Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.[NH:31]1[CH:35]=[CH:34][CH:33]=[N:32]1.C(=O)([O-])[O-].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>CS(C)=O.C(OCC)(=O)C.O.[Cu]I>[OH:29][C@@H:24]1[C@@H:23]([N:13]2[C:12](=[O:30])[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]4=[C:9]([CH2:8][C:5]4[CH:6]=[N:7][C:2]([N:31]5[CH:35]=[CH:34][CH:33]=[N:32]5)=[CH:3][CH:4]=4)[CH:10]=3)[N:15]=[CH:14]2)[CH2:28][CH2:27][O:26][CH2:25]1
Reactant: c1cn[nH]c1
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1c2cc(Cc3ccc(-n4cccn4)nc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Temperature: 120 °C

Procedure:
To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one (Example 1, 0.080 g, 0.19 mmol) and pyrazole (0.052 g, 0.15 mmol) in 2 mL of DMSO under an atmosphere of nitrogen was added potassium carbonate (0.57 mL, 1 N aqueous, 0.57 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (21.6 mg, 0.152 mmol), and copper(I) iodide (0.014 g, 0.076 mmol). The mixture was heated at 120° C. for 20 h, cooled to rt, and additional trans-N,N′-dimethylcyclohexane-1,2-diamine (21.6 mg, 0.152 mmol) and copper(I) iodide (0.014 g, 0.076 mmol) were added. The reaction was heated at 150° C. for 24 h, cooled to rt, and diluted with ethyl acetate and water. The aqueous layer was extracted 3× with ethyl acetate, and the combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane, to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 453.51 for [M+H]+: 1H NMR (400 MHz, CD3OD) δ 8.93 (d, J=7.3 Hz, 1H), 8.46 (s, 1H), 8.30 (s, 1H), 8.26 (s, 1H), 7.90 (s, 1H), 7.86 (d, J=9.2 Hz, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.66-7.57 (m, 2H), 7.50 (d, J=8.5 Hz, 1H), 6.39 (s, 1H), 6.30 (s, 1H), 4.86-4.84 (m, 1H), 4.36 (s, 2H), 4.23-4.13 (m, 2H), 4.12-4.04 (m, 1H), 3.56-3.50 (m, 1H), 3.34-3.32 (m, 1H), 2.24-2.19 (m, 1H), 2.00-1.97 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19](Br)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH:41]=2)O1.ClCCl.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:16]=4)[CH:18]=[C:19]([C:36]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH:37]=3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Nc1ncnn2c(Br)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 75 °C
Yield: 68.9 %

Procedure:
To a stirred suspension of 5-(2-benzyl-2H-indazol-6-yl)-7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (660 mg, 1.57 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (see Eastwood, P. R. Tetrahedron Lett 2000, 41, 3705 for preparation) (730 mg, 2.36 mmol), and 1,1′-bis(diphenylphosphino)-ferrocene]dichloro palladium(II)-complex with dichloromethane (115 mg, 0.16 mmol) in degassed DME (12 mL) was added aqueous Na2CO3 solution (2 M, 2.4 mL). The reaction was heated (75° C.) for 17 h and was then cooled to rt. The mixture was partitioned between ethyl acetate (25 mL) and H2O (25 mL). The layers were separated and the organic layer was washed with brine, dried (Na2SO4), and concentrated to dryness. The crude residue was purified by ISCO® chromatography using a gradient of 50 to 75% ethyl acetate in hexanes to afford 564 mg (69%) of the desired product, which was approximately 50% pure. ES-MS m/z 522.12 [M+H]+, HPLC RT (min) 3.20.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:15]([OH:17])=[O:16].[CH2:18](Br)[CH2:19][CH3:20]>CN(C=O)C>[CH2:18]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:15]([OH:17])=[O:16])[CH2:19][CH3:20]
Reactant: CCCBr
Reactant: O=C(O)c1ccc2[nH]c(C(=O)O)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1c(C(=O)O)cc2cc(C(=O)O)ccc21
Temperature: 25 °C
Yield: 68.8 %

