Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=2[N:12]2[C:20]([CH2:23][CH3:24])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.Cl.C(=O)([O-])[OH:27].[Na+].[Cl:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[Cl:41])[C:35](Cl)=[O:36]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:14]1[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=1[N:12]1[C:20]([CH2:23][CH3:24])=[N:21][N:22]=[C:11]1[CH2:10][NH:9][C:35](=[O:36])[C:34]1[CH:38]=[CH:39][C:40]([Cl:41])=[C:32]([Cl:31])[CH:33]=1)=[O:27]
Reactant: CCc1cc2c(s1)-n1c(CC)nnc1CN=C2c1ccccc1Cl
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(CC)nnc2CNC(=O)c2ccc(Cl)c(Cl)c2)s1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4-(2-Chlorophenyl)-2,9-diethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine (1.8 g) was added to 2.5% hydrochloric acid (35 ml), and the mixture was stirred at 60° C. overnight. Then, sodium hydrogencarbonate was added to the reaction mixture to make the mixture alkaline. Chloroform (40 ml) and 3,4-dichlorobenzoyl chloride (1.15 g) were added, and the mixture was stirred at room temperature for 2 hours. Then, the organic layer was washed with an aqueous citric acid solution and saturated brine, and dried over magnesium sulfate. After the solvent was evaporated, the residue was purified by silica gel column chromatography (developing solvent:ethyl acetate) and recrystallized from ethyl acetate to give 0.73 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-ethyl[1,2,4]triazol-3-ylmethyl)-3,4-dichlorobenzamide.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Br:9]Br>>[BrH:9].[Br:9][C:7]1[CH:6]=[CH:5][C:3]([NH2:4])=[C:2]([F:1])[CH:8]=1
Reactant: BrBr
Reactant: Nc1ccccc1F
Product: Br
Product: Nc1ccc(Br)cc1F

Procedure:
adding 2-fluoroaniline to a mixture of bromine and quaternary ammonium bromide in an inert solvent to produce 4-bromo-2-fluoroaniline hydrobromide salt as a precipitate in a mother liquor;
Reaction SMILES: [F:1][N:2]([F:26])C1(N(F)F)CN([N+]([O-])=O)CC([N+]([O-])=O)([N+]([O-])=O)CN([N+]([O-])=O)C1.[N+:27]([C:30]1([N+:63]([O-:65])=[O:64])[CH2:37][N:36]([S:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[N+:47]([O-:49])=[O:48])(=[O:40])=[O:39])[CH2:35][C:34](=O)[CH2:33][N:32]([S:51]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[N+:60]([O-:62])=[O:61])(=[O:53])=[O:52])[CH2:31]1)([O-:29])=[O:28].[NH:66]([F:68])[F:67]>>[F:1][N:2]([F:26])[C:34]1([N:66]([F:68])[F:67])[CH2:35][N:36]([S:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[N+:47]([O-:49])=[O:48])(=[O:40])=[O:39])[CH2:37][C:30]([N+:63]([O-:65])=[O:64])([N+:27]([O-:29])=[O:28])[CH2:31][N:32]([S:51]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[N+:60]([O-:62])=[O:61])(=[O:53])=[O:52])[CH2:33]1
Reactant: FNF
Reactant: O=C1CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC([N+](=O)[O-])([N+](=O)[O-])CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])C1
Reactant: O=[N+]([O-])N1CC(N(F)F)(N(F)F)CN([N+](=O)[O-])CC([N+](=O)[O-])([N+](=O)[O-])C1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CC(N(F)F)(N(F)F)CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC([N+](=O)[O-])([N+](=O)[O-])C1

Procedure:
In a preferred embodiment of the present invention, the method of making a 3,3-bis(difluoramino)octahydro-1,5,7,7-tetranitro-1,5-diazocine comprises reacting a hexahydro-7,7-dinitro-1,5-bis(nitrobenzenesulfonyl)-1,5-diazocin-3(2H)-one with a difluoramine source to produce a 3,3-bis(difluoramino)octahydro-7,7-dinitro-1,5-bis(nitrobenzenesulfonyl)-1,5-diazocine and reacting said 3,3-bis(difluoramino)octahydro-7,7-dinitro-1,5-bis(nitrobenzenesulfonyl)-1,5-diazocine with a highly reactive nitrating reagent in the presence of a strong Lewis acid, such as antimony pentafluoride, boron triflate or boron fluorosulfonate.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:17](=[O:18])[C:16]3[S:19][C:20]([CH2:22][OH:23])=[CH:21][C:15]=3[N:14]=[CH:13]2)=[CH:8][CH:7]=1.Br[CH2:26][CH:27]1[CH2:30][CH2:29][CH2:28]1>>[CH:27]1([CH2:26][O:23][CH2:22][C:20]2[S:19][C:16]3[C:17](=[O:18])[N:12]([C:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:24])[CH3:1])=[CH:7][CH:8]=4)[CH:13]=[N:14][C:15]=3[CH:21]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: BrCC1CCC1
