Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([C:6]1[C:7]([C:17]([O:19]CC)=[O:18])=[N:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([F:5])[CH2:3][CH3:4].[OH-].[Na+]>C(O)C>[F:1][C:2]([C:6]1[C:7]([C:17]([OH:19])=[O:18])=[N:8][O:9][C:10]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([F:5])[CH2:3][CH3:4]
Reactant: CCOC(=O)c1noc(-c2ccccc2)c1C(F)(F)CC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(F)(F)c1c(C(=O)O)noc1-c1ccccc1
Yield: 99.8 %

Procedure:
A solution of ethyl 4-(1,1-difluoropropyl)-5-phenylisoxazole-3-carboxylate (8.9 mg, 0.030 mmol) and 1N aqueous sodium hydroxide (36 μL, 0.036 mmol) in ethanol (1 mL) was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The residue was suspended in water (0.5 mL) and acidified with 1N aqueous hydrochloric acid to a pH of ˜3. The aqueous solution was extracted with ethyl acetate (3×2 mL), and the combined organic layers were washed with water (1 mL), washed with brine (1 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 4-(1,1-difluoropropyl)-5-phenylisoxazole-3-carboxylic acid (8.0 mg). The compound had an HPLC ret. time=2.69 min.−Column. YMC COMBISCREEN® ODS-A 4.6×50 mm S-5; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH−90% Water−0.1% TFA; Solvent B=90% MeOH−10% water−0.1% TFA.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14]O)[O:10][N:9]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=O.Cl.[N:31]1([C:37]([O:39][CH2:40][C:41]([NH:43][CH3:44])=[O:42])=[O:38])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][N:34]3[CH2:33][CH2:32][N:31]([C:37]([O:39][CH2:40][C:41]([NH:43][CH3:44])=[O:42])=[O:38])[CH2:36][CH2:35]3)[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: OCCc1cc(-c2ccc(Cl)cc2)no1
Reactant: CNC(=O)COC(=O)N1CCNCC1
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)COC(=O)N1CCN(CCc2cc(-c3ccc(Cl)cc3)no2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 0.100 g (0.447 mmol) of 2-[3-(4-chlorophenyl)isoxazol-5-yl]ethanol, prepared in step 6.1., and 0.082 ml (0.47 mmol) of diisopropylethylamine in 5 ml of dichloromethane, is admixed with 0.036 ml (0.469 mmol) of methanesulphonyl chloride. The mixture is stirred at ambient temperature for 4 hours and then washed with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution. It is concentrated under reduced pressure. The residue is taken up in 5 ml of acetonitrile, and 0.107 g (0.45 mmol) of 2-(methylamino)-2-oxoethyl piperazine-1-carboxylate hydrochloride, prepared in accordance with Example 3.3., and 0.186 g (1.35 mmol) of potassium carbonate are added. The mixture is heated at 75° C. for 16 hours. After cooling to ambient temperature, it is concentrated under reduced pressure. The residue is taken up in ethyl acetate and washed with water and then with saturated aqueous sodium chloride solution. The mixture is evaporated and the residue is purified by chromatography on silica gel, eluting with dichloromethane and then with a 90/10 mixture of dichloromethane and methanol. This gives 0.054 g (0.132 mmol) of product in the form of a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]([C:19]1[CH:30]=[CH:29][C:22]([O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=1)=[O:18])#[N:2].[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[NH4+].Cl>CN(C=O)C.O.C(Cl)(Cl)Cl>[NH:31]1[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=2)=[O:18])=[N:2][N:33]=[N:32]1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)COc1ccc(C(=O)Nc2ccccc2Sc2ccccc2C#N)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)COc1ccc(C(=O)Nc2ccccc2Sc2ccccc2-c2nnn[nH]2)cc1
Reaction time: 8 h
Yield: 33 %

Procedure:
In 10 ml of DMF were suspended 1.1 g of methyl 4-[2-(2-cyanophenylthio)phenylcarbamoyl]phenoxyacetate, 0.85 g of sodium azide and 0.7 g of ammonium chloride, and the mixture was Stirred at 110°-120° C. for 8 hours. After cooling, the reaction mixture was acidified with concentrated hydrochloric acid and diluted with water. The resulting precipitate was subjected to silica gel column chromatography (chloroform→chloroform-ethanol=50:1) to give 0.4 g of the title compound as white crystals, m.p. 204°-205° C.
Reaction SMILES: [C:1]1([C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:19])=O>>[C:1]1([C:11]2([C:14]([Cl:19])=[O:16])[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1(c2cccc3ccccc23)CC1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C1(c2cccc3ccccc23)CC1

