Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[NH:16][N:17]=2)[N:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[C:19]([O-])([O-])=O.[K+].[K+].[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1CBr>CN(C=O)C.CCOC(C)=O>[F:36][C:26]([F:25])([F:35])[C:27]1[CH:28]=[CH:31][C:32]([CH2:19][N:16]2[C:15](=[O:18])[N:4]3[N:5]=[CH:6][C:7]([C:8]4[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=4)=[C:2]([Cl:1])[C:3]3=[N:17]2)=[CH:33][CH:34]=1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Temperature: 55 °C
Yield: 88.2 %

Procedure:
To a solution of 8-chloro-7-(4-chlorophenyl)-2H-[1,2,4]triazolo[4,3-b]pyridazin-3-one (0.54 g, 1.91 mmol), prepared as described in Example 354, in DMF (5 mL) at RT was added K2CO3 (0.40 g, 2.87 mmol) and 2-(trifluoromethyl)benzyl bromide (0.595 g, 2.49 mmol). The reaction mixture was heated at 55° C. for 4 h. After this time, the mixture was diluted with EtOAc (150 mL). The resultant solution was washed with water and saturated aqueous NaCl. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using hexanes:EtOAc (2:1) to afford 0.74 g of the title compound, 2-(4-(trifluoromethyl)benzyl-8-chloro-7-(4-chloro-phenyl)-2H-[1,2,4]triazolo[4,3-b]pyridazin-3-one as a yellow solid. HPLC RT: 3.84 min; MS, M+H=439. 1H NMR (CDCl3): δ 8.08 (s, 1H), 7.44-7.61 (m, 8H), 5.30 (s, 2H).
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH:17]=[C:16]([C:31]#[C:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:40])C.[OH-].[Na+].Cl>C(O)C>[CH3:40][C:8]1[CH:9]=[C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:30])[F:28])[CH:22]=3)[CH:17]=[C:16]([C:31]#[C:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:15]=2)[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:41])=[O:3]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(Oc3cccc(C(F)(F)F)c3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Sc2cc(C#CCN3CCOCC3)cc(Oc3cccc(C(F)(F)F)c3)c2)ccc1OCC(=O)O
Reaction time: 16 h

Procedure:
{2-Methyl-4-[3-(3-morpholin-4-yl-prop-1-ynyl)-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (160 mg; 0.27 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate, dried and evaporated to dryness. The organic phase was purified by preparative HPLC (method B). Yield: 128 mg (84%). HPLC-MS: m/z: 558.4 (M+H)+; Rt: 1.91 min. δH(400 MHz; CDCl3) 2.26 (s, 3H), 3.05-3.55 (m, 4H), 3.91-4.04 (m, 4H), 4.11 (s, 2H), 4.70 (s, 2H), 6.71-6.78 (m, 3H), 6.81-6.84 (m, 1H), 7.11-7.16 (m, 1H), 7.19-7.23 (m, 1H), 7.27-7.33 (m, 2H), 7.37-7.41 (m, 1H), 7.43-7.49 (m, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:16][N:17]([CH3:31])[C:18]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.C(O)(=O)C>ClCCCl>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH:4]2[CH2:5][CH2:6][N:1]([CH:21]3[CH2:20][CH2:19][C:18]([N:17]([CH3:31])[CH3:16])([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:23][CH2:22]3)[CH2:2][CH2:3]2)=[CH:8]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(C)C1(c2ccccc2)CCC(N2CCC(c3c[nH]c4ccccc34)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-piperidine-4-yl-1H-indole (200 mg, 1 mmole) and 4-dimethylamino-4-phenylcyclohexanone (217 mg, 1 mmole) were dissolved in dry 1,2-dichloroethane (20 ml). Glacial acetic acid (1 mmole) and sodium triacetoxy boron hydride (300 mg, 1.4 mmole) were added to this mixture. The reaction mixture was then stirred for 24 hours at RT. The reaction mixture was worked up by distilling off the 1,2-dichloroethane and diluting with water (10 ml). The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (3×20 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The product was a mixture of two diastereoisomeric compounds, which were separated by chromatography with methanol. The polar and the non-polar diastereoisomers were obtained in each case as a colourless oil in a yield of 90 mg (22%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[CH2:11][CH:10]([C:25](O)=[O:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:29]=[C:30]([CH:32]1[CH2:34][CH2:33]1)[NH2:31]>>[CH:32]1([C:30]2[N:31]=[C:25]([CH:10]3[CH2:11][CH:12]([C:14]4[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:18][CH:19]=4)[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9]3)[O:26][N:29]=2)[CH2:34][CH2:33]1
