Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:7]=[CH:6][C:5]=1[NH2:18].[OH-].[Li+]>O.CO>[NH2:18][C:5]1[CH:6]=[CH:7][C:8]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:9][C:4]=1[C:3]([OH:19])=[O:2]
Reactant: COC(=O)c1cc(CN2CCN(C)CC2)ccc1N
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1CCN(Cc2ccc(N)c(C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a suspension of 2-amino-5-(4-methyl-piperazin-1-ylmethyl)benzoic acid methyl ester (4.30 g, 10.0 mmol) in water (30 mL) and methanol (10 mL) was added lithium hydroxide (1.26 g, 30.0 mmol); the mixture was stirred at room temperature for 12 hours. An additional amount of lithium hydroxide (0.6 g, 15.0 mmol) was added, and heated at 40° C. for 15 hours; TLC indicated completion of the reaction. The mixture was cooled, concentrated, the residue was adjusted to pH ˜5 with 6 N HCl, and evaporated to dryness, to provide crude 2-amino-5-(4-methyl-piperazin-1-ylmethyl)benzoic acid. Yield: 6.2 g, along with inorganic salt. It was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.[Li]CCCC.CN([CH:21]=[O:22])C.O>C1COCC1>[CH3:10][C:7]1([CH3:11])[C:6]2[CH:12]=[C:2]([CH:21]=[O:22])[CH:3]=[CH:4][C:5]=2[O:9][CH2:8]1
Reactant: CN(C)C=O
Reactant: CC1(C)COc2ccc(Br)cc21
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)COc2ccc(C=O)cc21
Temperature: -50 °C
Reaction time: 0.08 h
Yield: 106.6 %

Procedure:
To a solution of 5-bromo-3,3-dimethyl-2,3-dihydro-benzofuran (example 1f) (15.90 g, 70.01 mmol) in dry THF (100 mL) at −78° C., under argon, was added dropwise n-BuLi (1.6 M in hexane, 105 mmol, 42 mL). The mixture was stirred for 5 minutes then DMF (16.3 mL, 210 mmol) was added and the mixture was quickly warmed up to −50° C. and then to 0° C. for 3 hrs. Water was added slowly and the solution extracted with ethyl acetate. The organic layer was further washed with water, brine, dried (MgSO4), filtered and evaporated to give 13.15 g of 3,3-dimethyl-2,3-dihydro-benzofuran-5-carbaldehyde use as this in the next step. 1H NMR (300 MHz; CDCl3): 1.38 (s, 6H), 4.36 (s, 2H), 6.89 (d, J=7.8 Hz, 1H), 7.68 (m, 2H), 9.85 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[N:8]([CH2:22][CH2:23][CH3:24])[C:7]=2[CH:25]=1.C(OC)(OC)OC.[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH:38]=O.[BH4-].[Na+]>CO>[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH2:38][NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:16][CH2:17][CH3:18])[CH2:19][CH2:20][CH3:21])[N:8]([CH2:22][CH2:23][CH3:24])[C:7]=2[CH:25]=1
Reactant: CCCN(CCC)CCCCc1nc2ccc(CN)cc2n1CCC
Reactant: O=Cc1ncc[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: CCCN(CCC)CCCCc1nc2ccc(CNCc3ncc[nH]3)cc2n1CCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
The compound (130 mg) obtained in Example 125-6 was dissolved in methanol (3.0 ml) and added with trimethyl orthoformate (0.130 ml) and 2-imidazole carboxaldehyde (37.3 mg), followed by stirring for 1 hour. Then, the solution was cooled to 0° C. The solution was added with sodium borohydride (21.5 mg) and stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform. The solution was washed with a 1 mol/l sodium hydroxide aqueous solution and then subjected to extraction with chloroform. The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. Then, the residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (64.0 mg) as a pale-yellow viscous substance.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34])[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:12]3=[C:11](I)[C:10]=2[CH:9]=1)#[N:2].[CH2:36]1COCC1.[Cl-].C[Zn+]>>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34])[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:12]3=[C:11]([CH3:36])[C:10]=2[CH:9]=1)#[N:2]
Reactant: C1CCOC1
Reactant: CC(C)Oc1ccc(COc2ccc3c(c2)c(I)c2n3CCC2CC(=O)OC(C)(C)C)cc1C#N
Agent: C[Zn+]
Agent: [Cl-]
Product: Cc1c2n(c3ccc(OCc4ccc(OC(C)C)c(C#N)c4)cc13)CCC2CC(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
tert-Butyl 2-(7-(3-cyano-4-isopropoxybenzyloxy)-9-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.717 g, 1.223 mmol) was dissolved in anhydrous THF (12.2 mL, 1.223 mmol). The solution was degassed with nitrogen for about 5 min using a syringe needle. Bis(tri-t-butylphosphine)Pd(0) (0.056 g, 0.110 mmol) and 2.0 M methylzinc chloride in THF (1.83 mL, 3.67 mmol) were added. The reaction vessel was purged with nitrogen, sealed, and heated at 70° C. After 2 h, the reaction mixture was cooled to 25° C. and slowly added saturated NaHCO3 (5 mL). After stirring for about 5 min, the reaction was diluted with EtOAc (20 mL), filtered through a celite pad, and the celite pad was washed with EtOAc (3×20 mL). The organic layer was washed with water (2×20 mL), brine (10 mL), and dried over MgSO4. The solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography to give the title compound as an oil (0.470 g). LCMS m/z=475.4 [M+H]+; 1H NMR (400 MHz, Acetonitrile-d3) δ ppm 1.36 (d, J=5.94 Hz, 6H), 1.41 (s, 9H), 2.19 (s, 3H), 2.27-2.37 (m, 1H), 2.46 (dd, J=15.66, 9.22 Hz, 1H), 2.72-2.86 (m, 2H), 3.60-3.69 (m, 1H), 3.93 (m, 1H), 4.00-4.10 (m, 1H), 4.75 (dt, J=12.13, 6.06 Hz, 1H), 5.03 (s, 2H), 6.77 (dd, J=8.72, 2.40 Hz, 1H), 7.00 (d, J=2.40 Hz, 1H), 7.11 (d, J=8.72 Hz, 1H), 7.13 (d, J=8.72 Hz, 1H), 7.63-7.68 (m, 1H), 7.69 (d, J=2.27 Hz, 1H).
Reaction SMILES: C([CH2:3][O:4][C:5](=[O:17])[CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)#N.C(N(CC)CC)C>CO>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:10]=[CH:9][CH2:8][CH2:7][CH2:6][C:5]([O:4][CH3:3])=[O:17]
Reactant: N#CCOC(=O)CCCC=Cc1ccccn1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CCCC=Cc1ccccn1
Yield: 115.3 %

