Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=O.[N:12]#[C:13][NH2:14]>C(O)(=O)C.Cl>[NH2:14][C:13]1[N:12]=[N+:9]([O-:11])[C:3]2[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: N#CN
Agent: Cl
Solvent: CC(=O)O
Product: Nc1nc2ccc(O)cc2[n+]([O-])n1
Temperature: 100 °C
Reaction time: 0.12 h
Yield: 51.6 %

Procedure:
7.7 g (0.05 mol) of 4-amino-3-nitrophenol was dissolved in 20 mL of glacial acetic acid and the resulting bright-red solution was heated to approximately 100° C. in 500 mL round-bottom flask equipped with a long condenser. To this solution was added a solution of 16.81 g (8.0 equivalent, 0.4 mol) of cyanamide in 20 mL of concentrated hydrochloric acid. In approximately 5-10 min the reaction mixture started to boil vigorously, so the heating was removed and it was stirred without heating until boiling subsided. Then the heating was reapplied and the reaction mixture was refluxed for 48 hrs. Then 150 mL of 30% NaOH was added and the resulting dark-reddish solution was refluxed for additional 3 hrs. Then it was cooled down to room temperature and dark-red slurry was formed. The red precipitate was filtered, re-dissolved in 200 mL of water and 1N HCl was added in portions with stirring until pH reached 5-4. The solution changed color from dark-red into light-yellow and a light-yellow fine precipitate was formed. The precipitate was filtered, washed twice with 50 mL of water, twice with 50 mL of acetonitrile and finally twice with 50 mL of diethyl ether and dried in vacuum to give 4.6 g of a bright-yellow solid. Yield: 51.7%.
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[C:9]2[N:10]=[C:11]([CH2:13][CH3:14])[O:12][C:8]=2[C:7]([C:15]([OH:17])=O)=[CH:6][CH:5]=1.[CH2:19]([C:21]1[C:25]([NH2:26])=[C:24]([CH3:27])[O:23][N:22]=1)[CH3:20]>C(OCC)C.CCCCCC>[CH2:19]([C:21]1[C:25]([NH:26][C:15]([C:7]2[C:8]3[O:12][C:11]([CH2:13][CH3:14])=[N:10][C:9]=3[C:4]([O:3][CH:2]([F:1])[F:18])=[CH:5][CH:6]=2)=[O:17])=[C:24]([CH3:27])[O:23][N:22]=1)[CH3:20]
Reactant: CCc1noc(C)c1N
Reactant: CCc1nc2c(OC(F)F)ccc(C(=O)O)c2o1
Solvent: CCCCCC
Solvent: CCOCC
Product: CCc1nc2c(OC(F)F)ccc(C(=O)Nc3c(CC)noc3C)c2o1
Yield: 54.6 %

Procedure:
Starting from 4-difluoromethoxy-2-ethylbenzooxazole-7-carboxylic acid (0.20 g) and 3-ethyl-5-methylisoxazol-4-ylamine (0.20 g). Purification by column chromatography on silica eluting 20-50% ethyl acetate in heptane afforded, after trituration with diethyl ether-hexane, the title compound as a white solid (0.155 g).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:7][CH:6]=1)=[O:4].[N:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1>C(#N)C>[N:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:31][CH2:32][N:33]([CH2:2][C:3]([C:5]3[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][S:14]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)(=[O:16])=[O:15])=[CH:7][CH:6]=3)=[O:4])[CH2:34][CH2:35]2)=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)NCCc2ccc(C(=O)CBr)cc2)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)NCCc2ccc(C(=O)CN3CCN(c4ccncc4)CC3)cc2)cc1
Reaction time: 18 h

