Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C-:3]([C:6]#[N:7])[C:4]#[N:5])#[N:2].[K+].[CH2:9]([NH:11][CH3:12])[CH3:10].CS(O)(=O)=O>C(COC)OC>[NH2:2][C:1]([N:11]([CH2:9][CH3:10])[CH3:12])=[C:3]([C:6]#[N:7])[C:4]#[N:5]
Reactant: CCNC
Reactant: N#C[C-](C#N)C#N
Agent: CS(=O)(=O)O
Agent: [K+]
Solvent: COCCOC
Product: CCN(C)C(N)=C(C#N)C#N
Reaction time: 48 h
Yield: 57.4 %

Procedure:
An attempted preparation by the method of Example VI, part C, was unsuccessful. Thus, a mixture of 129 g of potassium tricyanomethanide, 59 g of ethylmethylamine, and 2000 ml of dimethoxyethane was treated with 65 ml (96 g) of methanesulfonic acid added dropwise during 30 min. The reaction was mildly exothermic and solid formation was noted during addition of the methanesulfonic acid. The reaction mixture was heated under reflux for one hour and was allowed to stand two days at ambient temperature. The solids were removed by filtration and the filter cake was washed with toluene. The combined filtrate and washings were evaporated under reduced pressure. The residue was heated to 200° in an oven. The residue was removed from the oven and water was added immediately. The near boiling aqueous suspension was treated with charcoal and filtered through a mat of Filter-Aid® diatomaceous earth in a large, steam heated, Buchner funnel. The aqueous filtrate was allowed to cool, producing crystals. The crystals were collected by filtration, dried, and recrystallized from acetonitrile to yield 86 g of 3-amino-2-cyano-3-(ethylmethylamino)propenenitrile, mp 140°-141°. The ir spectrum was consistent with the assigned structure.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:10]([C:33]([F:36])([F:35])[F:34])=[C:11]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[C:28]4[CH2:29][NH:30][CH2:31][CH2:32][C:27]=4[NH:26][N:25]=3)=[O:23])[CH2:18][CH2:17]2)[CH:12]=[CH:13][C:14]=1[F:15].[O:37]1[CH2:40][C:39](=O)[CH2:38]1>>[F:8][C:9]1[C:10]([C:33]([F:34])([F:35])[F:36])=[C:11]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]([C:24]3[C:28]4[CH2:29][N:30]([CH:39]5[CH2:40][O:37][CH2:38]5)[CH2:31][CH2:32][C:27]=4[NH:26][N:25]=3)=[O:23])[CH2:20][CH2:21]2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: O=C(c1n[nH]c2c1CNCC2)N1CCC(c2ccc(F)c(F)c2C(F)(F)F)CC1
Reactant: O=C1COC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1n[nH]c2c1CN(C1COC1)CC2)N1CCC(c2ccc(F)c(F)c2C(F)(F)F)CC1

