Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:42])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:41])=[CH:17]/[CH:18]=[CH:19]/[CH:20]=[C:21](/[CH:23]=[CH:24]/[CH:25]=[C:26](/[CH:28]=[CH:29]/[CH:30]=[C:31](/[CH:33]=[CH:34]/[C:35]([C:37]([OH:40])([CH3:39])[CH3:38])=[O:36])\[CH3:32])\[CH3:27])\[CH3:22].[Na].S(=O)(=O)(O)O>C(Cl)Cl.CO>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:42])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:41])=[CH:17]/[CH:18]=[CH:19]/[CH:20]=[C:21](/[CH:23]=[CH:24]/[CH:25]=[C:26](/[CH:28]=[CH:29]/[CH:30]=[C:31](/[CH:33]=[CH:34]/[C@@H:35]([OH:36])[C:37]([OH:40])([CH3:39])[CH3:38])\[CH3:32])\[CH3:27])\[CH3:22]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C=C(C)/C=C/C(=O)C(C)(C)O)C(C)(C)CCC1
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CO
Solvent: ClCCl
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C=C(C)/C=C/[C@@H](O)C(C)(C)O)C(C)(C)CCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 17.4 %

Procedure:
70.0 g (123 mmol) of 2'-dehydroplectaniaxanthin are dissolved in 2000 ml of methylene chloride and 500 ml of methanol. At 16-18° C. 4.70 g (123 mmol) of sodium borohyride are added in portions, and the mixture is stirred for 1.5 hours at room temperature. The resulting solution is then cooled to 10° C., and approx. 150 ml of 1N sulphuric acid are added at such a rate that the temperature is maintained between 10° and 15° C. until a pH between 7 and 8 is obtained. The resulting mixture is then extracted three times with 500 ml of methylene chloride in each case. The organic layer is washed several times with 500 ml of ice-water, then dried over anhydrous sodium sulphate and evaporated at 35° C. using a water jet vacuum. The resulting crystalline mass is stirred with 1500 ml of diethyl ether and the resulting suspension filtered. In this way there are obtained 12.2 g (HPLC purity 97%) of racemic plectaniaxanthin crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:61]2[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][CH:62]=2)([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[O:10][CH2:11][C@@H:12]2[C@@H:16]([OH:17])[C@:15]([F:19])([CH3:18])[C@H:14]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][C:23]([NH:31][C:32]([C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=3)([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:24][C:25]=4[O:29][CH3:30])[O:13]2)=[CH:5][CH:4]=1.[CH:69]1[CH:74]=[CH:73][C:72]([CH2:75][O:76][C:77](Cl)=[O:78])=[CH:71][CH:70]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:77](=[O:78])([O:17][C@H:16]1[C@:15]([F:19])([CH3:18])[C@H:14]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][C:23]([NH:31][C:32]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)([C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:24][C:25]=3[O:29][CH3:30])[O:13][C@@H:12]1[CH2:11][O:10][C:9]([C:61]1[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][CH:62]=1)([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[O:76][CH2:75][C:72]1[CH:73]=[CH:74][CH:69]=[CH:70][CH:71]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccc(C(Nc2nc(OC)c3ncn([C@@H]4O[C@H](COC(c5ccccc5)(c5ccc(OC)cc5)c5ccc(OC)cc5)[C@@H](O)[C@@]4(C)F)c3n2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C(Nc2nc(OC)c3ncn([C@@H]4O[C@H](COC(c5ccccc5)(c5ccc(OC)cc5)c5ccc(OC)cc5)[C@@H](OC(=O)OCc5ccccc5)[C@@]4(C)F)c3n2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 94.7 %

Procedure:
To a solution of nucleoside 114 (2.52 g, 2.75 mmol) in anhydrous DCM (8 mL) was added DMAP (1.01 g, 8.2 mmol) and the solution was cooled at 0° C. in an ice-water bath. Cbz-Cl (0.77 g, 4.2 mmol) was added via a syringe to the mixture and resulted in a cloudy reaction mixture. The mixture was stirred at room temperature for 24 hours and sat. NaHCO3 (10 mL) was added. The mixture was partitioned in DCM and water. The organic layer was dried over Na2SO4 and concentrated to a white foam solid. The residue was purified via column chromatography (1060% EtOAc in hexanes) to afford 2.74 g product, 115, as a white foam solid (yield, 95%).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH3:21])[C:12]2=[O:29])[CH:5]=1.[OH-].[Li+]>C1COCC1.O>[F:28][C:25]1[CH:24]=[CH:23][C:22]([C:20](=[C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]([CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:30])=[O:2])[C:12]2=[O:29])[CH3:21])=[CH:27][CH:26]=1
Reactant: COC(=O)c1cccc(CN2C(=O)C(=C(C)c3ccc(F)cc3)c3ccccc32)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=C1C(=O)N(Cc2cccc(C(=O)O)c2)c2ccccc21)c1ccc(F)cc1
Reaction time: 12 h
Yield: 31.5 %