Procedure:
A solution of N-(2-[4-bromoacetylphenyl]ethyl)-4-methylphenylsulphonamide (485 mg) in acetonitrile (10 ml) was added to a stirred solution of 1-(4-pyridyl)piperazine (400 mg) in acetonitrile (10 ml) and the mixture was stirred for 18 hours. The solvent was evaporated in vacuo and the residue purified by flash chromatography on silica, eluting with 10% v/v methanol/dichloromethane. On evaporation of the eluant fraction crystallisation occured. These crystals on filtration and washing with dichloromethane gave the title compound, 230 mg, as an off-white solid: m.p. 133°-135° C.; NMR(d6DMSO) δ 8.14(2H,bd), 7.90(2H,d), 7.65(2H,d), 7.59(1H,t), 7.35(2H,d), 7.29(2H,d), 6.81(2H,d), 3.37(2H,s), 3.33(4H,t), 2.98(2H,q), 2.76(2H,t), 2.63(4H,t), 2.38(3H,s); m/e 479(M+H)+ ; calculated for C26H30N4O3S: C, 65.2; H, 6.3; N, 11.7; found. C 65.0; H, 6.3; N, 11.4%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11]([O-])(=O)[CH3:12].[K+]>CC(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]2[N:6]([C:11]([CH3:12])=[N:9][N:8]=2)[N:7]=1
Reactant: CC(=O)[O-]
Reactant: NNc1nnc(Cl)cc1N
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1nnc2c(N)cc(Cl)nn12
Temperature: 170 °C
Reaction time: 4 h
Yield: 82.2 %

Procedure:
A MW vial was charged with 6-chloro-3-hydrazinylpyridazin-4-amine (Step 112.2) (475 mg, 2.98 mmol) and potassium acetate (467 mg, 4.76 mmol) in AcOH (5 mL). The MW vial was sealed and the resulting mixture was heated up and stirred at 170° C. for 4 hr. The reaction was cooled down to RT and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (NH3 1%/CH2Cl2/MeOH 1-3%) to afford the title product (450 mg, 2.451 mmol, 82% yield). tR: 2.32 min (HPLC 1); tR: 0.55 min (LC-MS 2); ESI-MS: 184 [M+H]+ (LC-MS 2); ESI-MS: 182 [M−H]− (LC-MS 2); Rf=0.45 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[CH:6][CH:5]=[N:4]1)[CH3:2].[Cl:9][C:10]1[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13].C1(N=C=NC2CCCCC2)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:12](=[O:13])[C:11]2[CH:15]=[CH:16][C:17]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:18][C:10]=2[Cl:9])[CH:5]=[N:4]1)[CH3:2]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Reactant: CCn1nccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)cc2Cl)c1O
Temperature: 90 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
After 2.35 g (0.021 mol) of 1-ethyl-5-hydroxypyrazole was dissolved in 20 ml of tert.-amyl alcohole, the mixture was succesively added with 4.69 g (0.02 mol) of 2-chloro-4-methanesulfonyl benzoic acid, 5.33 g (0.021 mol) of N,N'-dicyclohexyl carbodiimide and 1.52 g (0.011 mol) of anhydrous potassium carbonate, and heated at 50°-60° C. for 5 hours, followed by additional stirring for 1 hour at 90° C. Then, the reaction was ceased. After cooling, solvent was distilled off from the reaction solution, and the residue was added with 50 ml of 5% aqueous solution of potassium hydroxide to dissolve the soluble matter. After insoluble matter was filtered off, the aqueous layer was washed with chloroform and separated. This operation was twice carried out. The obtained aqueous layer was adjusted to pH <1 by adding concentrated hydrochloric acid, and the precipitated solid product was dissolved in chloroform and extracted. After the chloroform layer was dried over sodium sulfate anhydrate, the solvent was distilled off to give a crude product of the objective product. Then, the crude product was recrystallized from 95% ethanol to obtain 5.38 g of 1-ethyl-4-(2-chloro-4-methanesulfonylbenzoyl)-5-hydroxypyrazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13]([CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[N:14][CH:15]=[CH:16][N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:11])[NH:9][CH3:10].[ClH:31].O1CCOCC1>CO>[ClH:31].[ClH:31].[ClH:31].[F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:14][CH:15]=[CH:16][N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]([NH:9][CH3:10])=[O:11]
Reactant: CNC(=O)c1ccc(-c2nccnc2C2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CNC(=O)c1ccc(-c2nccnc2C2CCNCC2)cc1F
Temperature: 25 °C
Reaction time: 96 h
Yield: 100 %

Procedure:
To a RBF was added tert-butyl 4-(3-(3-fluoro-4-(methylcarbamoyl)phenyl)pyrazin-2-yl)piperidine-1-carboxylate (2.40 g, 5.79 mmol) and methanol (20 mL) was added 4M HCl in dioxane (5 mL, 20.00 mmol). The solution was stirred at room temperature. After 96 h, the reaction was concentrated in vacuo to give 2-fluoro-N-methyl-4-(3-(piperidin-4-yl)pyrazin-2-yl)benzamide trihydrochloride (2.46 g, 5.81 mmol, 100% yield), as a yellow foam. The 3 HCl equivalent was determined from the weight of the compound, without further characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:21]=[CH:20][N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:21]=[CH:20][N:19]=[CH:18][C:7]=3[CH2:8][N+:9]([O-:32])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: Fc1ccccc1C1=NCc2cncnc2-c2ccc(Cl)cc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][N+]1=C(c2ccccc2F)c2cc(Cl)ccc2-c2ncncc2C1