Procedure:
Following general procedure GP-D1, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone (36) and 3-oxetanone were converted to (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(oxetan-3-yl)-4,5,6,7-tetrahydro-Hpyrazolo[4,3-c]pyridin-3-yl)methanone as a white solid (28 mg, 27%): mp 212-215° C.; 1H NMR (300 MHz, DMSO-d6) δ 12.847 (s, 1H), 7.796-7.684 (m, 1H), 7.546-7.458 (m, 1H), 5.151 (d, 1H), 4.737-4.554 (m, 3H), 4.554-4.423 (m, 2H), 3.755-3.600 (m, 1H), 3.379 (s, 2H), 3.222-3.050 (br s, 2H), 2.844-2.643 (m, 3H), 1.898-1.515 (br s, 4H); ESI MS m/z 471.2 [M H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].S(Cl)([Cl:16])=O.CN(C=O)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[C:11]([Cl:16])=[O:13]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cl)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 3-fluoro-4-nitrobenzene carboxylic acid (18.0 g 1.0 eq, 0.10 mol) in THF (360 ml) at 0° C. was added thionyl chloride (56.7 ml, 8.0 eq, 0.78 mol) and DMF (1 ml.). The reaction was warmed to room temperature and stirred for 3.5 hours, after this point all starting material had been consumed. Thionyl chloride was then removed in vacuo to give 3-fluoro-4-nitrobenzoyl chloride as a yellow solid. This was dissolved in DCM (360 ml) and the solution added dropwise to a cooled solution of 880 ammonia in water (360 ml) with vigorous stirring. After the addition the reaction was stirred at room temperature for 15 minutes. The resultant precipitate was collected by filtration, and the filtrate was then filtered a further two more times. The three precipitates were each washed with cyclohexane (2×100 ml), dried in vacuo and combined to give the title compound as a yellow solid (13.32 g, 72 mmol, 74%). LCMS: [M+H]+=na, Rt=1.41 min, 100% purity.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O-:18])=[CH:14][CH:13]=1.[Na+].N>O>[CH:4]1[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=[C:2]([O:18][C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: [O-]c1ccc(Cl)cc1
Agent: N
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
157.6 g of p-chloronitrobenzene and 150.5 g of sodium 4-chlorophenolate were initially introduced into a steel autoclave. At temperature, 150 g of liquid ammonia were pumped into the vessel, the mixture was brought to 80° C. and stirred at this temperature for 10 hours. 150 g of water were then pumped in the vessel, the mixture was cooled to room temperature, the pressure vessel was let down while removing the ammonia at the same time by distillation, and the reaction mixture was filtered off through a suction filter. The crystalline product was washed with water and dried to give 4-chloro-4'-nitrodiphenyl ether with a yield of 226.7 g=92.3% of the theoretical yield. The product is almost 100% pure.
Reaction SMILES: [CH:1]([CH2:3][CH2:4][C:5]1[CH:9]([C:10]([CH3:12])=[CH2:11])[CH2:8][CH2:7][C:6]=1[CH3:13])=[O:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH:1]([CH2:3][CH2:4][C:5]1[CH:9]([CH:10]([CH3:11])[CH3:12])[CH2:8][CH2:7][C:6]=1[CH3:13])=[O:2]
Reactant: [H][H]
Reactant: C=C(C)C1CCC(C)=C1CCC=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1=C(CCC=O)C(C(C)C)CC1

Procedure:
3.6 g of 2-(2-formylethyl)-3-isopropenyl-1-methyl-cyclopent-1-ene were hydrogenated in 80 ml of ethyl acetate in the presence of 500 mg of palladium on calcium carbonate (5%). After the uptake of one equivalent of hydrogen, the solution was filtered over Celite, concentrated and subjected under a high vacuum to a short-path distillation. 2-(2-Formylethyl)-3-isopropyl-1-methyl-cyclopent-1-ene having a fresh, woody fragrance was obtained in quantitative yield; boiling point 0.001 about 70°C; nD20 = 1.4703; IRfilm : μmax = 2740, 1728, 1470, 1385, 1368 and 1100 cm-1.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[N:20]1([CH2:26][CH2:27][NH2:28])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:28][CH2:27][CH2:26][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: NCCN1CCOCC1
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CCCCN1C(=O)C(NCCN2CCOCC2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 2-morpholin-4-ylethanamine in a similar manner as described for e.g. Example 6 and 7. 1H NMR (500 MHz CDCl3): δ 7.58-7.50 (m, 2H), 7.50-7.00 (m, 3H), 6.05 (t, 1H), 3.78-3.65 (m, 6H), 2.92-2.88 (m, 2H), 2.46-2.32 (m, 6H), 1.88-1.80 (m, 2H), 1.50-1.42 (m, 2H), 1.00 (t, 3H); 13C NMR (125 MHz CDCl3): δ 159.2, 135.9, 131.6, 129.8, 128.9, 125.3, 107.2, 67.1, 56.4, 53.2, 40.3, 40.2, 30.5, 20.3, 13.8; Mass Spectrum: M+H+ 394.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[C:5]=1[OH:19])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([NH:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:11])[C:5]=1[OH:19]
Reactant: O=C(Nc1ccccc1)c1cccc([N+](=O)[O-])c1O
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(C(=O)Nc2ccccc2)c1O
Yield: 87.6 %

