Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:6]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:8])[C:5]([OH:21])=[CH:4][CH:3]=1.[OH-].[Na+:23]>C(O)C>[CH2:7]([OH:8])[CH3:6].[Cl:1][C:2]1[CH:20]=[C:6]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O-:19])=[O:18])=[O:8])[C:5]([OH:21])=[CH:4][CH:3]=1.[Na+:23].[Na+:23].[Cl:1][C:2]1[CH:20]=[C:6]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O-:19])=[O:18])=[O:8])[C:5]([OH:21])=[CH:4][CH:3]=1
Reactant: O=C(O)CCCCCCCNC(=O)c1cc(Cl)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])CCCCCCCNC(=O)c1cc(Cl)ccc1O
Temperature: 55 °C

Procedure:
A 12 L, Pyrex glass, four-neck, round bottom flask was equipped with an overhead stirrer, thermocouple temperature read out, reflux condenser, and heating mantle. The flask was purged with dry nitrogen and the following reaction was conducted under an atmosphere of dry nitrogen. The flask was charged with 1000 g of N-(5-chloro-salicyloyl)-8-aminooctanic acid and 3000 mL of absolute ethanol. This slurry was heated to 55° C. with stirring to obtain a slightly hazy solution. The reactor was then charged with 2276 g of 11.2 wt % sodium hydroxide dissolved in absolute ethanol as rapidly as possible. There was a slight exothermic reaction causing the temperature in the reactor to rise to about 64° C. and a precipitate began to form. The reflux condenser was removed and the reactor set for distillation. The reaction mixture was distilled over the next three hours to obtain about 2566 g of distillate. The pot slurry was allowed to cool slowly to room temperature. The product solids in the slurry were recovered by vacuum filtration through a sintered glass funnel to obtain 1390 g of ethanol wet cake. The wet cake was transferred to glass trays and placed in a vacuum oven. The cake was dried to constant weight at about 45° C. and full vacuum. The dry product had a weight of about 1094.7 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[NH:9][CH:10]([CH2:13][N:14]([C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])C(=O)C)[CH2:11][O:12][C:7]=2[CH:6]=[CH:5][CH:4]=1>Cl>[CH3:1][O:2][C:3]1[C:8]2[NH:9][CH:10]([CH2:13][NH:14][C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH2:11][O:12][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1NC(CN(C(C)=O)[C@H](C)c1ccccc1)CO2
Agent: Cl
Product: COc1cccc2c1NC(CN[C@H](C)c1ccccc1)CO2

Procedure:
The product from Example 7D (24.8 g, 72.9 mmol) in 2.0M HCl (500 mL) was refluxed for 16 hours, cooled, concentrated to a volume of 100 mL, basified to pH 14 with 50% NaOH and extracted with ethyl acetate. The organic layer was dried (MgSO4) and concentrated. The residue was chromatographed on silica gel with ethyl acetate to provide two diastereomers, Rf 0.62 (ethyl acetate) and Rf 0.60 (ethyl acetate). 1H NMR (300 MHz, CDCl3, for Rf 0.62) δ1.35 (d, 3H), 1.55 (bs, 1H), 2.50-2.62 (m, 2H), 3.33 (bm, 1H), 3.73 (q, 1H), 3.83 (s, 3H), 3.90 (dd, 1H), 4.18 (dd, 1H), 4.35 (bs, 1H), 6.43 (m, 2H), 6.59 (t, 1H), 7.20-7.40 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[C:20]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)=[O:21]>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[C:20]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: c1ccncc1
Product: O=C(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
4-Bromo-benzenesulfonyl chloride 27.5 g (107 mmol) was dissolved in 180 ml of anhydrous pyridine. To this solution was added (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone 25 g (107 mmol). The reaction mixture was stirred under nitrogen 5 hour at 80° C. and pyridine was then evaporated under vacuum. The resulting crude material was dissolved in dichloromethane, and extracted with saturated bicarbonate solution. The combined organic layer was washed with brine dried over magnesium sulfate, filtered and concentrated, then ethyl acetate (50 mL) added to the solid, the solid was filtered, washed again with ethyl acetate, to yield a pale yellow solid: LC-MSD, m/z for C18H12BrClN2O3S [M+H]+: 452.9
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@H:10]2[O:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([NH:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@H:10]2[O:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1)(=[O:25])=[O:24]
Reactant: Nc1cccc(OC[C@@H]2CO2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1cccc(OC[C@@H]2CO2)c1
Reaction time: 0.25 h
Yield: 45 %