Procedure:
To 6-(pyridin-2-yl)-5-hexenoic acid cyanomethyl ester (4.83 g, 21.0 mmol) was added methanol (50 ml) and triethylamine (0.405 g, 4.0 mmol) and the mixture was heated under reflux overnight and then evaporated to remove the solvent. The resultant residue was subjected to purification using column chromatography on silica gel to afford a target product, methyl 6-(pyridin-2-yl)-5-hexenoate (4.97 g, quantitative).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].C(N1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])(OCC)=O>O1CCCC1.C(N(CC)CC)C>[C:19]1(=[O:28])[N:7]([CH2:6][C:5]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]12
Reactant: COc1ccc(CN)cc1OC
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CN2C(=O)c3ccccc3C2=O)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
To a stirred solution of 3,4-dimethoxybenzylamine (0.836 grams, 5.00 mmol) and N-carbethoxyphthalimide (1.10 grams, 5.00 mmol) in 20 milliliters of tetrahydrofuran was added 1 drop of triethylamine and the mixture stirred overnight. After 24 hours at room temperature, the mixture was refluxed for 16 hours, then allowed to cool to room temperature without stirring. Crystals formed on cooling. The mixture was filtered, the solid dried in vacuo to afford 0.89 grams (60%) of 1-phthalimido-1-(3′,4′-dimethoxyphenyl)methane as small white needles: mp 160-161° C.; 1H NMR (CDCl3/TMS) δ7.8 (m, 2 H), 7.7 (m, 2 H), 7.03 (m, 2 H), 6.8 (m, 1 H), 4.78 (s, 2 H), 3.88 (s, 3 H, OCH3), 3.84 (s, 3 H, OCH3); 13C NMR (CDCl3/TMS) δ168.0, 148.9, 148.7, 133.9, 132.1, 129.0, 123.3, 121.3, 112.1, 111.1, 55.9, 41.4. Anal. Calcd for C17H15NO4. Theory C, 68.68; H, 5.09; N, 4.71. Found C, 68.49; H, 4.99; N, 4.67.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[O:23]1[CH:27]=[CH:26][C:25]([NH2:28])=[N:24]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([NH:28][C:25]2[CH:26]=[CH:27][O:23][N:24]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Nc1ccon1
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)Nc2ccon2)cc1Cl
Reaction time: 2 h
Yield: 33.3 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 93 mg, 0.27 mmol), isoxazol-3-ylamine (29 □L, 0.30 mmol) and N,N-diisopropylethylamine (141 μL, 0.81 mmol) were combined in acetonitrile (1.25 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (103 mg, 0.27 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 25% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-N-isoxazol-3-yl-acetamide (37 mg, 33%) as a slightly yellow solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C17H18ClN3O5S [M+] 411.07, found 412 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.67 (m, 4 H, 2×CH2), 1.88 (m, 4 H, 2×CH2), 3.31 (s, 3 H, SO2CH3), 4.94 (m, 1 H, OCH), 7.07 (d, J=1.7 Hz, 1 H, Ar), 7.56 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.66 (d, Jm=1.5 Hz, 1 H, Ar), 8.20 (d, Jo=8.2 Hz, 1 H, Ar), 8.33 (d, J=1.7 Hz, 1 H, Ar), 9.40 (s, 1 H, NH).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.[C:22]12[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=1)[NH:27]C(=O)O[C:23]2=[O:24].C(Cl)(Cl)Cl>ClCCl>[NH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:22]=1[C:23]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:5][CH2:4]1)=[O:24]
Reactant: NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Nc1ccccc1C(=O)NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 1 h

