Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(OC)(OC)OC.[CH2:20](O)[CH2:21][OH:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.C(N(CC)CC)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]2([O:22][CH2:21][CH2:20][O:12]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture that consists of 7.35 g of 4-oxocyclohexylcarboxylic acid ethyl ester, 28 ml of trimethyl orthoformate, 64 ml of ethylene glycol and 100 mg of p-toluenesulfonic acid in 120 ml of dichloromethane is stirred for 12 hours at 25° C. Then, 2 ml of triethylamine is added. It is washed with saturated sodium bicarbonate solution and then with saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a vacuum. The crude product that is obtained is purified by column chromatography on silica gel. 9.22 g of product is obtained.
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:2]([C:5]([OH:7])=O)([CH3:4])[CH3:3].[CH3:15][NH:16][O:17][CH3:18].Cl.CCN(C(C)C)C(C)C.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:11]([O:10][C:8](=[O:9])[NH:1][C:2]([C:5](=[O:7])[N:16]([O:17][CH3:18])[CH3:15])([CH3:3])[CH3:4])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: CNOC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 120 h
Yield: 80 %

Procedure:
To a stirred mixture of Boc-Aib-OH (5 g, 24.61 mmol, 1 eq), MeNHOMe.HCl (2.88 g, 29.53 mmol, 1.2 eq), DMAP (3.61 g, 29.53 mmol, 1.2 eq), i-Pr2NEt (5.02 mL, 29.53 mmol, 1.2 eq) and CH2Cl2 (100 mL) was added DCC (6.09 g, 29.53 mmol, 1.2 eq). The mixture was stirred at room temperature for 5 days. The mixture was filtered to remove precipitated N,N′-dicyclohexylurea and the filtrate was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL), washed with 10% aqueous citric acid (3×200 mL), 10% aqueous NaHCO3 (3×200 mL) and saturated aqueous sodium chloride (3×200 mL), and dried over MgSO4. Removal of the solvent yeided the crude product which was purified by column chromatography (hexane/ethyl acetate 60:40) to afford [1-(methoxy-methyl-carbamoyl)-1-methyl-ethyl]-carbamic acid tert-butyl ester (4.85 g, 80%) as a white solid. 1H NMR (200 MHz, CDCl3) δ(ppm): 1.43 (s, 6H), 1.58 (s, 9H), 3.22 (s, 3H), 3.69 (s, 3H), 6.95 (bs, 1H). MS (ESI, +ve ion): m/z 247.2 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C:4]#[C:5][CH:6]([OH:9])[CH2:7][CH3:8].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:1][O:2][C:3](=[O:10])[C:4]#[C:5][C:6](=[O:9])[CH2:7][CH3:8]
Reactant: CCC(O)C#CC(=O)OC
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CCC(=O)C#CC(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.9 %

Procedure:
To a solution of methyl-4-hydroxy-2-hexynoate (25.0 g, 176 mmol) in acetone (200 mL), cooled in an ice water bath, was added Jones reagent (70 mL of 3.2 M chromium VI oxide in 1:3 sulfuric acid:water). The reaction mixture was allowed to stir at room temperature for 3 h then filtered through a plug of diatomaceous earth and the filter cake was rinsed with dichloromethane (2×100 mL). The organic phase was saved and the aqueous phase was extracted with dichloromethane (2×100 mL). The combined organic phases were washed with saturated sodium bicarbonate (2×200 mL), dried (sodium sulfate) and concentrated to provide 17.0 g (69%) of 4-oxo-hex-2-ynoic acid methyl ester.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:4].[C:15]([NH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN(C)C.Cl>CN(C)C=O>[CH2:11]1[C:12]2[C:7](=[CH:6][C:5]([C:3](=[O:4])[CH2:2][N:27]3[CH2:28][CH2:29][CH:24]([NH:23][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:25][CH2:26]3)=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10]1
Reactant: O=C(CCl)c1ccc2c(c1)CCCC2
Reactant: O=C(NC1CCNCC1)c1ccccc1
Agent: CN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(CN1CCC(NC(=O)c2ccccc2)CC1)c1ccc2c(c1)CCCC2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 6-chloroacetyl-1,2,3,4-tetrahydro napthalene (20.87 g.), 4-benzamidopiperidine (20.4 g.) and trimethylamine (11.1 g.) in dimethylformamide (200 ml.). was stirred for 3 days at room temperature. The crystals which had formed during this time were then filtered off, washed and dried. A portion of this crystalline solid (4.0 g.) was dissolved in ethanol (50 ml.) and acidified with ethanol hydrogen chloride to give 4.0 g. of the hydrochloride of the title compound, m.p. 270° C. (decomp.). (Found: C, 69.5; H, 7.2; N, 6.8; C24H28N2O2.HCl requires C, 69.8; H, 7.1; N, 6.8%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-])=O)=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8]>CO.[C].[Pd]>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: Cc1ccc([N+](=O)[O-])c(C(N)=O)c1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(N)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.1 %

