Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([Cl:35])[C:17]=1[O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH:20]=1)[C:11](OC)=[O:12]>C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([Cl:35])[C:17]=1[O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH:20]=1)[CH2:11][OH:12]
Reactant: COC(=O)c1cc(Cl)c(Oc2ccc(OC)c(Cc3ccc(F)cc3)c2)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Oc2c(Cl)cc(CO)cc2Cl)cc1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.4 %

Procedure:
To a stirred suspension of LiAlH4 (0.26 g, 6.95 mmol) in THF (40 mL) at 0° C. was slowly added a solution of methyl 3,5-dichloro-4-[3′-(4-fluorobenzyl)-4′-methoxyphenoxy]benzoate (1.2 g, 2.76 mmol) in THF (10 mL). The reaction mixture was stirred at room temperature for 20 h and cooled to 0° C. The reaction mixture was quenched with 15% aqueous NaOH (1.5 mL), diluted with H2O (3.0 mL) and stirred for 1 h. The reaction mixture was filtered through a Celite plug and the filtrate was extracted with ethyl acetate (100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1:1) to afford 3,5-dichloro-4-[3′-(4-fluorobenzyl)-4′-methoxyphenoxy]benzyl alcohol as an oil (0.78 g, 70%): 1H NMR (300 MHz, CDCl3): δ 7.47 (s, 2H), 7.16 (dd, J=6.0, 8.7 Hz, 2H), 7.04 (t, J=8.7 Hz, 2H), 6.84 (d, J=9.0 Hz, 1H), 6.67 (d, J=3.0 Hz, 1H), 6.45 (dd, J=5.4, 9.3 Hz, 1H), 5.45 (t, J=5.7 Hz, 1H), 4.48 (d, J=5.7 Hz, 2H), 3.82 (s, 2H), 3.69 (s, 3H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (2:3); Rf=0.45.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]3[C:10](=[C:11]([CH:13]([O:15][CH2:16][C:17]4([C:30]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=5)[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)[CH3:14])[CH:12]=2)[NH:9][N:8]=[CH:7]3)[CH2:3][CH2:2]1.C1(C2C=C(C(OCC3(C4C=CC(F)=CC=4)CCN(C(OC(C)(C)C)=O)CC3)C)C3C(=CN(COCC[Si](C)(C)C)N=3)C=2)CC1>FC(F)(F)C(O)=O>[CH:1]1([C:4]2[CH:5]=[C:6]3[C:10](=[C:11]([CH:13]([O:15][CH2:16][C:17]4([C:30]5[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=5)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH3:14])[CH:12]=2)[NH:9][N:8]=[CH:7]3)[CH2:3][CH2:2]1
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C2CC2)cc2cn[nH]c12
Agent: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C2CC2)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: O=C(O)C(F)(F)F
Product: CC(OCC1(c2ccc(F)cc2)CCNCC1)c1cc(C2CC2)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Enantiomer B of tert-Butyl 4-((1-(5-cyclopropyl-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate. Enantiomer B of tert-Butyl 4-((1-(5-cyclopropyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate(46 mg, 0.074 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 1.6 mL) and stirred at room temperature for 4 h. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 30 mg of Enantiomer B of 5-cyclopropyl-7-(1-((4-(4-fluorophenyl)piperidin-4-yl)methoxy)ethyl)-1H-indazole (quant.). The crude amine (30 mg, 0.076 mmol) in dichloromethane (2 mL) was cooled to 0° C. and treated with di-tert-butyl dicarbonate (33.3 mg, 0.152 mmol). The reaction was stirred at 0° C. for 1 h and was quenched by addition of 2 M ammonia in methanol and concentrated. The residue was purified by column chromatography (25% EtOAc/Hex) to give 28 mg (74.4%) as oil. 1H-NMR (CDCl3, 300 MHz) δ 7.85 (s, 1H), 7.23 (m,2H), 7.03 (m, 3H), 6.76 (s, 1H), 4.46 (q, J=6 Hz, 1H), 3.57-3.75 (m, 2H), 3.32 (d, J=9 Hz, 1H), 3.22 (d, J=9 Hz, 1H), 2.9-3.1(m, 2H), 2.01-2.22 (m,2H), 1.65-1.8 (m, 2H), 1.37-1.41 (m, 12H), 0.91 (m, 2H), 0.64 (m, 2H); Mass spec.: 494.48 (MH)+.
Reaction SMILES: I.[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([CH2:17][CH3:18])[CH2:15][NH:14][CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1.BrC1C=C2C(Cl)=C(C(N)=O)C=NN2C=1.Cl[C:38]1[N:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][N:39]=1.C(=O)([O-])[O-].[K+].[K+]>>[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([CH2:17][CH3:18])[CH2:15][N:14]([C:38]4[N:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][N:39]=4)[CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1
Reactant: N#Cc1cnc(Cl)nc1
Reactant: CC[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: I
Agent: NC(=O)c1cnn2cc(Br)cc2c1Cl
Agent: O=C([O-])[O-]
Product: CC[C@H]1CN(c2ncc(C#N)cn2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reaction time: 0.17 h
Yield: 84 %