Procedure:
Compound 16b-S (0.4 g, 2.4 mmol) dissolved in 20 ml anhydrous DCM, and N,N-diisopropyl-N-ethylamine (0.45 ml, 2.6 mmol) was added at 0° C. After stirring for 15 minutes, methanesulfonyl chloride (0.2 ml, 2.6 mmol) was added to the reaction mixture at 0° C. After stirring overnight, the reaction mixture was extracted with water and washed with brine. The organic phase was dried and evaporated. The residue was purified with flash chromatography using ethyl acetate:DCM (30:70) solvent to give a colorless oil (45% yield).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]2)=[N:3][CH:2]=1.[N:17]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][N:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]1[C:6]2=[N:7][CH:8]=[CH:9][C:5]2=[C:4]([N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:23]([C:20]3[CH:21]=[CH:22][N:17]=[N:18][CH:19]=3)=[O:24])[CH2:14][CH2:15]2)[N:3]=[CH:2]1
Reactant: O=C(O)c1ccnnc1
Reactant: NC1CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CCN(c2nc[nH]c3nccc2-3)CC1)c1ccnnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine D2 (100 mg), 4-pyridazinecarboxylic acid (57.1 mg, 0.460 mmol), HATU (210 mg, 0.552 mmol) and HOAt (37.60 mg, 0.276 mmol) in DMF (2.3 mL) was added DIPEA (386 μL, 2.209 mmol). The reaction mixture was stirred at room temperature for 2 hours then the solvent was removed in vacuo. The crude mixture was purified by MDAP using a formic acid method to afford E13 (44 mg), 1H NMR (d6-DMSO) δ 11.70 (1H, brs), 9.55 (1H, s), 9.42 (1H, d), 8.80 (1H, d), 8.17 (1H, s), 8.0 (1H, d), 7.20 (1H, d), 6.60 (1H, d), 4.70 (2H, dt), 4.15 (1H, m), 3.25 (2H, dt), 1.90 (2H, m), 1.60 (2H, m), MS(ES+) 324 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][NH2:44])=[CH:41][CH:40]=1>CC(N(C)C)=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:44][CH2:43][C:42]2[CH:45]=[CH:46][C:39]([CH3:38])=[CH:40][CH:41]=2)=[O:15])[CH:3]=1
Reactant: CCOc1nc(C(=O)O)cc(N)c1C#N
Reactant: Cc1ccc(CN)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Product: CCOc1nc(C(=O)NCc2ccc(C)cc2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a 20 mL scintillation vial, 4-amino-5-cyano-6-ethoxy-pyridine-2-carboxylic acid (19 mg, 0.09 mmol) was dissolved in DMA (0.7 mL). Then TBTU (30 mg, 0.09 mmol) dissolved in DMA (0.7 mL) was added, followed by the addition of 4-methylbenzylamine (12 mg, 0.11 mmol, 1.2 eq.) in DMA (0.6 mL). Then TEA (9.37 mg, 0.09 mmol) dissolved in DMA (0.7 mL) was added. The reaction mixture was shaken at room temperature for 24 hours. The crude mixture was purified using reverse phase HPLC (TFA). 1H NMR (500 MHz, DMSO-D6/D2O) 1.23-1.36 (m, 3H) 2.20-2.34 (m, 3H) 4.37-4.55 (m, 4H) 7.04-7.22 (m, 4H) 8.97-9.10 (m, 1H). MS (ESI) positive ion 311 (M+H)+; negative ion 309 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]=[CH:15][C:16]([NH:18][C:19]3[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=3[C:21]([O:23]C)=[O:22])=[O:17])[CH:5]=[CH:4][C:3]1=2.C1COCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1([CH3:29])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH:14]=[CH:15][C:16]([NH:18][C:19]3[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=3[C:21]([OH:23])=[O:22])=[O:17])[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccccc1NC(=O)C=Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(C=CC(=O)Nc3ccccc3C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
540 mg (1.38 mmol) of methyl 2-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)acryloylamino]benzoate, 5 ml of THF and 5 ml of methanol are introduced into a round-bottomed flask. 5.5 ml of methanolic sodium hydroxide solution (2N) are added and the mixture is stirred at room temperature for four hours. The reaction medium is poured into water, acidified to pH 1 with hydrochloric acid and extracted with ethyl acetate, and the organic phase is separated out after settling has taken place, washed with water, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (95/5). After evaporating the solvents, 400 mg (77%) of the expected acid, with a melting point of 185-6° C., are collected.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH3:16][CH:17](O)[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>>[C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:15])=[C:7]([CH:17]([CH3:16])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: COc1ccc(C(C)O)cc1
Product: COc1ccc(C(C)c2cc(C(C)(C)C)cc(C(C)(C)C)c2O)cc1

