Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.[F-].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].N(P(Cl)Cl)(C1CCCCC1)C1CCCCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(Cl)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: ClP(Cl)N(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(OC)cc2)cc1
Reaction time: 24 h
Yield: 99.4 %

Procedure:
The general procedure from Example 12 was followed using 4-chloroanisole (143 mg, 1.0 mmol) and 4—MeOC6H4B(OH)2 (228 mg, 1.5 mmol) with Pd2(dba)3 (13.3 mg, 0.0145 mmol) and (Me3C)2PH(O) from Experiment 2 (9.6 mg, 0.058 mmol) and CsF (456 mg, 3.0 mmol) in 3.0 mL of 1,4-dioxane. After 24 h, the reaction mixture was chromatographed with 5% ethyl acetate/hexane to give 213 mg (99% yield) of 4-(4-methoxyphenyl)anisole. It was >95% pure by 1H NMR and GC/MS. 1H NMR (500 MHz, CDCl3): δ7.38 (d, J=8.68 Hz, 4H), 6.86 (d, J=8.68 Hz, 4H), 3.74 (s, 6H) ppm. 13C NMR (125 MHz, CDCl3): δ158.7, 133.5, 127.7, 114.2, 55.3 ppm.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[C:13]1([C:19]2[CH:20]=[CH:21][C:22](=[O:25])[NH:23][N:24]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+].C([O-])(O)=O.[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1>[C:13]1([C:19]2[CH:20]=[CH:21][C:22](=[O:25])[N:23]([CH2:2][C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][CH:12]=3)[N:9]=[CH:8][CH:7]=[CH:6]4)[N:24]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: BrCc1ccc2ncccc2c1
Reactant: O=c1ccc(-c2ccccc2)n[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Br-]
Solvent: c1ccccc1
Product: O=c1ccc(-c2ccccc2)nn1Cc1ccc2ncccc2c1
Temperature: 25 °C
Yield: 18.3 %

Procedure:
To a 25 mL round-bottomed flask containing 6-(bromomethyl)quinoline (0.35 g, 1.6 mmol) was added benzene (10 mL), 6-phenyl-3(2H)-pyridazinone (0.15 g, 0.87 mmol, Aldrich), tetrabutylammonium bromide (0.056 g, 0.17 mmol) and potassium hydroxide (0.15 g, 2.6 mmol). The mixture was stirred at 25° C., then poured into aq. NaHCO3 (100 mL) and extracted with EtOAc (3×50 mL). The combined extracts were washed with brine (50 mL), dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (0.5 to 5.0% MeOH (2 M in NH3)/CH2Cl2) afforded the title compound as a white solid (0.050 g, 18% yield). MS (ESI pos. ion) m/z (MH+): 314. Calc'd exact mass for C20H15N3O: 313. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.88 (dd, J=4.2, 1.7 Hz, 1 H), 8.38 (dd, J=8.4, 0.8 Hz, 1 H), 8.11 (d, J=9.6 Hz, 1 H), 8.01 (d, J=8.6 Hz, 1 H), 7.88-7.93 (m, 3 H), 7.78 (dd, J=8.8, 2.0 Hz, 1 H), 7.43-7.54 (m, 4H), 7.13 (d, J=9.8 Hz, 1 H), 5.54 (s, 2 H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[N:11]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[N:12]1.B(Br)(Br)Br.O.[OH-].[Na+]>C(Cl)Cl>[CH3:17][C:13]1[CH:14]=[C:15]([CH3:16])[N:11]([C:4]2[CH:5]=[CH:6][C:7]([OH:9])=[CH:8][C:3]=2[OH:2])[N:12]=1
Reactant: COc1ccc(-n2nc(C)cc2C)c(OC)c1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)n(-c2ccc(O)cc2O)n1
Reaction time: 1 h
Yield: 68.9 %

Procedure:
118.4 mg of 1-(2,4-dimethoxyphenyl)-3,5-dimethyl-1H-pyrazol was dissolved in 2.3 ml of methylene chloride, and 1.7 ml of 1M solution of boron tribromide in methylene chloride was added at room temperature and stirred for 1 hour. The reaction mixture was added to 30 ml of water, neutralized with 1N-sodium hydroxide, and extracted with 50 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and purified using preparative thin-layer silica gel column chromatography (hexane:ethyl acetate=1:2) to yield 71.7 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]3[N:14]=[C:15]([CH2:17][OH:18])[CH:16]=[C:10]3[C:9]2=[O:19])=[CH:4][CH:3]=1.Cl[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]3[N:14]=[C:15]([CH2:17][O:18][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH:16]=[C:10]3[C:9]2=[O:19])=[CH:4][CH:3]=1
Reactant: Clc1ccccn1
Reactant: O=C1c2cc(CO)nn2CCN1c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: O=C1c2cc(COc3ccccn3)nn2CCN1c1ccc(F)cc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 64752.6 %