Procedure:
1-(1-Naphthyl)cyclopropane carboxylic acid (6.7 g, prepared in a similar manner to that described in Example H20), was added to thionyl chloride (25 ml) and the mixture heated at 90°-95° C. for 1 hour. Excess thionyl chloride was removed in vacuo to yield 1-(1-naphthyl)cyclopropanecarbonyl chloride (7.1 g) which was used without further purification.
Reaction SMILES: O[C:2]1([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][C:17]=2[O:25][CH3:26])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-:14])=[O:13])[C:3]1=[O:15].S(Cl)([Cl:29])=O>>[Cl:29][C:2]1([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][C:17]=2[O:25][CH3:26])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-:14])=[O:13])[C:3]1=[O:15]
Reactant: COc1cc(C(C)C)ccc1C1(O)C(=O)c2cccc([N+](=O)[O-])c2C1=O
Reactant: O=S(Cl)Cl
Product: COc1cc(C(C)C)ccc1C1(Cl)C(=O)c2cccc([N+](=O)[O-])c2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-4-nitro-2H-inden-1,3-dione (1.00 g, 2.8 mmol) was dissolved in excess of thionyl chloride (10 ml), stirred at room temperature for 2 hrs. The reaction mixture was concentrated in a vacuum, and extracted with aq. sodium bicarbonate and ethylacetate. The organic layer was concentrated to afford the title compound (1.05 g, 77%).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[Cl:12][C:13]1[CH:14]=[C:15]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25]CO)[CH2:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1.[Na]>C1(C)C=CC=CC=1>[C:1]([O:10][CH2:11][CH2:25][N:22]1[CH2:21][CH2:20][N:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([Cl:12])[CH:14]=2)[CH2:24][CH2:23]1)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4]
Reactant: OCCN1CCN(c2cccc(Cl)c2)CC1
Reactant: COC(=O)c1ccccc1N
Agent: [Na]
Solvent: Cc1ccccc1
Product: Nc1ccccc1C(=O)OCCN1CCN(c2cccc(Cl)c2)CC1
Yield: 72 %

Procedure:
10.6 G. (0.07 mol) of methyl anthranilate, 12.1 g. (0.05 mol) of 2-(4-m-chlorophenylpiperazino)-ethanol, 150 ml. of dry toluene and 0.09 g. of sodium are heated in a distillation apparatus for 2 1/2 hours on an oil bath, while slowly distilling the methanol eliminated in the transesterification reaction. The toluene solution is filtered while hot to remove a small amount of insoluble matter, the toluene is evaporated from the filtrate, and the residue is triturated in petroleum ether, filtered and recrystallised from isopropyl alcohol to give 13 g. (yield = 72%) of 2-(4-m-chlorophenylpiperazino)-ethyl anthranilate, which melts at 77°C., and which is found to be identical to the product prepared in Example 18 using a mixed melting point.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[NH:14]1[CH2:19][CH2:18][S:17][CH2:16][CH2:15]1>>[N:14]1([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:19][CH2:18][S:17][CH2:16][CH2:15]1
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: C1CSCCN1
Product: N#Cc1ccc(N2CCSCC2)c2ccccc12
Yield: 20.2 %