Procedure:
Similarly, 4,6-di-t-butyl-2-(α-methyl-4-methoxybenzyl)phenol was prepared from 2,4-di-t-butylphenol and α-methyl-4-methoxybenzyl alcohol. A yellow oil (b.p. 180° at 1.0 mm Hg) which crystallized was obtained. The product was recrystallized from methanol to give colorless needles melting at room temperature (Found: C, 81.0; H, 9.45 Calc. for C23H32O2 : C, 81.1; H, 8.47%). The pmr spectrum determined as above exhibited the following: δ1.35, 9H, S; δ1.37, 9H, S; δ1.63, 3H, D (J=7 Hz); δ3.78, 3H, S; δ4.17, Q, 1H (J=7 Hz); δ4.62, 1H, S; δ6.84, 2H, D (J=8 Hz); δ7.10-7.30, 4H, M.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:16])[O:10][CH2:11][C:12]#CCO)[CH:5]=[CH:6][CH:7]=1.CN(C)C=O.C(Cl)([Cl:24])=O>C(Cl)CCl.C1C=CC=CC=1>[CH:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([NH:8][C:9]([O:10][C:11]#[C:12][Cl:24])=[O:16])[CH:5]=1
Reactant: O=C(Nc1cccc(Cl)c1)OCC#CCO
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Cl)c1)OC#CCl
Reaction time: 2 h

