tetrahydro-pyran-3-carboxylic acid (2.831 g, 21.752 mmol) in dichloromethane (60 mL) and N,N-dimethylformamide (5 drops) was treated with oxalyl chloride (2.0 mL, 23.927 mmol). After stirring at room temperature for 2 h, benzyl alcohol (2.5 mL, 23.927 mmol) was added. After stirring at room temperature for 2 h and standing overnight, the volatiles were removed in vacuo and the residue was purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 4:1 to afford the title compound (4.587 g, 96%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.58-1.88 (m, 3H), 2.03-2.13 (m, 1H), 2.62-2.72 (m, 1H), 3.47 (ddd, J=11.4, 9.6, 3.4 Hz, 1H), 3.63 (dd, J=11.4, 9.1 Hz, 1H), 3.85 (app dt, J=11.1, 3.8 Hz, 1H), 4.06 (ddd, J=11.4, 4.0, 1.6 Hz, 1H), 5.12, 5.17 (ABq, JAB=12.5 Hz, 2H), 7.31-7.46 (m, 5H).
Reaction SMILES: C([OH:3])C.[Br:4][C:5]1[CH:6]=[C:7]([N+:13]([O-])=O)[C:8]([C:11]#[N:12])=[N:9][CH:10]=1.C(OCC)(=O)C>[Ni].CCCCCC>[NH2:13][C:7]1[C:8]([C:11]([NH2:12])=[O:3])=[N:9][CH:10]=[C:5]([Br:4])[CH:6]=1
Reactant: CCO
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: NC(=O)c1ncc(Br)cc1N
Temperature: 25 °C
Reaction time: 14 h
Yield: 23 %

Procedure:
To a 100 mL round bottom flask, Raney Nickel (2.5 g) and ethanol (15 mL) were added. To the same flask, was added 5-bromo-3-nitropyridine-2-carbonitrile (5 g, 0.0219 mol). The reaction mass was stirred under hydrogen atmosphere for 14 hours at ambient temperature. The catalyst was removed by filtration. The clear filtrate was evaporated to provide the crude product. The crude material was subject to column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to provide title compound as a light yellow solid (1.1 g, 23%). 1H NMR (300 MHz, DMSO-d6): δ 7.89 (br s, 1H), 7.79 (d, J=1.8 Hz, 1H), 7.40 (br s, 1H), 7.38 (d, J=1.8 Hz, 1H), 7.04 (br s, 2H).
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=[O:15])[C:7]3=[C:8]2[C:3](=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[CH:6]3)[CH:2]=1)=O.[NH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24]>C(O)(=O)C>[N+:16]([C:5]1[CH:4]=[C:3]2[CH:2]=[CH:1][CH:10]=[C:9]3[C:8]2=[C:7]([CH:6]=1)[C:14](=[O:15])[N:19]([CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:11]3=[O:13])([O-:18])=[O:17]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])cc3cccc1c23
Reactant: NCCCC(=O)O
Solvent: CC(=O)O
Product: O=C(O)CCCN1C(=O)c2cccc3cc([N+](=O)[O-])cc(c23)C1=O

Procedure:
The compound was prepared from 3-nitro-1,8-naphthalic anhydride (1.00 g, 4.1 mmol) and 4-aminobutyric acid (0.42 g, 4.1 mmol) in 100 mL glacial acetic acid using the general procedure shown in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[S:11]([N:14]([CH:28]([CH3:30])[CH3:29])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)(=[O:13])=[O:12].O.O.Cl[Sn]Cl>CCO>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([S:11]([N:14]([CH:28]([CH3:29])[CH3:30])[C:15]2[CH:16]=[CH:17][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:23])[F:24])=[CH:19][CH:20]=2)(=[O:13])=[O:12])[CH:4]=1
Reactant: CC(C)N(c1ccc(C(C)(O)C(F)(F)F)cc1)S(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CC(C)N(c1ccc(C(C)(O)C(F)(F)F)cc1)S(=O)(=O)c1cc(N)ccc1Cl
Temperature: 75 °C
Reaction time: 2 h

