Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:28][CH3:29])=[C:10]([N:13]3[CH2:18][C@H:17]([CH3:19])[N:16](CC4C=CC=CC=4)[C@H:15]([CH3:27])[CH2:14]3)[CH:11]=2)[CH2:6][CH2:5]1)(=O)C>Cl.[Pd]>[CH3:27][C@H:15]1[NH:16][C@@H:17]([CH3:19])[CH2:18][N:13]([C:10]2[CH:11]=[C:12]3[C:7]([CH2:6][CH2:5][NH:4]3)=[CH:8][C:9]=2[O:28][CH3:29])[CH2:14]1
Reactant: COc1cc2c(cc1N1C[C@@H](C)N(Cc3ccccc3)[C@@H](C)C1)N(C(C)=O)CC2
Agent: [Pd]
Agent: Cl
Product: COc1cc2c(cc1N1C[C@@H](C)N[C@@H](C)C1)NCC2

Procedure:
The title compound was prepared from D4 by hydrogenation over 10% Pd/C using a similar procedure to Example 45 (98%), followed by hydrolysis in 2M HCl using a similar procedure to Description 3 (80%) to afford the product as a pale brown solid
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:38]([C:41]1[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[CH:43][CH:42]=1)([O-:40])=[O:39].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[O:17]=[C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:18])[N:8]1[C@H:5]1[CH2:4][CH2:3][C@H:2]([O:1][C:45](=[O:46])[C:44]2[CH:43]=[CH:42][C:41]([N+:38]([O-:40])=[O:39])=[CH:49][CH:48]=2)[CH2:7][CH2:6]1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](O)CC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)CC1)c1ccc([N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
To a solution of trans-2-(4-Hydroxy-cyclohexyl)-isoindole-1,3-dione (38 g, 154.9 mmol), triphenylphosphine (65 g, 248 mmol), and 4-nitrobenzoic acid (41.4 g, 248 mmol) in 1500 mL of THF was added dropwise diisopropyl azodicarboxylate (50.1 g, 248 mmol) at room temperature. The reaction mixture was stirred overnight. The solvent was evaporated, and the resulting solid was recrystallized from methanol. Yield: 53 g (86.7% of theory). 1H NMR (300 MHz, CDCl3): δ 8.40-8.36 (m, 4H), 7.79 (ddd, J=0.12, 0.02, and 0.02 Hz, 4H), 5.39 (s, 1H), 4.37-4.22 (m, 1H), 2.82-2.65 (m, 2H), 2.27-2.16 (m, 2H), 1.84-1.65 (m, 4H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[N:24]1([S:29]([C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([S:29]([C:32]2[CH:38]=[CH:37][C:35]([NH:36]/[C:13](=[C:6]3\[C:5](=[O:23])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[CH:10][CH:11]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: Nc1ccc(S(=O)(=O)N2CCCC2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Product: O=C1Nc2ccccc2/C1=C(/Nc1ccc(S(=O)(=O)N2CCCC2)cc1)c1ccccc1

Procedure:
Prepared analogously to Example 1c from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-(pyrrolidin-1-ylsulphonyl)-aniline.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].C1C(=O)N([Br:20])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>ClC1C=CC=CC=1>[Br:20][CH2:12][C:4]1[C:3]([O:2][CH3:1])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(C(=O)O)c1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: COc1cccc(C(=O)O)c1CBr

Procedure:
for the synthesis of the title compound, 6.64 g (0.040 mol) of 3-methoxy-2-methylbenzoic acid, 7.1 g (0.040 mol) of NBS and 0.25 g of AIBN in 150 ml of chlorobenzene are reacted by method H (variant 1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=1)([O-:3])=[O:2]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccncc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccnc(N2CCOCC2)c1
Reaction time: 8 h
Yield: 56.5 %

Procedure:
To a solution of 2-chloro, 4-nitropyridine (0.2 g, 1.27 mmol) in THF (3 mL) was added morpholine (328 mg, 38.1 mmol). The reaction was heated to 80 C and stirred overnight. The solvent was evaporated and the residue purified by column chromatography (2/1 Hex/EtOAc) to yield 150 mg of the target compound.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:5]=2[N:6]=1.N1C=CC=CC=1.Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20].O>O1CCCC1>[Cl:11][C:8]1[CH:9]=[CH:10][C:4]2[O:3][C:2]([NH:1][C:19](=[O:20])[O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[N:6][C:5]=2[CH:7]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1nc2cc(Cl)ccc2o1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1nc2cc(Cl)ccc2o1)OCC(Cl)(Cl)Cl