Procedure:
Palladium (II) acetate (9 mg, 0.038 mmol) was added to a stirred suspension of 5-(4-fluoro-phenyl)-2-hydroxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (0.74 g, 2.83 mmol), 2-chloropyridine (0.4 mL, 4.25 mmol), cesium carbonate (1.84 g, 5.66 mmol) and (2-biphenylyl)di-tert-butylphosphine (0.17 g, 5.66 mmol) in toluene (15 mL) in a sealed tube and under nitrogen. The mixture was stirred at 120° C. for 16 hours, then filtered through a pad of diatomaceous earth and washed with AcOEt. The solvents were evaporated in vacuo and the crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 100/0). The desired fractions were collected, the solvents evaporated in vacuo and triturated with DIPE to yield 5-(4-fluorophenyl)-2-(pyridin-2-yloxymethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (620 g, 65% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 4.12-4.20 (m, 2H), 4.54 (dd, J=6.9, 5.1 Hz, 2H), 5.44 (s, 2H), 6.81 (d, J=8.6 Hz, 1H), 6.90 (ddd, J=7.1, 5.2, 0.7 Hz, 1H), 7.03 (s, 1H), 7.08-7.17 (m, 2H), 7.28-7.35 (m, 2H), 7.55-7.63 (m, 1H), 8.19 (dd, J=5.0, 1.3 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:11][CH:10]2[C:12]([OH:14])=O)=[CH:5][CH:4]=1.[CH:15]1[CH:20]=[CH:19][C:18]([C@@H:21]([NH2:24])[CH2:22][OH:23])=[CH:17][CH:16]=1.CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1>ClCCl>[OH:23][CH2:22][CH:21]([NH:24][C:12]([C@@H:10]1[CH2:11][C@@H:9]1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[O:14])[C:18]1[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(C2CC2C(=O)O)cc1
Reactant: N[C@@H](CO)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1ccc([C@H]2C[C@H]2C(=O)NC(CO)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
To a 250 mL RB flask fitted with magnetic stirrer was charged with 70 mL of dichloromethane. To the stirred solvent were added 2-(4-methoxyphenyl)cyclopropanecarboxylic acid (4.5 g, 33 mmol), D-(−)-α-phenylglycinol (3.2 g, 50 mmol). The reaction mixture was brought to 0° C., followed by the addition of N-(3-dimethylaminopropyl)-N-ethylcarbodimide hydrochloride (6.7 g, 50 mmol), N-hydroxybenzotriazole (3.1 g, 33 mmol) and the reaction mixture was allowed to stir at room temperature for 8 h. The reaction mixture was diluted with dichloromethane (100 mL) and washed with water (100 mL). The organic layer was washed with brine solution (25 mL). The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as white solid (2 g, yield: 27.44%).
Reaction SMILES: [K].[K].[C:3]12([C:13]3[CH:18]=[C:17]([C:19]45[CH2:28][CH:23]6[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]6)[CH2:20]4)[CH2:26]5)[C:16]([O:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]([OH:38])=[O:37])=[CH:32][CH:31]=4)=[CH:15][C:14]=3[O:39][C:40]3[CH:45]=[CH:44][C:43]([C:46]([OH:48])=[O:47])=[CH:42][CH:41]=3)[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[Cl:49]CCCl.S(Cl)([Cl:55])=O.C1(C=CC(O)=CC=1)O>CN(C)C=O>[Cl-:49].[Cl-:55].[C:3]12([C:13]3[CH:18]=[C:17]([C:19]45[CH2:20][CH:21]6[CH2:27][CH:25]([CH2:24][CH:23]([CH2:22]6)[CH2:28]4)[CH2:26]5)[C:16]([O:29][C:30]4[CH:31]=[CH:32][C:33]([C:36]([OH:38])=[O:37])=[CH:34][CH:35]=4)=[CH:15][C:14]=3[O:39][C:40]3[CH:45]=[CH:44][C:43]([C:46]([OH:48])=[O:47])=[CH:42][CH:41]=3)[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2
Reactant: ClCCCl
Reactant: O=S(Cl)Cl
Agent: O=C(O)c1ccc(Oc2cc(Oc3ccc(C(=O)O)cc3)c(C34CC5CC(CC(C5)C3)C4)cc2C23CC4CC(CC(C4)C2)C3)cc1
Agent: Oc1ccc(O)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: [Cl-]
Temperature: 0 °C
Reaction time: 3 h