Procedure:
Sodium hydride (60% suspension, 125 mg, 5 mmol) was added to a stirred solution of 1H-indole-2,5-dicarboxylic acid (525 mg, 2 mmol) in dry DMF (10 mL) and maintained at ambient temperature for 1 hour. The reaction was cooled to 0° C. and then propyl bromide (0.275 mL, 3 mmol) was added. After 3 days the reaction was quenched by addition of 5% aqueous NH4Cl. The mixture was concentrated to dryness and then purified on a silica gel column using 5% EtOAc/toluene. The product was then dissolved in 30 mL ethanol and 10 mL of 2 M NaOH was added. The solution was heated at 55° C. for 2 days. The ethanol was removed in vacuo and the resulting aqueous solution was acidified with 0.01 M HCl to pH 3. The resulting precipitate was filtered and rinsed twice with water. The isolated product was dried by evaporation from absolute ethanol (3×) to give 340 mg (67%) of 87.
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[C:6]([C:11]([F:14])([F:13])[F:12])=[N:7][NH:8][C:9]=1[NH2:10].O=[C:21]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[CH2:22][C:23](OCC)=[O:24].C(=O)(O)[O-].[Na+]>OS(O)(=O)=O.O1CCOCC1>[Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[C:6]([C:11]([F:13])([F:14])[F:12])=[N:7][N:8]2[C:23]([OH:24])=[CH:22][C:21]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[N:10][C:9]=12
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: Nc1[nH]nc(C(F)(F)F)c1Cc1cccc(Cl)c1Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: Oc1cc(-c2ccncc2)nc2c(Cc3cccc(Cl)c3Cl)c(C(F)(F)F)nn12
Temperature: 120 °C
Reaction time: 16 h
Yield: 9.6 %

Procedure:
A mixture of 4-(2,3-dichlorobenzyl)-3-(trifluoromethyl)-1H-pyrazol-5-amine (100 mg, 0.332 mmol), ethyl 3-oxo-3-(pyridin-4-yl)propanoate (75 mg, 0.387 mmol) in conc. H2SO4 (1.5 mL) and dioxane (15 mL) was placed in a sealed tube and stirred at 120° C. for 16 h. After cooled to room temperature, the pH of the mixture was carefully adjusted to 8 with saturated aq. sodium bicarbonate solution. The resulting mixture was extracted with DCM (50 mL×3). The combined organic layers were washed with water and brine, dried over sodium sulphate, filtered and concentrated. The residue was purified by silica gel column and reverse-phase Prep-HPLC to give the title product (14 mg, 10%) as a yellow solid; LC/MS: MS (ES+) m/e 439 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 4.29 (s, 2H), 6.35 (s, 1H), 6.89 (dd, J=1.2, 7.8 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H), 7.52 (dd, J=1.2, 7.8 Hz, 1H), 7.83 (d, J=6.0 Hz, 2H), 8.80 (d, J=6.0 Hz, 2H), 12.81 (s, 1H).
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:9](=[O:10])[O:8][C:6](=[O:7])[CH2:5]1)=[O:2].[CH3:11][O:12][C:13](=[O:23])[C@H:14]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH2:15]>C(OCC)(=O)C>[CH3:11][O:12][C:13](=[O:23])[C@H:14]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:15][C:9](=[O:10])[C@H:4]([CH2:5][C:6](=[O:7])[OH:8])[NH:3][CH:1]=[O:2]
Reactant: O=CN[C@H]1CC(=O)OC1=O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC=O
Temperature: 25 °C
Yield: 87 %