Procedure:
A solution of 2-chloro-N-isopropyl-5-nitro-N-[4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl]benzenesulfonamide (11) (704 mg, 1.50 mmol, 1.0 equiv) in EtOH (40 mL) was treated with SnCl2.2H2O (1.70 g, 7.50 mmol, 5.0 equiv). After stirring at 75° C. for 2 h, the reaction mixture was concentrated under reduced pressure, diluted (EtOAc) and washed (3×1 M aqueous NaOH and 1×brine). The organics were dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue (SiO2, 30-40% EtOAc/Hexane, gradient elution) gave the product as a white foam. 1H NMR (DMSO-d6, 500 MHz) δ 7.59 (d, J=8.6 Hz, 2H), 7.28 (d, J=8.6 Hz, 1H), 7.12 (d, J=8.6 Hz, 2H), 7.08 (d, J=2.8 Hz, 1H), 6.73 (dd, J=2.8, 8.6 Hz, 1H), 6.65 (s, 1H), 5.67 (s, 1H), 4.50-4.42 (m, 1H), 1.67 (s, 3H), 1.04 (d, J=6.6 Hz, 3H), 1.03 (d, J=6.6 Hz, 3H). MS (ESI) 437 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][Cl:9])[N:3]=1.[C:10]1([CH3:16])[CH:15]=CC=C[CH:11]=1.ClC(Cl)([O:20][C:21](=O)[O:22]C(Cl)(Cl)Cl)Cl.[OH-].[Na+]>O.C(O)(C)(C)C>[C:10]([O:22][C:21](=[O:20])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][Cl:9])[N:3]=1)([CH3:16])([CH3:15])[CH3:11]
Reactant: Nc1cccc(CCl)n1
Reactant: Cc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(CCl)n1

Procedure:
2.43 g (10 millimoles) of 2-amino-6-chloromethylpyridine, toluene (30 mL), 10 mL of t-butyl alcohol and 1.48 g (5 millimoles) of triphosgene were added to a reaction system followed by refluxing for 1 hour. Water and 28% sodium hydroxide were sequentially added while holding the internal temperature at 0° C. or lower. After separating the liquid, the aqueous phase was extracted with ethyl acetate. The organic phases were combined and mixed. A portion of the organic phase was sampled and subjected to quantitative analysis by HPLC. The target (6-chloromethyl-pyridin-2-yl)-carbamic acid tert-butyl ester was not formed at all. 1,3-bis-(6-chloromethyl-pyridin-2-yl)-urea (urea compound) constituted the main product.
Reaction SMILES: [OH-].[K+].[OH-].[Na+].C([O:7][C:8]([C:10]1([CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)=[O:9])C>O.C(O)C>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][C:10]([CH2:23][CH:24]([CH3:26])[CH3:25])([C:8]([OH:9])=[O:7])[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)C1(CC(C)C)CCN(C(=O)OC(C)(C)C)CC1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)CC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
A solution of potassium hydroxide (85% assay, 2.69 g, 0.041 mol) and sodium hydroxide (1.94 g, 0.048 mol) in demineralized water (8 mL) is added to a solution of 4-isobutylpiperidine-1,4-dicarboxylic acid-1-tertbutyl ester-4-ethyl ester (0.95 g, 0.003 mol) in ethanol (15 mL). The reaction mixture is refluxed for 48 hrs. It is cooled to room temperature, concentrated under reduced pressure, and then treated with demineralized water (10 mL). The pH is adjusted to ˜3-4 using 2N HCl (10 mL) and the aqueous layer is extracted with ethyl acetate (2×15 mL). The combined extract is dried over sodium sulfate. Removal of solvent gives a crude residue which is purified by column chromatography (230-400 mesh, ethyl acetate:n-hexane 1:3) to furnish 4-isobutylpiperidine-1,4-dicarboxylic acid monotertbutyl ester.
Reaction SMILES: C[N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O.[NH2:18][C:19]1[N:20]=[CH:21][NH:22][C:23]=1C#N.[C:26](O)(=O)C>>[CH3:26][C:3]1[CH:4]=[C:5]([C:7]2[CH:8]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:11][CH:12]=2)[N:20]2[CH:21]=[N:22][C:23]([C:19]#[N:18])=[C:17]2[N:2]=1
Reactant: CC(=O)O
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: N#Cc1[nH]cnc1N
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)n2cnc(C#N)c2n1

Procedure:
A mixture of 0.01 mole of 3-dimethylamino-3'-(trifluoromethyl)acrylophenone, 50 ml. of glacial acetic acid and 0.01 mole of 4-amino-5-imidazolecarbonitrile is refluxed for 5 hours. The solvent is removed under reduced pressure and the residue worked up as for Example 29 to give the product of the example.