Procedure:
The title compound (6 mg, 20% yield) was prepared as described for 196MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg, 0.117 mmol) and thiomorpholine (48 mg, 0.468 mmol).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:32]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][N:29]([C:38]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[O:39])[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Nc1ncnn2c(C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncnn2c(C3CCN(C(=O)N4CCOCC4)C3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
(5-(2-benzyl-2H-indazol-6-yl)-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (75 mg, 0.183 mmol) was dissolved in tetrahydrofuran (2 mL). Morpholine-4-carbonyl chloride (27 mg, 0.183 mmol) was added to the reaction mixture followed by triethylamine (51 uL, 0.366 mmol). The suspension was stirred at rt overnight. The reaction was concentrated under vacuum. The compound was triturated with 1:1 ether-hexanes to yield desired product (70 mg, 73%). 1H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1 H), 7.92 (s, 1 H), 7.79 (d, 1 H), 7.58 (m, 3 H), 7.35-7.32 (m, 4 H), 7.13 (d, 1 H), 6.67 (s, 1 H), 5.64 (s, 2 H), 3.90-2.50 (m, 13 H), 2.50-2.10 (m, 2 H); ES-MS m/z 523.3 [M+H]+, HPLC RT (min) 2.47.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:12]=[C:11]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[F:27][C:28]1[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[F:27][C:28]1[CH:33]=[CH:32][C:31]([NH:2][C:3]2[CH:12]=[C:11]([CH2:13][S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=[CH:9][C:4]=2[C:5]([O:7][CH3:8])=[O:6])=[CH:30][CH:29]=1
Reactant: Fc1ccc(I)cc1
Reactant: COC(=O)c1ccc(CSc2ccccc2)cc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CSc2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To toluene 9.5 mL suspension of methyl 2-amino-4-((phenylthio)methyl)benzoate hydrochloride 0.96 g, rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl 19 mg, palladium acetate 7 mg and cesium carbonate 3.0 g was added 1-fluoro-4-iodobenzene 1.1 mL, and it was heated and refluxed under nitrogen atmosphere for 3 hours. After the reaction mixture was cooled to room temperature, palladium acetate 7.0 mg was added to it, and it was heated and refluxed for 14 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=20:1] to give methyl 2-(4-fluoroanilino)-4-((phenylthio)methyl)benzoate 0.48 g of pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:21])([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](OC)=[O:11].[H-].C([Al+]CC(C)C)C(C)C.CO.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.O>[F:1][C:2]([F:21])([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[O:11]
Reactant: CCCCCCCC(F)(F)CCCCCCCC(=O)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCC(F)(F)CCCCCCCC=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, methyl 9,9-difluoro-hexadecanoate (No. 6804231; 990 mg, 3.23 mmol) was dissolved in toluene (14 mL), and cooled to −78° C. While maintaining the temperature at −78° C., a dilution of diisobutylaluminum hydride (DIBAlH, 1.5 M solution in toluene, 2.59 mL, 3.88 mmol) with toluene (3.8 mL) was added dropwise, and the mixture was stirred at −78° C. for 2.0 hours. Methanol (0.86 mL) was added to the reaction solution, and the mixture was stirred at −78° C. for 10 minutes to stop the reaction. A saturated Rochelle salt aqueous solution (4.0 mL) and water (12 mL) were further added and the mixture was stirred at 0° C. for 1 hour. After insoluble material was filtered off and washed with dichloromethane, the filtrate was extracted with dichloromethane, the organic layer was washed with water, and dried over anhydrous sodium sulfate. Subsequently, the organic layer was filtered and dichloromethane was distilled off to obtain a crude product of 9,9-difluoro-hexadecanal (No. 6893452).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:12][C:11](=[O:13])[CH2:10][O:9][C:8]=2[CH:14]=1)([O-:3])=[O:2].Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:12]([CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[C:11](=[O:13])[CH2:10][O:9][C:8]=2[CH:14]=1)([O-:3])=[O:2]
Reactant: ClCCN1CCCC1
Reactant: O=C1COc2cc([N+](=O)[O-])ccc2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1COc2cc([N+](=O)[O-])ccc2N1CCN1CCCC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 65.3 %

Procedure:
A suspension of 7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (0.5 g, 2.575 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (0.43 g, 2.575 mmol) and K2CO3 (1.06 g, 7.726 mmol) in dry DMF (5 mL) was stirred at 100° C. overnight (18 hours). The reaction was brought to room temperature, diluted with water (100 mL), and the product was extracted into ethyl acetate (2×25 mL). The combined ethyl acetate layers were washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated, and the crude material was purified by column chromatography (3:97 (2M NH3 in MeOH):CH2Cl2) to obtain the title compound (0.49 g, 65%) as a solid. 1H NMR (DMSO-d6) δ 1.62-1.70 (m, 4H), 2.46-2.54 (m, 4H, merged with DMSO-d6 resonance), 2.60 (t, 2H, J=6.9 Hz), 4.08 (t, 2H, J=6.9 Hz), 4.80 (s, 2H), 7.44 (d, 1H, J=9.3 Hz), 7.80 (d, 1H, J=2.4 Hz), 7.96 (dd, 1H, J=2.7, 9.0 Hz); ESI-MS (m/z, %): 292 (MH+, 100).
Reaction SMILES: [OH:1][C@H:2]1[C:6]([CH3:8])([CH3:7])[CH2:5][O:4][C:3]1=[O:9].C(N(C(C)C)CC)(C)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21].Cl>ClCCl.CCOC(C)=O>[CH3:7][C:6]1([CH3:8])[CH2:5][O:4][C:3](=[O:9])[CH:2]1[O:1][C:19](=[O:22])[CH:20]=[CH2:21]
Reactant: C=CC(=O)Cl
Reactant: CC1(C)COC(=O)[C@H]1O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C=CC(=O)OC1C(=O)OCC1(C)C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
Acrylic acid 4,4-dimethyl-2-oxo-tetrahydro-furan-3-yl ester (R) was prepared in the following manner: 3-(S)-Hydroxy-4,4-dimethyl-dihydro-furan-2-one (2.60 g, 20 mmol) and diisopropylethylamine (5.2 mL, 30 mmol) in dichloromethane (25 mL) was cooled to −10° C. and treated dropwise with acryloyl chloride (2.03 mL, 25 mmol) and stirred for 2 h. 1M HCl (20 mL) was added and the organic layer was washed with sodium bicarbonate and water. The organic layer was dried over sodium sulfate, filtered and concentrated. Flash chromatography (10-40% EtOAc, hexanes) afforded 2.09 g (57% yield) of the desired acrylic acid 4,4-dimethyl-2-oxo-tetrahydro-furan-3-yl ester (R) as a clear oil. This substrate was used to prepare the acid chloride of (1R)-4-methyl-cyclohex-3-enecarboxylic acid analogous to the procedure described in Scheme 15 and Scheme 16.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:22](=[O:24])[CH3:23])([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](OC)(=[O:30])[C:26]([O:28]C)=[O:27].[H-].[Na+].C(=O)(O)[O-].[Na+].Cl>C(COC)OC.O1CCCC1>[ClH:21].[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:22](=[O:24])[CH2:23][C:25](=[O:30])[C:26]([OH:28])=[O:27])([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)C1(Cc2ccc(Cl)cc2)CCCN(Cc2ccccc2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: COCCOC
Solvent: C1CCOC1
Product: O=C(O)C(=O)CC(=O)C1(Cc2ccc(Cl)cc2)CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 10.8 %