Procedure:
A solution of 3.2 g (10 mmoles) of 9-chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine, 3 g (15 mmoles) of 85% m-chloroperbenzoic acid in 100 ml of methylene chloride was stirred at room temperature for 4 hours. The reaction mixture was washed with an excess of ice cold dilute sodium hydroxide, dried over anhydrous sodium sulfate and filtered over hyflo. The filtrate was concentrated at reduced pressure to dryness. The residue was crystallized from a mixture of methylene chloride and ether to give the crude product, m.p. 185°-186° C. Recrystallization from a mixture of methylene chloride and ether gave the pure product, m.p. 187°-188° C.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][O:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=1.N>>[CH3:10][O:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([N+:6]([O-:9])=[O:7])=[CH:14][N:13]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ncccc1C
Agent: N
Agent: O=S(=O)(O)O
Product: COc1ncc([N+](=O)[O-])cc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
Concentrated sulfuric acid (5 ml) and fuming nitric acid (5 ml) were added to 2-methoxy-3-methylpyridine (1.61 g, 13.1 mmol) under ice cooling, and stirred at 0° C. for 1 hour and further stirred at room temperature overnight. The reaction mixture was poured onto ice, neutralized with ammonia solution, extracted with ethyl acetate, dried over magnesium sulfate, the solvent was evaporated, thereby yielding the title compound (1.63 g, 9.71 mmol, and 74%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc(Cl)nc1
Product: Fc1cnc(Cl)nc1Nc1ccc(Cl)nc1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-amino-6-chloropyridine gave 2-chloro-N4-(6-chloropyridin-3-yl)-5-fluoro-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.53 (d, 1H, J=3 Hz), 8.25 (dd, 1H, J=3 and 9 Hz), 8.15 (d, 1H, J=2.4 Hz), 7.39 (d, 1H, J=8.7 Hz), 7.00 (bs, 1H); LCMS: purity: 98%; MS (m/e): 259 (M+).
Reaction SMILES: F[C:2]1C=C(F)C=CC=1[N+]([O-])=O.CN1CCNCC1.[CH2:19]([NH:21][C:22]1[CH:27]=[C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:24][C:23]=1[N+:34]([O-:36])=[O:35])[CH3:20]>>[CH2:19]([NH:21][C:22]1[CH:27]=[C:26]([N:28]2[CH2:29][CH2:30][N:31]([CH3:2])[CH2:32][CH2:33]2)[CH:25]=[CH:24][C:23]=1[N+:34]([O-:36])=[O:35])[CH3:20]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CCNc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Agent: CN1CCNCC1
Product: CCNc1cc(N2CCN(C)CC2)ccc1[N+](=O)[O-]

Procedure:
N-ethyl-5-(4-methyl-1-piperazinyl)-2-nitroaniline was prepared from 2,4-difluoro-1-nitrobenzene and methylpiperazine using the same method described for N-ethyl-2-nitro-5-(1-piperazinyl)aniline and was obtained as yellow solid (99%). 1H NMR (CDCl3) δ 8.30 (br s, 1H), 8.08-8.04 (m, 1H), 6.25-6.20 (m, 1H), 5.89-5.86 (m, 1H), 3.45-3.39 (m, 4H), 3.35-3.25 (m, 2H), 2.56-2.50 (m, 4H), 2.35 (s, 3H), 1.37 (tr, J=7.2 Hz, 3)); 13C NMR δ (CDCl3) 155.92, 147.72, 128.99, 124.19, 104.30, 94.37, 54.78, 47.05, 46.25, 37.73, 14.43; MS (posESI) m/z=found 264.1575, calc 264.1586. Anal. (C13H20N4O2.0.5H2O) C, H, O.
Reaction SMILES: [CH3:1][CH:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].Cl[S:21]([OH:24])(=[O:23])=[O:22].Cl.C[O-].[Na+:28]>C(Cl)(Cl)Cl>[S:21]([O-:24])([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:23])=[O:22].[Na+:28]
Reactant: CCCCCCCCCCC(C)CCCCCCO
Reactant: O=S(=O)(O)Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCC(C)CCCCCCOS(=O)(=O)[O-]
Temperature: 27.5 °C
Reaction time: 1 h