Procedure:
To a solution of 2-amino-5-chlorobenzoxazole (1.00 g, 5.39 mmol) and pyridine (0.564 ml, 7.12 mmol) in tetrahydrofuran (20 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (0.850 ml, 7.12 mmol), and the mixture was stirred at room temperature for 2 hours and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was poured to the residue, and 394 mg (19.3%) of the desired product as a solid was separated by filtration.
Reaction SMILES: C(=O)([O-])[O-].[Mg+2:5].[NH2:6][CH2:7][C:8]([OH:10])=[O:9].[N+]([O-])([O-])=O>O>[NH2:6][CH2:7][C:8]([O-:10])=[O:9].[Mg+2:5].[NH2:6][CH2:7][C:8]([O-:10])=[O:9]
Reactant: NCC(=O)O
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])[O-]
Agent: [Mg+2]
Solvent: O
Product: NCC(=O)[O-]

Procedure:
Magnesium glycinate was prepared by reacting 1.8 g. of basic magnesium carbonate (26.1% Mg) with 3 g. of glycine in 30 g. of water, while agitating at 75° C. for one half hour. To the cooled slurry was added 50 g. of zirconyl nitrate solution [ZrO(NO3)2 ; 4.27% Zr] with agitation. The resultant clear solution had a pH of 3.2. The product was oven-dried at 55° C. under a vacuum of 35 cm. of Hg and found to contain 22.8% Zr, 4.79% Mg and 30.6% glycine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.[Sn].[Cl-].[OH-].[Na+]>C(O)C>[NH2:9][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: O=[N+]([O-])c1cc(F)ccc1O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(F)ccc1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 105.5 %

Procedure:
A mixture of 4-fluoro-2-nitrophenol (1 g, 4.64 mmol) and tin (to) chloride (5.4 g, 24.2 mmol) in ethanol (50 mL) was heated at 80° C. under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH is made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2Cl2) gave the desired product (622 mg, 85 %). 1H NMR (CD3, D): d 6.51 (dd, 1H), 6.32 (dd, 1H), 6.17 (ddd, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Cl:10][CH2:11][C:12](OCC)(OCC)OCC.O>C(O)C>[Cl:10][CH2:11][C:12]1[O:9][C:3]2[CH:4]=[CH:5][C:6]([Br:8])=[CH:7][C:2]=2[N:1]=1
Reactant: CCOC(CCl)(OCC)OCC
Reactant: Nc1cc(Br)ccc1O
Solvent: O
Solvent: CCO
Product: ClCc1nc2cc(Br)ccc2o1
Temperature: 25 °C