Procedure:
In a 2 L four-neck flask provided with a thermometer, a Dimroth condenser and an agitator, the obtained 62.5 g of 4,6-di(1-adamantyl)-1,3-bis(4-carboxy-phenoxy)benzene dipotassium salt (0.09 mol) and 200 mL of 1,2-dichloroethane were charged and cooled to 0° C. 178.5 g of thionyl chloride (1.5 mol) was added dropwise at 5° C. or below for one hour. Then, 1.5 mL of dimethylformamide and 1.5 g of hydroquinone were added therein and the mixture was agitated at 45 to 50° C. for three hours. After cooling, crystal was removed therefrom by filtration and washed with 50 mL of chloroform. Filtrate and washing solution was condensed together under reduced pressure at 40° C. or less, and a residue obtained was subject to two times of extraction and filtration with 200 mL of diethyl ether. Diethyl ether was removed from an extract under reduced pressure to obtain a semisolid crude product. The semisolid crude product was washed with dried n-hexane and recrystallized with diethyl ether, thus obtaining 38.9 g of 4,6-di(1-adamantyl)-1,3-bis(4-carboxy-phenoxy)benzene dichloride (0.0594 mol; the yield was 66.0%).
Reaction SMILES: [F:1][C:2]1[C:3]([F:53])=[CH:4][C:5]2[C:10]3[C:11]4[C:50](=[O:51])[NH:49][C:48](=[O:52])[C:12]=4[C:13]4[C:14]5[C:19]([N:20]([C@@H:22]6[O:43][C@H:42]([CH2:44][OH:45])[CH2:41][C@H:32]([O:33][CH2:34][C:35]7[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=7)[C@H:23]6[O:24][CH2:25][C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)[C:21]=4[C:9]=3[NH:8][C:6]=2[CH:7]=1)=[CH:18][C:17]([F:46])=[C:16]([F:47])[CH:15]=5.C(N(CC)CC)C.CS(Cl)(=O)=O.[Na+].[I-:67]>ClCCl.CN(C1C=CN=CC=1)C.CC(C)=O>[F:1][C:2]1[C:3]([F:53])=[CH:4][C:5]2[C:10]3[C:11]4[C:50](=[O:51])[NH:49][C:48](=[O:52])[C:12]=4[C:13]4[C:14]5[C:19]([N:20]([C@@H:22]6[O:43][C@H:42]([CH:44]([I:67])[OH:45])[CH2:41][C@H:32]([O:33][CH2:34][C:35]7[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=7)[C@H:23]6[O:24][CH2:25][C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)[C:21]=4[C:9]=3[NH:8][C:6]=2[CH:7]=1)=[CH:18][C:17]([F:46])=[C:16]([F:47])[CH:15]=5
Reactant: [I-]
Reactant: O=C1NC(=O)c2c1c1c3cc(F)c(F)cc3[nH]c1c1c2c2cc(F)c(F)cc2n1[C@@H]1O[C@H](CO)C[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=C1NC(=O)c2c1c1c3cc(F)c(F)cc3[nH]c1c1c2c2cc(F)c(F)cc2n1[C@@H]1O[C@H](C(O)I)C[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 2 h
Yield: 39 %

