Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:33]4[CH2:36][C:35]([F:38])([F:37])[CH2:34]4)[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:33]4[CH2:36][C:35]([F:37])([F:38])[CH2:34]4)[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCCN4CC(F)(F)C4)c4ccc(OC(F)F)cc34)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CCCN4CC(F)(F)C4)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.7 %

Procedure:
To a pale yellow solution of N-tert-butyl-2-(1-(3-(3,3-difluoroazetidin-1-yl)propyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (38 mg, 57.2 μmol) in dichloromethane (4.00 mL) was added TFA (1.48 g, 1.00 mL, 13.0 mmol27), the reaction mixture turned orange and was stirred at 25° C. for 18 h, mixture concentrated and the residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1) and stirred at 25° C. for 1 h, then evaporated to a yellow solid, which was dissolved in dichloromethane and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. The pure product dissolved in dichloromethane and cyclohexane added to allow solid formation, off-white solid was separated by decantation and dried under high vacuum to give N-tert-butyl-2-(1-(3-(3,3-difluoroazetidin-1-yl)propyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (29.5 mg, 55.3 μmol, 96.6%). MS (M+H)+=534; 1H NMR (DMSO-d6) δ: 9.07 (s, 1H), 8.37 (s, 1H), 8.19 (s, 1H), 7.81-7.96 (m, 2H), 7.40 (d, J=8.3 Hz, 1H), 7.19 (t, J=74.4 Hz, 1H), 4.56 (br. s., 2H), 3.56 (t, J=12.5 Hz, 4H), 2.54 (br. s., 2H), 1.95 (m, J=6.2 Hz, 2H), 1.49 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][C:3]1=[O:8].CC(C)([O-])C.[K+].[N:15](OCC(C)C)=[O:16].Cl>O1CCCC1.C(O)C>[N:15](=[C:4]1[C:3](=[O:8])[N:2]([CH3:1])[CH2:7][CH2:6][O:5]1)[OH:16]
Reactant: CC(C)CON=O
Reactant: CN1CCOCC1=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Product: CN1CCOC(=NO)C1=O

Procedure:
While maintaining the temperature near -55°, a solution of 11.5 grams of 4-methyltetrahydro-1,4-oxazin-3-one dissolved in 100 ml of anhydrous tetrahydrofuran was added over a period of twenty minutes to a slurry of 14.6 grams of potassium t-butoxide in 100 ml of tetrahydrofuran vigorously stirring under a nitrogen atmosphere. After equilibrating the resultant mixture for 30 minutes at -60°, a solution of 11.4 grams of isobutyl nitrite in 50 ml of tetrahydrofuran was added over 15 minutes while maintaining the temperature at -60° with external cooling. After a 15-minute equilibration at -60°, the reaction mixture was brought to 25° and stirred for 3 hours. The solution was then cooled to 0° and neutralized to pH 5 with 65 ml of a solution of 18 ml of conc. hydrochloric acid diluted to 100 mls. with absolute ethanol. After a 15-minute equilibration, potassium chloride was filtered off and the solvent removed in vacuuo. The resulting oil was triturated with 50 ml of ethyl acetate and the resulting solid was collected and then recrystallized from 150 ml. of acetonitrile yielding 5.07 g of the oxime product, mp. 199°-201°.
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][C:20]4[CH:39]=[CH:38][C:23]([O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]5[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=5)[C:32](O)=[O:33])=[CH:22][CH:21]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[CH:41]([NH2:44])([CH3:43])[CH3:42].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1([CH3:40])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][C:20]4[CH:39]=[CH:38][C:23]([O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]5[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=5)[C:32]([NH:44][CH:41]([CH3:43])[CH3:42])=[O:33])=[CH:22][CH:21]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CC(C)N
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(C(=O)O)c5)cc4)C(=O)O3)ccc2O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cccc(COCCOc2ccc(CCN3C[C@@H](c4ccc5c(c4)COC(C)(C)O5)OC3=O)cc2)c1
Reaction time: 8 h
Yield: 115.9 %