Procedure:
To a warm (50°) stirred solution of 4-hydroxy-2-butynyl N-(3-chlorophenyl)carbamate (59.9 g., 0.500 mole) and dimethylformamide (0.6 g) in 150 ml of EDC was added 250 ml of 12.5% phosgene in benzene over a period of about 30 minutes. The reaction mixture was heated at 50° for 4.5 more hours, then at 60° for 2 hours. Evaporation of solvent afforded a quantitative yield of technical barban.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([NH2:10])[C:6]([NH2:9])=[CH:7][CH:8]=1.[CH:11](O)=O.C([O-])(O)=O.[Na+]>Cl>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]2[N:9]=[CH:11][NH:10][C:5]=2[CH:4]=1
Reactant: O=CO
Reactant: CSc1ccc(N)c(N)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CSc1ccc2nc[nH]c2c1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
4-(Methylthio)benzene-1,2-diamine (10.7 g, 69.2 mmol) was dissolved in 230 mL of aqueous 4N HCl with stirring. Formic acid (7.85 mL, 208 mmol) was added and the reaction was refluxed for 1 h. The reaction was cooled to rt then concentrated in vacuo to a dark solid. The dark solid was dissolved In 500 mL of MeOH with stirring, NaHCO3 (51.0 g, 607 mmol) was added and the reaction was stirred for 1 h. The reaction was then filtered, and the filtrate concentrated in vacuo to a solid. The solid was stirred in 400 mL of EtOAc and heated to reflux, then filtered. The filtrate was concentrated in vacuo to a solid. The solid dissolved in 400 mL of DCM with stirring, then dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to give 11.3 g (99%) of the crude 6-(methylthio)-1H-benzimidazole as a dark oil. 1H NMR (400 MHz, CD3OD) δ 8.12 (s, 1H), 7.52 (m, 2H), 7.24 (m, 1H), 2.50 (s, 3H). MS m/z 165 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH2:15])[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][N:10]=2)[CH:5]=[C:4]([CH3:19])[N:3]=1.[H-].[Na+].[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:24]=1[C:25](Cl)=[O:26]>CN(C)C=O>[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:24]=1[C:25]([NH:15][C:13]1[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][N:10]=[C:9]([NH:8][C:6]2[CH:5]=[C:4]([CH3:19])[N:3]=[C:2]([CH3:1])[N:7]=2)[CH:14]=1)=[O:26]
Reactant: Cc1cc(Nc2cc(N)c([N+](=O)[O-])cn2)nc(C)n1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Nc2cc(NC(=O)c3c(Cl)cccc3Cl)c([N+](=O)[O-])cn2)nc(C)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.4 %

Procedure:
To a cooled (0° C.) solution of N-(2,6-dimethylpyrimidin-4-yl)-5-nitropyridine-2,4-diamine (0.348 g, 1.337 mmol) in anhydrous N,N-dimethylformamide (10 mL) under nitrogen was added sodium hydride (0.064 g, 2.67 mmol, 60% dispersion in mineral oil) in one portion. The reaction mixture was stirred at 0° C. for 15 mins and then a solution of 2,6-dichlorobenzoyl chloride (220 uL, 1.5 mmol) in DMF (1.5 mL) was added dropwise. The mixture was stirred at room temperature for 3.5 hours and then quenched with water (60 mL). The mixture was extracted with ethyl acetate (200 mL). The organic layer was dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (20-80% ethyl acetate/heptane) to give 2,6-dichloro-N-(2-(2,6-dimethylpyrimidin-4-ylamino)-5-nitropyridine-4-yl)benzoamide (0.57 g, yield: 100%). LCMS (ESI) m/z: 433.1 [M+H+].
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][Si:5]1([CH3:19])[O:12][Si:11]([CH3:14])([CH3:13])[O:10][Si:9]([CH3:16])([CH3:15])[O:8][Si:7]([CH3:18])([CH3:17])[O:6]1.C(N(CC)CC)C.[F:27][C:28]([C:73]([F:76])([F:75])[F:74])([O:32][C:33]([F:72])([F:71])[C:34]([F:70])([C:66]([F:69])([F:68])[F:67])[O:35][C:36]([F:65])([F:64])[C:37]([F:63])([C:59]([F:62])([F:61])[F:60])[O:38][C:39]([F:58])([F:57])[C:40]([F:56])([C:52]([F:55])([F:54])[F:53])[O:41][C:42]([F:51])([F:50])[C:43]([F:49])([F:48])[C:44]([F:47])([F:46])[F:45])[C:29](F)=[O:30]>>[F:27][C:28]([C:73]([F:74])([F:75])[F:76])([O:32][C:33]([F:71])([F:72])[C:34]([F:70])([C:66]([F:67])([F:68])[F:69])[O:35][C:36]([F:64])([F:65])[C:37]([F:63])([C:59]([F:62])([F:61])[F:60])[O:38][C:39]([F:57])([F:58])[C:40]([F:56])([C:52]([F:55])([F:54])[F:53])[O:41][C:42]([F:51])([F:50])[C:43]([F:49])([F:48])[C:44]([F:47])([F:46])[F:45])[C:29]([O:1][CH2:2][CH2:3][CH2:4][Si:5]1([CH3:19])[O:12][Si:11]([CH3:14])([CH3:13])[O:10][Si:9]([CH3:16])([CH3:15])[O:8][Si:7]([CH3:18])([CH3:17])[O:6]1)=[O:30]
Reactant: C[Si]1(C)O[Si](C)(C)O[Si](C)(CCCO)O[Si](C)(C)O1
Reactant: O=C(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: C[Si]1(C)O[Si](C)(C)O[Si](C)(CCCOC(=O)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F)O[Si](C)(C)O1
Yield: 71.8 %