Procedure:
To a solution of 5-methyl-2-nitrobenzamide (15.0 g, 83.3 mmol) in methanol (300 mL) was added 10% palladium carbon (2.50 g), and the mixture was stirred at room temperature for 12 hr under hydrogen atmosphere (1 atm). The insoluble material was filtered off, and the filtrate was concentrated to give 2-amino-5-methylbenzamide as a white powder (12.4 g, 99%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([Cl:15])=[O:6]
Reactant: COc1ccc(C(=O)O)cc1F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)Cl)cc1F

Procedure:
To a slurry of 3-fluoro-4-methoxybenzoic acid (30.0 g) in toluene (100 ml) was added thionyl chloride (25 ml). The reaction was heated under reflux for 2 hrs and then distilled. The residue was dried under high vacuum to give 32 g of 3-fluoro-4-methoxybenzoyl chloride. To a solution of 2-amino-2-methyl-1-propanol (35 ml) in dichloromethane (200 ml) was added a solution of the 3-fluoro-4-methoxybenzoyl chloride in dichloromethane (150 ml). The reaction mixture was stirred for 1 hr at ambient temperature, dichloromethane (500 ml) was added, and washed with 2N hydrochloric acid (1 l). The layers were separated and the organic extract was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. To the residue was added thionyl chloride (25 ml) at 0° C. The reaction mixture was stirred for 30 min, diethyl ether (200 ml) was added, and the mixture was stirred for 10 min. The supernatant was decanted. 10% Sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo to give 36 g (91%) of product, mp 59-60° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]=[C:6]1[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1)[CH3:2].C(O)(C)C>[Pd].C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]1[CH2:15][CH2:14][C:9]2([O:10][CH2:11][CH2:12][O:13]2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)C=C1CCC2(CC1)OCCO2
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CCOC(=O)CC1CCC2(CC1)OCCO2
Reaction time: 24 h
Yield: 94.6 %

Procedure:
Second Step: 267.3 g of the compound (11), 5.0 g of Pd/C, 500 mL of isopropyl alcohol (IPA) and 500 mL of toluene were added to a reactor, and stirred under hydrogen atmosphere for 24 hours. After confirming that the reaction had been completed by GC analysis, the Pd/C was filtered off, and the solvent was removed by distillation under reduced pressure to obtain a residue. The resulting residue was purified by silica gel column chromatography using heptane as eluent, and the solvent was distilled off under reduced pressure to obtain 255.2 g of (1,4-dioxaspiro[4,5]dec-8-yl)acetic acid ethyl ester (12) as a colorless liquid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]([C:10](=[O:24])[NH:11][C@:12]2([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][C@H:13]2[CH:15]=[CH2:16])[CH2:8][CH:7]([O:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([O:36][CH3:37])=[CH:33][CH:34]=3)[N:29]=[C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:27]=2)[CH:6]=1)=[O:4].C(OC([C@@H](NC(C1C(C(O)=O)=CC(OC2C3C(=CC(OC)=CC=3)N=C(C3C=CC=CC=3)C=2)C1)=O)CCC)=O)(C)(C)C>>[C:20]([O:19][C:17]([C@@:12]1([NH:11][C:10]([CH:9]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]([O:25][C:26]3[C:35]4[C:30](=[CH:31][C:32]([O:36][CH3:37])=[CH:33][CH:34]=4)[N:29]=[C:28]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:27]=3)[CH2:8]2)=[O:24])[CH2:14][C@H:13]1[CH:15]=[CH2:16])=[O:18])([CH3:21])([CH3:22])[CH3:23]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C=C1C(=O)OC)C(=O)OC(C)(C)C
Agent: CCC[C@H](NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C=C1C(=O)O)C(=O)OC(C)(C)C
Product: C=C[C@@H]1C[C@]1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C=C1C(=O)O)C(=O)OC(C)(C)C