Procedure:
A solution of 3-{3-[1-(4-fluoro-phenyl)-ethylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester (0.33 g, 0.82 mmol) was dissolved in THF 5 ml. Then a solution of lithium hydroxide (0.35 g, 8.2 mmol) in water (2.0 ml) was added. After stirring for 12 hours, the solvent was removed under reduced pressure. The residue was dissolved in 2 ml DMF for prepared HPLC to give 3-{3-[1-(4-fluoro-phenyl)-ethylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid as yellow powder (100 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.78 (s, 3H) 5.06 (s, 2H) 6.08 (d, J=7.83 Hz, 1H) 6.68 (t, J=7.45 Hz, 1H) 6.92 (d, J=7.83 Hz, 1H) 7.11 (t, J=7.45 Hz, 1H) 7.38 (t, J=8.84 Hz, 2H) 7.43-7.51 (m, 1H) 7.46 (dd, J=8.72, 5.68 Hz, 2H) 7.60 (d, J=7.58 Hz, 1H) 7.85 (d, J=7.83 Hz, 1H) 7.92 (s, 1H) 13.03 (s, 1H). MS calcd. for C24H18FNO3 387.4, obsd. (ESI+) [(M+H)+] 388.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]([O:16]C)=O)[O:11][N:10]=1.[CH:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1(C)C=CC=CC=1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[N:13]=[C:12]([C:14](=[O:16])[NH:24][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[O:11][N:10]=1
Reactant: NC1CCCCC1
Reactant: COC(=O)c1nc(-c2c(Cl)cccc2Cl)no1
Solvent: Cc1ccccc1
Product: O=C(NC1CCCCC1)c1nc(-c2c(Cl)cccc2Cl)no1

Procedure:
To a solution of 1 g of 3-(2,6-dichlorophenyl)-5-methoxycarbonyl-1,2,4-oxadiazole in 5 ml of toluene, was added 0.4 g of cyclohexylamine at room temperature.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[OH:12]O>C(O)(=O)C>[NH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:8][N+:7]=1[O-:12]
Reactant: OO
Reactant: Nc1ccc(C(F)(F)F)cn1
Solvent: CC(=O)O
Product: Nc1ccc(C(F)(F)F)c[n+]1[O-]

Procedure:
The title compound was prepared by following the procedure described for Intermediate-40 using 5-(trifluoromethyl)pyridin-2-amine (0.500 g, 3.08 mmol), acetic acid (5.0 mL) and 50% hydrogen peroxide (2.0 mL) to afford 0.475 g of the desired product. 1HNMR (DMSO-d6): δ 6.88 (d, J=8.7 Hz, 1H), 7.40 (d, J=8.7 Hz, 1H), 7.49 (s, 2H), 8.49 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]2[N:9]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)=[CH:11][C:3]=12.C([Sn](CCCC)(CCCC)[C:33]1[S:37][CH:36]=[N:35][CH:34]=1)CCC.O>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:8][C:7]1[C:2]([C:33]2[S:37][CH:36]=[N:35][CH:34]=2)=[C:3]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[N:9]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=3)(=[O:19])=[O:20])[C:4]2=[N:5][CH:6]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(Cl)c(Cl)cnc32)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(-c4cncs4)c(Cl)cnc32)cc1
Temperature: 100 °C

