Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:16]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:15][N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH:32]12[CH2:37][CH:35]([CH2:36]1)[CH2:34][NH:33]2>>[CH:32]12[CH2:37][CH:35]([CH2:36]1)[CH2:34][N:33]2[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:16]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:15][N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(I)c3)nc12
Reactant: C1NC2CC1C2
Agent: Cl
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(N4CC5CC4C5)c3)nc12

Procedure:
1-[2-[3-(2-Azabicyclo[2.1.1]hex-2-yl)-phenyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one was prepared from 1-[2-(3-Iodo-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one and 2-azabicyclo[2.1.1]hexane hydrochloride as described above (34%; MS=361 M+H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:32]([O:36][C:37]([N:39]1[CH:44]([CH2:45][OH:46])[CH2:43][CH:42]2[CH:40]1[CH2:41]2)=[O:38])([CH3:35])([CH3:34])[CH3:33].O[C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1>O1CCCC1>[C:32]([O:36][C:37]([N:39]1[CH:44]([CH2:45][O:46][C:48]2[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=2)[CH2:43][CH:42]2[CH:40]1[CH2:41]2)=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1C(CO)CC2CC21
Reactant: Oc1cccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(COc2cccnc2)CC2CC21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
To an ice cold solution of triphenylphosphine (1.66 grams, 6.4 mmol) in dry tetrahydrofuran (7 mL) was added diethyl azodicarboxylate (1.0 mL, 6.4 mmol). The mixture was warmed to room temperature and stirred for 30 minutes. The reaction mixture was cooled to 0° C. and a solution of 3-Hydroxymethyl-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (obtained in step (vii) of preparation 1) (0.9 grams, 4.2 mmol) in dry tetrahydrofuran (7 mL) was added followed by a solution of 3-hydroxypyridine (0.6 grams, 6.4 mmol) in dry tetrahydrofuran (14 mL). The reaction mixture was gradually warmed to room temperature and stirred for 0.16 hours. The volatiles were evaporated under reduced pressure and crude obtained was purified by flash column chromatography using 230-400 mesh silica gel to obtain title compound 0.83 grams as gummy liquid. Yield: 68%.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20](=[O:25])N(OC)C)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>CCOCC>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH:20]=[O:25])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Yield: 83.8 %

Procedure:
To a mixture of lithium aluminum hydride (1M THF solution, 4.4 ml) in ether (4 ml) was added dropwise at −60 C4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (1 g, 3.67 mmols) in ether (6 ml). The reaction mixture was allowed to warm to 0-5 C and then re-cooled to −60 C. Celite was added and reaction was quenched with a solution of KHSO4 (19) in water (3 ml), filtered through Celite. The filtrate was washed with cold 1N HCl, saturated NaHCO3, brine and dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel eluting with ethyl acetate in hexanes (1:1) to provide title compound (656 mg, 84%). (Org. Prep. Proced. Int., 2000, 32, 96.)