Procedure:
2-Amino-4-bromophenol (1.6 g) prepared according to U.S. Pat. No. 4,157,444 was dissolved in ethanol (5 ml) and 2-chloro-1,1,1-triethoxyethane (1.9 g) was added. The resulting solution was warmed on a steambath for 1.5 hour. After cooling the reaction mixture to room temperature, cold water (5 ml) was added. The precipitated solid was collected and air-dried to obtain the product (1.12 g; m.p. 63°-65° C.
Reaction SMILES: [CH3:1][C:2]([O:41][CH2:42][C@@H:43]1[CH2:45][O:44]1)([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:13]2)=[O:11])=[N:5]1.C(O)(C)C.[OH-].[NH4+:51]>C(Cl)Cl>[NH2:51][CH2:45][C@H:43]([OH:44])[CH2:42][O:41][C:2]([CH3:1])([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:38])([CH3:39])[CH3:37])[NH:13]2)=[O:11])=[N:5]1
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@@H]3CO3)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@@H](O)CN)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 24.1 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {1-[2-methyl-2-((S)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3-yl}-amide (203 mg, 0.307 mmol), isopropyl alcohol (2 mL), and ammonium hydroxide (2.5 mL) was microwaved at 130° C. for 15 min. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-((S)-3-amino-2-hydroxy-propoxy)-2-methyl-propyl]-1H-pyrazol-3-yl}-amide (50.2 mg, 24.1%) as an white powder. HRMS (ES+) m/z Calcd for C33H40Cl2F2N6O3+H [(M+H)+]: 677.2580. found: 677.2577.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(O)(C)(C)C.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]=[C:37]([CH:47]([CH3:49])[CH3:48])[C:36]=2[CH2:50][OH:51])=[CH:31][CH:30]=1>ClCl.C(Cl)Cl>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]=[C:37]([CH:47]([CH3:49])[CH3:48])[C:36]=2[CH:50]=[O:51])=[CH:31][CH:30]=1
Reactant: CC(C)c1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: ClCl
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: CC(C)c1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1C=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
A solution of Dess-Martin periodinane (1.54 gm, 3.63 mmol) in dry CH2 Cl2 (17 ml) was treated with t-butanol (267 mg, 3.60 mmol) and stirred for 15 minutes at room temperature. A solution of 4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinemethanol (895 mg, 2.78 mmol) in CH2Cl2 (12 ml) was then added and stirring was continued 30 minutes, after which time the mixture was quenched by the addition of Et2O (70 ml) and 1N NaOH (35 ml). The biphasic mixture was stirred for 10 minutes and the layers were separated. The organic layer was washed with 1N NaOH, H2O and brine, then dried (Na2 SO4), filtered and stripped. The solid residue was chromatographed (Flash, Merck SiO2, 10% EtOAc in hexane) to afford pure 4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinecarboxaldehyde (782 mg, 88%) as a white solid. Analytically pure material was obtained by recrystallization of the solid from a minimum amount of hot hexane.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:11]2[N:12]=[C:13]([NH:16][CH3:17])[S:14][CH:15]=2)[CH:10]=[CH:9][O:8][NH:7]1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[CH3:17][NH:16][C:13]1[S:14][CH:15]=[C:11]([C:6]2([C:4]([OH:5])=[O:3])[CH:10]=[CH:9][O:8][NH:7]2)[N:12]=1
Reactant: CCOC(=O)C1(c2csc(NC)n2)C=CON1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNc1nc(C2(C(=O)O)C=CON2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ethyl-3-[2-(methylamino)-1,3-thiazol-4-yl]isoxazole-3-carboxylate (65 mg, 0.26 mmol) in ethanol (3.0 mL) was treated with 1N aqueous sodium hydroxide (0.30 mL, 0.28 mmol) and the mixture was stirred at room temperature for 2 h. The mixture was neutralized with 1 N aqueous hydrochloric acid and concentrated in vacuo to give the crude which was used without purification. MF=C8H7N3O3S; LCMS calculated for C8H7N3O3S (M+H)+: m/z=226.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:21]2[CH2:25][C:24](OC)=[CH:23][C:22]2=[O:28])[C:8]([NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[N:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:30][O:31][CH2:32][C@@H:33]([OH:35])[CH3:34].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[CH:1]1([CH2:6][C@H:7]([N:21]2[CH2:25][C:24]([O:35][C@@H:33]([CH3:34])[CH2:32][O:31][CH3:30])=[CH:23][C:22]2=[O:28])[C:8]([NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C:17]([OH:20])([CH3:18])[CH3:19])[N:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC[C@H](C)O
Reactant: COC1=CC(=O)N([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COC[C@H](C)OC1=CC(=O)N([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)C1
Temperature: 25 °C
Yield: 7.4 %

Procedure:
A solution of (S)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamide (prepared as in Example 1, 35 mg, 0.09 mmol) in a hydrochloric acid (gas) saturated acetic acid (5 mL) solution was heated in a sealed tube at 75° C. for 2 h. After that, the reaction mixture was cooled to room temperature, and concentrated. The residue was added to (S)-1-methoxy-propan-2-ol (162 mg, 1.76 mmol), and toluene-4-sulfonic acid hydrate (10 mg). The mixture was heated to 90° C., for 18 h. The reaction mixture was concentrated and the residue was dissolved in dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, and dried over magnesium sulfate. The crude product was purified using reverse phase HPLC (Biosystems MDS-SCIEX LC/MS, Pursuit C-18 2×10 mm, water/acetonitrile 0.05% trifluoroacetic acid) to afford (S)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-((S)-2-methoxy-1-methyl-ethoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionamide (3 mg, 9%) as a white foam: LR-ES-MS m/z calculated for C23H36N4O5 [M]+ 448, observed [M+H]+ 449; 1H NMR (300 MHz, CDCl3) δ ppm 1.08-1.25 (m, 2H) 1.16 (s, 6H) 1.32 (d, J=6.3 Hz, 3H) 1.43-2.07 (m, 9H) 3.40 (s, 3H) 3.44-3.59 (m, 2H) 3.66 (br. s., 1H) 3.90-4.00 (d, J=17.8 Hz, 1H) 3.95 (s, 2H) 4.08 (d, J=17.8 Hz, 1H) 4.34-4.47 (m, 1H) 4.80 (dd, J=8.9, 6.5 Hz, 1H) 5.12 (s, 1H) 6.67 (d, J=2.0 Hz, 1H) 7.30 (d, J=2.0 Hz, 1H) 8.85 (br. s., 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([F:30])[CH:24]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[F:30][C:25]1[CH:24]=[C:23]([NH:22][C:11](=[O:13])[CH2:10][C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:14])[CH:28]=[CH:27][C:26]=1[OH:29]
Reactant: Nc1ccc(O)c(F)c1
Reactant: O=C(O)CC(=O)Nc1ccc(F)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CC(=O)Nc1ccc(O)c(F)c1)Nc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 68.9 %