Procedure:
A solution of 4-aminomethyl-1-diphenylmethylpiperidine (2.5 g, 9.15 mmol) in dichloromethane (10 ml) was added to a suspension of isatoic anhydride (1.0 g, 6.1 mmol) in dichloromethane (25 ml) at room temperature. The reaction mixture was stirred for 1 hour and then poured into chloroform and washed with 5% NaHCO3 solution. The organic layer was concentrated. The residue was dissolved in dichloromethane (25 ml) and poured into hexane (400 ml) to give 2-amino-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide as precipitate (100%): mp 153°-154° C.
Reaction SMILES: [C:1]1([C:7]2[C:19]3[CH2:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]=3[C:10]([C:20]#[N:21])=[C:9]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1C[O:33]CC1>>[O:33]=[C:18]1[C:19]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:9]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)=[C:10]([C:20]#[N:21])[C:11]=2[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: N#Cc1c(N2CCCCC2)cc(-c2ccccc2)c2c1-c1ccccc1C2
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2ccccc2)c2c1-c1ccccc1C2=O
Temperature: 2.5 °C

Procedure:
A solution of 1-phenyl-3-(piperidin-1-yl)-9H-fluorene-4-carbonitrile (350 mg) in THF was added sodium hydride (34 mg) and was stirred at 0-5° C. for less than five minutes. After completion, the reaction solvent was evaporated under vacuum and the crude solid obtained was quenched with ice water and subsequently neutralized by dilute HCl. The precipitate thus obtained was filtered and purified on a silica gel column using ethyl acetate-hexane as eluent. Yellow solid; mp 166-168° (C; ESIMS 365 (M++1); IR (KBr) 2219 (CN), 1705 cm−1 (CO); 13C NMR (75.53 MHz, CDCl3): δ 22.68, 24.67, 51.55, 95.24, 115.94, 118.11, 120.97, 121.16, 122.41, 126.70, 127.64, 129.33, 133.10, 133.94, 135.61, 139.20, 145.60, 149.61, 158.96, 188.36.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH2:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1.Br[C:15]([CH3:20])([CH3:19])[C:16](Br)=[O:17]>C(Cl)Cl>[CH3:19][CH:15]1[CH2:20][C:11]2[C:10](=[CH:9][C:8]3[CH2:7][CH2:6][CH2:5][C:13]=3[CH:12]=2)[C:16]1=[O:17]
Reactant: c1ccc2c(c1)CCC2
Reactant: CC(C)(Br)C(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1Cc2cc3c(cc2C1=O)CCC3
Temperature: 25 °C
Reaction time: 17 h
Yield: 98.8 %