Procedure:
A mixture of 6-bromo-4-(((3S,4S)-4-ethylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide hydroiodide (0.250 g, 0.521 mmol, prepared from Intermediates 2 and 8 using the methods in Example 52 and Step 1 of Example 158), 2-chloropyrimidine-5-carbonitrile (0.087 g, 0.625 mmol), and potassium carbonate (0.216 g, 1.562 mmol) in a sealed vial was placed in a 90° C. heating block for 3 h. The mixture was triturated with water (5 mL). The resulting suspension was stirred for 10 min and filtered. The solid was washed with water (20 mL) and dried under vacuum to give 6-bromo-4-(((3S,4S)-1-(5-cyanopyrimidin-2-yl)-4-ethylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide as yellow solid (199 mg, 84% yield). 1H NMR (400 MHz, 1:1 mixture of chloroform-d/methanol-d4) δ ppm 8.57 (d, J=2.9 Hz, 1H), 8.51 (d, J=3.1 Hz, 1H), 8.11 (s, 1H), 7.64 (d, J=1.8 Hz, 1H), 6.92 (d, J=1.8 Hz, 1H), 4.89 (t, J=4.4 Hz, 1H), 4.18-4.01 (m, 2H), 4.00-3.88 (m, 1H), 3.52 (t, J=11.6 Hz, 1H), 2.71-2.50 (m, 1H), 1.85-1.68 (m, 2H), 1.05 (t, J=7.5 Hz, 3H); MS (ES+) m/z: 455.1 (M+H); LC retention time: 4.085 min (analytical HPLC Method H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5]O)[OH:4].[CH3:7][C:8]([CH2:10][OH:11])=[O:9]>O>[CH2:2]([OH:1])[CH:3]([OH:4])[CH3:5].[OH:11][CH2:10][C:8](=[O:9])[CH3:7]
Reactant: OCC(O)CO
Agent: CC(=O)CO
Solvent: O
Product: CC(O)CO

Procedure:
Dehydration of 80 wt % glycerol followed by acetol hydrogenation in a single step at 220° C. in 20 g of water as a solvent using 0.01 g/ml of 67% Cu+33% Cr catalyst in 5 h gave 21% conversion of glycerol with selectivity's of 69% to 1,2-propylene glycol and 31% to hydroxyacetone.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1.[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][O:15][C:2]2[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=2)=[CH:12][CH:11]=1
Reactant: CSc1nsc(Cl)n1
Reactant: OCc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nsc(OCc2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
Into 2 ml of N,N-dimethylformamide were dissolved 150 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole and 154 mg of 4-chlorobenzyl alcohol, 43 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 0.5 hour under ice-cooling and for 4 hours at room temperature. The reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 170 mg of 5-(4-chlorobenzyloxy)-3-methylthio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (4)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11](=[O:15])(=[O:14])[NH:12][CH3:13])[NH:7][CH2:6][CH2:5]2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(Cl)(Cl)Cl>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11](=[O:15])(=[O:14])[NH:12][CH3:13])[NH:7][CH:6]=[CH:5]2
Reactant: CNS(=O)(=O)c1cc2c(cc1Br)CCN2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CNS(=O)(=O)c1cc2[nH]ccc2cc1Br
Temperature: 80 °C