Procedure:
Reaction of 10 (35 mg, 59 mmol) according to the method described for the preparation of 11 (33 mg, 97%) provided the title compound as a yellow salt.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:13]1(=O)[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH2:14]1>C(O)(=O)C>[Br:12][C:3]1[C:2]([NH:1][C:13]2[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH:14]=2)=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCCC(=O)C1
Reactant: COC(=O)c1cccc(N)c1Br
Solvent: CC(=O)O
Product: COC(=O)c1cccc(NC2=CC(=O)CCC2)c1Br
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
Methyl 3-amino-2-bromobenzoate (2.39 g, 10.0 mmol) and cyclohexane-1,3-dione (1.12 g, 10.0 mmol) were dissolved in 10 mL of acetic acid at 25° C., under nitrogen. The mixture was stirred at 80° C. for 8 hours. The resultant solid was purified by chromatography column on silica gel (elution with hexane/ethyl acetate) to afford 2.46 g (76%) of methyl 2-bromo-3-((3-oxocyclohex-1-en-1-yl)amino)benzoate as a tan foam. 1H NMR (CDCl3-d1) δ 7.53-7.55 (m, 2H), 7.37 (dd, 1H, J=7.2, 8.4 Hz), 6.34 (br s, 1H), 5.57 (s, 1H), 3.95 (s, 3H), 2.56-2.59 (m, 2H), 2.40-2.42 (m, 2H), and 2.08-2.11 (m, 2H). MS (ESI) m/e [M+1]+ 324.0.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[F-:12].[Cs+].[F-].[K+].C1S(=O)(=O)CCC1>>[F:12][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [F-]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: [Cs+]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: O=[N+]([O-])c1ccc(F)c(F)c1
Yield: 10.3 %

Procedure:
1,500 parts of 3-chloro-4-fluoronitrobenzene, 25 parts of cesium fluoride and 1,000 parts of potassium fluoride are heated in 1,500 parts of tetramethylenesulfone for 16 hours at 230° C. The mixture is worked up as described in Example 1(a). 139 parts (10.3% of theory) of 3,4-difluoronitrobenzene of boiling point 54° C./1 mm Hg are obtained.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[CH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([O:15][CH3:16])[CH:8]=1)C.COC1C=C(CCC(OCC)=O)C=C(OC)C=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:16][O:15][C:9]1[CH:8]=[C:7]([CH2:6][CH2:5][CH2:4][OH:3])[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=1
Reactant: CCOC(=O)C=Cc1cc(OC)cc(OC)c1
Agent: CCOC(=O)CCc1cc(OC)cc(OC)c1
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CCCO)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Synthesized from 3-(3,5-dimethoxyphenyl)acrylic acid ethyl ester according to an analogous synthetic method to Example 22, ethyl 3-(3,5-dimethoxyphenyl)propionate (38.4 g) was added dropwise to a solution of lithium aluminum hydride (12.3 g) in tetrahydrofuran (200 ml) on an ice bath, and the solution was stirred for 15 minutes at room temperature. To the reaction solution were sequentially added water (12 ml), an aqueous solution of 5N sodium hydroxide (12 ml) and water (28 ml), the suspension was filtered, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (24.3 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])([O-])=O.[Na+].[Na+]>O>[C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Ic1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: c1ccc(-c2ccccc2)cc1
Temperature: 110 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
Complexes 7a, 7b, 7c are used for Suzuki coupling reaction of iodobenzene and benzeneboronic acid, as shown in scheme 2, above. Iodobenzene (2.5 mmol, 1 equiv.), benzeneboronic acid (2.75 mmol, 1.1 equiv.), Na2CO3 (560 mg, 5.28 mmol, 2.1 equiv.), palladium complex (0.03 mmol) and water (2.5 ml) are mixed with [C4mim][BF4] (5 ml). The mixture is heated to 110° C. with vigorous stirring for 12 hours, then cooled and extracted with diethyl ether (3×15 ml). The combined organic phase is dried over MgSO4 and filtered. The product, biphenyl, is obtained in 100% yield. If a nitrile ionic liquid, [C3CNmim][BF4], is used in place of the [C4mim][BF4], a similar yield is obtained. Significantly, using [C3CNmim][BF4] the yields can be maintained at above 90% even after six runs of catalysis, while yields decrease rapidly for [C4mim][BF4]. Dissolving PdCl2 in the [C3CNmim][BF4] gives the same result as using complexes 6 and 7.
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]C.CCCCCCCCCCCCCCCCC.[C:38]([OH:57])(=[O:56])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]/[CH:46]=[CH:47]\[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>CCCCCCCCCCCC.[Pd]>[CH3:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1].[C:38]([OH:57])(=[O:56])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: [Pd]
Agent: CCCCCCCCCCCCCCCCC
Solvent: CCCCCCCCCCCC
Product: CCCCCCCCCCCCCCCCCC(=O)O

