Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:5]=[CH:4][C:3]=1[N:17]1[C:21](=[O:22])[CH2:20][CH:19]([C:23]([OH:25])=O)[CH2:18]1.[CH3:26][NH2:27]>>[CH3:26][NH:27][C:23]([CH:19]1[CH2:20][C:21](=[O:22])[N:17]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)=[CH:7][C:2]=2[F:1])[CH2:18]1)=[O:25]
Reactant: CN
Reactant: O=C(O)C1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2F)C1
Product: CNC(=O)C1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2F)C1

Procedure:
The title compound is prepared in analogy to Example 20d) from (RS)-1-[2-fluoro-4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid and methylamine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19])[C:9]([CH3:25])([CH3:24])[CH2:8]2)=[O:4].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.Cl.C[N:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1.O1CCC(N)C1>ClCCl.C(OCC)(=O)C>[CH3:24][C:9]1([CH3:25])[CH2:8][C:13]2[C:12](=[CH:7][CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:14]=2)[NH:11][CH:10]1[C:15]1[CH:23]=[CH:22][CH:21]=[C:17]([C:18](=[O:19])[NH:49][CH:50]2[CH2:54][CH2:53][O:52][CH2:51]2)[CH:16]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)O)c1)N2
Reactant: CN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)NC3CCOC3)c1)N2
Reaction time: 8 h
Yield: 131.3 %

Procedure:
To a suspension of 3-(6-(methoxycarbonyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid (150 mg, 0.44 mmol.) in dichloromethane (10 mL) was added N-hydroxybenzotriazole (89.2 mg, 0.66 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.hydrochloric acid (253 mg, 1.32 mmol.), followed by 4-methylmorpholine (133.5 mg, 1.32 mmol) and the resultant mixture was stirred at room temperature for 1 h. Then tetrahydrofuran-3-amine (57.5 mg, 0.66 mmol) was added to the flask and the reaction mixture was stirred under nitrogen overnight. Thin layer chromatography (petroleum ether:ethyl acetate=1:1) and LC-MS showed the reaction was complete. The reaction was quenched with water and extracted with dichloromethane (twice). The combined organic layers were washed with 2% sodium hydroxide aqueous solution (twice) and water (3 times), dried over anhydrous sodium sulfate. Removal of the solvent in vacuo gave 236 mg methyl 3,3-dimethyl-2-(3-(tetrahydrofuran-3-ylcarbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate of as a white solid, which was dissolved in methanol and treated with sodium borohydride (24 mg, 0.63 mmol) for an additional 2 h. LC-MS showed the reaction was complete. The reaction was quenched with water and extracted with ethyl acetate/tetrahydrofuran, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford 192 mg of desired product as a white solid, which was pure enough for next step without further purification.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OCCCl)=O>C(Cl)Cl>[F:24][C:22]([F:23])([F:25])[O:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:26])=[CH:20][CH:19]=1
Reactant: O=C(c1ccc(OC(F)(F)F)cc1)C1CCN(Cc2ccccc2)CC1
Agent: O=C(Cl)OCCCl
Solvent: ClCCl
Product: O=C(c1ccc(OC(F)(F)F)cc1)C1CCNCC1
Reaction time: 0.5 h
Yield: 36 %

Procedure:
1-Benzyl-4-(4-trifluoromethoxybenzoyl)piperidine (4.8 g, 13.2.2 mmol) prepared in Reference Example 148 was dissolved in methylene chloride (60 ml), and this solution was cooled in an ice-bath. 2-Chloroethyl chloroformate (2.9 ml, 26.4 mmol) was added dropwise to the solution, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, methanol (100 ml) was added to the residue, and the resulting mixture was heated under reflux for 15 minutes. Water was added to the reaction mixture, which was stirred for 30 minutes, and neutralized with sodium hydroxide aqueous solution. The mixture was extracted with methylene chloride. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography(n-hexane/ethyl acetate=1/1) to afford 4-(4-trifluoromethoxybenzoyl)piperidine (1.3 g, yield 36%) as a pale orange-colored crystalline powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:8]=[C:9]([NH2:11])[CH:10]=1)=[O:4].C(N(CC)CC)C.ClCCl.[C:29](Cl)(=[O:33])[CH:30]([CH3:32])[CH3:31]>O.Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:8]=[C:9]([NH:11][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:10]=1)=[O:4]
Reactant: COC(=O)c1cc(N)cc(-c2ccc(C)cc2)c1
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cc(NC(=O)C(C)C)cc(-c2ccc(C)cc2)c1
Yield: 101.4 %