Procedure:
To a stirred solution of 5-bromo-6-methylsulfamoylindoline, 55.92 g (0.19 mol) in 150 ml dioxane was added 41.79 gm (0.184 mol) of 2,3-dichloro-5,6-dicyanobenzoquinone at 25° C. The resulting brown solution was heated to 80° C. for 2 hours when thin layer chromatography using chloroform showed that the reaction was complete. The reaction mixture was allowed to cool, filtered through Celite and the filtrate concentrated under reduced pressure. The resulting brown solid was stirred in a mixture of methylene chloride/ether 50/50 and then filtered. This procedure was carried out two additional times and gave 35.2 g (63.9% by weight yield) of 5-bromo-6-methylsulfamoylindole.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:40][N:41]([CH:49]=[O:50])[O:42]C2CCCCO2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][N:11]2[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>CC(O)=O.O>[CH:1]1([CH2:6][C@H:7]([CH2:40][N:41]([CH:49]=[O:50])[OH:42])[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][N:11]2[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)Nc2nccc(-c3ccccn3)n2)CCN1C(=O)OCc1ccccc1)OC1CCCCO1
Solvent: O
Solvent: CC(=O)O
Product: O=CN(O)C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)Nc2nccc(-c3ccccn3)n2)CCN1C(=O)OCc1ccccc1
Yield: 9.1 %

Procedure:
A solution of phenylmethyl (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoyl)-3-({[4-(2-pyridinyl)-2-pyrimidinyl]amino}carbonyl)-1-pyrazolidinecarboxylate in AcOH/water (5 mL, 4:1) was stirred at rt for 48 h. The solvents were removed under vacuum and the residue was purified by RP-HPLC to provide the title compound (32 mg, 9.1%) as light-yellow gum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]1[CH2:14][CH2:13]1)[C:6]([C:15]([O:17]C)=[O:16])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]1[CH2:14][CH2:13]1)[C:6]([C:15]([OH:17])=[O:16])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1
Reactant: COC(=O)c1c(C2CC2)nc2ccc(Cl)cc2c1-c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c(C2CC2)nc2ccc(Cl)cc2c1-c1cccc(Cl)c1
Temperature: 25 °C
Yield: 74.4 %

Procedure:
To a white suspension of methyl 6-chloro-4-(3-chlorophenyl)-2-cyclopropylquinoline-3-carboxylate (45 mg, 0.12 mmol, 1 eq) in ethanol (2 ml) was added 1N NaOH (604 μl, 0.60 mmol, 5 eq) and the reaction mixture was refluxed overnight. The clear solution was then cooled to room temperature and concentrated in vacuo. The residue was diluted with water and the pH was adjusted to 3 with 1N HCl. The aqueous layer was extracted with ethyl acetate (×3) and the organic phases were combined and washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (1:1 ethyl acetate:heptane with 5% AcOH) to give 6-chloro-4-(3-chloro-phenyl)-2-cyclopropyl-quinoline-3-carboxylic acid (32 mg, 74%) as a white solid. MS (ESI): 358.1 (M+H)+.
Reaction SMILES: C([NH:9][C:10]1[CH:25]=[CH:24][N:13]([C@@H:14]2[O:23][C@H:20]([CH2:21][OH:22])[C@@H:18]([OH:19])[C@H:15]2[O:16]C)[C:12](=[O:26])[N:11]=1)(=O)C1C=CC=CC=1.COC1C=CC(C(Cl)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1>N1C=CC=CC=1>[C@@H:14]1([N:13]2[CH:24]=[CH:25][C:10]([NH2:9])=[N:11][C:12]2=[O:26])[O:23][C@H:20]([CH2:21][OH:22])[C@@H:18]([OH:19])[C@H:15]1[OH:16]
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=O
Agent: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N4 -Benzoyl-2'-O-methylcytidine (28 g, 0.077 mol) was evaporated under reduced pressure to an oil with pyridine (400 mL). To the residue was added 4,4'-dimethoxytriphenylmethyl chloride (DMT-Cl, 28.8 g, 0.085 mol) and pyridine (400 mL). The mixture was stirred at 25° C. for 2 h and then quenched by the addition of methanol (10 mL) for 30 min. The mixture was concentrated under reduced pressure and the residue was chromatographed on silica gel (500 g, hexanes-ethyl acetatetriethylamine 60:40:1 and then ethyl acetate-triethylamine 99:1). The appropriate fractions were combined, evaporated under reduced pressure and dried at 40° C./0.2 mmHg for 2 h to give 26 g (74%, 16% from cytidine) of foam; TLC homogenous (Rf 0.45, ethyl acetate); PMR (DMSO) δ 11.3 (H-N4), 8.4-6.9 (H-6, H-5, Bz), 5.95 (H-1'), 5.2 (HO-3'), 3.7 (s, 6, CH3O-trit.), 3.5 (s, 3, CH3O-2')
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1)[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[N:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCc1ccc2ccccc2n1
Product: FCc1cccc(C#CCCc2ccc3ccccc3n2)n1
Reaction time: 0.25 h
Yield: 53 %