Procedure:
A solution of N-Benzyl-3-acetyl-3-(4-chlorobenzyl)piperidine (492 mg, 1.44 mmol) and dimethyl oxalate (201 mg, 1.7 mmol) in dimethoxyethane (20 mL) was treated with sodium hydride (140 mg of a 60% dispersion in mineral oil, 3.4 mmol) and heated to reflux for 5 hours. The reaction was then cooled to room temperature, poured into saturated sodium bicarbonate (100 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The crude ester thus obtained was purified by chromatography on silica gel eluting with 10% methanol/chloroform. The material thus obtained was dissolved in tetrahydrofuran (5 mL) and 3 N HCl (20 mL) and heated to reflux for 1 hour. The reaction was then cooled to room temperature, and concentrated at reduced pressure. The residue was triturated with tetrahydrofuran and the solid collected by filtration and crystallized from isopropanol to give 35 mg of the title compound. mp. 160° -165° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:35]=[CH:34][C:23]([O:24][C:25]3[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=3)[C:28]([OH:30])=[O:29])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([CH3:36])[CH:3]=1.Cl.[NH2:38][OH:39].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[CH:22][C:23]([O:24][C:25]3[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=3)[C:28]([OH:30])=[O:29])=[CH:34][CH:35]=2)[CH2:9]/[C:10](=[N:38]\[OH:39])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([CH3:36])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Oc2cccc(C(=O)O)c2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Oc2cccc(C(=O)O)c2)cc1

Procedure:
In analogy to example 151, step 3, 3-{4-[1-(4-chloro-2-methyl-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-propyl]-phenoxy}-benzoic acid was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound containing 9% of the corresponding Z isomer as a colourless solid, MS (ESI−): m/z=515.3 [M−H]−.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:8]=1)=O.[C:27]1([NH:33]N)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CO>[C:27]1([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[CH:16][C:17]([N:20]5[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]5)=[CH:18][CH:19]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NNc1ccccc1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccc(N3CCCCC3)cc2)ccc1=O
Solvent: CO
Product: O=c1ccn(-c2ccc(N3CCCCC3)cc2)nc1-c1ccnn1-c1ccccc1
Yield: 4 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(4-piperidin-1-ylphenyl)pyridazin-4(1H)-one (crude 700 mg, 1.99 mmol) in 20 mL of methanol was added phenylhydrazine (858 mg, 7.94 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 3-(1-phenyl-1H-pyrazol-5-yl)-1-(4-piperidin-1-ylphenyl)pyridazin-4(1H)-one (30 mg, 4% for two steps) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[N:10]([CH3:11])[C:9](=[O:12])[CH2:8][C@@H:7]1[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[O:5])[CH3:2].N1C=CN=C1.[CH3:25][C:26]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])[CH3:27].Cl>CN(C=O)C>[CH2:1]([O:3][C:4]([C@@H:6]1[N:10]([CH3:11])[C:9](=[O:12])[CH2:8][C@@H:7]1[C:13]1[CH:14]=[CH:15][C:16]([O:19][Si:29]([CH3:31])([CH3:30])[C:26]([CH3:28])([CH3:27])[CH3:25])=[CH:17][CH:18]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)[C@H]1[C@@H](c2ccc(O)cc2)CC(=O)N1C
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1[C@@H](c2ccc(O[Si](C)(C)C(C)(C)C)cc2)CC(=O)N1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.6 %