Procedure:
50.71 g (377 mmol) of anhydrous aluminum trichloride were slowly added at 0° C. to a mixture of 19.3 g (163 mmol) of indane and 38.3 g of 2-bromoisobutyryl bromide in 500 ml of methylene chloride over a period of 30 minutes. The reaction mixture became dark red. The suspension was stirred at room temperature for 17 hours and subsequently poured onto 200 g of ice. The phases were separated. The organic phase was washed once with 200 ml of 1 normal hydrochloric acid, twice with 200 ml each time of saturated sodium hydrogencarbonate solution and twice with 200 ml each time of water. The organic phase was dried over anhydrous sodium sulfate and filtered. Removal of the solvent under reduced pressure gave 30 g (99% yield) of the compound (1a) as reddish brown oil. According to GC-MS, the content of (1a) in the oil was 99%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:20])[CH2:7][CH2:8][CH3:9])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:28][N:29]1[C:37]2[C:32](=[C:33]([CH3:38])[CH:34]=[CH:35][CH:36]=2)[C:31]([CH2:39][N+](C)(C)C)=[CH:30]1.[I-]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[N:12]([CH2:39][C:31]2[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])[N:29]([CH3:28])[CH:30]=2)[C:11]1=[O:20])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCC(CC(=O)OCC)n1c(=O)[nH]c2ccc(C)cc21
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC(CC(=O)OCC)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccc(C)cc21
Temperature: 80 °C

Procedure:
To a solution of 3-(6-Methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-hexanoic acid ethyl ester (50 mg, 0.17 mmol) in DMF (2 mL) were added K2CO3 (71 mg, 0.52 mmol) and (1,4-Dimethyl-1H-indol-3-ylmethyl)-trimethyl-ammonium; iodide (90 mg, 0.26 mmol). The reaction mixture was heated to 80° C. for 16 h. The reaction mixture was then diluted with ethyl acetate and washed with water (×4). The organic phase was then dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 4:1 Hexanes:ethyl acetate as an eluent to afford 35 mg of the desired product as oil. LCMS (ESMS): m/z 448.82 (M+H+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([CH2:39][CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[C:36]([OH:38])=O)=[CH:31][C:30]=1[N+:45]([O-:47])=[O:46].[NH2:48][C:49]1[CH:54]=[CH:53][C:52]([Br:55])=[CH:51][N:50]=1>C(Cl)Cl>[Br:55][C:52]1[CH:53]=[CH:54][C:49]([NH:48][C:36](=[O:38])[CH:35]([C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[C:30]([N+:45]([O-:47])=[O:46])[CH:31]=2)[CH2:39][CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)=[N:50][CH:51]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Br)cn1)C(CC1CCCC1)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 56.8 %

Procedure:
A solution of triphenylphosphine (241 mg, 0.92 mmol) in methylene chloride (3 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (164 mg, 0.92 mmol). The reaction mixture was stirred at 0° C. for 10 min and then treated with 2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 64, 250 mg, 0.84 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-amino-5-bromopyridine (320 mg, 1.85 mmol). The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) to afford N-(5-bromo-pyridin-2-yl)-2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-propionamide (216 mg, 57%) as a pale yellow solid: mp 128-130° C.; EI-HRMS m/e calcd for C19H19BrClN3O3 (M+) 451.0298, found 451.0300.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:16]([C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[S:26])=[CH:20][CH:19]=1)#[N:17].CCOCC>C1(C)C=CC=CC=1>[CH2:9]([O:8][C:7]1[C:2]([NH:1][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([C:16]#[N:17])=[CH:19][CH:20]=2)=[S:26])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: N#Cc1ccc(N=C=S)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: N#Cc1ccc(NC(=S)Nc2ncccc2OCc2ccccc2)cc1

Procedure:
A stirring mixture of 2-amino-3-benzyloxy pyridine (5.68 g, 0.0284 mol) and 4cyanophenyl isothiocyanate (5 g, 0.0312 mol) in toluene (20 ml) was heated under reflux for 2 h. After allowing to cool, the solution was treated with ether, and the resulting solid filtered off, washed and dried. Yield 9.4 g (92%), m.p. 163°-165 ° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:17][CH2:18][CH:19]1[CH2:21][CH2:20]1.C1C(=O)N([Br:29])C(=O)C1>C(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:3]([O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[CH:4][C:5]([C:8]2([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:6][C:7]=1[Br:29]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1(c2ccc(N)c(OCC3CC3)c2)CCC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)C1(c2cc(Br)c(N)c(OCC3CC3)c2)CCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.2 %