Reactant: CN(C)CCOc1ccc(-n2cnc3cc(CO)sc3c2=O)cc1
Product: CN(C)CCOc1ccc(-n2cnc3cc(COCC4CCC4)sc3c2=O)cc1

Procedure:
3-[4-(2-Dimethylaminoethoxy)phenyl]-6-hydroxymethyl-3H-thieno[3,2-d]pyrimidin-4-one was reacted with (bromomethyl)cyclobutane by method V. The product with the molecular weight of 413.54 (C22H27N3O3S) was obtained in this way; MS (ESI): 414 (M+H+).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]([F:27])([F:26])[C:7]([N:9]1[CH2:16][CH2:15][C@:14]2([CH3:20])[C:17]([CH3:19])([CH3:18])[C@H:10]1[CH2:11][C:12]1[C:24]([OH:25])=[CH:23][CH:22]=[CH:21][C:13]=12)=[O:8]>C(O)(=O)C>[F:27][C:6]([F:5])([F:26])[C:7]([N:9]1[CH2:16][CH2:15][C@:14]2([CH3:20])[C:17]([CH3:19])([CH3:18])[C@H:10]1[CH2:11][C:12]1[C:24]([OH:25])=[C:23]([N+:1]([O-:4])=[O:2])[CH:22]=[CH:21][C:13]=12)=[O:8]
Reactant: O=[N+]([O-])O
Reactant: CC1(C)[C@H]2Cc3c(O)cccc3[C@]1(C)CCN2C(=O)C(F)(F)F
Solvent: CC(=O)O
Product: CC1(C)[C@H]2Cc3c(ccc([N+](=O)[O-])c3O)[C@]1(C)CCN2C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Nitric acid (0.4 mL) is slowly added to a solution of 2,2,2-trifluoro-1-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone (2.9 g) in acetic acid (5 mL) chilled in an ice bath. The ice bath is removed and the solution is stirred at ambient temperature overnight. The solution is poured into ice-cold water and the resulting mixture is extracted with ethyl acetate. The combined extracts are washed with brine and dried (Na2SO4). After removal of the solvent under reduced pressure, the residue is purified by chromatography on silica gel (ethyl acetate/cyclohexane 1:9->1:3).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](OCC)=[O:29])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C1COCC1.[CH3:38][NH2:39]>O>[CH3:38][NH:39][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=[C:4]1[CH2:1][CH2:2][CH3:3]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCCCCCCCCC(=O)OCC
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CCCc1nc2cnc3ccccc3c2n1CCCCCCCCCCCC(=O)NC
Temperature: 80 °C

Procedure:
A mixture of ethyl 12-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)dodecanoate (4.0 g, 9.1 mmol), THF (5 mL), and methylamine (available as a 40% solution in water, 8 mL) was sealed in a high-pressure vessel and heated at 80° C. overnight. The solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane. The resulting solution was washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 3.8 g of N-methyl-12-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)dodecanamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([NH:16][C:17]2[N:22]=[C:21](SC#N)[C:20]([N+:26]([O-:28])=[O:27])=[CH:19][N:18]=2)[CH:3]=1.Cl.[F:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:40]=1[O:39][CH2:38][CH2:37][C@H:36]2[NH2:41].C(N(CC)C(C)C)(C)C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[C:4]([NH:16][C:17]2[N:22]=[C:21]([NH:41][C@H:36]3[C:35]4[C:40](=[C:31]([F:30])[CH:32]=[CH:33][CH:34]=4)[O:39][CH2:38][CH2:37]3)[C:20]([N+:26]([O-:28])=[O:27])=[CH:19][N:18]=2)[CH:3]=1
Reactant: N[C@@H]1CCOc2c(F)cccc21
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(SC#N)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(N[C@@H]2CCOc3c(F)cccc32)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94 %

Procedure:
tert-Butyl 4-fluoro-2-(5-nitro-4-thiocyanatopyrimidin-2-ylamino)phenylcarbamate (2.0 g) was added to a solution of (R)-8-fluorochroman-4-amine hydrochloride (1.1 gram) and N,N-diisopropylethylamine (2.2 mL) in THF (anhydrous, 50 mL). The mixture was stirred for 6 hr at room temperature then partitioned between water and EtOAc and separated. The aq. layer was washed with additional EtOAc and the combined organics were dried over Na2SO4 and concentrated in vacuo to give the title product in 94% yield. MH+=515, 459 (-tBu).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][O:8][CH2:9][CH2:10][C:11]12[CH2:18][CH2:17][C:14]([C:19]3[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=3)([CH2:15][CH2:16]1)[O:13][CH2:12]2)([CH3:4])([CH3:3])[CH3:2].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:29]([C:21]1[CH:20]=[C:19]([C:14]23[CH2:17][CH2:18][C:11]([CH2:10][CH2:9][O:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])([CH2:16][CH2:15]2)[CH2:12][O:13]3)[CH:24]=[CH:23][CH:22]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(B(O)O)c3)(CC1)OC2