Procedure:
A solution of 3-{[2-(4-{2-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethoxy]methyl}benzoic acid (90 mg) and isopropyl amine (9.7 mg) in DMF (2 ml) was cooled to 0° C. and treated with diisopropylethylamine (0.057 ml) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (62 mg). This was then stirred for 8 h before diluting in EtOAc and washing sequentially with 2M HCl, NaHCO3 (aq) and brine. The combined organic layers were then dried (MgSO4) and concentrated in vacuo to give the title compound(112 mg). LCMS RT=3.36 min.
Reaction SMILES: [CH:1]1([C:5]2[C:6]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:21][S:22]([CH2:25][C:26]([NH2:34])([CH3:33])[C:27]1[N:31]=[C:30]([CH3:32])[O:29][N:28]=1)(=[O:24])=[O:23]>>[CH3:21][S:22]([CH2:25][C:26]([NH:34][C:11]([C:8]1[CH:7]=[C:6]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])[C:5]([CH:1]2[CH2:2][CH2:3][CH2:4]2)=[CH:10][N:9]=1)=[O:13])([CH3:33])[C:27]1[N:31]=[C:30]([CH3:32])[O:29][N:28]=1)(=[O:23])=[O:24]
Reactant: Cc1nc(C(C)(N)CS(C)(=O)=O)no1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1CCC1)C(F)(F)F
Product: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(C3CCC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 23b, using 5-Cyclobutyl-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid (Example 110e) and 2-Methanesulfonyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 109d) as starting materials and isolated (77 mg, 57%) as a white solid; MS (ESI, m/z): 491.6 (M+H+).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][CH:5](OS(C)(=O)=O)[CH2:6][C:7]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH2:10][CH:9]=[CH:8]1>C1(C)C=CC=CC=1>[CH3:4][CH:5]([N:2]([CH3:3])[CH3:1])[CH2:6][C:7]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH2:10][CH:9]=[CH:8]1
Reactant: CNC
Reactant: CC(CC1(c2ccccc2)C=CCC=C1)OS(C)(=O)=O
Solvent: Cc1ccccc1
Product: CC(CC1(c2ccccc2)C=CCC=C1)N(C)C
Reaction time: 16 h

Procedure:
1.1 ml. (about 3 equivalents) of condensed dimethylamine are added at -10° C. to 1.5 g. of methanesulfonic acid 1-methyl-2-(1-phenyl-2,5-cyclohexadien-1-yl)-ethyl ester in 5 ml. of toluene. The mixture is then held at 150° C. in a pressure vessel for 16 hours. Subsequently, the mixture is cooled down and worked-up as follows: The toluene phase is washed with water, concentrated, treated with ether and 3 N aqueous hydrochloric acid and shaken out. The aqueous extract is made basic with concentrated ammonia and extracted with ether. There is obtained an oily residue which is chromatographed on a thick-layer plate with methylene chloride/methanol (10:1). There is obtained α,N,N-trimethyl-1-phenyl-2,5-cyclohexadien-1-ethylamine which is converted in the usual manner into the hydrochloride.
Reaction SMILES: N1C2OCC(N)C=2C=CN=1.CO[N:13]=[C:14]1[C:22]2[C:17](=[N:18][C:19]([CH3:23])=[CH:20][CH:21]=2)[O:16][CH2:15]1>>[CH3:23][C:19]1[N:18]=[C:17]2[O:16][CH2:15][CH:14]([NH2:13])[C:22]2=[CH:21][CH:20]=1
Reactant: CON=C1COc2nc(C)ccc21
Agent: NC1COc2nnccc21
Product: Cc1ccc2c(n1)OCC2N