Procedure:
To a solution of 2-nitro-6-phenylaminocarbonylphenol (1 g, 4.0 mmol) in methanol(250 mL) was added 10% Pd/C (100 mg). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5% MeOH/CH2Cl2) gave the desired product(800 mg, 91%). 1H NMR (CD3OD): δ 7.73-7.57 (m, 2H), 7.43-7.27 (m, 3H), 7.25-7.10 (m, 1H), 6.94 (t, 1H), 6.74 (t, 1H).
Reaction SMILES: [CH2:1]1[S:5][C@@H:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[C@H:3]2[NH:14][C:15]([NH:17][C@@H:2]12)=[O:16].O[N:19]=[C:20]([NH2:36])[CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[C:29]2[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:28]=2[O:27][C:26]1=[O:35].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C.ClCCl>[O:16]=[C:15]1[NH:17][C@H:2]2[CH2:1][S:5][C@@H:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]/[N:19]=[C:20](\[NH2:36])/[CH2:21][CH2:22][CH2:23][CH2:24][N:25]3[C:29]4[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:28]=4[O:27][C:26]3=[O:35])=[O:12])[C@H:3]2[NH:14]1
Reactant: O=C(O)CCCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: Cc1ccc2oc(=O)n(CCCCC(N)=NO)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2oc(=O)n(CCCC/C(N)=N/OC(=O)CCCCC[C@@H]3SC[C@@H]4NC(=O)N[C@@H]43)c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.6 %

Procedure:
To a suspension of homobiotin 83 (10 mg, 0.039 mmol) and compound 13 (11 mg, 0.043 mmol) in anhydrous DMF (0.5 ml) was added EDCl (7 mg, 0.047 mmol) and DIPEA (6 mg, 0.045 mmol) and stirred under a nitrogen atmosphere at ambient temperature for 12 h. The reaction mixture was diluted with dichloromethane (25 ml) and washed with water (25 ml) and brine (25 ml). The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 19:1 dichloromethane/methanol to give a yellow oil (18 mg, 46%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[CH:23]=[C:22]([CH:24]=O)[N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.[CH2:37]([P:46](=[O:53])([O:50][CH2:51][CH3:52])[O:47][CH2:48][CH3:49])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[CH:23]=[C:22](/[CH:24]=[CH:37]/[P:46](=[O:53])([O:47][CH2:48][CH3:49])[O:50][CH2:51][CH3:52])[N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COc1cc(COc2cc(C=O)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cc(OCc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)nn1-c1ccccc1)OCC
Reaction time: 1 h
Yield: 67.4 %

Procedure:
To a mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-5-carbaldehyde (0.50 g), tetraethyl methylenediphosphonate (0.32 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.05 g) at room temperature, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-5-yl}ethenylphosphonate as a colorless oil (0.43 g, yield 69%) from a fraction eluted with ethyl acetate-hexane (3:1, v/v).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C@H:6]2[C@H:15]3[CH2:16][CH2:17][N:18]([C:19]([C@H:21]4[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]4[NH:27][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:20])[C@H:14]3[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7]2)=[CH:2]1.S1C=CC([C@H]2[C@@H]3CCN(C([C@H]4CCCC[C@H]4NC(=O)C4C=CC=CC=4)=O)[C@@H]3C3C=CC=CC=3N2)=C1>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:15]3[CH2:16][CH2:17][N:18]([C:19]([C@H:21]4[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]4[NH:27][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:20])[C:14]=3[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=2)=[CH:2]1
Reactant: O=C(N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ccsc3)Nc3ccccc3[C@@H]21)c1ccccc1
Agent: [Mn+4]
Agent: O=C(N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H]1c1ccccc1N[C@H]2c1ccsc1)c1ccccc1
Agent: [O-2]
Solvent: Cc1ccccc1
Product: O=C(N[C@@H]1CCCC[C@@H]1C(=O)N1CCc2c(-c3ccsc3)nc3ccccc3c21)c1ccccc1
Yield: 17 %