Reactant: BrCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(Cc4ccccc4)c3)(CC1)OC2
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of (3-(4-(2-(2-(tert-butoxy)-2-oxoethoxy)ethyl)-2-oxabicyclo[2.2.2]octan-1-yl)phenyl)boronic acid (49A; 20 mg, 0.051 mmol), benzyl bromide (0.012 mL, 0.102 mmol), and Na2CO3 (16 mg, 0.15 mmol) in 1,4-dioxane (1 mL)/water (0.2 mL) was degassed under Ar for 3 min using an ultrasonicator and then (Ph3P)4Pd (59 mg, 0.051 mmol) was added. The reaction was stirred at 100° C. under Ar for 18 h, then was cooled to rt and partitioned between EtOAc (5 mL) and water, dried (MgSO4), and concentrated in vacuo to give the crude product as a yellow oil, which was used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][CH:31]1[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNC3CCNCC3)ccc21
Yield: 194.3 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (34.5 mg, 0.0840 mmol) was dissolved in acetonitrile (1 mL), and the solution was treated with 4-amino-1-(tert-butoxycarbonyl)piperidine (70.1 mg, 0.350 mmol), acetic acid (0.100 mL, 1.74 mmol) and sodium triacetoxyborohydride (44.0 mg, 0.208 mmol). The reaction mixture was added with water and sodium carbonate to adjust the pH to 9. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(piperidin-4-ylaminomethyl)indol-2-yl]isoindolinone (80.8 mg).
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[F:11][C:12]1[C:13]([NH2:22])=[C:14]([NH2:21])[C:15]([F:20])=[C:16]([F:19])[C:17]=1[F:18]>>[F:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[C:15]([F:20])=[C:14]2[C:13]=1[NH:22][C:2](=[O:4])[C:1](=[O:8])[NH:21]2
Reactant: Nc1c(N)c(F)c(F)c(F)c1F
Reactant: CCOC(=O)C(=O)OCC
Product: O=c1[nH]c2c(F)c(F)c(F)c(F)c2[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound (Allison, et al., J. Fluorine Chem. 1:59 (1971)) was prepared using an adaptation of the method of Cheeseman (Cheeseman, G. W. H., J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (2.86 mL, 4.1 mmol) and 3,4,5,6-tetrafluoro-1,2-diaminobenzene (380 mg, 2.11 mmol) was heated to reflux with stirring under N2 for 8 h. The reaction was cooled to room temperature and a small amount of purple precipitate was observed. The excess diethyl oxalate was evaporated and the resulting solid was suspended in 20 ml hexanes, vacuum filtered and the solid rinsed with hexanes (20 mL) and ethyl acetate (10 mL). The solid was air dried to yield 244.8 mg (49.9%). mp 330°-331° C. (lit. ca. 300° C. dec.). 1H NMR (d6 -DMSO) δ12.33 (br s, NH). 19F NMR (C6F6 external standard, δ-162.9), δ-157.7(m), -167.9(m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=1[F:33])=[O:24])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([O:17]C)=[O:16])[S:14][C:7]=12.[OH-].[Na+].Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=1[F:33])=[O:24])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([OH:17])=[O:16])[S:14][C:7]=12
Reactant: COC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)c2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)O)sc34)cc2F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 7-(3-fluoro-4-(3-(2-fluoro-5-methylphenyl)ureido)phenoxy)thieno[3,2-b]pyridine-2-carboxylate (1.84 g, 3.92 mmol) was taken up in 100 mL THF followed by the dropwise addition of 1N sodium hydroxide (4.8 mL, 4.8 mmol). The solution was stirred at room temperature for 3 hours, at which time an additional 2.4 mL of 1N sodium hydroxide was added. The solution was stirred at room temperature for overnight and the resulting mixture was diluted with 75 mL of water and acidified using 1N HCl. The insoluble material was separated by filtration and the filter cake was suspended in ethyl acetate and stirred for several minutes before filtering. The filter cake was washed several times with ethyl acetate and dried under high vacuum to give 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid as an off white solid. Yield: 1.6 g (90%); MS [M+H]+456.1; 1HNMR (DMSO-d6) δ: 13.9 (bs, 1H), 9.2 (s, 1H), 9.0 (s, 1H), 8.6 (d, 1H), 8.3 (t, 1H), 8.1 (s, 1H), 8.0 (d, 1H), 7.5 (d, 1H), 7.2 (m, 2H), 6.8 (m, 2H), 2.1 (s, 3H) ppm.