Procedure:
Into a dried 1 L 3 neck round bottom flask fitted with a nitrogen inlet, dropping funnel, thermometer, mechanical stirring and nitrogen outlet is added chloroform (300 ml) and 7-Methylheptadecanol (102 g, 0.378 mol), prepared as an intermediate in Example III. Chlorosulfonic acid (46.7 g, 0.40 mol) is slowly added to the stirred mixture while maintaining 25-30° C. temperature with a ice bath. Once HCl evolution has stopped (1 hr.) slowly add sodium methoxide (25% in methanol) while keeping temperature at 25-30° C. until an aliquot at 5% concentration in water maintains a pH of 10.5. To the mixture is added hot methanol (45° C., 1 L) to dissolve the branched sulfate followed immediately by vacuum filtration to remove the inorganic salt precipitate and repeated a second time. The filtrate is then cooled to 5° C. at which time 1 L of ethyl ether is added and let stand for 1 hour. The precipitate is collected by vacuum filtration. The product is dried in a vacuum oven at 50C for 3 hrs. to obtain a white solid (89 g, 88% active by cat SO3 titration). HNMR of the final product (in deuterium oxide) indicates a CH2 --OSO3- triplet at the 3.8 ppm resonance, CH2 --CH2 --OSO3- multiplet at the 1.5 ppm resonance, CH2 of the alkyl chain at the 0.9-1.3 ppm resonance and CH--CH3 branch point overlapping the R--CH2CH3 terminal methyl group at the 0.8 ppm resonance. Mass spectrometry data shows a molecular ion peak with a mass of 349.1 corresponding to the 7-methylheptadecyl sulfate ion. Also shown is the methyl branch at the 7 position due to the loss of 29 mass units at that position.
Reaction SMILES: C(O[C:5]1[N:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([C@H:16]2[CH2:18][C@@H:17]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])[CH3:12])=[CH:7][CH:6]=1)(C)C.C[S:26]([C:29]1N=CC([C@@H](N)C)=C[CH:30]=1)(=[O:28])=[O:27].CS(C1N=CC(C(=O)C)=CC=1)(=O)=O.BrC1C=CC(S(C)(=O)=O)=NC=1>>[CH2:29]([S:26]([C:5]1[N:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([C@H:16]2[CH2:18][C@@H:17]2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:15])[CH3:12])=[CH:7][CH:6]=1)(=[O:28])=[O:27])[CH3:30]
Reactant: CC(C)Oc1ccc([C@H](C)NC(=O)[C@H]2C[C@@H]2c2ccccc2)cn1
Reactant: C[C@H](N)c1ccc(S(C)(=O)=O)nc1
Agent: CC(=O)c1ccc(S(C)(=O)=O)nc1
Agent: CS(=O)(=O)c1ccc(Br)cn1
Product: CCS(=O)(=O)c1ccc([C@H](C)NC(=O)[C@H]2C[C@@H]2c2ccccc2)cn1

Procedure:
Prepared analogously to Compound 1 using IM46 and (S)-1-(6-Methanesulfonyl-pyridin-3-yl)-ethylamine (prepared from 1-(6-Methanesulfonyl-pyridine-3-yl)-ethanone analogously to IM24, which was prepared from commercially available 5-Bromo-2-methanesulfonyl-pyridine CAS 98626-95-0). Yield from IM48=1.54 g (68%). 1H-NMR (500 MHz, DMSO) δ 8.80 (d, 1H), 8.72 (s, 1H), 8.02 (m, 2H), 7.27 (m, 2H), 7.20 (s, 1H), 7.12 (d, 2H), 5.08 (m, 1H), 3.27 (s, 3H), 2.20 (m, 1H), 1.95 (m, 1H), 1.42 (d, 3H), 1.37 (m, 1H), 1.22 (m, 1H), LC-MS (m/z) 345.1 (MH+), tR=1.21 min (method A).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:10]([CH3:11])[C:9](=[O:12])[N:8]2[C:4](=[N:5][C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=32)[NH:3]1.[CH2:18]([N:22]=[C:23]=[O:24])[CH2:19][CH2:20][CH3:21]>>[CH2:18]([NH:22][C:23]([N:5]1[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[N:8]2[C:9](=[O:12])[N:10]([CH3:11])[C:2]([CH3:17])([CH3:1])[N:3]=[C:4]12)=[O:24])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCN=C=O
Reactant: CN1C(=O)n2c(nc3ccccc32)NC1(C)C
Product: CCCCNC(=O)N1C2=NC(C)(C)N(C)C(=O)N2c2ccccc21