Procedure:
A mixture of N-((1R,2S)-2-{[(3aR*,4R*,9bR*)-4-(3-thienyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl]carbonyl}cyclohexyl)benzamide and N-((1R,2S)-2-{[(3aS*,4R*,9bS*)-4-(3-thienyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl]carbonyl}cyclohexyl)benzamide (422 mg, 0.87 mmol) was dissolved in toluene (30 ml), manganese dioxide (7.6 g, 87 mmol) was added and the mixture was refluxed overnight. The reaction mixture was filtered through celite and washed with methanol. The filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography using silica gel (30 g), and eluted with hexane-ethyl acetate (9:1-2:1, v/v). Crystallization from diisopropyl ether gave the title compound (70 mg, 17%) as pale-brown crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][C:8]([C:12]3[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=3)=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:22][O:23][CH3:24])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][N:33]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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]>[CH3:24][O:23][CH2:22][C:4]1[CH:3]=[C:2]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:40])([F:39])[F:41])=[CH:34][N:33]=2)[C:11]2[C:6](=[N:7][C:8]([C:12]3[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=3)=[CH:9][CH:10]=2)[N:5]=1
Reactant: COCc1cc(Cl)c2ccc(-c3ncccc3C(F)(F)F)nc2n1
Reactant: Nc1ccc(C(F)(F)F)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COCc1cc(Nc2ccc(C(F)(F)F)cn2)c2ccc(-c3ncccc3C(F)(F)F)nc2n1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a de-gassed mixture of 4-chloro-2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-[1,8]naphthyridine (1 mmol), cesium carbonate (2 mmol), 2-amino-5-trifluoromethyl pyridine (1 mmol) in dioxane (10 mL) under nitrogen, add Pd2dba3 (0.05 mmol) and xantphos (0.05 mol). Stir the mixture at 90° C. overnight, concentrate, and extract with EtOAc. Dry over Na2SO4 and concentrate under vacuum. Purify by column chromatography eluting with dichloromethane/methanol/ammonium hydroxide mixture to give 2-methoxymethyl-7-[3-(trifluoromethyl) pyridin-2-yl]-N-[5-(trifluoromethyl)pyridin-2-yl]-[1,8]naphthyridin-4-amine. MS 480 (M+1). 1H NMR δ (CDCl3) 8.88 (1H, d), 8.62 (1H, s), 8.18 (1H, d), 8.07 (1H, s), 7.88 (1H, dd), 7.84 (1H, d), 7.56 (1H, d), 7.54 (1H, d), 7.30 (1H, d), 4.77 (2H, s), 3.52 (3H, s), 2.63 (1H, br s).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([C:7]#[N:8])=[CH:3][CH:2]=1.[N-:10]=[N+:11]=[N-:12].[Na+].Cl.C(NCC)C>C1(C)C=CC=CC=1>[C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([C:7]2[NH:12][N:11]=[N:10][N:8]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCNCC
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nnn[nH]2)cc1

Procedure:
In an environment of nitrogen, a mixture of p-tolunitrile (35.15 g, 300 mmol.), sodium azide (29.25 g, 450 mmol.), diethylamine hydrochloride (49.32 g, 450 mmol), and toluene (500 mL) was refluxed for 12 hours. After it was allowed to cool down, the beige suspension obtained was extracted with water (3×500 mL). Concentrated HCl was then drop-added into the water extracts to reach a pH value of around 3. The resulting white precipitates were filtered and dried in a vacuum oven all night. 5-(p-Tolyl)-1H-tetrazole in a form of white crystals (43.25 g, 90.0%) was obtained and used for the next step without any further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:5][CH:4]=1)=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH3:25][C:22]1[CH:23]=[CH:24][C:19](/[N:18]=[CH:1]/[C:3]2[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:5][CH:4]=2)=[CH:20][CH:21]=1
Reactant: Cc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)COc1ccc(C=O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(/N=C/c2ccc(OCC(=O)OC(C)(C)C)cc2)cc1