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH2:3][CH3:4].[H-].[Na+].[H][H].Cl[CH2:18][N:19]1[C:23]([Cl:24])=[C:22]([Cl:25])[N:21]=[CH:20]1>CN(C)C=O>[CH3:1][CH:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:18][N:19]2[C:23]([Cl:24])=[C:22]([Cl:25])[N:21]=[CH:20]2)=[CH:10][CH:11]=1)[CH2:3][CH3:4]
Reactant: [H][H]
Reactant: ClCn1cnc(Cl)c1Cl
Reactant: CCC(C)Oc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C)Oc1ccc(OCn2cnc(Cl)c2Cl)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
Under a nitrogen blanket and at room temperature (about 20° C.), 5.0 g of 4-(1-methyl-1-propyloxy)-phenol in 20 ml of anhydrous dimethylformamide is dripped into 0.79 g of 80% strength sodium hydride in 50 ml of anhydrous dimethylformamide. After the exothermic reaction has subsided (evolution of hydrogen), the mixture is stirred for a further 30 minutes at 60° C. Subsequently, 6.12 g of 1-chloromethyl-4,5-dichloroimidazole in 20 ml of anhydrous dimethylformamide is dripped in at room temperature. The whole is poured into 150 ml of ice water, followed by extraction three times with ethyl acetate. The organic phases are washed with 5% strength sodium hydroxide solution and with water. Drying over sodium sulfate and concentration under reduced pressure gives a crude product which is purified by chromatography on silica gel using toluene/ethyl acetate (9:1) as eluant. There is obtained 4.3 g of 1-[4-(1-methyl-1-propyloxy)-phenoxymethyl]-4,5-dichloroimidazole; nD22 =1.5475.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:30])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=O)[NH2:28])[CH:22]=1.COC(OC)[N:34]([CH3:36])C.C[N:40](C=O)C>>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:30])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[NH:34][CH:36]=[N:40][N:28]=2)[CH:22]=1
Reactant: CN(C)C=O
Reactant: COC(OC)N(C)C
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(C(N)=O)c2)c1N
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(-c3nnc[nH]3)c2)c1N
Temperature: 80 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a stirred solution of 3-[5-amino-4-(3-carbamoyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide (120 mg) in DMF (2 mL), was added N,N-dimethylformamide dimethyl acetal (5 ml) and the solution was stirred at 80° C. overnight. The solvent was removed, residue was dissolved in AcOH (5 ml), hydrazine monohydrate (3 ml) was added and the mixture stirred at 90° C. overnight. The solution was acidified with hydrochloric acid to pH - land stirred at 80° C. overnight. The solvent was removed and the residue was resuspended in EtOAc, then washed by aqueous K2CO3 solution, water, and brine, and concentrated. The crude product was purified by column chromatography on silica gel eluted with EtOAc to provide product as a white solid (65 mg, 51%). HPLC (4 minute 10-90 gradient) tR 1.58 min; MS m/z 428.18 [M+H]+.