Reactant: NC(=NO)C1CC1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)CC(c2ccc(OC(F)(F)F)cc2)C1
Product: CC(C)(C)OC(=O)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1

Procedure:
1.00 g (2.57 mmol) of the compound from Example 173A and 386 mg (3.86 mmol) of the compound from Example 78A were reacted according to the General Method 2. Yield: 185 mg (16% of theory)
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][C:23]2([C:26]([O:28]C)=O)[CH2:25][CH2:24]2)=[O:21])=[CH:15][CH:14]=1.[H-].[Na+]>CN(C=O)C>[OH:28][C:26]1[C:23]2([CH2:25][CH2:24]2)[O:22][C:20](=[O:21])[C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)C1(OC(=O)Cc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1OC2(CC2)C(O)=C1c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.5 %

Procedure:
To a 0° C. solution of methyl 1-(2-(4-(quinolin-2-ylmethoxy)phenyl)acetoxy)cyclopropanecarboxylate (2.0 g, 6.825 mmol) in DMF (20 mL), NaH (49 mg, 20.477 mol) was added and the mixture was stirred at RT for 12 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was quenched with ice water (3 mL) and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layer were washed with water (30 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford crude 7-hydroxy-6-(4-(quinolin-2-ylmethoxy)phenyl)-4-oxaspiro[2.4]hept-6-en-5-one (2.0 g, 83%) as a light yellow solid.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].O.[CH3:8][C:9]1[CH:32]=[CH:31][CH:30]=[CH:29][C:10]=1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=1B1OC(C)(C)C(C)(C)O1.Br[C:34]1[N:39]=[C:38]([CH2:40][NH:41][C:42]2[C:47]([CH:48]([CH3:50])[CH3:49])=[CH:46][CH:45]=[CH:44][C:43]=2[CH:51]([CH3:53])[CH3:52])[CH:37]=[CH:36][CH:35]=1>C1(C)C=CC=CC=1.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.CO>[CH:51]([C:43]1[CH:44]=[CH:45][CH:46]=[C:47]([CH:48]([CH3:50])[CH3:49])[C:42]=1[NH:41][CH2:40][C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([C:14]2[C:13]([CH2:12][NH:11][C:10]3[CH:29]=[CH:30][CH:31]=[CH:32][C:9]=3[CH3:8])=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:19])[N:39]=1)([CH3:53])[CH3:52]
Reactant: CC(C)c1cccc(C(C)C)c1NCc1cccc(Br)n1
Reactant: Cc1ccccc1NCc1cccc(C)c1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: Cc1ccccc1NCc1cccc(C)c1-c1cccc(CNc2c(C(C)C)cccc2C(C)C)n1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A mixture of 5.50 g (19 mmol) of Na2CO3×10H2O, 100 ml of water and 30 ml of methanol was purged with argon for 30 min. The obtained solution was added to a mixture of 2.60 g (7.7 mmol) of 2-methyl-N-[3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]aniline, 2.68 g (7.7 mmol) of N-[(6-bromopyridin-2-yl)methyl]-2,6-diisopropylaniline, and 0.44 g (0.39 mmol) of Pd(PPh3)4 in 120 ml of toluene. This mixture was stirred for 12 h at 70° C., then cooled to room temperature. The organic layer was separated, the aqueous layer was extracted with 3×50 ml of ethyl acetate. The combined organic extract was washed with brine, dried over Na2SO4, and evaporated to dryness. The residue was purified by flash chromatography on silica gel 60 (40-63 um; eluent: hexane-triethylamine=20:1, vol.). Yield 2.10 g (57%) of white crystalline solid. Anal. calc. for C33H39N3: C, 82.97; H, 8.23; N, 8.80. Found: C, 83.19; H, 8.45; N, 8.62. 1H NMR (CDCl3): δ 7.71 (m, 1H), 7.37 (m, 1H), 7.28-7.32 (m, 2H), 7.22-7.26 (m, 2H), 7.00-7.13 (m, 5H), 6.61 (m, 1H), 6.47 (m, 1H), 4.25 (s, 2H), 4.10 (s, 2H), 3.98 (br.s, 1H), 3.82 (br.s, 1H), 3.31 (s, J=6.9 Hz, 2H), 2.14 (s, 3H), 2.09 (s, 3H), 1.21 (d, J=6.9 Hz, 12H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1.Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([Cl:25])[N:17]=1.O>C1COCC1>[Cl:25][C:18]1[N:17]=[C:16]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([F:3])=[CH:5][C:6]=2[C:11]([F:12])([F:13])[F:14])[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: Nc1ccc(F)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)nc1Nc1ccc(F)cc1C(F)(F)F