Procedure:
This compound was prepared using a method analogous to that of 5,6-dihydrofuro[2,3-c]pyridazin-5-amine (A.2.3.4), 6-methylfuro[2,3-b]pyridin-3(2H)-one O-methyl oxime replacing furo[2,3-c]pyridazin-5(6H)-one O-methyl oxime;
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](OS(C(F)(F)F)(=O)=O)=[CH:7][CH:6]=1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1B(O)O.[F-].[Cs+]>C(COC)OC>[CH:28]1[C:29]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:27]=1[C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:2])=[O:19])=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: OB(O)c1ccc2ccccc2c1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: O=C(O)Cc1ccc(-c2ccc3ccccc3c2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
Tetrakis triphenyphosphine palladium (65 mg, 7.4 mol %) was added to a dimethoxy ethane (5.4 mL) solution of (4-Trifluoromethanesulfonyloxy-phenyl)-acetic acid methyl ester (447 mg, 1.5 mmol), 2-naphthaleneboronic acid (286 mg, 1.67 mmol) and cesium fluoride (505 mg, 3.33 mmol). The reaction was flushed with nitrogen and heated in an oil bath to 100° C. while stirring for 3 hours. The reaction was then diluted with ethyl acetate and extracted with water, 1M sodium hydroxide, water and brine. The organic portion was dried over magnesium sulfate and concentrated in vacuo. The resulting residue was chromatographed on a Biotage Flash 40S column eluting with 5% ethyl acetate in hexanes to give the title compound as a clear oil (273 mg, 66%). 1H NMR (400 MHz, CDCl3) δ 8.01-7.38 (m, 11H), 3.72 (s, 3H), 3.69 (2H) E. (4-Trifluoromethanesulfonyloxy-phenyl)-acetic acid methyl ester
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[CH3:5][N:6]([CH3:25])[CH2:7][CH:8]([CH3:24])[C:9]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10][NH2:11]>O.Cl>[CH3:25][N:6]([CH3:5])[CH2:7][CH:8]([CH3:24])[C:9]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:10][NH:11][C:2]([NH2:3])=[O:1]
Reactant: N#C[O-]
Reactant: CC(CN(C)C)C(CN)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(CN(C)C)C(CNC(N)=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 120 g of potassium cyanate in 200 ml of water was added while stirring to a solution of 220 g of N4,N4 -dimethyl-2,2-diphenyl-3-methyl-1,4-butanediamine in 1000 ml of water and 200 ml of concentrated hydrochloric acid at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, filtered, and made basic with 9N sodiumhydroxide. The crystalline product was filtered and washed with water. The product was taken up in 1 liter of methanol and 200 ml water, and then 70 ml of glacial acetic acid were added. The solution was filtered, and 25% ammonium hydroxyde was added dropwise to pH=9. The product was filtered and washed successively with 500 ml methanol, 500 ml water and 500 ml methanol. The product was dried overnight in vacuo at 70° C. Yield: 204 g of pure N-(4-dimethylamino-2,2-diphenyl-3methyl-1-butyl)urea as a white powder, melting at 226°-228° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[CH:13]=[C:14]([NH:18][CH:19]([CH:28]([CH3:30])[CH3:29])[C:20]([NH:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[O:21])[CH:15]=[N:16][CH:17]=3)=[CH:10][N:9](COCC[Si](C)(C)C)[C:6]2=[N:7][CH:8]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+].C(N)CN>ClCCl>[NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[CH:13]=[C:14]([NH:18][CH:19]([CH:28]([CH3:30])[CH3:29])[C:20]([NH:22][CH2:23][C:24]([F:25])([F:26])[F:27])=[O:21])[CH:15]=[N:16][CH:17]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1
Reactant: CC(C)C(Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(CN)cc23)c1)C(=O)NCC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(Nc1cncc(-c2c[nH]c3ncc(CN)cc23)c1)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.5 %

Procedure:
To 2-(5-(5-(aminomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-ylamino)-3-methyl-N-(2,2,2-trifluoroethyl)butanamide 10-1b (211 mg, 0.364 mmol) dissolved in dichlormethane (2.0 ml) was added TFA (2.0 ml, 26.0 mmol). The reaction stirred at room temp for 1.5 hrs, concentrated and the residue dissolved in MeOH (2.0 ml). NaOH (0.255 ml, 2.55 mmol) and ethylenediamine (0.049 ml, 0.728 mmol) were added and the reaction stirred for 2 hrs at room temperature. The reaction was then acidified with trifluoroacetic acid, filtered and purified by RP-HPLC (water:acetonitrile w/0.1% TFA, C-18, 15-50%). The pure fractions concentrated to remove acetonitrile and mixture neutralized with saturated sodium bicarbonate. The product was extracted with ethyl acetate (3×10 mL). The combined organics were then washed with brine, dried with sodium sulfate, filtered and concentrated to afford the product 10-1c (140 mg, 89%).
Reaction SMILES: C(OC(=O)[N:7]([C@H:12]1[CH2:16][C@@H:15]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20]([Cl:32])=[N:21][C:22]=3[NH:26][CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[C@H:14]([OH:33])[C@@H:13]1[OH:34])[C:8](=[O:11])[CH2:9][CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:32][C:20]1[N:19]=[C:18]2[C:23]([N:24]=[CH:25][N:17]2[C@@H:15]2[CH2:16][C@H:12]([NH:7][C:8](=[O:11])[CH2:9][CH3:10])[C@@H:13]([OH:34])[C@H:14]2[OH:33])=[C:22]([NH:26][CH:27]([CH2:28][CH3:29])[CH2:30][CH3:31])[N:21]=1
Reactant: CCC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(NC(CC)CC)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NC(CC)CC)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
{(1S,2R,3S,4R)-4-[2-Chloro-6-(1-ethyl-propylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionyl-carbamic acid tert-butyl ester (300 mg, 0.59 mmol) is dissolved in DCM (5 mL). TFA (2 mL) is added and the reaction mixture is stirred at RT. The reaction is shown to be complete by LCMS after 1 hour. The solvent is removed in vacuo and the residue is partitioned between DCM (50 mL) and saturated NaHCO3 (50 mL). The organic layer is washed with water (20 mL) and brine (20 mL), dried over MgSO4, filtered and the solvent is removed in vacuo to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].O[CH2:11][CH2:12][C@H:13]([N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[O:9][CH2:11][CH2:12][C@H:13]([N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])[CH3:14]
Reactant: Oc1c(Cl)cccc1Cl
Reactant: C[C@H](CCO)N1C(=O)c2ccccc2C1=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@H](CCOc1c(Cl)cccc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 302.6 %