Reaction SMILES: C([Si]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[F:17])(C)C)(C)(C)C.CN(C)CCN(C)CCN(C)C.C([Li])CCC.CN(C)[CH:37]=[O:38]>O1CCCC1.CCCCCCC.O>[F:17][C:10]1[C:9]([OH:8])=[CH:14][C:13]([O:15][CH3:16])=[CH:12][C:11]=1[CH:37]=[O:38]
Reactant: COc1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: COc1cc(O)c(F)c(C=O)c1
Temperature: -72 °C
Reaction time: 3 h
Yield: 80.8 %

Procedure:
To a flask, tert-butyl(2-fluoro-5-methoxyphenoxy)dimethylsilane (6.00 g, 23 mmol), N,N,N′,N″,N″-pentamethyldiethylenetriamine (4.87 g, 28 mmol), and tetrahydrofuran (48.0 mL) were added, and the resulting mixture was cooled to −72° C. under nitrogen atmosphere. To the solution, n-butyllithium (10.2 mL, 28 mmol, 2.76 M, in hexane) was added dropwise, and the resulting mixture was stirred at −56° C. for 3 hours. To the solution, a solution of N,N-dimethylformamide (3.42 g, 47 mmol) in tetrahydrofuran (6.0 mL) was added, and the resulting mixture was warmed to 10° C., after which water was added thereto, and the two-layer reaction solution was stirred overnight at room temperature. Heptane was added to the reaction mixture, and the aqueous layer was collected. Toluene was added to the aqueous layer. To the resulting mixture, 5 N hydrochloric acid was added to adjust the pH to 2, and the resulting mixture was extracted. The organic layer was washed with water and concentrated under reduced pressure, after which a mixture of toluene and ethyl acetate was added to the resulting concentration residue, and the resulting mixture was purified by suspension. The purified product obtained was filtered and dried to obtain the captioned compound (3.16 g) as a light brown solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:19][C:20]([C@@H:22](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](=[O:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C@@:23]([OH:34])([CH2:31][CH2:32][OH:33])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[C:52](OC(=O)C)(=[O:54])[CH3:53].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>ClCCl>[C:52]([O:33][CH2:32][CH2:31][C@:23]([OH:34])([C@@H:22]([C:20](=[O:21])[NH:19][C@H:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:11][CH:10]=1)/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](=[O:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])(=[O:54])[CH3:53]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)OC(C)(C)C)C(=O)OCC)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCOC(C)=O)C(=O)OC(C)(C)C)C(=O)OCC)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
tert-Butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-ethoxycarbonyl-ethylcarbamoyl]-2-hydroxy-2-(2-hydroxy-ethyl)-12-oxo-nonadec-4-enoate (3.22 g, 4.51 mmol) was dissolved in dichloromethane (64 mL), and the mixture was then cooled to 0° C. in an ice bath. Acetic anhydride (1.07 mL, 11.3 mmol), triethylamine (0.63 mL, 4.52 mmol), and dimethylaminopyridine (55.1 mg, 0.451 mmol) were added in this order, and the mixture was then stirred at 0° C. for 1.5 hours. The mixture was quenched with water (46 mL), and then extracted with dichloromethane (46 mL). The organic layer was washed with a saturated aqueous solution (33 mL) of sodium chloride, then dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure. The residue was purified on Biotage (silica gel, n-hexane/ethyl acetate) to obtain 2.65 g (3.51 mmol, 78% yield) of No. 5328456.
Reaction SMILES: C(N)C1C=CC=CC=1.[CH:9]([NH:11][C:12]([CH2:30][CH2:31][CH3:32])([CH2:27][CH2:28][CH3:29])[C:13]1[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)=O>>[CH2:30]([C:12]([NH:11][CH3:9])([CH2:27][CH3:28])[C:13]1[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[CH3:31].[CH3:9][NH:11][C:12]([CH2:30][CH2:31][CH3:32])([CH2:27][CH2:28][CH3:29])[C:13]1[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1
Reactant: CCCC(CCC)(NC=O)c1ccc(C#Cc2ccccc2)cc1
Solvent: NCc1ccccc1
Product: CCC(CC)(NC)c1ccc(C#Cc2ccccc2)cc1
Product: CCCC(CCC)(NC)c1ccc(C#Cc2ccccc2)cc1

Procedure:
When the above experiment is repeated using as alternate starting materials either N-formyl-α,α-diethyl- 4-phenylethynyl)-benzylamine of N-formyl-α,α-di(n-propyl)- 4-(phenylethynyl)-benzylamine there is obtained respectively α,α-diethyl-N-methyl-4-(phenylethynyl)-benzylamine or N-methyl-α ,α-di(n-propyl)-4-phenylethynyl benzylamine.