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
Sodium hydride (0.124 g, 5.18 mmol) was added to a chilled (0° C.) solution of 4-fluoro-2-(trifluoromethyl)aniline (0.464 g, 2.59 mmol) in THF (1 mL) and stirred for 30 min. 2,6-Dichloro-3-nitropyridine (0.500 g, 2.59 mmol) was then added and the reaction mixture stirred at 80° C. for 18 h. Water was added to quench excess sodium hydride and volatile solvents were removed under reduced pressure. The product was then extracted into DCM, solvent removed under reduced pressure, and the residue purified by preparative HPLC to give the title compound (0.624 g). LCMS m/z=336.0 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 6.87 (d, J=8.6 Hz, 1H), 7.34 (td, J1=8.4 Hz, J2=3.0 Hz, 1H), 7.43 (dd, J1=8.4 Hz, J2=3.0 Hz, 1H), 7.94 (dd, J1=9.0 Hz, J2=5.0 Hz, 1H), 8.49 (d, J=8.6 Hz, 1H), 10.26 (br s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[O:7](C)[S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9]>CCCCCC>[F:12][C:11]([F:14])([F:13])[S:8]([O-:10])(=[O:9])=[O:7].[CH3:1][N+:2]1([CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CN1CCCC1
Reactant: COS(=O)(=O)C(F)(F)F
Solvent: CCCCCC
Product: C[N+]1(C)CCCC1
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 72.5 °C
Yield: 198.1 %

Procedure:
141.13 g (1.657 mol) of 1-methylpyrrolidine in 800 ml of dry hexane are introduced into a round-bottomed flask fitted with a reflux condenser. 272 g (1.657 mol) of methyl triflate are added over the course of 45 minutes with constant stirring and cooling with the aid of an ice bath. The ice bath is then replaced by an oil bath, and the reaction mixture is refluxed for 15 minutes (oil-bath temperature 70-75° C.). After cooling to room temperature, the white precipitate is filtered off, washed twice with 100 ml of hexane and dried at 110° C. under a 30-100 Pa vacuum for three hours, giving 409 g (yield: 99.1%) of 1,1-dimethylpyrrolidinium trifluoromethanesulfonate as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:36]=[CH:35][C:14]([C:15]([N:17]([CH3:34])[C@:18]([CH3:33])([C:23]([NH:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[O:24])[C:19]([NH:21][CH3:22])=[O:20])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)=O.Cl.[CH3:38][O:39][CH2:40][CH2:41][O:42][CH:43]1[CH2:46][NH:45][CH2:44]1>>[CH3:38][O:39][CH2:40][CH2:41][O:42][CH:43]1[CH2:46][N:45]([CH2:1][C:3]2[CH:4]=[CH:5][C:6]([C:9]#[C:10][C:11]3[CH:12]=[CH:13][C:14]([C:15]([N:17]([CH3:34])[C@:18]([CH3:33])([C:23]([NH:25][O:26][CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][O:28]4)=[O:24])[C:19]([NH:21][CH3:22])=[O:20])=[O:16])=[CH:35][CH:36]=3)=[CH:7][CH:8]=2)[CH2:44]1
Reactant: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1
Reactant: COCCOC1CNC1
Agent: Cl
Product: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(CN3CC(OCCOC)C3)cc2)cc1

Procedure:
From (2S)-2-[{4-[(4-formylphenyl)ethynyl]benzoyl}(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (0.12 g) as obtained in Example 16-(1) and 3-(2-methoxyethoxy)azetidine hydrochloride (60 mg), (2S)-2-[{4-[(4-{[3-(2-methoxyethoxy)azetidin-1-yl]methyl}phenyl)ethynyl]benzoyl}(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (yellow oil) was obtained (0.10 g, 69%) in the same manner as in Example 16-1-(3).