Reaction SMILES: N[C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[CH:4][N:3]=1.C(=O)(O)O.[NH2:28][C:29]([NH2:31])=[NH:30].O>CN(C)C(=O)C>[NH2:30][C:29]1[N:31]=[C:8]([NH2:9])[C:7]2[C:2](=[N:3][CH:4]=[C:5]([C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:22])([F:21])[F:23])[CH:11]=3)[N:6]=2)[N:28]=1
Reactant: N#Cc1nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cnc1N
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1nc(N)c2nc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cnc2n1

Procedure:
Under a nitrogen atmosphere, a stirred solution of 1.0 gram (0.003 mole) of 2-amino-3-cyano-5-[3,5-di(trifluoromethyl)phenyl]pyrazine and 1.3 grams (0.007 mole) of guanidine carbonate in 10 mL of N,N-dimethylacetamide is heated at about 150° C. for 40 hours. After this time, the reaction mixture is poured into 50 mL of water. The resultant solid is collected by filtration and is then slurried in 25 mL of diethyl ether. The solid is again collected by filtration and is then recrystallized from ethanol, yielding 2,4-diamino-6-[3,5-di(trifluoromethyl)phenyl]pteridine.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][C@H:4]([OH:7])[CH2:3]1.Cl[C:9]1[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([S:17][CH3:18])[N:10]=1>C1COCC1>[OH:7][C@H:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([S:17][CH3:18])[N:10]=2)[CH2:3]1
Reactant: N[C@H]1CC[C@H](O)C1
Reactant: CSc1ncc(C#N)c(Cl)n1
Solvent: C1CCOC1
Product: CSc1ncc(C#N)c(N[C@H]2CC[C@H](O)C2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
TEA (0.84 mL, 6.04 mmol) was added to a solution of trans-3-amino-cyclopentanol (1.83 g) in anhydrous THF (10 mL), under argon atmosphere. 4-Chloro-2-methylsulfanyl-pyrimidine-5-carbonitrile (1.13 g, 6.04 mmol) was then added in two portions and the resulting mixture was stirred, at RT, under argon atmosphere, for 2 h. The liquid layer was decanted and THF was added to the gummy residue. The extraction procedure was repeated and the combined extracts were evaporated under reduced pressure. The crude residue was absorbed onto silica gel and purified by flash chromatography (EtOAc/hexane) to give 1.0 g of trans-4-(3-hydroxy-cyclopentylamino)-2-methylsulfanyl-pyrimidine-5-carbonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4](F)[CH:3]=1.O.[NH2:12][NH2:13]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:6]=[N:12][NH:13]2)=[CH:8][CH:9]=1
Reactant: NN
Reactant: O=Cc1ccc(Cl)cc1F
Solvent: O
Solvent: CC(=O)N(C)C
Product: Clc1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A DMA (250 mL) solution containing 4-chloro-2-fluorobenzaldehyde (50 g, 315 mmol) and hydrazine monohydrate (230 mL, 4730 mmol) was stirred for 30 minutes at room temperature. The solution was then stirred at 100° C. for 17 hours. The reaction mixture, which was a thick white slurry, was cooled to room temperature. The solid was collected by filtration, washed with water and dried under vacuum to give the indicated product.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-])=O>[Pd].CO>[CH3:1][N:2]([CH3:14])[C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10]
Reactant: CN(C)C(=O)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)c1ccccc1N
Reaction time: 3 h
Yield: 101.4 %

Procedure:
Palladium on charcoal (0.54 g, 10% Pd by weight) was added to a solution of 2.1 g N,N-dimethyl-2-nitrobenzamide in 150 mL methanol. The resulting suspension was hydrogenated at room temperature at atmospheric pressure for three hours. After filtration of the catalyst, the solvent was removed in vacuo affording N,N-dimethyl-2-aminobenzamide (1.8 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[Br-:12].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)(Cl)Cl>[Br:12][C:9]1[CH:8]=[CH:7][C:6]([OH:11])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:10]=1