Procedure:
The resin used carries sulphonic acid groups on a polystyrene matrix and has an exchange capacity of 5 meq. per gram of dry resin. Consequently the ratio of the acid equivalents of the resin acid groups to the moles of N-formyl-L-aspartic anhydride is 0.1. The mass is agitated in the flask to obtain a suspension. The solution of L-phenylalanine methyl ester in ethyl acetate is added to this agitated suspension by means of the dropping funnel over a time of about 8 minutes, while maintaining the temperature of the mass at about 25° C. At the end of this time a solution is obtained from which the cation exchange resin is separated by filtration. The solution is then cooled to 0° C. and a crystalline precipitate is obtained constituted by a mixture of the α and β isomers of N-formyl-L-aspartyl-L-phenylalanine methyl ester (14.1 g, yield 87%). This precipitate is subjected to HPLC analysis in order to check the ratio of the α to the β by comparison with known samples. The HPLC determinations are carried out using a Perkin-Elmer chromatograph, series 3, with a 7 micron RP8 column, 250×4 mm; eluent used: continuous gradient between solvents: (A) 65 parts of monobasic potassium phosphate 0.07 molar at pH 4+35 parts of methanol; and (B) 65 parts of water +35 parts of methanol; flow rate 1 ml per minute.
Reaction SMILES: Cl[C:2]1[C:3]2[S:14][CH:13]=[CH:12][C:4]=2[N:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[CH:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[I-].C[N+]1(C)C=CN=C1.[H-].[Na+]>C1COCC1.O>[C:16]1([C:15]([C:2]2[C:3]3[S:14][CH:13]=[CH:12][C:4]=3[N:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=2)=[O:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: FC(F)(F)c1nc(Cl)c2sccc2n1
Reactant: O=Cc1ccccc1
Agent: C[N+]1(C)C=CN=C1
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1ccccc1)c1nc(C(F)(F)F)nc2ccsc12
Temperature: 25 °C
Yield: 72.1 %

Procedure:
A suspension of 4-chloro-2-trifluoromethylthieno[3,2-d]pyrimidine (0.3 g, 1.26 mmol), benzaldehyde (0.28 g, 2.64 mmol) and N,N-dimethylimidazolium iodide (0.2 g, 0.89 mmol) in THF (8 mL) was treated with NaH (60% dispersion in oil, 0.112 g, 2.8 mmol), refluxed for 15 min, cooled to room temperature, treated with water (4 mL) and the organic phase separated. The aqueous phase was extracted with CH2Cl2 (2×20 mL), the combined organic phase washed with brine (10 mL), dried (MgSO4), concentrated in vacuo and the resulting brown oil purified by chromatography [SiO2; heptane-EtOAc (3:1)] then recrystallised from heptane to give the title compound (280 mg, 43%) as yellow needles.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2.