Procedure:
To a stirred solution of ethyl 1-(4-amino-3-(cyclopropylmethoxy)phenyl)cyclobutanecarboxylate (2.4 g, 8.3 mmol) in dry CHCl3 (50 mL), NBS (1.4 g, 7.8 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 h at room temperature. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography to yield ethyl 1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclobutanecarboxylate (1.5 g) as a yellow solid.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[C:11]([O:14][CH2:15][CH3:16])(=[O:13])[CH3:12].[C:17]1([C:23]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=2)=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH3:33][O:32][C:28]1[CH:27]=[C:26]([CH2:25][C:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([OH:24])[CH2:12][C:11]([O:14][CH2:15][CH3:16])=[O:13])[CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(C)=O
Reactant: COc1cccc(CC(=O)c2ccccc2)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)(Cc1cccc(OC)c1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
Lithium hexamethyldisilazane (88.5 mL, 88.5 mmol) was added to THF (150 mL) at −78° C. After 15 minutes, ethyl acetate (7.79 g, 88.5 mmol) was added over 10 minutes and stirred at −78° C. for 30 minutes. The m-methoxybenzyl phenyl ketone in (10.0 g, 44.25 mmol) THF (100 mL) was added over 15 minutes and kept at that temperature for 3 hours. The reaction mixture was quenched at that temperature with saturated ammonium chloride (15 mL). The reaction mixture was diluted with ether (200 mL) and the organic layer was washed with brine, (100 mL), dried and concentrated to afford the desired product (12 g, 86% yield). NMR was consistent with the desired structure.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[CH3:17][NH:18][CH3:19]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([N:18]([CH3:19])[CH3:17])=[O:10])[CH2:6]1
Reactant: O=C(Cl)N1CC(Oc2ccc(Cl)cc2Cl)C1
Reactant: CNC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)N1CC(Oc2ccc(Cl)cc2Cl)C1
Reaction time: 5 h

Procedure:
A stirred solution of 4.8 g (0.017 mole) of 3-(2,4-dichlorophenoxy)-1-azetidinecarbonyl chloride in 20 mL of tetrahydrofuran was treated with 5.8 mL (0.05 mole) of 40% aqueous dimethylamine. After stirring for 5 h, the reaction mixture was diluted with 200 mL of water and the oil which separated was extracted into methylene chloride (3×30 mL). The combined extracts were dried (Whatman PS paper) and concentrated in vacuo, (5 g). The crude oil solidified on standing and was recrystallized from ligroin yielding 3.4 g (69.2%) of silver plate-like crystals, mp 62°-63° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH:16]2[CH2:18][CH2:17]2)(=[O:15])=[O:14])=[C:9]([Cl:19])[CH:8]=1.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.Cl>O1CCCC1>[Cl:19][C:9]1[CH:8]=[C:7]([B:20]([OH:25])[OH:21])[CH:12]=[CH:11][C:10]=1[S:13]([CH:16]1[CH2:18][CH2:17]1)(=[O:15])=[O:14]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: O=S(=O)(c1ccc(Br)cc1Cl)C1CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(B(O)O)cc1Cl)C1CC1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
n-Butyllithium (1.6 M solution in hexane, 9.2 mL) was added dropwise to a solution of 4-bromo-2-chloro-1-(cyclopropylsulfonyl)benzene obtained in Reference Example 5-30 (1.45 g) and triisopropyl borate (5.54 g) in tetrahydrofuran (15 mL) under cooling at an external temperature of −78° C. in a nitrogen atmosphere, after which the mixture was stirred at the same temperature for three hours. 1 M hydrochloric acid (10 mL) was added and the reaction solution, still basic, was extracted with chloroform. The aqueous layer was made acidic with 1 M hydrochloric acid (10 mL), followed by extraction with chloroform. The solvent was evaporated from the organic layer under reduced pressure to give a crude product of 3-chloro-4-(cyclopropylsulfonyl)phenylboronic acid (1.02 g).
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)[CH:8]=[CH:9][CH:10]=1.CO.[CH:21]([NH2:24])([CH3:23])[CH3:22]>CCOCC>[OH:1][CH:2]([CH2:18][NH:24][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CCC(c2cccc(OCC3CO3)c2)=NN1
Reactant: CC(C)N
Solvent: CO
Solvent: CCOCC
Product: CC(C)NCC(O)COc1cccc(C2=NNC(=O)CC2)c1
Yield: 95.8 %

Procedure:
A stirred mixture of 6-[3-(2,3-epoxypropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (10 g, 0.04 mole), methanol (100 ml), and isopropylamine (20.8 ml, 0.24 mole) was heated under reflux for 90 minutes. Evaporation of the solution under reduced pressure gave a white solid which, when treated with ether, gave crude 6-[3-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (11.7 g, 94%, m.p. 137°-141° C). The hemisulphate, recrystallised from aqueous methanol-ether, had m.p. 256°-258° C.