Procedure:
A 50 mL round bottom flask equipped with a magnetic stirring bar and an addition funnel was charged with 6.2 g of 98% (3-hydroxypropyl)heptamethylcyclotetrasiloxane (18 mmoles) and 1.8 g of triethylamine (18 mmoles). The mixture was stirred and 15.0 g of 95% perfluoro-2,5,8,11-tetramethyl-3,6,9,12-tetraoxapentadecanoyl fluoride (17 mmoles) was added dropwise. After complete addition of the acid fluoride a gas chromatographic analysis indicated that essentially all of the acid fluoride and most of the cyclosiloxane were consumed with predominately the formation of one product. A 25 mL portion of dilute hydrochloric acid was added to the flask and the two phase mixture was transferred into a separatory funnel and the aqueous layer was separated from the siloxane layer. The siloxane layer was washed with two 25 mL portions of water and the siloxane layer was transferred into a 50 mL round bottom flask and distilled at 118°-28° C. and 0.05 mmHg to yield a fraction of 14.0 g (71% yield) of 99% [3-(perfluoro-2,5,8,11-tetramethyl-3,6,9,12-tetraoxapentadecan-oyl)oxypropyl]heptamethylcyclotetrasiloxane (12.2 mmoles), which corresponds to formula (I) wherein m is 1, n is 3, X is OC(O), and RF is given by formula (II) wherein p is 4, or more specifically as shown in formula (VII) wherein p=4. The product was analyzed by spectroscopy with the following results:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[N:20]=[N:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[O:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:21]([C:18]2[N:19]=[N:20][C:15]([O:14][CH2:13][C:12]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=[N:10][C:11]=3[CH3:24])=[CH:16][CH:17]=2)=[O:23])[CH2:27][CH2:28]1
Reactant: NC1CCOCC1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)nn1
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC2CCOCC2)nn1
Yield: 81 %

Procedure:
As described for example 75b, 6-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyridazine-3-carboxylic acid (85 mg, 0.26 mmol), was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (86 mg, 81%) which was obtained as a white solid. MS: m/e=413.3 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.Br[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][O:18][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: OCCc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)OCCc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Sodium hydride (0.8 g., 80% w/w dispersion in mineral oil) was added to a stirred solution of 2-[4-(4-chlorophenyl)phenyl]-ethanol (5.0 g.) in dimethylformamide (20 ml.). The mixture was stirred at room temperature under nitrogen for 5 hours. Ethyl 2-bromopropionate (3 ml.) was then added and the mixture was stirred at room temperature. After 18 hours the mixture was partitioned between ethyl acetate (100 ml.) and 4-N-hydrochloric acid (100 ml.). The organic phase was separated, washed with water (30 ml.), and evaporated to give ethyl 2-{2-[4-(4-chlorophenyl)phenyl]ethoxy}propionate as an oil (7.0 g.).
Reaction SMILES: [C:1]([CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=O)(=O)[CH3:2].Cl.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][NH2:25])=[CH:20][CH:19]=1>C(O)C.O>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:5]3[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[CH2:12][CH2:13][C:4]=3[C:1]([CH3:2])=[N:25]2)=[CH:20][CH:19]=1
Reactant: CC(=O)C1CCc2ccccc2C1=O
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(-n2nc(C)c3c2-c2ccccc2CC3)cc1
Temperature: 80 °C