Procedure:
The title compound was prepared in accordance with the general method of Example 108(C), from 2-bromo-6-(fluoromethyl)-pyridine (157 mg, 0.83 mmol) and 2-but-3-ynyl-quinoline (150 mg, 0.83 mmol, Example 118(B)). Microwave conditions: 120° C. for 15 minutes. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 127 mg (0.44 mmol, 53%) of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)quinoline as an orange solid (M.P.=70.2-74.3° C.).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.I[CH2:11][CH:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:11]([N:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1]1)[CH:12]([CH3:14])[CH3:13]
Reactant: c1ccc2[nH]nnc2c1
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cn1nc2ccccc2n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
A mixture of benzotriazole (11.91 g, 100 mmol), 1-iodo-2-methylpropane (13.8 mL, 120 mmol), potassium carbonate (41.46 g, 300 mmol), and dimethylformamide (200 mL) was stirred and heated under argon at 40° C. for 2 days. The reaction mixture was poured into ice/water (1 L) and extracted with toluene/hexanes (2:1, 2×500 mL). The extract was washed with 1 N HCl (2×200 mL) followed by brine (100 mL), dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was triturated with hexane (200 mL) and set aside at room temperature for 2 hours. The precipitate was separated and discarded, and the solution was filtered through a layer of silica gel (200 g). The silica gel was washed with hexane/dichloromethane/ethyl acetate (37:50:3, 2 L). The filtrate and washings were combined, and the solvent was removed under reduced pressure to give 2-isobutyl-2H-benzo[d][1,2,3]triazole (8.81 g, 50% yield) as an oily product. 1H NMR (400 MHz, CDCl3): δ 7.86 (m, 2H, benzotriazole), 7.37 (m, 2H, benzotriazole), 4.53 (d, J=7.3 Hz, 2H, i-Bu), 2.52 (m, 1H, i-Bu), 0.97 (d, J=7.0 Hz, 6H, i-Bu).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][N:10](C=O)C>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]#[N:10])=[N:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(Br)nc1
Product: N#Cc1ccc(Br)cn1
Temperature: 120 °C
Yield: 74 %

Procedure:
Referring now to Scheme 3, a mixture of 2,5-dibromopyridine (20 mmol) and Cu(1)CN (20 mmol) in DMF (120 mL) was refluxed for 12 hr at 120° C. The reaction mixture was poured onto water and the solid which formed was extracted by using ethylacetate (250 mL, 3 times). The solvent was evaporated and the precipitate purified (SiO2, hexanes/EtOAc 90:10). Yield 74%, mp 125–126° C. 1H nmr (DMSO-d6); δ 8.03 (d, J=8.1 Hz, 1H), 8.37 (dd, J=8.1, 2.1 Hz, 1H). 8.92 (d, J=2.1 Hz, 1H). 13C nmr; δ 152.2, 140.6, 131.1, 130.3, 125.1, 117.0.
Reaction SMILES: NC1C=CC(N2CCC[C@H](C(N3CCN(C)CC3)=O)C2)=CC=1OC.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([N:36]([CH3:47])[C:37](=[O:46])[CH2:38][N:39]2[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]2)[CH:30]=[CH:31][C:32]=1[N+:33]([O-])=O>>[NH2:33][C:32]1[CH:31]=[CH:30][C:29]([N:36]([CH3:47])[C:37](=[O:46])[CH2:38][N:39]2[CH2:40][CH2:41][N:42]([CH3:45])[CH2:43][CH2:44]2)=[CH:28][C:27]=1[O:26][CH3:25]
Reactant: COc1cc(N(C)C(=O)CN2CCN(C)CC2)ccc1[N+](=O)[O-]
Agent: COc1cc(N2CCC[C@H](C(=O)N3CCN(C)CC3)C2)ccc1N
Product: COc1cc(N(C)C(=O)CN2CCN(C)CC2)ccc1N