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]([O:20][CH3:21])(=[O:19])[CH2:17]O.N1C=CC=CC=1>C(Cl)Cl>[F:5][C:4]([F:7])([F:6])[S:1]([O:8][CH2:17][C:16]([O:20][CH3:21])=[O:19])(=[O:3])=[O:2]
Reactant: COC(=O)CO
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)COS(=O)(=O)C(F)(F)F
Reaction time: 1.5 h
Yield: 68 %

Procedure:
To a solution of triflic anhydride (3.7 ml, 20.0 nmmol) in methylene chloride (10 ml) at -5° C. under argon, was added dropwise over 30 minutes a solution of methyl glycolate (1.8 g, 20.0 mmol), pyridine (1.55 ml, 20.0 mmol), and anhydrous methylene chloride (5 ml). The reaction was allowed to stir at between 0°-5° C. for 1.5 h. The mixture was then washed with water several times. The organic extract was then washed with water, brine, and dried (MgSO4). After removing the solvent under reduced pressure, flash chromatography of the residue (silica gel, methylene chloride) afforded the title compound as a colorless oil (3.0 g, 68%).
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.C[Si](Cl)(C)C.[CH2:15]([O:17][C:18](=[O:47])[CH2:19][CH2:20][N:21]([C:39]1([C:44](Cl)=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40]1)[S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH3:16].Cl>ClCCl>[CH2:15]([O:17][C:18](=[O:47])[CH2:19][CH2:20][N:21]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:39]1([C:44](=[O:45])[NH:2][OH:3])[CH2:43][CH2:42][CH2:41][CH2:40]1)[CH3:16]
Reactant: CCOC(=O)CCN(C1(C(=O)Cl)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: NO
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CCN(C1(C(=O)NO)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.37 g (19.7 mmol, 1.3 equivalents) of hydroxylamine hydrochloride in 9.2 mL (114 mmol, 7.5 equivalents) of dry pyridine at 0° C. was treated with 5.8 mL (45 mmol, 3.0 equivalents) of trimethylsilyl chloride, causing white solids to precipitate. The mixture was allowed to warm to ambient temperature overnight. This mixture was then cooled to 0° C. and treated with a solution of 7.54 g (15.1 mmol) of 3-{(1-chlorocarbonylcyclopentyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}propionic acid ethyl ester in 73 mL of dichloromethane, prepared as described above, without isolation, causing an exotherm to about 8° C. This mixture was stirred at 0° C. for 30 minutes and at ambient temperature for about one hour. The reaction was then treated with 50 mL of 2N aqueous hydrochloric acid and was stirred at ambient temperature for one hour. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with 2N aqueous hydrochloric acid (2×50 mL) and water (50 mL). This solution of 3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoylcyclopentyl)amino]propionic acid ethyl ester in dichloromethane was used for the preparation of 3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoylcyclopentyl)amino]propionic acid without isolation. An aliquot was concentrated to a foam.