Procedure:
To a solution of 2-acetyl-1-tetralone (329 mg, 1.75 mmol) in ethanol (12 mL) was added 4-methoxyphenyl hydrazine hydrochloride. The stirred suspension was heated to 80° C. overnight. The reaction was cooled to room temperature and diluted with water (100 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water, 10% NaOH, 10% HCl, brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue purified on silica gel using a 5% EtOAc to 25% EtOAc in hexane gradient (yield 396 mg). LC-MS (C19H18N2O calculated 290) m/z 291 (M+H).
Reaction SMILES: O.[CH2:2]([N:4]([CH2:20][CH3:21])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=1[O:18][CH3:19])=[O:6])[CH3:3]>[Fe].C(O)(=O)C>[CH2:20]([N:4]([CH2:2][CH3:3])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=1[O:18][CH3:19])=[O:6])[CH3:21]
Reactant: CCN(CC)C(=O)CNc1cc([N+](=O)[O-])ccc1OC
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CCN(CC)C(=O)CNc1cc(N)ccc1OC
Temperature: 90 °C

Procedure:
Into 120 ml of water, one adds 28 g of iron powder and 10 ml of acetic acid. The mixture is brought to a temperature of 85° C. under agitation. Then one adds, little by little, 0.1 mol (28 g) of 2-diethylcarbamylmethylamino-4-nitro anisole. The reaction medium is maintained for 10 minutes at a temperature of 90° C. Then one adds 14 ml of 10 N. soda solution. It is filtered boiling on a heated filter. By cooling the filtrate the expected product crystallizes. After recrystallization in water and vacuum drying it melts at 111° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][NH:25][CH3:26])[CH2:20][CH2:19]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C@H:18]2[CH2:19][CH2:20][C@H:21]([CH2:24][NH:25][CH3:26])[CH2:22][CH2:23]2)=[CH:3][C:2]([C:32]2[CH:33]=[C:28]([Cl:27])[C:29]([OH:44])=[C:30]([Cl:43])[CH:31]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CNC[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CNC[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)CC1
Temperature: 80 °C

Procedure:
To a suspension of (6-bromo-4-((trans-4-((methylamino)methyl)cyclohexyl)amino)quinolin-3-yl)(cyclopropyl)methanone (42 mg, 0.10 mmol), 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.15 mmol) and Pd(dppf)Cl2 (11 mg, 0.015 mmol) in dioxane (4 mL) was added Cs2CO3 (1.0 M in H2O, 0.4 mL, 0.4 mmol). N2 gas was bubbled through the reaction mixture and the mixture was then heated at 80° C. for 2 h. The solution was allowed to cool to room temperature, diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The resultant residue was purified by preparative HPLC (C18 silica, 10-90% methanol/water with 0.05% TFA). The residue was eluted through an ion-exchange column (using methanol and 7 N methanol in ammonia) to obtain the desired product (14.7 mg, 29%) as a yellow solid. 1H NMR (500 MHz, MeOD+TFA-d) δ 9.35 (br s, 1H), 8.47 (br s, 1H), 8.27 (dd, J=8.8, 1.8 Hz, 1H), 7.98 (d, J=8.7 Hz, 1H), 7.74 (s, 2H), 4.52 (br s, 1H), 2.94 (d, J=6.9 Hz, 2H), 2.83 (br s, 2H), 2.73 (s, 3H), 2.46-2.42 (br s, 2H), 2.05 (d, J=13.0 Hz, 2H), 1.88 (br s, 1H), 1.77-1.68 (m, 2H), 1.36-1.19 (m, 6H). ESI MS m/z 498 [C27H29Cl2N3O2+H]+; HPLC>99% (AUC), tR=11.08 min.