Procedure:
5-Amino-4′-methyl-biphenyl-3-carboxylic acid methyl ester (0.10 g, 2.49 mmol) and triethylamine (6.75 g, 7.47 mmol) were added to dichloromethane (40 mL) and stirred under nitrogen atmosphere. Isobutyryl chloride (0.318 g, 2.98 mmol) was added slowly, and the reaction mixture was stirred for 2.5 hours at room temperature. The mixture was diluted with water and 1N aqueous HCl, and the organic layer was separated, washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure to give 0.786 g of 5-isobutyrylamino-4′-methyl-biphenyl-3-carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][C@@H:5]([CH3:8])[CH2:4][N:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[F:16][C:17]1[CH:24]=[C:23](F)[CH:22]=[CH:21][C:18]=1[C:19]#[N:20].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN1C(=O)N(C)CC1.C(#N)C>[C:19]([C:18]1[CH:21]=[CH:22][C:23]([N:6]2[C@@H:5]([CH3:8])[CH2:4][N:3]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[C@H:2]([CH3:1])[CH2:7]2)=[CH:24][C:17]=1[F:16])#[N:20]
Reactant: N#Cc1ccc(F)cc1F
Reactant: C[C@@H]1CN[C@@H](C)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCN(C)C1=O
Solvent: CC#N
Product: C[C@@H]1CN(c2ccc(C#N)c(F)c2)[C@@H](C)CN1C(=O)OC(C)(C)C
Temperature: 120 °C
Reaction time: 48 h
Yield: 38.9 %

Procedure:
Into a solution of 9.74 g of tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate in 25 ml of DMI and 25 ml of acetonitrile were added 5 g of 2,4-difluorobenzonitrile and 11.4 g of cesium carbonate, followed by 2 days of stirring at 120° C. The reaction solution was poured into water, followed by extraction with ethyl acetate. After the organic layer was washed with saturated saline, it was dried over anhydrous sodium sulfate. The solvent was removed by evaporation and the resulting residue was purified by silica gel column chromatography to obtain 4.66 g of the title compound from an eluate eluted with hexane-ethyl acetate (80:20, v/v).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C@H:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH2:29][CH2:28][CH:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:26][CH:25]=3)=[CH:20][CH:19]=2)[C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:34])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C@H:14]([C:18]2[CH:19]=[CH:20][C:21]([C@H:24]3[CH2:25][CH2:26][C@@H:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:28][CH2:29]3)=[CH:22][CH:23]=2)[C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(C[C@@H](C(=O)O)c2ccc(C3=CCC(C(C)(C)C)CC3)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(C[C@@H](C(=O)O)c2ccc([C@H]3CC[C@@H](C(C)(C)C)CC3)cc2)cc1