Procedure:
tert-Butyl (4-formylphenoxy)acetate (5.0 g, 21.2 mmol) was dissolved in dry toluene (100 mL) and p-toluidine (2.27 g, 21.2 mmol) was added. The mixture was refluxed in a Dean-Stark apparatus for 18 hours, cooled and concentrated under reduced pressure. Heptane was added and the mixture was concentrated under reduced pressure. This afforded the title compound.
Reaction SMILES: [O-]S([O-])(=O)=O.[Mg+2].[CH2:7]1[C@H:12]([NH2:13])[C@@H:11]([O:14][C@H:15]2[O:20][C@H:19]([CH2:21]N)[C@@H:18]([OH:23])[C@H:17]([OH:24])[C@H:16]2O)[C@H:10]([OH:26])[C@@H:9]([O:27][C@H:28]2[O:33][C@H:32]([CH2:34][OH:35])[C@@H:31]([OH:36])[C@H:30]([NH2:37])[C@H:29]2[OH:38])[C@@H:8]1[NH2:39].[CH3:40][CH2:41][N:42]1[C:48]2[N:49]=[C:50]([CH3:53])[CH:51]=[CH:52][C:47]=2[C:45](=[O:46])[C:44]([C:54]([OH:56])=[O:55])=[CH:43]1>>[CH3:21][C@H:19]1[O:20][C@H:15]([O:14][C@H:11]2[C@H:10]([OH:26])[C@@H:9]([O:27][C@H:28]3[O:33][C@H:32]([CH2:34][OH:35])[C@@H:31]([OH:36])[C@H:30]([NH2:37])[C@H:29]3[OH:38])[C@H:8]([NH2:39])[CH2:7][C@@H:12]2[NH2:13])[CH2:16][C@@H:17]([OH:24])[C@@H:18]1[OH:23].[CH3:40][CH2:41][N:42]1[C:48]2[N:49]=[C:50]([CH3:53])[CH:51]=[CH:52][C:47]=2[C:45](=[O:46])[C:44]([C:54]([OH:56])=[O:55])=[CH:43]1
Reactant: NC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](O)[C@@H](O)[C@@H]1O
Agent: CCn1cc(C(=O)O)c(=O)c2ccc(C)nc21
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: C[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)C[C@@H](O)[C@@H]1O
Reaction time: 0.03 h

Procedure:
The culture medium LB (Tryptone 10 g/L, yeast extract 5 g/L, NaCl 10 g/L) that once autoclaved was supplemented with 25 μg/mL of kanamycin was used to grow E. coli S17-1 λ pir. Once the stationary phase was achieved, 0.2-0.3 A600 units of the App culture and 0.6-0.8 A600 units of the E. coli culture were added to 1 mL of a 10 mM solution of MgSO4. Next it was centrifuged during 2 minutes at 15,000 g and the pellet so obtained was resuspended in 200 μl of a 10 mM MgSO4 solution. Once the mixture of both cultures had been done, this was extended on a 2.5 cm and 0.45 μM nitrocellulose filter previously placed on a Petri dish containing TSYN medium supplemented with 15 g/L Noble agar. After incubation during 6 hours at 37 C., the filter with the conjugation was placed in a tube containing 2 mL of PBS (Na2HPO410 mM, KH2PO4 1 mM, NaCl 137 mM, KCl 2 mM pH 7.4). After vigorous shaking, the filter was removed and the cell suspension was centrifuged during 2 minutes at 15,000 g and the pellet was resuspended in 500 μL of PBS. The so obtained suspension was distributed in Petri dishes with TSYN medium supplemented with 15 g/L Noble Agar, 50 μg/mL kanamycin and 50 μg/mL nalidixic acid, at a rate of 100 μL of cell suspension for each Petri dish. The resulting cultures were incubated at 37 C. for 24-36 hours. With this procedure 65 colonies resistant to kanamicin and nalidixic acid, were obtained for the conjugation with the plasmid pApxIΔH2, which equals a frequency of transformation of 1.3×10−7 for each receptor cell.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][NH:9][NH:10]C(OC(C)(C)C)=O)=[CH:6][CH:5]=1>O1CCOCC1>[ClH:1].[ClH:1].[CH3:2][O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][NH:9][NH2:10])=[CH:6][CH:5]=1
Reactant: COc1ccc(CNNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(CNN)cc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a solution of 4 N hydrogen chloride in dioxane (2000 mL, 8.00 mol HCl), add tert-butyl 2-(4-methoxybenzyl)hydrazinecarboxylate (324 g, 1.09 mol) dissolved in a minimal amount of dioxane, slowly over a period of 1 h. A precipitate gradually forms. Allow the solution to stir 16 h at 20±5° C. Collect the solids by filtration. Slurry the solids in heptane (2000 mL) and isolate the solids by filtration. Dry the solids using a nitrogen press to give the title compound (242.3 g, 1.08 mol, 98%). 1H NMR (400 MHz, DMSO-d6) δ 8.2-9.0 (bs, 5H), 7.3-7.4 (d, 2H), 6.8-7.0 (d, 2H), 4.0 (s, 2H), 3.7 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:22])[C:9](=[O:21])[C:10]([C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)([CH3:12])[CH3:11])=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[CH:3]=1.CN(C)C=O.Cl[C:36]([F:43])([F:42])C(OCC)=O>O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:22])[C:9](=[O:21])[C:10]([C:13]2[CH:18]=[C:17]([O:19][CH:36]([F:43])[F:42])[CH:16]=[C:15]([Cl:20])[CH:14]=2)([CH3:11])[CH3:12])=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[CH:3]=1
Reactant: CN(C(=O)C(C)(C)c1cc(O)cc(Cl)c1)c1cnc(Cl)cc1-c1ccccc1Cl
Reactant: CCOC(=O)C(F)(F)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)C(C)(C)c1cc(Cl)cc(OC(F)F)c1)c1cnc(Cl)cc1-c1ccccc1Cl
Temperature: 65 °C
Yield: 48.7 %