[S:16](Cl)([CH3:19])(=[O:18])=[O:17]>CN(C=O)C>[CH3:19][S:16]([N:11]1[C:12]2[C:7](=[CH:6][C:5]([O:4][CH3:3])=[CH:14][CH:13]=2)[CH2:8][CH2:9][C:10]1=[O:15])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2c(c1)CCC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCC(=O)N2S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a flame dried round bottom flask equipped with a nitrogen cap was placed 87 mg (2.17 mmol) of 60% sodium hydride in mineral oil and 15 ml of dimethylformaminde (DMF). The mixture was cooled to 0° C. and was treated with 350 mg (1.97 mmol) of 6-Methoxy-2-oxo-1,2,3,4-tetrahydro-quinoline (Preparation 2) in the minimum amount of DMF. The reaction mixture was stirred for 0.5 hours at 0° C. and was then treated with 226 mg (1.97 mmol) mesyl chloride. The mixture was slowly allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was quenched by the addition of 30 ml of saturated aqueous sodium bicarbonate solution and the mixture was extracted with methylene chloride (3×30 ml). The combined organics were washed with brine, dried over sodium sulfate and evaporated in vacuo. The crude oil was purified by silica gel chromatography eluting with 1/1 ethyl acetate/hexane to afford a light yellow oil in 35% yield (177 mg). Mass spectrum APCI m/e 256 (p+1).
Reaction SMILES: [OH-].[K+].[CH2:3]([C:10]1[N:15]=[N:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[N:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][N:23]=3)[C@H:18]([CH3:31])[CH2:17]2)=[C:12]([CH3:32])[C:11]=1[CH3:33])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)(=[O:36])C.C(O)(=O)C.IC1C=CC=CC=1.Cl.C([O-])(O)=O.[Na+]>CO.O>[CH2:3]([C:10]1[N:15]=[N:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[N:26][C:25]([C:28](=[O:30])[CH2:29][OH:36])=[CH:24][N:23]=3)[C@H:18]([CH3:31])[CH2:17]2)=[C:12]([CH3:32])[C:11]=1[CH3:33])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)O
Reactant: CC(=O)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c(C)c3C)C[C@H]2C)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Solvent: Ic1ccccc1
Solvent: O
Product: Cc1c(Cc2ccccc2)nnc(N2CCN(c3cnc(C(=O)CO)cn3)[C@H](C)C2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
To a solution of KOH (224 mg, 4.0 mmol) and CH3OH (10 mL) is added 1-[(R)-4-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl)-ethanone (400 mg, 1.0 mmol) in CH3OH (10 mL) and then iodobenzene diacetate (464 mg, 1.5 mmole) in portions at 0° C. The mixture is stirred at room temperature overnight. The solvent is removed and then extracted with DCM. The organic layer is washed with aqueous NH4Cl and afterwards concentrated to yield crude example 112. This material is dissolved in water and then 6 N HCl (5 mL) is added. The mixture is stirred at room temperature for 3 h. Afterwards it is made basic with NaHCO3 and extracted with DCM. The organic layer is concentrated to give a crude product that is purified by chromatography on silica gel (EtOAc/Heptane: 50%˜100%) to give the title compound (240 mg, 58%) as a yellow solid.
Reaction SMILES: [Na].[C:2]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:3][C:4]([C:6]([O:8]CC)=O)=O.C1(C)C=CC=CC=1.Cl.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][NH2:31]>C(O)(=O)C>[OH:8][C:6]1[N:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH3:23])[N:31]=[C:3]([C:2]([O:12][CH2:13][CH3:14])=[O:11])[CH:4]=1
Reactant: Cc1ccccc1NN
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(O)n(-c2ccccc2C)n1
Temperature: 25 °C
Yield: 21.8 %