Reactant: CC(C)(C)c1ccccc1O
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc(Br)ccc1O
Temperature: 25 °C

Procedure:
2-tert-Butyl-phenol (5 g, 0.033 mol) was dissolved in CHCl3 (100 mL) and magnetically stirred at room temperature. To this solution was added a solution of Tetrabutyl ammonium tribromide (16.05 g, 0.033 mol) in CHCl3 (100 mL). The resulting yellow solution was allowed to stir at room temperature for 1 hour. The reaction was quenched with a 5% solution of sodium thiosulfate (200 mL). The biphasic mixture was stirred for 15 min. The organics were separated and concentrated. The residue was dissolved in EtOAc (100 mL) and washed with water (2×100 mL) and brine (1×100 mL). The organics were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel) eluting with 3% EtOAc in Hexanes. The result was a clear oil (6.8 g, 89%) 1H NMR (CDCl3): δ 1.39 (s, 9H), 4.95 (s, 1H), 6.59 (d, J=8.5 Hz 1H), 7.19 (d, J=8.5 Hz, 1H), 7.24 (s, 1H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([Cl:12])[CH:5]=1.[OH-].[Na+].[ClH:16]>O>[Cl:12][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH3:11])[C:3]([Cl:16])=[O:2]
Reactant: Cl
Reactant: COC(=O)c1ccc(OC)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C(=O)Cl)cc1Cl

Procedure:
A mixture of 10.4 g. (0.052 mol.) of 3-chloro-4-methoxybenzoic acid methyl ester and 3.5 g. (0.09 mol.) of sodium hydroxide in 150 ml. of water was refluxed for two hours. The reaction mixture was cooled and acidified with 10% aqueous hydrochloric acid to precipitate 3-chloro-4-methoxybenzoic acid, m.p. 199°-202°. The acid was refluxed with thionyl chloride as described in the procedure of Example 9 to give 3-chloro-4-methoxybenzoic acid chloride, m.p. 55°-57°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[CH2:14])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH2:17][N:18]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:19][Si](C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:24]([N:18]1[CH2:17][CH2:14][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])([C:10]([O:12][CH3:13])=[O:11])[CH2:19]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=C(NC(=O)OC(C)(C)C)C(=O)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
To a solution of methyl 2-(tert-butoxycarbonylamino)acrylate (16.5 g, 82.0 mmol) and N-(Methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (19.5 g, 82.0 mmol) in DCM (400 mL) was added dropwise TFA (0.32 mL) at 0° C. under nitrogen. The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3 and brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (3% MeOH in DCM) to give methyl 1-benzyl-3-(tert-butoxycarbonylamino)pyrrolidine-3-carboxylate (21.7 g, 79%).
Reaction SMILES: [CH3:1][N:2]1[C:12]2[C:7](=[C:8]([C:15](=[O:18])[CH2:16]Cl)[CH:9]=[CH:10][C:11]=2[O:13][CH3:14])[CH:6]=[CH:5][C:3]1=[O:4].[CH:19]([NH2:22])([CH3:21])[CH3:20]>C(O)(C)C>[CH3:1][N:2]1[C:12]2[C:7](=[C:8]([C:15](=[O:18])[CH2:16][NH:22][CH:19]([CH3:21])[CH3:20])[CH:9]=[CH:10][C:11]=2[O:13][CH3:14])[CH:6]=[CH:5][C:3]1=[O:4]
Reactant: CC(C)N
Reactant: COc1ccc(C(=O)CCl)c2ccc(=O)n(C)c12
Solvent: CC(C)O
Product: COc1ccc(C(=O)CNC(C)C)c2ccc(=O)n(C)c12
Yield: 13.7 %

Procedure:
2.7 g of 1-methyl-5-chloroacetyl-8-methoxycarbostyril (IV) prepared as described in Example 1 was dissolved in 40 ml of isopropanol, and 9 g of isopropylamine (III) was added to the solution while heating the solution at a temperature of 55° to 60° C. over a period of 1.5 hours. After completion of the addition, the mixture was allowed to react for one hour while stirring. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in 40 ml of isopropanol. The solution was then filtered to remove any insoluble material, and the filtrate was adjusted to a pH of 2-3 with concentrated hydrochloric acid. The mixture was cooled with ice and the precipitate formed was filtered and recrystallized from ethanol to obtain 0.4 g of white amorphous 1-methyl-5-isopropylaminoacetyl-8-methoxycarbostyril (IIb) hydrochloride. The product thus obtained was confirmed by elemental analysis and IR spectral analysis.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=3[CH3:22])[CH:9]=[N:10][C:5]2=[C:4](Cl)[CH:3]=1.[CH3:24][O-:25].[Na+]>>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=3[CH3:22])[CH:9]=[N:10][C:5]2=[C:4]([O:25][CH3:24])[CH:3]=1
Reactant: Cc1c(Cn2cnc3c(Cl)cc(Cl)nc32)cccc1C(F)(F)F
Reactant: C[O-]
Agent: [Na+]
Product: COc1cc(Cl)nc2c1ncn2Cc1cccc(C(F)(F)F)c1C
Yield: 55.2 %

Procedure:
5,7-dichloro-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-3H-imidazo[4,5-b]pyridine (200 mg, 0.555 mmol) was suspended in Methanol (1.5 mL), sodium methoxide (0.150 mL, 0.656 mmol) was added and the mixture was irradiated in a microwave oven for 90 min at 110° C. Conversion to desired product was observed by LC/MS (5,7-dimethoxy product, 5-methoxy isomer and 7-OH-5-Cl derivative observed by mass as well). The mixture was diluted with water and the precipitate formed was collected by filtration, washed with water and dried. The solid was purified on silica gel (ISCO 0-60% EtOAc in hexanes) to give 5-chloro-7-(methyloxy)-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-3H-imidazo[4,5-b]pyridine (125 mg, 0.351 mmol, 63.3% yield) as a white powder. Additional material was prepared from 120 mg of 5,7-dichloro-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-3H-imidazo[4,5-b]pyridine, irradiated in a microwave for 30 min at 110° C. in the presence of NaOMe. After work-up, 5-chloro-7-(methyloxy)-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-3H-imidazo[4,5-b]pyridine (109 mg, 0.306 mmol, 55.2% yield) was obtained and carried on without further purification to the next step. MS (ES+) m/e 356 (MH+).
Reaction SMILES: [N+](C1C=C(C=CC=1)C(Cl)=O)([O-])=O.N1CCC(C(OCC)=O)CC1.[CH2:24]([O:26][C:27]([CH:29]1[CH2:34][CH2:33][N:32]([C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([N+:43]([O-])=O)[CH:38]=2)=[O:36])[CH2:31][CH2:30]1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([CH:29]1[CH2:30][CH2:31][N:32]([C:35]([C:37]2[CH:38]=[C:39]([CH:40]=[CH:41][CH:42]=2)[NH2:43])=[O:36])[CH2:33][CH2:34]1)=[O:28])[CH3:25]
Reactant: CCOC(=O)C1CCN(C(=O)c2cccc([N+](=O)[O-])c2)CC1
Agent: CCOC(=O)C1CCNCC1
Agent: O=C(Cl)c1cccc([N+](=O)[O-])c1
Product: CCOC(=O)C1CCN(C(=O)c2cccc(N)c2)CC1

Procedure:
In like manner to the preparation of 3-(N-morpholinocarbonyl)aniline, 3-nitrobenzoylchloride and ethyl isonipecotate were reacted to prepare 1-[4-(ethoxycarbonyl)piperidinocarbonyl]-3-nitrobenzene which underwent hydrogenation to provide 3-[4-(ethoxycarbonyl)piperidinocarbonyl]aniline.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH2:10])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1F>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1[NH:10][CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CC1CCN(CCN)CC1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CCN(CCNc2ccc([N+](=O)[O-])cc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 12.02 g (32.45 mmol) of 2-(4-methylpiperidin-1-yl)ethylamine in 100 mL of DMF is combined with 17.94 g (64.82 mmol) of potassium carbonate and stirred for 15 minutes at ambient temperature. Then 5.81 g (32.45 mmol) of 3-chloro-4-fluoronitrobenzene are added and the reaction mixture is stirred for 18 hours. Then the reaction mixture is poured into ice water and the crystalline residue is filtered off. Yield: 8.85 g (91.6% of theory); C14H20ClN3O2 (M=297.78); calc.: molecular ion peak (M+H)+: 298/300; found: molecular ion peak (M+H)+: 298/300.