Procedure:
3-(4-Fluorophenylamino)-3-oxopropanoic acid (197 mg, 1.00 mmol) was dissolved in 4 mL of dimethylformamide. Triethylamine (140 μL, 1.00 mmol) was added and the solution was cooled to 0° C. 4-Amino-2-fluorophenol (127 mg, 1.00 mmol, Aldrich) was added followed BOP reagent (442 mg, 1.00 mmol). The reaction was allowed to warm to room temperature and was then stirred at room temperature for 3 h. The reaction mixture was concentrated to remove methylene chloride and water was added to precipitate the product. Filtration and trituration with water gave the title compound (211 mg, 69%) as a white solid. 1H NMR (CD3OD) δ 7.61 (m, 2H), 7.51 (dd, 1H, J=13, 2.5 Hz), 7.08 (m, 3H), 6.88 (t, 1H, J=9.4 Hz), 3.51 (s, 2H); MS(ESI+) m/z 307.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=1[F:22])(=[O:11])=[O:10]>[Ni].C1COCC1>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][S:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])(=[O:11])=[O:10])=[C:14]([F:22])[CH:15]=1
Reactant: O=[N+]([O-])c1ccc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(F)c1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2,3-dichloro-N-(2-fluoro-4-nitrophenyl)benzenesulfonamide (5.0 g, 13.7 mmol) and Raney Nickel (0.600 g) in THF (200 mL) was applied positive H2 pressure through a balloon/needle. The reaction was stirred at room temperature for 4 hours and then filtered. The mixture was concentrated and triturated with CH2Cl2 to afford N-(4-amino-2-fluorophenyl)-2,3-dichlorobenzenesulfonamide as a grey solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[CH3:13])(C)(C)C.[CH3:21][C:22]1[C:23]([CH:29]=O)=[N:24][CH:25]=[C:26]([CH3:28])[CH:27]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:21][C:22]1[C:23]([CH2:29][N:11]([CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH3:13])[CH2:10][CH2:9][CH2:8][NH2:7])=[N:24][CH:25]=[C:26]([CH3:28])[CH:27]=1
Reactant: Cc1cnc(C=O)c(C)c1
Reactant: CC(NCCCNC(=O)OC(C)(C)C)c1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN(CCCN)C(C)c2ccccn2)c(C)c1

Procedure:
Using General Procedure B: Reaction of [3-(1-pyridin-2-yl-ethylamino)-propyl]-carbamic acid tert-butyl ester and 3,5-dimethyl-pyridine-2-carboxaldehyde with NaBH(OAc)3 in CH2Cl2 gave N1-(3,5-Dimethyl-pyridin-2-ylmethyl)-N1-(1-pyridin-2-yl-ethyl)-propane-1,3-diamine as a colorless oil. 1H NMR (CDCl3) δ 1.45-1.66 (m, 7H), 2.25 (s, 3H), 2.26 (s, 3H), 2.42-2.65 (m, 4H), 3.75 (d, 1H, J=12.6 Hz), 3.81 (d, 1H, J=12.6 Hz), 4.01 (q, 1H, J=6.6 Hz), 7.11-7.16 (m, 1H), 7.22 (br s, 1H), 7.38 (d, 1H, J=7.8 Hz), 7.62 (dt, 1H, J=7.8, 1.8 Hz), 8.18 (br s, 1H), 8.55 (d, 1H, J=4.5 Hz).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:11]=1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[F:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][O:16][C:12]1[CH:11]=[C:10]([CH2:9][CH2:8][NH2:7])[CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCc1cccc(OCc2cccc(F)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCc1cccc(OCc2cccc(F)c2)c1