Procedure:
A mixture of 2, 3, 9, 10-tetrafluoro-12-(2, 3-di-O-benzyl-4-deoxy-β-D-glucopyranosyl)-6, 7, 12, 13-tetrahydro(5H)indolo[2, 3-a]pyrrolo[3, 4-c]carbazole-5, 7-dione (2.00 g, 2.76 mmol) and freshly activated and pulverized 4A molecular sieves (0.60 g) in 100 mL of dichloromethane was cooled at 5C. under Ar and triethylamine (0.77 mL, 5.52 mmol), DMAP (0.20 g, 1.64 mmol) and methanesulfonyl chloride (0.32 mL, 4.14 mmol) were added sequentially. The mixture was stirred at the same temperature for 2 h and then it was filtered and the filter-cake was washed with ethyl acetate. The flitrate was diluted with ethyl acetate (200 mL) and ether (50 mL) and then it was washed (H2O×2, brine), dried (MgSO4) and evaporated to give a yellow glass. This material was taken up in 100 mL of acetone, NaI ( ) was added and the mixture was heated to reflux under Ar for 18 h. The cooled mixture was then evaporated to dryness and the residue was taken up in 10 mL of ethyl acetate, washed (H2O×2, brine) dried (MgSO4) and evaporated. The resulting solid was chromatographed (SiO2/2-32% ethyl acetate-hexane) to give the title compound (0.90 g, 39%) as an amorphous yellow solid: 1H NMR (CDCl3, 400 MHz) δ10.17 (s, 1H), 9.10 (dd, J=10.6, 8.4 Hz, 1H), 9.02 (dd, J=10.6, 8.5 Hz, 1H), 7.55 (m, 2H), 7.35 (m, 6H), 6.92 (t, J=7.4 Hz, 1H), 6.76 (t, J=7.6 Hz, 2H), 6.20 (d, J=7.6 Hz, 2H), 5.75 (d, J=9.2 Hz, 1H), 4.77 and 4.71 (ab q, J=11.5 Hz, 2H), 4.13 (m, 2H), 3.99 (t, J=8.7 Hz, 1H), 3.80 (m, 2H 3.63 (d, J=9.0 Hz, 1H), 3.48 (d, J=10.8 Hz, 1H), 2.42 (m, 1H), 2.32 (m, 1H). MS (ESI−) m/e 832 (M−H)−.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([CH3:36])([CH3:37])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:16][CH:17]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Oc1ccc(OCCCCCn2ccnc2)cc1
Reactant: CCOC(=O)C(C)(C)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)CCCCOc1ccc(OCCCCCn2ccnc2)cc1
Temperature: 60 °C

Procedure:
After 300 ml of ethanol was added to 35 g of p-[5-(1-imidazolyl)pentyloxy]phenol and 39 g of potassium carbonate, the mixture was heated at 60° C. with stirring and then cooled to room temperature. A solution of 43 g of ethyl 6-bromo-2,2-dimethylhexanoate in 50 ml of ethanol was added to the reaction mixture, and then the mixture was stirred under reflux overnight. The solvent was removed from the reaction mixture by distillation under reduced pressure and the residue was dissolved in chloroform. The solution was successively washed with a 1N aqueous sodium hydroxide solution, water, a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. After drying, the solvent was removed by distillation under reduced pressure and the residue was subjected to silica gel column chromatography. The product was eluted out using a chloroform-methanol liquid mixture (30:1) as an eluant. The solvent was removed from the eluate by distillation. The residue was recrystallized from a mixture of ethyl acetate-n-hexane to give the desired product, ethyl 6-[p-[5-(1-imidazolyl)pentyloxy]phenoxy]-2,2-dimethylhexanoate.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[NH2:14])[C:7]([O:9][CH3:10])=[O:8].[C:15](Cl)(=O)[CH2:16][CH2:17][CH3:18]>P(Cl)(Cl)(Cl)=O>[CH3:10][O:9][C:7]([C:6]1[CH:11]=[CH:12][C:13]2[N:14]=[C:15]([CH2:16][CH2:17][CH3:18])[NH:3][C:4]=2[CH:5]=1)=[O:8]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCCc1nc2ccc(C(=O)OC)cc2[nH]1

Procedure:
A solution of 23.9 g (100 mMol) of methyl 3,4-diaminobenzoate dihydrochloride and 11.7 g (110 mMol) of butyric acid chloride in 100 ml of phosphorus oxychloride is refluxed for 2 hours. Then about 80 ml of phosphorus oxychloride are distilled off and the residue is mixed with about 150 ml of water. The oily crude product precipitated is extracted three times with 50 ml of ethyl acetate and after evaporation purified by column chromatography (600 g of silica gel; eluant: methylene chloride/methanol (30:1)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=[O:20])=[CH:15][CH:14]=3)=[CH:11][CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]C#N)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:20][N:19]=[C:16]3[CH:17]=[CH:18][C:13]([C:12]4[N:8]([C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=5)[N:9]=[CH:10][CH:11]=4)=[CH:14][C:15]=23)=[CH:25][CH:24]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2cccc(F)c2)cc1
Product: Fc1ccc(-c2onc3ccc(-c4ccnn4-c4cccc(F)c4)cc23)cc1