Procedure:
To a solution of 0.700 g (1.56 mmol) N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3-chloro-5-hydroxy-phenyl)-N-methyl-isobutyramide in 10 ml N,N-Dimethylformamide 0.215 g (1.56 mmol) K2CO3 and 0.2 ml (1.56 mmol) ethyl chlordifluoroacetate was added and the resulting suspension heated at 65° C. for 15 h. After cooling to ambient temperature, the reaction mixture was poured into 75 ml water and extracted three times with 80 ml CH2Cl2. The combined organic solvents were dried (Na2SO4), filtered and evaporated. The residue was purified by flash-chromatography (SiO2, CH2Cl2/ethyl acetate 4:1) to give 0.38 g (49%) of the title compound as a white solid.
Reaction SMILES: CN(C)CCN1C2C=CC=CC=2C2C1=CC=CC=2.[N+]([O-])(O)=O.[CH3:23][N:24]([CH3:43])[CH2:25][CH2:26][N:27]1[C:39]2[CH:38]=[CH:37][C:36]([N+:40]([O-])=O)=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2>C(O)(=O)C>[CH3:23][N:24]([CH3:43])[CH2:25][CH2:26][N:27]1[C:39]2[CH:38]=[CH:37][C:36]([NH2:40])=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2
Reactant: CN(C)CCn1c2ccccc2c2cc([N+](=O)[O-])ccc21
Agent: CN(C)CCn1c2ccccc2c2ccccc21
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CN(C)CCn1c2ccccc2c2cc(N)ccc21
Temperature: 0 °C

Procedure:
23.7 g. (0.1 mol) 9-(β-dimethylaminoethyl)-carbazole (prepared in the manner described by O. Eisleb, Ber. dtsch. chem. Ges., 74, 1433/1941) in 100 ml. glacial acetic acid were placed in a 500 ml. three-necked flask equipped with a stirrer, thermometer and dropping funnel and placed in an ice-bath. A solution of 8.28 ml. (0.2 mol) anhydrous nitric acid in 50 ml. glacial acetic acid was added dropwise thereto at 15° - 20°C. The reaction mixture was further stirred for an hour at 20° - 25°C. and then poured into 500 ml. ice-water. The precipitated green crystals were filtered off with suction, well washed with water and dried at 80°C. in a drying cabinet. There were obtained 32.4 g. (94% of theory) 9-(β-dimethylaminoethyl)-3-nitrocarbazole which melted, with decomposition, at 190°C.