Procedure:
To a solution of 4-{(R)-2-[4-(4-tert-Butyl-cyclohex-1-enyl)-phenyl]-2-carboxy-ethyl}-benzoic acid tert-butyl ester (3.0 g) in ethyl acetate (100 mL) added 10% palladium on carbon (300 mg). The mixture was stirred under a balloon filled with hydrogen, until proton NMR indicated the disappearance of the olefinic signal. The reaction was filtered through a plug of celite, and the filtrate was concentrated under reduced pressure to give a mixture of cis/trans isomers (in a ratio of 1:1, based on 1H NMR). The cis1 and trans isomers were separated by reverse phase chromatography with the latter being cis (1.34 g, 2.9 mmol, 35%). 1H NMR (CDCl3): δ 0.95 (9H, s), 1.23-1.38 (4H, m), 1.58 (9H, s), 1.88-1.98 (4H, m), 2.39-2.56 (1H, m), 3.05-3.12 (1H, m), 3.19-3.50 (1H, m), 3.82-3.90 (1H, m), 7.19-7.22 (6H, m), 8.81 (2H, d).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:17]=[C:16]([C:18]([NH2:20])=[O:19])[O:15][N:14]=2)=[CH:9][CH:8]=1)(C)(C)C.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[F-].[K+].[Br:49][C:50]1[CH:57]=[CH:56][CH:55]=[CH:54][C:51]=1[CH2:52]Br>CN(C=O)C.O>[Br:49][C:50]1[CH:57]=[CH:56][CH:55]=[CH:54][C:51]=1[CH2:52][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:17]=[C:16]([C:18]([NH2:20])=[O:19])[O:15][N:14]=2)=[CH:11][CH:12]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cc(C(N)=O)on2)cc1
Reactant: BrCc1ccccc1Br
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccc(OCc3ccccc3Br)cc2)no1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.1 %

Procedure:
3-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 13; 40 mg, 0.126 mmol) was dissolved in DMF (1.5 mL). K2CO3 (19 mg, 0.14 mmol), 18-crown-6 (5 mg, 0.02 mmol), KF (8 mg, 0.14 mmol), and 2-bromobenzyl bromide (20 mg, 0.10 mmol) were added. The reaction mixture was stirred at room temperature for 10 min and then at 40° C. for 12 h. H2O (2.5 mL) was added and the mixture was extracted with EtOAc. The organic layer was evaporated and purified by chromatography (35% EtOAc/hexanes) to give 3-[4-(2-bromo-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (7.5 mg, 16%) as a white powder. LRMS (ESI+): m/z [M+H]+ 376.1. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.35 (s, 1H), 7.98 (s, 1H), 7.85 (d, J=8.8 Hz, 2H), 7.64-7.72 (m, 1H), 7.59 (d, J=7.7 Hz, 1H), 7.53 (s, 1H), 7.39-7.48 (m, 1H), 7.26-7.36 (m, 1H), 7.16 (d, J=8.8 Hz, 2H), 5.19 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C@H:6]([CH3:13])[NH:5]2.Cl[C:15]([O:17][C:18]([CH3:20])=[CH2:19])=[O:16]>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:15]([O:17][C:18]([CH3:20])=[CH2:19])=[O:16])[C:7](=[O:12])[C@H:6]([CH3:13])[NH:5]2
Reactant: C[C@@H]1Nc2nc(Cl)ccc2NC1=O
Reactant: C=C(C)OC(=O)Cl
Solvent: c1ccncc1
Product: C=C(C)OC(=O)N1C(=O)[C@H](C)Nc2nc(Cl)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The compound of Example 2 (988 mg, 5.0 mmol) was dissolved in 30 ml of anhydrous pyridine. After addition of 0.6 ml (5.5 mmol) of isopropenyl chloroformate, the mixture was stirred at room temperature for 4 h and subsequently concentrated. The residue was dissolved in ethyl acetate and washed three times with water, dried (sodium sulfate) and concentrated. After chromatography on silica gel (ethyl acetate/heptane=1:2), the desired compound was isolated and crystallized from diethyl ether/pentane; yield 380 mg (27%) of melting point 86°-87° C.
Reaction SMILES: [N+](=[C:3]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:4][S:5]([C@H:8]1[NH:11][C:10](=[O:12])[CH2:9]1)(=[O:7])=[O:6])=[N-]>COCCOC.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Rh+3].[Rh+3]>[S:5]1(=[O:7])(=[O:6])[C@@H:8]2[CH2:9][C:10](=[O:12])[N:11]2[C@@H:3]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:4]1
Reactant: [N-]=[N+]=C(CS(=O)(=O)[C@@H]1CC(=O)N1)C(=O)OCc1ccccc1
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: COCCOC
Product: O=C(OCc1ccccc1)[C@H]1CS(=O)(=O)[C@@H]2CC(=O)N12
Reaction time: 1.5 h
Yield: 53.5 %