Procedure:
The title compound, light grey solid (74 mg, 56%), MS (ISP) m/z=374.1 [(M+H)+], mp 175° C., was prepared in accordance with the general method of example 1 from 1-(3-fluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate D) (100 mg, 353 μmol) and commercially available 2-(4-fluoro-phenyl)-acetonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[N:11]=[N:10][NH:9]1.[CH3:14][C:15]1[S:16][CH:17]=[C:18]([CH3:27])[C:19]=1[N:20]([CH2:24][CH2:25][CH3:26])[C:21](Cl)=[O:22]>CN(C)C1C=CN=CC=1>[CH3:14][C:15]1[S:16][CH:17]=[C:18]([CH3:27])[C:19]=1[N:20]([CH2:24][CH2:25][CH3:26])[C:21]([N:11]1[C:12](=[O:13])[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:9]=[N:10]1)=[O:22]
Reactant: O=c1nn[nH]n1-c1ccccc1F
Reactant: CCCN(C(=O)Cl)c1c(C)csc1C
Agent: CN(C)c1ccncc1
Product: CCCN(C(=O)n1nnn(-c2ccccc2F)c1=O)c1c(C)csc1C

Procedure:
1.17 g (6.5 mmol) of 1,2-dihydro-1-(2-fluorophenyl)-5H-tetrazol-5-one, 1.5 g (6.5 mmol) of N-(2,4-dimethyl-thiophen-3-yl)-N-n-propylcarbamoyl chloride and 1.19 g (9.7 mmol) of 4-dimethylaminopyridine were reacted by the method of the process described in Example 1. Yield 1.9 g.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][NH:10][C:6]=2[N:7]=[CH:8][N:9]=1.Cl[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[CH2:16]([O:15][CH2:14][N:10]1[C:6]2[N:7]=[CH:8][N:9]=[C:4]([Cl:3])[C:5]=2[CH:12]=[CH:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCOCc1ccccc1
Reactant: Clc1ncnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ncnc2c1ccn2COCc1ccccc1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a oven dried 250 mL three-neck round bottom flask equipped with a stir bar, thermocouple, septa and nitrogen inlet was charged sodium hydride (NaH, 60 wt %, 1.56 g, 0.0391 mol, 1.2 equiv) and anhydrous tetrahydrofuran (THF, 25.0 mL, 0.308 mol) and the resulting mixture was chilled to 0-5° C. To a 100 ml oven dried round bottom flask was charged 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 5.00 g, 0.0326 mol) and anhydrous tetrahydrofuran (50 mL, 0.616 mol), and the resulting slurry was added portion wise via large bore canula over 20 minutes to the sodium hydride (NaH) suspension in THF. The cooling bath was removed after the addition is complete and the reaction mixture was stirred at room temperature for 1 hour. The slurry becomes green in color after it is warmed to 16.5° C. The mixture was cooled to 0-5° C. before neat benzyl chloromethyl ether (5.28 mL, 0.0342 mol, 1.05 equiv) was charged over 13 minutes via syringe. The cold bath was removed and the reaction mixture was warmed to room temperature gradually and stirred at room temperature for 20 h. The reaction mixture was quenched with 20% aqueous brine (50 mL) and diluted with ethyl acetate (100 mL) when the reaction was deemed complete. The two layers were separated, and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrate under reduced pressure. The residue was then purified by flash chromatography (SiO2, 10% to 15% ethyl acetate/hexane gradient elution) to afford 7-[(benzyloxy)methyl]-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3e, 6.31 g, 8.92 g theoretical, 70.7%) as a green oil. For 3e: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.69 (s, 1H), 7.90 (d, 1H, J=3.7 Hz), 7.26 (m 5H), 6.71 (d, 1H, J=3.7 Hz), 5.75 (s 2H), 4.51 (s, 2H); C14H12ClN3O (MW, 273.72), LCMS (EI) m/e 274/276 (M++H).
Reaction SMILES: F[C:2]1[C:26]([F:27])=[C:25]([F:28])[C:24]([F:29])=[CH:23][C:3]=1[C:4]([C:6](=[CH:12][NH:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:19]([O:18][C:16]([N:14]([N:13]1[C:23]2[C:3](=[CH:2][C:26]([F:27])=[C:25]([F:28])[C:24]=2[F:29])[C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12]1)[CH3:15])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)C(=CNN(C)C(=O)OC(C)(C)C)C(=O)c1cc(F)c(F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(N(C)C(=O)OC(C)(C)C)c2c(F)c(F)c(F)cc2c1=O
Temperature: 0 °C
Yield: 92.5 %