Procedure:
To a solution of 2,6-dichlorophenol (14.9 mg, 0.091 mmol) in THF (1.5 mL) was added (R)-2-(4-hydroxybutan-2-yl)isoindoline-1,3-dione (20 mg, 0.091 mmol) and triphenylphosphine (47.9 mg, 0.182 mmol) and the reaction mixture was cooled to 0° C. in an ice/water bath. DIAD (0.035 mL, 0.182 mmol) was added drop wise and the reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was allowed to warm to rt and was stirred at rt overnight. The reaction mixture was concentrated under vacuum to yield a yellow oil that was diluted with a minimal amount of DCM, loaded onto a 12 g ISCO column and purified by ISCO. Intermediate 13A (0.1003 g, 96% yield) was isolated as a clear oil. LC-MS (ESI) 365 (M+H), RT=2.84 min (Method A). NMR indicated that the final product contained reduced DIAD.
Reaction SMILES: [OH-].[Na+].[CH:3]1[CH2:7][CH:6]=[CH:5][CH:4]=1.[CH2:8](Br)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[CH2:8]([C:4]1[CH2:3][C:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCBr
Reactant: C1=CCC=C1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCC1=C(CCCCCCCC)C(CCCCCCCC)=C(CCCCCCCC)C1
Temperature: 10 °C
Reaction time: 6 h

Procedure:
A double-walled reactor having a volume of 1.5 L, provided with baffles, condenser, top stirrer, thermometer and dropping funnel was charged with 900 g of clear 50% strength NaOH (11.3 mol), followed by cooling to 10° C. Then 30 g of Aliquat 336 (74 mmol) and 48 g (0.72 mol) of freshly cracked cyclopentadiene were added. The reaction mixture was stirred turbulently for a few minutes. Then 577 g of octyl bromide (2.99 mol) were added in one hour's time, cooling with water taking place at the same time. After 1 hour's stirring at room temperature the reaction mixture was heated to 35° C., followed by a further 6 hours' stirring. Stirring was stopped and phase separation was awaited. The water layer was drawn off and 920 g (11.5 mol) of fresh 50% strength NaOH were added, followed by a further 5 hours' stirring at room temperature. GC was used to show that at that instant 10% of tri-, 83% of tetra- and 7% of penta(octyl)cyclopentadiene were present in the mixture. The product was distilled at reduced pressure. After vacuum distillation, 226.6 g of tetra(octyl)cyclopentadiene were obtained. Characterization of the product took place with the aid of GC, GC-MS, 13C- and 1H-NMR.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Cl-].[Cl-].[Zn+2:12]>C(O)C>[Zn:12].[C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: [Zn+2]
Agent: NC(=O)c1cccnc1
Agent: [Cl-]
Solvent: CCO
Product: [Zn]

Procedure:
4.89 g (0.04 mol) of nicotinamide is dissolved in 100 ml of ethanol, to which 2.73 g (0.02 mol) of ZnCl2 in 50 ml of ethanol is added and mixed. When stirred, white crystals immediately precipitate. The precipitate is filtered with a No. 5C filter paper, followed by washing with ethanol and then with diethyl ether. The washed product is allowed to stand for evaporating diethyl ether, and dried at 60° C. in an electric oven to obtain the desired compound.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:8]=[CH:7]2.[Br:20][C:21]1[N:22]=[C:23]([C:42]#[CH:43])[C:24]([N:27]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[N:25][CH:26]=1.C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C.FC(F)(F)C(O)=O>CO>[C:38]([O:37][C:35]([N:27]([C:28]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:34])[C:24]1[C:23]([C:42]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[C:6]4[C:10](=[CH:11][CH:12]=3)[N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:8]=[CH:7]4)[CH:43]=2)=[N:22][C:21]([Br:20])=[CH:26][N:25]=1)=[O:36])([CH3:41])([CH3:40])[CH3:39]
Reactant: C#Cc1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)n1ccc2cc(C=NO)ccc21
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1cc(-c2ccc3c(ccn3C(=O)OC(C)(C)C)c2)no1
Reaction time: 17 h
Yield: 16.5 %