Procedure:
To a stirred solution of 1.80 g of (4R)-4-(2'-diazo-2'-benzyloxycarbonylethylsulfonyl)-2-azetidinone in 100 ml of 1,2-dimethoxyethane was added 3 mg of dirhodium tetraacetate. The reaction mixture was stirred for 1.5 hours and then a further 3 mg of dirhodium tetraacetate was added. Stirring was continued for 2.5 hours, and then the solvent was removed by evaporation in vacuo. The residue was dissolved in ethyl acetate, and the solution was washed twice with water at pH 8.5. The ethyl acetate solution was dried (Na2SO4) and evaporated in vacuo to give 0.88 g of product. This crude product was chromatographed on 26 g of silica gel and the product containing fractions were combined and evaporated. The residue was dissolved in boiling chloroform and then hexane was added to induce precipitation. The precipitate was recovered by filtration giving 131 mg of the title compound. The NMR spectrum (60 MHz; CDCl3) showed absorptions at 7.22 (s, 5H), 5.10 (s, 2H), 4.70 (m, 1H), 4.35 (m, 1H), 3.47 (m, 2H) and 3.32 (m, 2H) ppm. The IR spectrum (film) showed absorptions at 1800 and 1735 cm-1.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[H-].[Na+].[O:14]1[CH2:16][CH:15]1[CH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>CN(C)C=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:16][CH:15]([OH:14])[CH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: c1cncc(CCC2CO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC(CCc1cccnc1)COc1ccc2ccccc2c1
Yield: 17 %

Procedure:
Prepared according to the method described in Example 5 from 2-naphthol (0.150 g), sodium hydride (0.044 g; 60% dispersion in oil) and (±)-3-(2-oxiranylethyl)pyridine (0.150 g) in dimethylformamide at 100° C. for 30 minutes to give the title compound as a solid (0.050 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:5]=[N:6][C:7]=1[C:8]#[N:9].[Br:25][C:26]1[CH:27]=[CH:28][C:29]([NH2:33])=[N:30][C:31]=1[CH3:32].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([NH:33][C:2]2[CH:3]=[C:4]([NH:10][C@@H:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]3[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:5]=[N:6][C:7]=2[C:8]#[N:9])=[N:30][C:31]=1[CH3:32]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Br)c1
Reactant: Cc1nc(N)ccc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1nc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cnc2C#N)ccc1Br
Temperature: 85 °C

Procedure:
Dioxane (25 ml) was added to a nitrogen purged flask containing tert-butyl (1S,2R)-2-(5-bromo-6-cyanopyridin-3-ylamino)cyclohexylcarbamate (PrepEx 1.1) (2500 mg, 6.32 mmol), 5-bromo-6-methylpyridin-2-amine (1540 mg, 8.22 mmol), Xantphos (732 mg, 1.27 mmol), Pd2(dba)3 (579 mg, 0.632 mmol) and cesium carbonate (3090 mg, 9.49 mmol). Nitrogen was bubbled through the reaction mixture for 5 minutes, and the reaction mixture was heated at 85° C. for 4.5 hours. The reaction was then cooled to room temperature and poured into 10% aq. KHSO4 (300 mL). The pH was adjusted to 4 with 10% aq. KHSO4, and the mixture was sonicated. The solids were collected by filtration, dried under nitrogen, and diluted with DCM (50 mL). Sonication of the resulting suspension afforded a thick slurry. The solids were collected by filtration, and washed with DCM (10 mL) and hexanes (20 mL) to afford tert-butyl (1S,2R)-2-(5-(5-bromo-6-methylpyridin-2-ylamino)-6-cyanopyridin-3-ylamino)cyclohexylcarbamate. MS ESI calc'd. for C23H30BrN6O2 [M+H]+ 501 and 503 found 501 and 503. 1H NMR (500 MHz, CD3OD) δ 7.78 (s, 1H), 7.73-7.71 (m, 2H), 7.75 (d, J=8.8 Hz, 1H), 3.85 (br s, 1H), 3.75 (br s, 1H), 2.54 (s, 3H), 1.90-1.10 (m, 8H), 1.34 (s, 9H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1Cl.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>CCO>[CH3:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[C:22]1[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=1
Reactant: COC(=O)c1cccnc1Cl
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1cccnc1-c1ccc(F)cc1
Temperature: 78 °C
Reaction time: 8 h