Procedure:
A suspension of ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-(2-tert-butoxycarbonyl-2-methylhydrazino)acrylate (10.50 g)and potassium carbonate (3.80 g)in dimethylformamide (31.5 ml)was heated at 60°~65° C. for one hour. The mixture was poured into ice-water (300 ml) to give a solid. The solid was filtered , dissolved in dichloromethane (100 ml), dried over magnesium sulfate, and concentrated under reduced pressure to give a residue. The residue was triturated with n-hexane to give ethyl 1-(N-tert-butoxycarbonyl-N-methylamino)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (9.25 g).
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[CH2:9]([O:12][C:13](=[O:19])[C@H:14]([CH:16]([CH3:18])[CH3:17])[NH2:15])[CH:10]=[CH2:11].C>O1CCOCC1>[N-:15]=[C:4]=[O:3].[CH2:9]([O:12][C:13](=[O:19])[C@H:14]([CH:16]([CH3:17])[CH3:18])[NH2:15])[CH:10]=[CH2:11]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: C=CCOC(=O)[C@@H](N)C(C)C
Solvent: C1COCCO1
Product: [N-]=C=O

Procedure:
0.35 mol diphosgene is added dropwise over 1 hour to a mixture of 0.28 mol of valine allyl ester, prepared as described by H. Waldmann and H. Kunz in Liebigs Ann. Chem., 1983, 1712-1725, and 0.4 g activated charcoal in 400 mL dioxane under N2. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is re-dissolved in 100 mL THF, and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the product is purified by fractional distillation to give valine allyl ester isocyanate.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[OH-].[Na+].[Cl:12][CH2:13][CH2:14][CH2:15]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[Cl:12][CH2:13][CH2:14][CH2:15][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: ClCCCBr
Reactant: c1ccc2[nH]nnc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: ClCCCn1nnc2ccccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
Benzotriazole (11.9 g, 0.10 mol) is dissolved into 100 ml of 30% wt. sodium hydroxide, 3-chlorobromopropane (31.4 g, 0.10 mol), tetrabutyl ammonium bromide (0.8 g) are added, and mixed for 5 min. The reaction solution is gradually heated to 60° C., stirred for reaction for 2 hours. Then the reaction solution was cooled down to ambient temperature, 100 ml of dichloromethane was added for extraction and liquid separation. To the aqueous phase, 100 of dichloromethane was added for extraction. Organic phases were mixed, washed with 100 ml of saturated saline. Liquid was separated, and organic phase was evaporated to dryness to produce oily product. Oily products were separated and purified by chromatography with neutral Al2O3, and eluted and separated with dichlormethane to produce 16.0 g of 1-(3-chloropropyl)-1H-benzotriazole, with a yield of 82.0%.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[C:13](=[O:14])[NH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)[CH:7]=1.Br[CH2:19][CH2:20]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[C:13](=[O:14])[N:12]3[C:11]([C:15](=[O:17])[O:16][CH2:19][CH2:20]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: BrCCBr
Reactant: Cc1cn(-c2ccc(C(=O)O)[nH]c2=O)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc3n(c2=O)CCOC3=O)cn1
Temperature: 90 °C

Procedure:
N,N-Dimethylformamide (850 mL) was added to a mixture of 5-(4-methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid hydrochloride salt (C3) (65 g, 250 mmol), 1,2-dibromoethane (52.5 g, 280 mmol) and cesium carbonate (124 g, 381 mmol), and the reaction mixture was heated to 90° C. for 6 hours. After allowing the reaction to cool to room temperature, the mixture was filtered through Celite, and the filtrate was concentrated in vacuo. The residue was dissolved in dichloromethane (500 mL), washed with saturated aqueous sodium chloride solution (100 mL), washed with water (50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was washed with acetonitrile to provide the product. Yield: 46.5 g, 190 mmol, 76%. 1H NMR (400 MHz, CDCl3) δ 2.30 (d, J=0.8 Hz, 3H), 4.38-4.42 (m, 2H), 4.66-4.70 (m, 2H), 7.15-7.17 (m, 1H), 7.43 (AB quartet, JAB=7.7 Hz, ΔνAB=33.4 Hz, 2H), 8.33 (d, J=1.4 Hz, 1H).