Procedure:
A solution of tert-butyl 5-((hydroxyimino)methyl)-1H-indole-1-carboxylate (260.3 mg, 1 mmol) in methanol (1 mL) was added slowly to a stirred solution of tert-butyl N-(5-bromo-3-ethynyl-pyrazin-2-yl)-N-tert-butoxycarbonyl-carbamate (438.1 mg, 1.100 mmol) and (diacetoxyiodo)benzene (354.3 mg, 1.100 mmol) in methanol (2 mL) containing trifluoroacetic acid (15 μL, 0.1947 mmol) at ambient temperature. The reaction was stirred at this temperature for 17 hours then concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 40 g column) loaded with dichloromethane and eluted with 0 to 50% ethyl acetate/petroleum ether. Product fractions were combined and concentrate in vacuo to give the sub-title product as a white solid (108 mg, 16% Yield). 1H NMR (400.0 MHz, DMSO-d6) δ 1.22 (s, 18H), 1.57 (s, 9H), 6.73 (d, 1H), 7.69 (d, 1H), 7.80 (s, 1H), 7.89 (dd, 1H), 8.11 (d, 1H), 8.23 (d, 1H) and 8.94 (s, 1H) ppm.
Reaction SMILES: [C:1]([N:5]([CH2:29][CH2:30][O:31][CH2:32][C:33]#C)[C:6](=[O:28])[C:7]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH:22]([CH3:24])[CH3:23])=[C:14]([O:19][CH3:20])[CH:15]=2)[CH:10]1[C:25](O)=O)=O)([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].[NH4+].[OH-]>C(OC(=O)C)(=O)C.O>[C:1]([N:5]1[C:6](=[O:28])[C:7]2[N:9]3[CH2:18][CH2:17][C:16]4[CH:15]=[C:14]([O:19][CH3:20])[C:13]([O:21][CH:22]([CH3:23])[CH3:24])=[CH:12][C:11]=4[C:10]3=[CH:25][C:33]=2[CH2:32][O:31][CH2:30][CH2:29]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: C#CCOCCN(C(=O)C(=O)N1CCc2cc(OC)c(OC(C)C)cc2C1C(=O)O)C(C)(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1cc2c(cc1OC(C)C)-c1cc3c(n1CC2)C(=O)N(C(C)(C)C)CCOC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
A solution of 264 mg of 18b and 500 mg of anhydrous sodium acetate in 7 ml of acetic anhydride was heated under N2 at 100° C. for 40 min. The mixture was cooled and diluted with 15 ml of water and stirred for 1 hr at ambient temperature. The mixture was then neutralized by dropwise addition of cold conc. aq. NH4OH and the product was extracted with ethyl acetate. The organic layer was washed with water, dried, concentrated and the residue was treated with diisopropyl ether to give 180 mg of 18c white crystalline material. Mp 125-127° C. MS-ESI: [M+1] 413.17.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCOP(OCC)([CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])=O.[C:29]([O:33][C:34]([N:36]1[C@@H:40]([CH2:41][CH:42]=O)[CH2:39][O:38][C:37]1([CH3:45])[CH3:44])=[O:35])([CH3:32])([CH3:31])[CH3:30]>O1CCCC1>[C:29]([O:33][C:34]([N:36]1[C@@H:40]([CH2:41]/[CH:42]=[C:18](/[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)\[CH3:19])[CH2:39][O:38][C:37]1([CH3:44])[CH3:45])=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: CCOP(=O)(OCC)C(C)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC=O)COC1(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C/C(=C\C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N,N-diisopropylamine (1.74 ml) in tetrahydrofuran (8 ml) at −78° C. was added dropwise a solution of n-butyllithium (7.71 ml, 1.6 M in hexane) and the reaction mixture was then warmed to 0° C. for 15 min. After re-cooling to −78° C., a solution of diethyl 1-phenylethyl phosphonate (2.76 ml) in tetrahydrofuran (8 ml) was added dropwise. The mixture was stirred at −78° C. for 30 min and then a solution of (S)-2,2-dimethyl-4-(2-oxo-ethyl)oxazolidine-3-carboxylic acid tert-butyl ester (2.00 g, CAS 147959-19-1) in tetrahydrofuran (8 ml) was added dropwise over 20 min. The mixture was then allowed to warm to room temparature and stirring continued at room temperature for 48 hours. The mixture was then quenched by addition of aqueous hydrochloric acid (2N) and then made basic by addion of aqueous sodium hydroxide solution (1N). The mixture was taken up in ethyl acetate and the phases separated. The organic layer was washed sequentially with water and with saturated brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, heptane/EtOAc gradient) to yield a yellow oil, (1.16 g, 44%); MS (ISP): 332.1 ([M+H]+).