Procedure:
The procedure of Example 10 was used to prepare the title compound from 1,2-dihydro-2,2,3-trimethyl-1,3,5-triazino[1,2-a]benzimidazol-4(3H)-one and n-butyl isocyanate. The confirmatory elemental analysis for the product, mp 95°-97° C., is shown in Table III.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([NH:13][NH2:14])[CH:6]=[CH:7][C:8]=1[S:9](=[O:12])(=[O:11])[NH2:10].[F:15][C:16]([F:35])([F:34])[C:17](=O)[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][CH:29]=[CH:30][CH:31]=2)=[C:23]([CH3:32])[CH:22]=1)=O>>[F:2][C:3]1[CH:4]=[C:5]([N:13]2[C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[O:28][CH:29]=[CH:30][CH:31]=4)=[C:23]([CH3:32])[CH:22]=3)=[CH:18][C:17]([C:16]([F:35])([F:15])[F:34])=[N:14]2)[CH:6]=[CH:7][C:8]=1[S:9]([NH2:10])(=[O:11])=[O:12]
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1-c1ccco1
Reactant: NNc1ccc(S(N)(=O)=O)c(F)c1
Agent: Cl
Product: Cc1cc(-c2cc(C(F)(F)F)nn2-c2ccc(S(N)(=O)=O)c(F)c2)ccc1-c1ccco1

Procedure:
The title compound was prepared according to the procedure of Example 60 using 3-fluoro-4-sulfamoylphenylhydrazine hydrochloride instead of 3-fluoro-4-(methylsulfonyl)phenylhydrazine hydrochloride and 4,4,4-trifluoro-1-[4-(2-furyl)-3-methylphenyl]butane-1,3-dione instead of 4,4,4-trifluoro-1-[4-(2-furyl)phenyl]butane-1,3-dione in step 2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.CN(C)[CH:25]=[O:26].[Cl-].[NH4+]>O1CCCC1>[CH:9]1([O:8][C:5]2[CH:6]=[CH:7][C:2]([CH:25]=[O:26])=[CH:3][CH:4]=2)[CH2:11][CH2:10]1
Reactant: CN(C)C=O
Reactant: Brc1ccc(OC2CC2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(OC2CC2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 1-bromo-4-(cyclopropoxy)benzene (492 mg, 2.31 mmol) in tetrahydrofuran (10 ml) was added dropwise a solution of 2.66 mol/L n-butyllithium in hexane (0.955 ml, 2.54 mmol) at −78° C. under argon atmosphere, and the mixture was stirred for 2.5 hours. Then, thereto was added dropwise N,N-dimethylformamide (0.358 ml, 4.62 mmol) at the same temperature, and the mixture was stirred for 3.5 hours with slowly warming to room temperature. To the reaction solution was added saturated aqueous ammonium chloride solution, and the mixture was stirred, and then extracted with ethyl acetate three times. The organic layer was combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a crude 4-(cyclopropoxy)benzaldehyde as a pale yellow liquid. The resulting compound was used in the next step without further purification. (2) A solution of the above crude product in methanol (5 ml) was cooled to 0° C., and then thereto was added sodium borohydride (175 mg, 4.62 mmol), and the mixture was stirred for 1 hour. Then, thereto was added saturated brine, and then the reaction solution was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with saturated brine, and the organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→3:2) to give the title compound, [4-(cyclopropoxy)phenyl]methanol (216 mg, 57%, yields for 2 steps) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=CN=[CH:9][CH:8]=2)[CH:2]=1.[N:13]1C=CC(C2C=CN=CC=2)=C[CH:14]=1.N1C2C(=CC=CC=2)C=CC=1.C1C2C(=CC=CC=2)C=CN=1>>[N:13]1[CH:14]=[CH:9][CH:8]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:12]=1
Reactant: c1cc(-c2ccncc2)ccn1
Reactant: c1cncc(-c2ccncc2)c1
Solvent: c1ccc2ncccc2c1
Solvent: c1ccc2cnccc2c1
Product: c1cncc(-c2cccnc2)c1