Procedure:
N-(4-Amino-3-methoxy-phenyl)-N-methyl-2-(4-methyl-piperazin-1-yl)-acetamide was prepared in an analogous fashion to [(S)-1-(4-Amino-3-methoxy-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone of Example 460c replacing [(S)-1-(3-Methoxy-4-nitro-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone with N-(3-Methoxy-4-nitro-phenyl)-N-methyl-2-(4-methyl-piperazin-1-yl)-acetamide. N-(4-Amino-3-methoxy-phenyl)-N-methyl-2-(4-methyl-piperazin-1-yl)-acetamide was purified by trituration with Et2O to give pure product as a brown solid, MP 115-118° C. (390 mg, 93%). LC/MS (E/I+) 293 (M−15).
Reaction SMILES: C1C=C2C=CC(O)=C(C3C4C(=CC=CC=4)C=CC=3O)C2=CC=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[CH2:34])[CH2:31][CH2:32][CH3:33])[C:25]=1[O:35][CH3:36].[F:37][C:38]([F:47])([F:46])[C:39](=[O:45])[C:40]([O:42][CH2:43][CH3:44])=[O:41]>C1(C)C=CC=CC=1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[F:23][C:24]1[C:25]([O:35][CH3:36])=[C:26]([C:30](=[CH:31][CH2:32][CH3:33])[CH2:34][C:39]([OH:45])([C:38]([F:46])([F:47])[F:37])[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)C(=O)C(F)(F)F
Reactant: C=C(CCC)c1cccc(F)c1OC
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Solvent: Cc1ccccc1
Product: CCC=C(CC(O)(C(=O)OCC)C(F)(F)F)c1cccc(F)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
698 mg (2.56 mmol) of 1,1′-bi-2-naphthol are admixed with 2.56 ml (1.28 mmol) of a 0.5 M titanium tetraisopropoxide solution in toluene and the red solution is stirred at room temperature for 2 hours. 4.26 g (21.9 mmol) of 2-fluoro-6-(1-methylenbutyl)anisole and 5.7 ml (44 mmol) of ethyl trifluoropyruvate are added and the mixture is heated at 140° C. for 18 hours. After cooling it is immediately purified by column chromatography on silica gel (hexane/ethyl acetate 0-15%) to give 5.82 g of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hept-4-enoate. 2.6 g (7.1 mmol) of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hept-4-enoate are dissolved in 65 ml of methanol and the solution is admixed with 260 mg of palladium on carbon (10%). The suspension is shaken under a hydrogen atmosphere at atmospheric pressure for 4 hours until the hydrogen uptake is 155 ml. The mixture is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. Removal of the solvent gives 2.6 g of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)heptanoate. 2.6 g (7.1 mmol) of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-heptanoate in 150 ml of diethyl ether are cooled to −10° C. and over 15 minutes 520 g (14.2 mmol) of solid lithium aluminum hydride are added in portions. The mixture is stirred at −15° C. for 1.5 hours, followed by dropwise addition in succession of ethyl acetate and water and by a further hour of stirring until a readily filterable precipitate is formed. The suspension is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo. Separation by column chromatography on silica gel (hexane/diisopropyl ether 0-15%) yields 2.1 g of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)heptanal as a mixture of the diastereomers.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].Br[C:13]1[CH:14]=[C:15]2[C:19](=[N:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2>CN(C)C=O.[Cu]Br>[N:1]1([CH2:7][CH2:8][O:9][C:13]2[CH:14]=[C:15]3[CH:16]=[CH:17][NH:18][C:19]3=[N:20][CH:21]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: OCCN1CCOCC1
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cc2cc(OCCN3CCOCC3)cnc2[nH]1
Temperature: 120 °C
Reaction time: 2 h
Yield: 49.2 %

Procedure:
To 4-morpholineethanol (30 mL, 0.2 mol) in N,N-dimethylformamide (30 mL) was slowly added sodium hydride (7 g, 60% dispersion in mineral oil, 0.2 mol). After the solution turned clear, a solution of 5-bromo-7-azaindole (44, 1.0 g, 0.0051 mol) in N,N-dimethylformamide (5 mL) and copper(I) bromide (1.4 g, 0.0098 mol) were added. The reaction mixture was stirred at 120° C. under nitrogen for 2 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and water. The organic layer was collected, washed with a solution of ammonium chloride and ammonium hydroxide (4:1), brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as an off-white solid (79, 0.62 g, 50%). MS (ESI) [M+H+]+=248.25.
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[C:4](=[N:5][C:6]([CH3:11])=[CH:7][CH:8]=2)[CH:3]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:6]1[N:5]=[C:4]2[CH:3]=[C:2]([Cl:1])[S:10][C:9]2=[CH:8][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2sc(Cl)cc2n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc2nc(CBr)ccc2s1
Temperature: 25 °C

Procedure:
A mixture of the product of Step 1 (0.371 g, 2.0 mmol), N-bromosuccinimide (0.396 g, 2.2 mmol), and benzoyl peroxide in 10 mL of carbon tetrachloride was refluxed under a sun lamp for 1 hr. After cooling to room temperature, the solvent was removed and the title bromide was purified by flash chromatography on silica (eluted with 5% EtOAc in hexane) to yield 0.284 g (46%).