Procedure:
The deoxygenation kinetics of stearic acid and oleic acids in H2 are closely similar, as shown in FIG. 10, with complete FFA conversion occurring in approximately 30 minutes and providing essentially 100% yield of n-heptadecane. Specifically shown in FIG. 10 is the results of stearic and oleic acid decarboxylation reactions in 10% H2 and dodecane solvent at 300° C. over 5% Pd/C catalyst for different reaction times. Shown are oleic acid conversion (Δ), oleic acid heptadecane yield (□), stearic acid heptadecane yield (∘), and oleic acid result with ½ catalyst (⋄).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]#[N:17])=[O:10])(C)(C)C.O.[ClH:20]>CCOCC>[ClH:20].[NH2:7][CH2:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]#[N:17])=[O:10]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C#N
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: N#C[C@@H]1CCCN1C(=O)CN
Reaction time: 1 h
Yield: 98 %

Procedure:
(S)-[2-(2-Cyano-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester 1c (13.7 g, 54.2 mmol) was dissolved in 140 mL of ether and 40 mL of water with stirring. Upon cooling by an ice-water bath, 37% hydrochloric acid (90 mL) was dropwise added and the reaction mixture was stirred for 1 hour at the same temperature. The mixture was concentrated under reduced pressure and the residue diluted with ether was filtered with a filtering centrifuge to obtain the title compound (S)-1-(2-amino-acetyl)-pyrrolidine-2-carbonitrile hydrochloride 1d (10 g, yield 98%) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N+:15]=2[O-])[CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:22]1C=CC=CC=1.CC1C=CC(S(Cl)(=O)=O)=CC=1.NCCO>C(#N)C>[NH2:22][C:16]1[N:15]=[C:14]([C:10]2[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=2)[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:19]([CH3:20])=[CH:18][CH:17]=1
Reactant: c1ccncc1
Reactant: Cc1ccc[n+]([O-])c1-c1cccc(C(=O)OC(C)(C)C)c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Solvent: NCCO
Product: Cc1ccc(N)nc1-c1cccc(C(=O)OC(C)(C)C)c1
Temperature: 75 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
2-(3-(tert-Butoxycarbonyl)phenyl)-3-methylpyridine 1-oxide (29.8 g, 104 mmol) was dissolved in a mixture of acetonitrile (662 mL) and pyridine (33.8 mL, 418 mmol) under an atmosphere of argon. 4-Methylbenzene-1-sulfonyl chloride (pTsCl, 25.9 g, 136 mmol) was added and the reaction mixture was heated at 75° C. for 5 hours. 2-Aminoethanol (166 mL, 2.75 mol) was added after allowing the reaction mixture to cool to room temperature. After one hour, the acetonitrile was evaporated and the crude product was partitioned between ethyl acetate and a saturated aqueous solution of sodium chloride. The layers were separated and the organic layer was evaporated to dryness and then purified on 1.5 kg of silica gel utilizing a gradient of 0-100% ethyl acetate in hexanes to yield tert-butyl 3-(6-amino-3-methylpyridin-2-yl)benzoate (15.2 g, 51%) as a white solid. ESI-MS m/z calc. 284.1, found 285.2 (M+1)+. Retention time 1.16 minutes. 1H NMR (400 MHz, DMSO-d6) δ 7.99-7.98 (m, 1H), 7.90-7.87 (m, 1H) 7.72-7.7.69 (m, 1H), 7.52 (t, J=7.7 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 6.42 (d, J=8.3 Hz, 1H), 5.83 (s, 2H), 2.11 (s, 3H), 1.54 (s, 9H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[O:20][CH2:19][CH2:18][O:17]2)=[CH:12][N:11]=1>[Zn].[Ni](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[CH2:1]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[O:17][CH2:18][CH2:19][O:20]2)=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Brc1ccc(C2OCCO2)cn1
Agent: Cl[Ni]Cl
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(Cc2ccc(C3OCCO3)cn2)cc1
Reaction time: 4 h
Yield: 61.7 %