Procedure:
3,4'-bipyridine; 4,4'-bipyridine; quinoline; isoquinoline;
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[F:10].[Li]CCCC.[F:16][CH:17]([F:23])[C:18](OCC)=[O:19]>CCOCC>[F:16][CH:17]([F:23])[C:18]([C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[F:10])=[O:19]
Reactant: COc1ccc(Br)c(F)c1
Reactant: CCOC(=O)C(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccc(C(=O)C(F)F)c(F)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To 1-bromo-2-fluoro-4-methoxybenzene (123 g, 0.6 mol) in 1300 mL Et2O at −78° C. was added n-BuLi (276 mL, 2.5 M) dropwise. After stirring at −78° C. for 2 hours, ethyl difluoroacetate (82.6 g, 0.67 mol) was added dropwise at −78° C. The reaction was stirred overnight at 25° C., and was quenched with saturated ammonium chloride solution at −20° C., followed by 1N HCl (final pH=4). The organic layer was separated and aqueous layer was extracted with Et2O. The combined extracts were dried over MgSO4, filtered and concentrated, and the residue was purified by column chromatography (PE/EA 20:1) to afford 2,2-difluoro-1-(2-fluoro-4-methoxyphenyl)ethanone as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N#N.C1C[O:23][CH2:22]C1.C([Li])CCC>CCCCCC.CN(C=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=2)=[C:9]([CH:10]=1)[CH:22]=[O:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)COC(c2ccc(C(C)(C)C)cc2)=N1
Reactant: C1CCOC1
Agent: N#N
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC1(C)COC(c2ccc(C(C)(C)C)cc2C=O)=N1

Procedure:
An oven dried 250 mL 3-neck round bottom flask was fitted with a thermometer, stir bar, septum, and nitrogen inlet. Added 8.02 g (34.7 mmol) of 2-(4-tert-butyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole. Established and maintained N2 atmosphere. Added 100 mL of anhydrous THF. Cooled the clear solution to −78°. Stirred rapidly and added 17 mL (43 mmol) of a 2.5 M solution of n-butyllithium in hexane dropwise over 10 minutes. Stirred the clear amber solution at −20° for 4 hr. The reaction mixture became red-amber and cloudy. Cooled the mixture to −78°. Stirred rapidly and added 12 mL of DMF dropwise at a rate to keep the temperature below −60°. Stirred at −78° for 15 min. Stirred at −20° for 1 hr. Stirred at room temperature for 1 hr. Quenched with 100 mL of 0.5 M aqueous KHSO4. The aqueous phase was still strongly basic. Added more 1.0 M KHSO4 until the pH was ˜2. Diluted the two phase solution with 300 mL Et2O. Separated phases and extracted the aqueous phase with 100 mL Et2O. Washed the combined organic phases with 200 mL brine and dried over K2CO3. Filtered through 120 g of silica gel and washed through with 300 mL Et2O to remove baseline impurities. Removed the solvent on rotavap to obtain 8.18 g of the title compound as a clear yellow liquid. MS (ESI) 260 (M+H)+.
Reaction SMILES: B.O1CCCC1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][N:18]([C@@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])[C:17](=O)[CH2:16][O:15]2)=[CH:10][CH:9]=1.CO>O1CCCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C@@H:14]2[O:15][CH2:16][CH2:17][N:18]([C@@H:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH3:21])[CH2:19]2)=[CH:12][CH:13]=1
Reactant: C[C@H](c1ccccc1)N1C[C@H](c2ccc(Br)cc2)OCC1=O
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
A borane-tetrahydrofuran complex (1.0M solution in tetrahydrofuran, 510 ml, 510 mm) was added to the ice-cooled solution of (6S)-6-(4-bromophenyl)-4-((1R)-1-phenyethyl)-morpholin-3-one (70.2 g) in tetrahydrofuran (500 ml) over 45 minutes and the solution was stirred at the same temperature for one hour and room temperature for 30 minutes. After careful addition of methanol (60 ml) to the ice-cooled solution, the solvent was removed under reduced pressure and the residue in methanol (750 ml) and 1M aqueous sodium hydroxide (280 ml) was stirred at 80° C. for one hour with addition of 1M aqueous sodium hydroxide (70 ml) in every 15 minutes. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. Removal of the solvent yielded (2S)-2-(4-bromophenyl)-4-((1R)-1-phenylethyl)morpholine (65.0 g, 96.3% yield, 2 steps) as white crystals.