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]=1[OH:21])[CH:4]=[CH2:5].CC1C=CC(S(O[CH2:33][C@@H:34]2[O:36][CH2:35]2)(=O)=O)=CC=1>CCCCCC.CN(C)C=O>[CH2:3]([O:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:10]=[CH:9][C:8]=1[O:21][CH2:33][CH:34]1[CH2:35][O:36]1)[CH:4]=[CH2:5]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: C=CCOc1cc(OCc2ccccc2)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C=CCOc1cc(OCc2ccccc2)ccc1OCC1CO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (4.3 g, 0.11 mole of 60% mineral oil dispersion) was washed with hexane and suspended in 100 mL of N,N-dimethylformamide. To this suspension was added a solution of 25.4 g (0.10 mole) of 2-allyloxy-4-(benzyloxy)phenol in 100 mL of DMF. The mixture was stirred at room temperature for 30 minutes and then 22.8 g (0.10 mole) of (2R)-(−)-glycidyl tosylate was added.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[CH3:10][N:11]([CH3:21])[C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](O)=[O:16].Cl.C1COCC1>O>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH:9][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[C:12]([N:11]([CH3:10])[CH3:21])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: NNc1ccc(Cl)nn1
Reactant: CN(C)c1cccc(C(=O)O)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1cccc(C(=O)NNc2ccc(Cl)nn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (6-chloropyridazin-3-yl)hydrazine, 3-dimethylaminobenzoic acid, WSCD hydrochloride and THF was stirred at room temperature for 2 hours. The reaction solution was combined with water, and the precipitate was collected by filtration, washed with water and isopropyl ether to obtain N′-(6-chloropyridazin-3-yl)-3-dimethylaminobenzohydrazide. To this, ethylene glycol was added and the mixture was stirred at 160° C. for 4 hours. After allowing to cool to room temperature, followed by purification by a standard method, 6-chloro-3-(3-dimethylaminophenyl)-1,2,4-triazolo[4,3-b]pyridazine was obtained. Dat (F:274).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.[Cl:13][C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=1)[O:17][CH2:18][C:19](OCC)=[O:20]>C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=1)[O:17][CH2:18][C:19](=[O:20])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CCOC(=O)COc1cccc(Cl)c1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)COc1cccc(Cl)c1)OC
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To 20.6 g (166 mmol, 238 mol %) of dimethyl methylphosphonate in 110 mL of THF at -78° C. was added dropwise 65 mL (162 mmol, 232 mol %) of a 2.5M solution of n-BuLi in hexanes. After addition was complete, the mixture was stirred for an additional 1 h, after which 15.0 g (69.9 mmol) of aryloxyester 10 in 40 mL of THF was added dropwise. The reaction was stirred for 1 h and then quenched by the addition of 100 mL of saturated NH4Cl. The mixture was poured into 200 mL of a 1/1 mixture of saturated NaCl/ethyl acetate, layers were separated, and the aqueous layer was further extracted with ethyl acetate (2×100 mL). Combined organic layers were dried over MgSO4, filtered, and concentrated, to afford 20.5 g (100%) of 11 as a viscous oil. 1H NMR δ 7.22 (t, J=8.1 Hz, 1 H), 7.05-6.90 (m, 2 H), 6.85-6.78 (m, 1 H), 4.72 (s, 2 H), 3.84 (s, 3 H), 3.78 (s, 3 H), 3.27 (d, J=22.8 Hz, 2 H).