Procedure:
To a mixture of diethyl oxalacetate sodium salt (10.5 g, 50 mmol), acetic acid (100 mL) and toluene (50 mL) was added an aqueous solution (50 mL) of (2-methylphenyl)hydrazine hydrochloride (7.93 g, 50 mmol) under stirring at room temperature, and the mixture was heated under reflux for 3 hr. After cooling, the reaction mixture was partitioned. The organic layer was washed with water and saturated brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-3/1) to give yellow crystals. This product was dissolved in acetic acid (36 mL), and the mixture was heated under reflux for 2 hr. After cooling, the reaction mixture was concentrated under reduced pressure, and recrystallized from hexane-ethyl acetate to give the title compound (2.69 g, yield 22%) as colorless crystals.
Reaction SMILES: [C:1]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:6])(=O)[CH3:2].N>>[CH3:2][C:1]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[NH:7][C:5](=[O:6])[N:4]=1
Reactant: COc1cccc(NC(=O)NC(C)=O)c1
Agent: N
Product: COc1ccc2c(C)nc(=O)[nH]c2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 1-acetyl-3(3-methoxyphenyl)urea (32.5 g, 0.156 m) and polyphosphoric acid (912.5 g) is heated at 120°-130° C. for 2 hours. After cooling to 50° C. the melt is poured on ice-water (2 liters), and the solution is made weakly basic with ammonia and left standing overnight. The brownish-red precipitate which forms is filtered off, washed with cold water followed by hot acetone, and crystallized from ethanol (after treatment with charcoal) to give the product as a pale yellow solid; yield 11.5 g (39.1%); mp 251°-254° C.
Reaction SMILES: [Cl-].[Li+].[CH3:3][N:4]1[C:8]2=[N:9][CH:10]=[C:11](Br)[CH:12]=[C:7]2[C:6]([CH3:15])([CH3:14])[C:5]1=[O:16].[CH2:17]([O:19]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:18]>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>[CH3:3][N:4]1[C:8]2=[N:9][CH:10]=[C:11]([C:17](=[O:19])[CH3:18])[CH:12]=[C:7]2[C:6]([CH3:15])([CH3:14])[C:5]1=[O:16]
Reactant: CN1C(=O)C(C)(C)c2cc(Br)cnc21
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: CC(=O)c1cnc2c(c1)C(C)(C)C(=O)N2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Under argon, suspend 482 mg (11.37 mmol) of lithium chloride and 90 mg (7.84×10-5 mol) of tetrakis(triphenylphosphine)palladium in 10 ml of anhydrous toluene. Add to that suspension a solution of 1 g (3.92 mmol) of 1,3-dihydro-1,3,3-trimethyl-5-bromo-2H-pyrrolo[2,3-b]pyridin-2-one and 1.46 mg (4.04 mmol) of (1-ethoxyvinyl)tributyltin in 20 ml of anhydrous toluene. After 5 hours at reflux, evaporate off the solvent and take up the residue in a 1:1 mixture (30 ml) of dioxane and 10% hydrochloric acid. After 30 minutes' stirring at room temperature, evaporate off the dioxane. Filter off the resulting tin salts over Celite. Extract the filtrate with dichloromethane and dry over magnesium sulfate. After purification on a silica column, 780 mg of the title product are obtained in a yield of 90% ##STR59##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.[CH2:17]([N:24]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@@H:25]([C@H:27]1[CH2:29][O:28]1)[CH3:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[CH2:30]([N:24]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C@H:25]([CH3:26])[C@@H:27]([OH:28])[CH2:29][N:11]([CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:12][C:13]([F:14])([F:15])[F:16])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C[C@H]([C@H]1CO1)N(Cc1ccccc1)Cc1ccccc1
Reactant: Fc1ccc(CCCNCC(F)(F)F)cc1
Solvent: CCO
Product: C[C@H]([C@@H](O)CN(CCCc1ccc(F)cc1)CC(F)(F)F)N(Cc1ccccc1)Cc1ccccc1