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=N)[CH2:6][C:7](OCC)=[O:8])[CH3:3].[Cl:13][C:14]1[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[CH:17]=[C:16]([Cl:24])[C:15]=1[NH:25][NH2:26].[Na].C(O)(=O)C>CO.O>[Cl:13][C:14]1[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[CH:17]=[C:16]([Cl:24])[C:15]=1[N:25]1[C:7](=[O:8])[CH:6]=[C:5]([O:4][CH2:2][CH3:3])[NH:26]1
Reactant: COC(=O)c1cc(Cl)c(NN)c(Cl)c1
Reactant: CCOC(=N)CC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CCOc1cc(=O)n(-c2c(Cl)cc(C(=O)OC)cc2Cl)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
Preparation using the method described in U.S. Pat. No. 3,615,506. A mixture of 11 g of ethyl β-ethoxy-β-iminopropionate hydrochloride and 12 g of 2,6 -dichloro-4-methoxycarbonylphenylhydrazine [Intermediate (h) used in Method (a) above] in 100 ml of methanol was stirred at room temperature for 1 hour. A solution containing 3g of metallic sodium dissolved in 50 ml of methanol was added dropwise to the mixture, and the mixture was further stirred at room temperature (about 20°-30°C) for 1 hour. After adding 15 ml of acetic acid, the reaction mixture was poured into 500 ml of water. The cyrstals formed were collected and recrystallized from methanol to obtain 11 g of 1-(2,6 -dichloro-4-methoxycarbonylphenyl)-3-ethoxy-5-pyrazolone having a melting point of 101°-102.5°C. A mixture of 8 g of the 3-ethoxy-5-pyrazolone compound and 4 g of 2,4 -dichloroaniline was heated to 140° C to form a uniform melt and after adding 1.4 g of methanesulfonic acid to the melt, the reaction was carried out at 140°-150°C for 3 hours with stirring while distilling off the ethanol formed. The reaction mixture was allowed to cool to 100°C and after adding 10 ml of methanol to dissolve the solid, the mixture was allowed to cool to room temperature to form cyrstals which were collected and recrystallized from methanol to obtain the desired compound. The melting point of the product was 132°-135°C and no lowering of the melting point was observed when it was melted together with 1-(2,6 -dichloro-4-methoxycarbonylphenyl)-3-(2,4 -dichloroanilino)-5-pyrazolone prepared by Method (a). The infrared spectra of both compounds were completely identical.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[F:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[CH2:13][CH2:14]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CCOC(C)=O>[F:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[CH2:13][CH2:14][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: Fc1cccc(CCBr)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cnn(CCc2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-nitro-1H-pyrazole (450 mg, 3.86 mmol) in acetone (15 mL), 3-fluorophenethyl bromide (784 mg, 3.86 mmol), K2CO3 (2.68 g, 19.301 mmol) and tetrabutylammonium bromide (120 mg, 0.38 mmol) was added. The white suspension was stirred at rt for 2 h, then the reaction mixture was diluted with H2O and EtOAc. The org. layer was separated and the aq. layer was extracted with EtOAc (1×). The combined org. layers were dried (MgSO4), filtered and the solvent was removed under reduced pressure. Purification of by FC (EtOAc/hept 3:7) gave 1-(3-fluorophenethyl)-4-nitro-1H-pyrazole as a off-white solid. LC-MS conditions B: tR=0.75 min, [M+H]+=no ionization.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@:7]2([CH3:23])[CH2:12][C:11](=[O:13])[N:10]([CH3:14])[C:9](=[N:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[NH:8]2)[S:5][CH:6]=1.[Li+].[CH3:25][Si]([N-][Si](C)(C)C)(C)C>C1COCC1.O.CO>[Br:1][C:2]1[CH:3]=[C:4]([C@:7]2([CH3:23])[C:12](=[CH2:25])[C:11](=[O:13])[N:10]([CH3:14])[C:9](=[N:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[NH:8]2)[S:5][CH:6]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CN1C(=O)C[C@@](C)(c2cc(Br)cs2)NC1=NC(=O)OC(C)(C)C