Reaction SMILES: [ClH:1].O1CCOCC1.[NH2:8][CH:9]([CH2:37][O:38]C(C)(C)C)[C:10]([NH:12][C:13]1[CH:18]=[C:17]([C:19]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=2)=[CH:20][C:21]#[N:22])[CH:16]=[CH:15][C:14]=1[O:35][CH3:36])=[O:11].CCOCC>C(Cl)Cl>[ClH:1].[NH2:8][CH:9]([CH2:37][OH:38])[C:10]([NH:12][C:13]1[CH:18]=[C:17]([C:19]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=2)=[CH:20][C:21]#[N:22])[CH:16]=[CH:15][C:14]=1[O:35][CH3:36])=[O:11]
Reactant: COc1ccc(C(=CC#N)c2cc(OC)c(OC)c(OC)c2)cc1NC(=O)C(N)COC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1ccc(C(=CC#N)c2cc(OC)c(OC)c(OC)c2)cc1NC(=O)C(N)CO
Temperature: 25 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
A solution of 4N HCl/dioxane (1 mL) was added to a stirred solution of 2-amino-N-{5-[2-cyano-1-(3,4,5-trimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-3-t-butoxy-propionamide (0.5 g, 1.1 mmol) in CH2Cl2 (10 mL). The resulting mixture was stirred at room temperature for 1 day. Ether (20 mL) was added and the mixture was stirred for 2 h. The slurry was filtered and washed with ether to afford mixture isomers of 2-amino-N-{5-[2-cyano-1-(3,4,5-trimethoxy-phenyl)-vinyl]-2-methoxy-phenyl}-3-hydroxy-propionamide hydrochloride (0.4 g, 78%) as white solid: mp 151-153° C.; 1H NMR (DMSO-d6) δ 9.89 (9.94) (s 1H), 8.31 (b, 3H), 7.98-7.95 (m, 1H), 7.39-7.16 (m, 2H), 6.68 (6.65)-(s, 2H), 6.12 (6.25) (s, 1H), 5.63 (b, 1H), 4.18 (b, 1H), 3.91 (d, J=8 Hz, 2H), 3.87-3.70 (m, 12H); 13C NMR (DMSO-d6) δ 166.20, 161.24 (160.99), 152.62, 151.52 (150.82), 139.43 (138.36), 133.54 (132.24), 129.80 (128.56), 126.60 (126.29), 126.16 (125.31), 122.99 (122.32), 118.51 (118.47), 111.50 (111.16), 106.91 (106.26), 94.46 (93.64), 66.33, 60.33 (60.15), 56.15, 56.02, 54.43; Anal Calcd for C22H26N3O6Cl+0.2H2O: C, 56.52; H, 5.69; N, 8.99; Cl, 7.58. Found: C, 56.29; H, 5.81; N, 8.63; Cl, 7.35.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([NH2:19])[CH2:16][CH2:17][CH3:18]>>[CH2:15]([NH:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH2:16][CH2:17][CH3:18]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1O
Reactant: CCCCN
Product: CCCCNc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
Using the general method of Example 41, 4-hydroxy-3-nitroquinoline (38.4 g, 0.2 moles) was chlorinated then reacted with n-butylamine (24.7 mL, 0.4 mole) to provide the desired product as a yellow sold.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[C:3]=1[CH2:12][OH:13].N1C=CC=CC=1.[C:20](Cl)(=[O:22])[CH3:21].Cl>C1(C)C=CC=CC=1>[C:20]([O:13][CH2:12][C:3]1[C:4]([CH3:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1])(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1CO
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OCc1c(C)ccc([N+](=O)[O-])c1C
Temperature: 0 °C
Yield: 75.2 %

Procedure:
A stirred solution of 2,6-dimethyl-3-nitrobenzene-1-methanol (51.3 g, 0.283 mole) and 25 ml of pyridine in 350 ml of toluene was warmed to 70°. During a ten minute period, acetyl chloride (22.2 g, 0.283 mole) was added to the reaction mixture. The reaction mixture was heated at 85° for 21/2 hours, then poured over 300 g of ice, and 100 ml of a 4 N hydrochloric acid solution was added thereto. The organic phase was separated and washed with 100 ml of aqueous 2 N hydrochloric acid, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed from the filtrate under reduced pressure to give (2,6-dimethyl-3-nitrophenyl)methyl acetate (47.5 g) as an oil.