Procedure:
The product of Step c (3.48 g, 15.0 mmol, 1 eq.), (1R)-N,N-dibenzyl-1-[(2S)-oxiran-2-yl]ethanamine (the synthesis of which is described in Example 100) (3.96 g, 15.0 mmol, 1 eq.) and ethanol (20 mL) were mixed at 25° C. under N2 then refluxed for 4 days. Worked up by stripping off the ethanol then purifying the residue by flash chromatography in 3:1 Hexanes/EtOAc. Obtained to 3.78 g of a yellow oil. By NMR, the oil is product and some minor impurities and was carried on to the next step. MS (ESI) detects (M+H)+=503.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13](=[O:15])[CH3:14])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:18][O:19][C:20](=O)[O:21]C>>[O:15]=[C:13]([C:9]1[N:8]=[C:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:12]=[CH:11][N:10]=1)[CH2:14][C:20]([O:19][CH3:18])=[O:21]
Reactant: CC(=O)c1nccc(N2CCCCC2)n1
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Product: COC(=O)CC(=O)c1nccc(N2CCCCC2)n1
Temperature: 90 °C
Yield: 52 %

Procedure:
To a stirred solution of 1-[4-(piperidin-1-yl)pyrimidin-2-yl]ethanone (Intermediate 52, 0.6 g, 2.92 mmol) in dimethylcarbonate (10 mL), sodium hydride (0.281 g, 11.7 mmol, 60%) was added portion wise at 0-5° C. over a period of 10 min. The reaction mixture was heated to 90° C. for 4 h. The reaction mixture was quenched by adding ice water. The aqueous layer pH was adjusted to neutral with dilute HCl, the aqueous layer was extracted with ethyl acetate (2×50 mL). The organic layer was dried and concentrated. The crude product was purified by column chromatography (75% ethylacetate & pet ether) to obtain methyl 3-oxo-3-[4-(piperidin-1-yl)pyrimidin-2-yl]propanoate 0.4 g (52%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:14]2[N:15]([CH3:29])[C:16]([C:19]3[C:20]([C:25]([F:28])([F:27])[F:26])=[N:21][CH:22]=[CH:23][CH:24]=3)=[N:17][N:18]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9]C.B(Br)(Br)Br>ClCCl>[CH3:29][N:15]1[C:16]([C:19]2[C:20]([C:25]([F:27])([F:28])[F:26])=[N:21][CH:22]=[CH:23][CH:24]=2)=[N:17][N:18]=[C:14]1[C:5]1[CH:4]=[C:3]([OH:2])[C:8]([OH:9])=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1
Reactant: COc1cc(-c2nnc(-c3cccnc3C(F)(F)F)n2C)cc([N+](=O)[O-])c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1c(-c2cc(O)c(O)c([N+](=O)[O-])c2)nnc1-c1cccnc1C(F)(F)F
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a stirred suspension of 3-(5-(3,4-dimethoxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-2-(trifluoromethyl)pyridine (0.192 g, 0.47 mmol) in dichloromethane (20 mL) at −78° C. under argon was added boron tribromide (0.47 g, 1.88 mmol) dropwise. The resulting purple suspension was then allowed to stir at room temperature for seven hours before being cooled in an ice-water bath. The mixture was carefully quenched by the addition of methanol. After stirring at room temperature for thirty minutes, the volatiles were evaporated and the residue stirred with 2 N hydrochloric acid (5 mL) for thirty minutes. The resulting solid was filtered off, washed with water (25 mL) and then cold isopropanol (5 mL) to give, after drying, 5-(4-methyl-5-(2-(trifluoromethyl)pyridin-3-yl)-4H-1,2,4-triazol-3-yl)-3-nitrobenzene-1,2-diol was obtained as an orange solid, 0.154 g (86%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16].Cl>C1C=CC=CC=1>[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([C:6]2[CH:14]=[CH:13][CH:9]=[CH:8][CH:7]=2)=[O:11])=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16]
Reactant: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C(c1ccccc1)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 73 %

Procedure:
To a stirred mixture of 496 parts of aluminum chloride in 900 parts of benzene was added dropwise a solution of 256 parts of 4-fluoro-3-nitrobenzoyl chloride in 225 parts of benzene at ±10° C. Upon complete addition, stirring was continued first for 1.5 hours in an ice bath and then for 8 hours at room temperature. The mixture was heated to 60° C., cooled again and poured into crushed ice and 180 parts of concentrated hydrochloric acid. The separated organic layer was dried, filtered and concentrated. The concentrate was dissolved in 2100 parts of 2,2'-oxybispropane, the solution was treated with diatomaceous earth and activated charcoal. After filtration, the filtrate was concentrated. The crystallized product was filtered off and dried, yielding 223 parts (73%) of (4-fluoro-3-nitrophenyl) phenylmethanone; mp. 59° C. (int. 62).
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.C[Al]C.[C:9](Cl)([CH3:12])([CH3:11])[CH3:10]>ClC1C=CC=CC=1>[C:9]([C:2]1[CH2:1][CH:5]=[CH:4][CH:3]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: C1=CCC=C1
Reactant: CC(C)(C)Cl
Agent: C[Al]C
Solvent: Clc1ccccc1
Product: CC(C)(C)C1=CC=CC1

Procedure:
In runs 1 through 10, five ml. of 0.025 M dimethylaluminum cyclopentadiene (Me2AlCPD) in chlorobenzene was dispensed by pipette into 20×150 mm test tubes. The tubes were then capped with screw caps fitted with self-sealing gaskets and Teflon® liners. The reaction tubes were placed in a constant temperature bath. After allowing sufficient time for the tubes and contents to attain bath temperature, 0.12 M tert.-butyl chloride solution in chlorobenzene (tBuCl) already at bath temperature was added by syringe fitted with hypodermic needle. After the desired time, the reactions were quenched by the addition of normal-butyl alcohol.