Procedure:
To a solution of (±)-(4R*,5R*)-5-ethoxycarbonyl-1-methyl-4-(4-hydroxyphenyl)pyrrolidin-2-one (Intermediate W, 0.400 g, 1.53 mmol) in anhyd. DMF (1.5 mL) was added imidazole (0.240 g, 3.05 mmol), followed by TBDMSCl (0.250 g, 1.68 mmol) and the mixture stirred at room temperature for 18 h. The resulting mixture was poured into a 0.5N HCl solution and extracted with EtOAc. The combined organic layers were dried (MgsO4) and concentrated under reduced pressure give a clear oil which was purified by flash chromatography (gradient from 67% to 100% EtOAc/hex) to yield (±)-(4R*,5R*)-5-ethoxycarbonyl-1-methyl-4-[4-(1,1,2,2-tetramethyl-1-silapropoxy)-phenyl)pyrrolidin-2-one (512 mg, 89%) as a light yellow oil: 1H NMR (DMSO-d6) δ 0.13 (s, 6H), 0.75 (t, J=7.0 Hz, 3H), 0.91 (s, 9H), 0.24-0.70 (m, 5H), 3.55-3.76 (m, 2H), 3.88 (q, J=9.1 Hz, 1H), 4.43 (d, J=9.1 Hz, 1H), 6.75-6.79 (m, 2H), 7.07-7.13 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[C:5]([NH2:17])=[N:4][CH:3]=1.C[C@@H](N)C1C=CC=CC=1.NC1C(Br)=NC(Br)=CN=1.CCC[CH2:39][OH:40]>>[C:11]1([C@H:9]([N:8]2[C:6]3=[N:7][CH:2]=[CH:3][N:4]=[C:5]3[NH:17][C:39]2=[O:40])[CH3:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Br:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])[C:5]([NH2:17])=[N:4][CH:3]=1
Reactant: CCCCO
Agent: C[C@@H](N)c1ccccc1
Agent: C[C@@H](Nc1nc(Br)cnc1N)c1ccccc1
Agent: Nc1ncc(Br)nc1Br
Product: C[C@H](c1ccccc1)n1c(=O)[nH]c2nccnc21

Procedure:
(R)-6-Bromo-N2-(1-phenylethyl)pyrazine-2,3-diamine. The title compound was prepared using (R)-α-methylbenzylamine (2.28 mL, 17.93 mmol), 2-amino-3,5-dibromo-pyrazine (3.00 g, 11.96 mmol), and n-BuOH (30 mL) as described in General Procedure A. The crude compound was purified via silica gel chromatography (20%-30% EtOAc in hexanes). Clean fractions were combined and condensed, and subsequently triturated from methanol with water while sonicating to afford 1.92 g (6.54 mmol, 55%) of (R)-6-bromo-N2-(1-phenylethyl)pyrazine-2,3-diamine. MS (ESI) m/z 294.0 [M+1]+.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[C:16]([C:20]1[CH:25]=[CH:24][C:23](O)=[C:22]([N+:27]([O-:29])=[O:28])[CH:21]=1)([CH3:19])([CH3:18])[CH3:17].N1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:16]([C:20]1[CH:25]=[CH:24][C:23]([O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])=[C:22]([N+:27]([O-:29])=[O:28])[CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ccc(O)c([N+](=O)[O-])c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86.7 %

Procedure:
Triflic anhydride (4.14 mL, 24.6 mmol) was added dropwise to a solution of 4-tert-butyl-2-nitrophenol (4.00 g, 20.5 mmol) and pyridine (2.16 mL, 26.7 mmol) in methylene chloride (50 mL) at 0° C. The yellow solution was stirred 0.25 h at 0° C., poured onto saturated aqueous NaHCO3 and extracted with methylene chloride. The combined extracts were washed with saturated aqueous NaHCO3, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by filtration through a plug of silica-gel (methylene chloride) to provide trifluoro-methanesulfonic acid 4-tert-butyl-2-nitro-phenyl ester (5.82 g, 87%) as a pale yellow oil which was utilized without further purification.