Procedure:
To a nitrogen purged flask was charged Pd(Ph3)4 (1.84 g, 1.6 mmoles, 0.005 eq), sodium carbonate (42.8 g, 404 mmoles, 1.3 eq), 52 (55.5 g, 320.6 mmoles, 1.0 eq), p-fluorophenylboronic acid (53.8 g, 384.7 mmoles, 1.2 eq), followed by 1.3 L denatured EtOH. The reaction was heated to 78° C. with vigorous stirring under N2 overnight. HPLC analysis [Tret 52=10 min, Tret 54=12 min] of the reaction mixture showed that the starting material was completely consumed and a later-eluting peak produced. The reaction was cooled to room temperature and the solvents removed under vacuum. The residue was dissolved in EtOAc, washed, dried (MgSO4), filtered through celite, and concentrated to afford a pale yellow solid 54.
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].S(Cl)([Cl:15])(=O)=O>C(Cl)Cl>[Cl:11][C:2]([Cl:1])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[C:8]([Cl:15])[CH:9]=1)=[O:4]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(c1cc(Cl)c[nH]1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,2,2-trichloro-1-(1H-pyrrol-2-yl)ethanone (1 eq.) in dry DCM (1 M) at 0° C. was added sulfuryl chloride (1.15 eq.) dropwise. The mixture was stirred overnight at RT, washed with water (2×) and sat. aq. NaHCO3 solution. The organic phase was separated, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by on chromatography on silica gel, eluting with petroleum ether/Et2O to afford the title compound as a colorless solid. 1H NMR (400 MHz, CDCl3) δ: 9.45 (1H, br. S), 7.26 (1H, s), 7.09 (1H, s).
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([OH:16])[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[N:21]1[C:28](Cl)=[N:27][C:25](Cl)=[N:24][C:22]=1Cl>CS(C)=O.O1CCOCC1>[CH:1]1([O:7][N:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH:11]([O:16][C:22]3[N:24]=[C:25]([O:16][CH:11]4[CH2:10][C:9]([CH3:18])([CH3:17])[N:8]([O:7][CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)[C:13]([CH3:14])([CH3:15])[CH2:12]4)[N:27]=[C:28]([O:16][CH:11]4[CH2:12][C:13]([CH3:14])([CH3:15])[N:8]([O:7][CH:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[C:9]([CH3:18])([CH3:17])[CH2:10]4)[N:21]=3)[CH2:12][C:13]2([CH3:14])[CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: CC1(C)CC(Oc2nc(OC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)nc(OC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
A mixture of 30.0 g (0.117 mol) of 1-cyclohexyloxy-4-hydroxy-2,2,6,6-tetramethylpiperidine, 2.8 g (0.117 mol) of sodium hydride, a few drops of dimethyl sulfoxide, and 150 ml of 1,4-dioxane is heated at reflux for two hours, then allowed to cool. To this mixture is added over 15 minutes solution of 7.2 g (0.039 mol) of cyanuric chloride in 50 ml of dioxane. Salt formation is observed, and the reaction temperature rises from 20° C to 50° C during the addition. The reaction mixture is then heated at reflux for 30 minute and stirred overnight at room temperature. Salts are removed by filtration, and the salt cake is slurried in water and filtered to remove salt from the product, a solid. The crude product is dissolved in boiling methanol and residual salt is removed by filtration. Additional product is recovered from the dioxane filtration. Crude solids are combined and heated in refluxing 2-propanol. Th resulting suspension is allowed to cool, and the solid is isolated by filtration to afford 19.4 g (59% yield) of the title compound, a white solid, m.p. 242°-5° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](N)([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[NH:4][N:3]=1.NC1N=NC(Cl)=CC=1.N1CCCC1.CN(C)C1C=CC=CC=1>[Cu].C(O)(C)C>[NH2:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: NC1=NNC(N)(N2CCCC2)C=C1