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C=C1C(=O)N(C)C(=NC(=O)OC(C)(C)C)N[C@]1(C)c1cc(Br)cs1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 85.6 %

Procedure:
The synthesis was adapted from the synthetic procedure by Pedregal et. al. Tetrahedron: Asymmetry 1994, 5, 921-926. Thus, to a solution of (S)-tert-butyl 4-(4-bromothiophen-2-yl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate (C1, 1.0 g, 2.48 mmol) in anhydrous THF (7 mL) at −70° C. was added dropwise a solution of LiHMDS (1M, 5 mL, 2 eq, 4.96 mmol) in THF. After stirring at −78° C. for 40 min, N,N-dimethylmethylene iminium iodide (Eschenmoser's salt, 0.92 g, 4.96 mmol) was added. The reaction mixture was allowed to warm up to rt and stirred for 16 h. The resulting reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with brine, dried (MgSO4), and concentrated in vacuo to give a crude product mixture containing C2 which was dissolved in methanol (8.0 mL), followed by addition of Mel (5.7 mL). The reaction mixture was stirred at rt for 16 h followed by evaporation of solvent. The residue was partitioned between saturated NaHCO3 (10 mL) and EtOAc (15 mL) and the organic layer was separated, washed with brine, dried (MgSO4). The solution was concentrated to give a yellow oil which was purified by column chromatography using 1:1 EtOAc/Hexane as eluent to give 0.88 g (85%) of (S)-tert-butyl 4-(4-bromothiophen-2-yl)-1,4-dimethyl-5-methylene-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate C3 as a yellow oil. 1HNMR (CDCl3, 300 MHz): δ 7.14 (s, 1H), 6.8 (s, 1H), 6.49 (s, 1H), 5.73 (s, 1H), 3.29 (s, 3H), 1.52 (br s, 9H). MS (ESI): MH+=415.6; MH++1=416.6; M+−55=359.9;
Reaction SMILES: C(OC([NH:8][C:9]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[C:28]([C:41]([F:44])([F:43])[F:42])[CH:27]=2)=[CH:22][N:21]=1)(C(OCC)=O)[C:10](OCC)=[O:11])=O)(C)(C)C.[Li+].[BH4-].C(O)C>C1COCC1>[NH2:8][CH:9]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[C:28]([C:41]([F:44])([F:42])[F:43])[CH:27]=2)=[CH:22][N:21]=1)[CH2:10][OH:11]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(NC(=O)OC(C)(C)C)(C(=O)OCC)C(=O)OCC)nc2)cc1C(F)(F)F
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2ccc(C(N)CO)nc2)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
Diethyl 2-(tert-butoxycarbonylamino)-2-(5-(4-(octyloxy)-3-(trifluoromethyl)-phenyl)-pyridin-2-yl)malonate 5a (110 mg, 0.176 mmol, 1.0 equiv) in THF (2.0 mL) was added LiBH4 (57 mg, 2.64 mmol, 15.0 equiv) at 0° C., followed by addition of ethanol (0.8 mL) carefully. The resultant was warmed up to room temperature for 10 minutes. LC-MS indicated the completion of the reaction. The reaction was terminated by addition of water. Extraction with ethyl acetate and the organic layer was washed with brine and dried over sodium sulfate and condensed. The residue (crude reduction product with significant decarboxylation) was treated with 2M HCl in THF to afford the title compound after preparative HPLC purification. MS (ESI, M+H+)=411.1; 1H NMR (400 MHz, DMSO-d6) δ 8.95 (d, 1H, J=2.4 Hz), 8.39 (s, 3H), 8.22 (dd, 1H, J=8.4 Hz, J=2.4 Hz), 8.01 (dd, 1H, J=8.4 Hz, J=2.0 Hz), 7.93 (d, 1H, J=2.0 Hz), 7.60 (d, 1H, J=8.4 Hz), 7.39 (d, 1H, J=9.2 Hz), 5.48 (br, 1H), 4.48 (br, 1H), 4.17 (t, 2H, J=6.0 Hz), 3.86-3.72 (m, 2H), 1.75 (m, 2H), 1.44 (m, 2H), 1.29 (m, 8H), 0.86 (t, 3H, J=6.8 Hz).