Procedure:
A solution of 10.36 g (30 mmol) of [2-[3-(3-fluoro-benzyloxy)-phenyl]-ethyl]-carbamic acid tert-butyl ester in 100 ml of dichloromethane and 15 ml of trifluoroacetic acid was stirred at room temperature overnight. The solvent was removed, a 5% K2CO3 solution in water was added and the product was extracted with ethyl acetate to obtain the title compound in quantitative yield as a sticky oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[C:24]1[C:29]([C:30]2[N:35]=[C:34]([CH3:36])[N:33]=[C:32]([N:37]([CH2:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=3)[CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[N:31]=2)=[CH:28][C:27]([CH2:56][N:57]2[CH2:62][CH2:61][N:60]([S:63]([CH3:66])(=[O:65])=[O:64])[CH2:59][CH2:58]2)=[CH:26][N:25]=1>C1COCC1>[CH3:55][O:54][C:51]1[CH:50]=[CH:49][C:48]([CH2:47][N:37]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=2)[C:32]2[N:33]=[C:34]([CH3:36])[N:35]=[C:30]([C:29]3[C:24]([NH:1][C:2]4[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=4)=[N:25][CH:26]=[C:27]([CH2:56][N:57]4[CH2:62][CH2:61][N:60]([S:63]([CH3:66])(=[O:65])=[O:64])[CH2:59][CH2:58]4)[CH:28]=3)[N:31]=2)=[CH:53][CH:52]=1
Reactant: CC(=O)Nc1ccc(N)cc1F
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(NC(C)=O)c(F)c3)n2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24.8 %

Procedure:
A mixture of N-(4-amino-2-fluorophenyl)acetamide (0.110 g, 0.654 mmol) in THF (5 mL) was cooled to 0° C. under N2. Lithium bis(trimethylsilyl)amide, 1.0 M solution in tetrahydrofuran (Aldrich) (0.636 mL, 3.27 mmol) was added and the mixture was stirred at 0° C. for 30 min before 4-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.447 g, 0.720 mmol) was added. The resulting mixture was stirred at 0° C. for 10 min, and then the ice bath was removed and stirring was continued for 2 h. The reaction was quenched with sat. NH4Cl. The resulting mixture was partitioned between pH 7 buffer (1 M TRIS-HCl) and CHCl3. The aqueous layer was extracted with CHCl3 (2×15 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (40 g, 3% MeOH and 12% EtOAc in DCM) to give the product as a yellow solid (0.125 g). m/z (ESI, +ve ion) 770.0 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 11.99 (br. s., 1H); 8.73 (s, 1H); 8.28 (s, 1H); 8.02-8.16 (m, 1H); 7.91 (s, 1H); 7.22 (d, J=7.45 Hz, 5H); 6.96 (d, J=8.33 Hz, 1H); 6.88 (d, J=8.18 Hz, 4H); 4.86 (br. s., 4H); 3.81 (d, J=2.92 Hz, 6H); 3.52 (s, 2H); 3.19 (br. s., 4H); 2.72 (s, 3H); 2.61 (s, 3H); 2.48-2.59 (m, 4H); 2.21 (s, 3H).
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Br[C:19]1[CH:20]=[C:21]2[O:27][C:26](=[O:28])[N:25]([CH3:29])[C:22]2=[N:23][CH:24]=1>O1CCCC1.[Zn].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:29][N:25]1[C:22]2=[N:23][CH:24]=[C:19]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:20]=[C:21]2[O:27][C:26]1=[O:28]
Reactant: Cn1c(=O)oc2cc(Br)cnc21
Reactant: BrCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: Cn1c(=O)oc2cc(Cc3ccccc3)cnc21
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Zinc (227 mg, 3.48 mmol) is suspended in tetrahydrofuran (10 ml) and 1,2-dibromoethane (0.22 ml, 0.2 mmol) is added. The mixture is heated at 60° C. for 3 minutes, the solution is allowed to cool until the temperature is 35° C., and trimethylsilyl chloride (0.06 ml, 0.5 mmol) is slowly added. Stirring is maintained for 30 minutes and then benzyl bromide (0.11 ml, 0.9 mmol) is added. Wait a further 30 minutes before introducing 6-bromo-3-methyloxazolo[4,5-b]pyridin-2(3H)-one (200 mg, 0.87 mmol) and tetrakis(triphenylphosphine)palladium (4 mg). Heat at 50° C. for 20 minutes. After the solution has been cooled, the zinc is removed by filtration, the filtrate is taken up in water, and then a 10% aqueous hydrochloric acid solution is added until the aqueous phase becomes clear. Extraction is carried out with dichloromethane. The organic phase is dried over magnesium sulfate and filtered, and then the solvent is evaporated off under reduced pressure. The title product is purified by chromatography on silica gel (eluant: dichloromethane). The yield obtained is 91%. ##STR51##