Agent: [Cu]
Agent: Nc1ccc(Cl)nn1
Solvent: C1CCNC1
Solvent: CN(C)c1ccccc1
Solvent: CC(C)O
Product: Nc1ccc(N2CCCC2)nn1
Temperature: 30 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
A better procedure for preparing 3-amino-6-amino-6-(1-pyrrolidinyl)pyridazine is given as follows: a mixture containing 80 g. of 3-amino-6-chloropyridazine, 105 ml. of pyrrolidine, 1.2 liters of N,N-dimethylaniline and 1 g. of copper bronze powder was heated with stirring at 130°-135° C. for 18 hours. When a TLC test indicated that starting material was still present, an additional 50 ml. portion of pyrrolidine in 200 ml. of N,N-dimethylaniline was added to the reaction mixture followed by more copper bronze powder and the reaction mixture was heated for an additional 24 hours. The reaction mixture was cooled to 30° C. and filtered. The filtrate was concentrated under oil pump vacuum to leave a crystalline solid. The solid was slurried with isopropyl alcohol while chilling the mixture in an ice bath. The solid was collected, washed with a small amount of cold isopropyl alcohol and dried in a vacuum oven at 60° C. to produce 53 g. (76% yield) of 3-amino-6-(1-pyrrolidinyl)-pyridazine, m.p. 209°-211° C. A TLC check of the filtrate indicated that it contained more of the product, which was not isolated. The intermediate 3-amino-6-(1-pyrrolidinyl)pyridazine prepared by said better procedure was used in the preparation of the final product as described in the second paragraph of (Example D-4) described hereinbelow.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].Cl.[C:11](OC(=O)C)(=[O:13])[CH3:12].C([O-])(=O)C.[Na+]>O>[CH3:2][CH2:1][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:11]([CH3:12])=[O:13])=[CH:5][CH:4]=1
Reactant: CCc1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCc1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
Into a 10-liter reaction flask were introduced 243.8 g (2.01 mol) of 4-ethylaniline, 2 liters of water, 230 g of concentrated hydrochloric acid, and 250 g of acetic anhydride. A solution prepared by dissolving 200 g of sodium acetate in 800 ml of water was added dropwise thereto at 10 to 20° C. This mixture was stirred overnight at room temperature, and the resultant precipitate was taken out by filtration. The crystals were washed with water and recrystallized from methanol (200 ml) to obtain 150 g of the target compound.
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Hg](C#N)C#N.[C:15]([O:18][C@@H:19]1[C@@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:23]([O:29][C:30](=[O:32])[CH3:31])[CH2:22][S:21][C@@H:20]1Br)(=[O:17])[CH3:16]>>[C:15]([O:18][C@@H:19]1[C@@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:23]([O:29][C:30](=[O:32])[CH3:31])[CH2:22][S:21][C@H:20]1[S:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])(=[O:17])[CH3:16]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Reactant: N#Cc1ccccc1S
Agent: N#C[Hg]C#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccccc2C#N)SC[C@H]1OC(C)=O
Yield: 50 %

Procedure:
If the procedure described in Preparation I is followed starting from 9.70 g (72.10-3 mol) of 2-mercaptobenzonitrile, 19.45 g (77.10-3 mol) of mercuric cyanide, Hg(CN)2, and 27.4 g (77.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 14.7 g (yield: 50%) of the expected product are obtained.