Procedure:
To a suspension of zinc (5.0 g, 77 mmol, highly reactive Rieke metal, 100 mL tetrahydrofuran suspension) and tetrahydrofuran (300 mL) was added dropwise benzyl bromide (7.9 mL, 66 mmol) at 0° C., which was stirred for 4 hours at the same temperature. To this suspension were added bis(triphenylphosphine) nickel (II) chloride (5.8 g, 8.8 mmol) and 2-bromo-5-[1,3]dioxolan-2-yl-pyridine (11 g, 49 mmol) described in Manufacturing Example 210-1-2, which was stirred for another 2 hours at room temperature. The reaction solution was partitioned into ethyl acetate and an ammonium chloride aqueous solution. The organic layer was separated and concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1, 1:1) to obtain the title compound (7.3 g, 62%).
Reaction SMILES: [C:1](=[S:4])([S-:3])[NH2:2].[NH4+].Br[CH2:7][C:8](=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10].C(O)C.C(OCC)(=O)C>O>[CH2:12]([O:11][C:9]([C:8]1[N:2]=[C:1]([SH:3])[S:4][CH:7]=1)=[O:10])[CH3:13]
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)[S-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1csc(S)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ammonium dithiocarbamate ##STR5## (1.10 g) in water (10 ml) were added ethyl bromopyruvate (1.95 g) and ethanol (5 ml) at ice-cooling. After stirring at room temperature for 1 hour, the mixture was poured into a mixture of water and ethyl acetate. The separated organic layer was washed with saturated sodium chloride solution (×2), dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent: ethyl acetate/n-hexane) to give 4-ethoxycarbonyl-2-mercaptothiazole (1.21 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([CH2:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: CCc1ccc(Cl)cc1C(=O)OC
Agent: O=S(=O)(O)O
Product: CCc1c(C(=O)OC)cc(Cl)cc1[N+](=O)[O-]
Temperature: -5 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
A solution of methyl 5-chloro-2-ethylbenzoate (1.08 g, 5.4 mmol) in concentrated sulphuric acid (7.0 ml) was cooled to −5° C. in an acetone/ice bath. A mixture of 70% nitric acid (0.45 ml, 7.1 mmol) and concentrated sulphuric acid (0.5 ml) was added dropwise to the reaction mixture at −5° C. over 15 minutes. The resulting pale yellow reaction mixture was stirred at −5° C. for 1 hour before being poured onto ice (100 ml) and extracted with CH2Cl2 (3×20 ml). The combined organic phases were washed with deionized water (20 ml), brine (20 ml), dried over Na2SO4, filtered and concentrated in-vacuo. The resulting oil was added to a solution containing methanol (25 ml) and thionyl chloride (0.75 ml) at 0° C. Following addition, the mixture was heated under gentle reflux for 6 hours, before cooling to room temperature and concentrating in-vacuo to give the title compound (1.2 g) as an orange oil which was used without further purification in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[C:12]=1[Cl:13])[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[CH3:17]O>>[Cl:13][C:12]1[C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:6]([C:7]([O:9][CH3:17])=[O:8])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CO
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Product: COC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reaction time: 15 h

Procedure:
2.96 ml of SOC12 is added at 0° C., under an inert atmosphere and dropwise to 10 g of 3,5-dinitro-4-chlorobenzoic acid (JANSSEN) in 150 ml of methanol and agitation is carried out under reflux of methanol for 2 hours then for 15 hours at ambient temperature. The reaction medium is poured into ice and precipitation of the product is observed. After drying, 10.3 g of expected product is obtained.
Reaction SMILES: O=S(Cl)Cl.[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[Cl:17])[C:11]([OH:13])=[O:12])([O-:7])=[O:6].[CH3:21]O>>[Cl:17][C:16]1[C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:10]([C:11]([O:13][CH3:21])=[O:12])=[CH:9][C:8]=1[N+:5]([O-:7])=[O:6]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reaction time: 15 h

Procedure:
2.96 ml of SOCl2 is added at 0° C., under an inert atmosphere and dropwise to 10 g of 3,5-dinitro-4-chloro-benzoic acid (JANSSEN) in 150 ml of methanol and agitation is carried out under reflux of methanol for 2 hours then for 15 hours at ambient temperature. The reaction medium is poured into ice and precipitation of the product is observed. After drying, 10.3 g of expected product is obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].[CH2:8]([O:10][C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])[CH3:9].C([N-]C(C)C)(C)C.[Li+]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:8]([O:10][C:11](=[O:15])[C:12]([CH3:14])([CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7])[CH3:9]
Reactant: CCOC(=O)C(C)C
Reactant: BrCCCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(C)(C)CCCCCBr
Yield: 31 %

Procedure:
Using the method described in Example 5(i). 1,5-dibromopentane (23 g, 0.1 mol) and ethylisobutyrate (10.4 g, 0.09 mol) were reacted in the presence of lithium diisopropylamide (0.1 mol) and hexamethylphosphoramide (22 g) to give the title compound as an oil (7.4 g).