Procedure:
A solution of Example 113C (0.148 g, 0.351 mmol) and 5-(tributylstannyl)thiazole (0.184 g, 0.492 mmol), in N,N-dimethylformamide (1.3 mL) was degassed via nitrogen sparge for 5 minutes. The reaction was treated with bis(triphenylphosphine)palladium (II) chloride (0.025 g, 0.35 mmol) and heated at 100° C. for 6 hours. The reaction was cooled to ambient temperature, treated with water (20 mL) and extracted with ethyl acetate (80 mL). The aqueous layer was extracted with additional ethyl acetate (40 mL). The combined organic layers were washed with water (2×25 mL) and brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by flash chromatography on a silica gel column, eluting with a gradient of from 0% to 50% ethyl acetae in hexanes, to provide the title compound as an off-white solid. MS ESI(+) m/z 470.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:14])[O:10][C:11](=[O:13])[NH:12][C:7]=2[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].IC.O(C(C)C)[CH:20](C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:14])[O:10][C:11](=[O:13])[N:12]([CH3:20])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2[nH]c(=O)oc(=O)c12
Reactant: CC(C)OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccc2c1c(=O)oc(=O)n2C
Temperature: 0 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
To a stirred and cooled (<10° C.) solution of 9.65 parts of 5-methoxy-2H-3,1-benzoxazine-2,4(1H)-dione in 54 parts of N,N-dimethylformamide were added portionwise 2.64 parts of a sodium hydride dispersion 50%. After stirring for 1 hour in an ice bath. 7.81 parts of iodomethane were added dropwise at <15° C. When the reaction mixture was solidified, 45 parts of N,N-dimethylformamide were added and a sodium hydride dispersion 50% was further added dropwise. Upon complete addition, stirring was continued overnight while the reaction mixture was allowed to reach room temperature. The reaction mixture was poured into ice water and 2,2'-oxybispropane was added. The precipitated product was filtered off, washed with water and dried, yielding 8.37 parts (80.7%) of 5-methoxy-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione; mp. 215.8° C. (interm. 2)
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[C:10](Br)[CH2:11]2.[CH:23]1([Mg]Br)[CH2:25][CH2:24]1.O1CCCC1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C1(C)C=CC=CC=1>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[C:10]([CH:23]1[CH2:25][CH2:24]1)[CH2:11]2
Reactant: Br[Mg]C1CC1
Reactant: BrC1=Cc2c(cccc2-c2ccccc2-c2ccccc2)C1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C1=C(C2CC2)Cc2cccc(-c3ccccc3-c3ccccc3)c21
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 37 %

Procedure:
A solution of compound 9 (10 g, 28.8 mmol, 1 equiv) and anhydrous toluene (100 mL) was treated with bis(triphenylphosphine)-palladium(II)dichloride (2.35 g, 2.9 mmol, 0.1 equiv). After stirring for 10 minutes, 0.5 M cyclopropylmagnesium bromide in tetrahydrofuran (300 mL, 149.7 mmol, 5.2 equiv) was added dropwise. The reaction was heated at 60° C. overnight. Additional bis(triphenylphosphine)-palladium(II)dichloride (2.35 g, 2.9 mmol, 0.1 equiv) was added and the reaction heated at 60° C. for an additional 24 hours. The reaction was concentrated under reduced pressure and the residue partitioned between water (1 L) and ethyl acetate (1 L). The layers were separated and the aqueous layer washed with ethyl acetate (1 L). The combined organic layers were washed with saturated brine (1 L), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified over silica gel (200 g) eluting with heptanes to give compound 10 (3.3 g, 37% yield) as a light yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[OH:14])[CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7].OS(O)(=O)=O.[CH3:20][C:21](=[CH2:23])[CH3:22].C([O-])(O)=O.[Na+]>O1CCOCC1.O>[I:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[OH:14])[CH2:5][C@@H:6]([C:8]([O:10][C:21]([CH3:23])([CH3:22])[CH3:20])=[O:9])[NH2:7]
Reactant: N[C@@H](Cc1ccc(O)c(I)c1)C(=O)O
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)c(I)c1
Temperature: 25 °C
Yield: 58 %

Procedure:
A mixture of 5.0 g of 3-iodo-L-tyrosine (Aldrich) and 2.5 mL of conc. H2SO4 in 85 mL of 1,4-dioxane was added to 30 mL of liquid isobutylene (condensed at −78° C.) in a 300 mL pressure bottle. The vessel was stoppered and the contents stirred at RT. After 3 days the bottle was cooled in an ice water bath, opened and the solution poured into a mixture of 10 g of NaHCO3 in 150 mL of water. The resulting mixture was subjected to rotary evaporation to remove isobutylene and dioxane. A white solid resulted which was collected by filtration and dried in vacuo. Analysis by tlc (SiO2, 95:5 CH2Cl2:MeOH) indicated major and minor components at Rf=0.52 and 0.60 respectively. The crude product was purified by flash chromatography on silica gel (95:5 CH2Cl2:MeOH) to afford 3.4 g (58%) of tert-butyl 3-iodo-L-tyrosinate as a white crystalline solid, m.p. 158-159° C.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@@H:9]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=1)[C@H:10]([O:24]CC1C=CC=CC=1)[C@H:11]1[CH2:16][O:15][C@@H:14]([O:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@H:13]([CH3:23])[NH:12]1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:8][C@@H:9]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=1)[C@@H:10]([C@H:11]1[CH2:16][O:15][C@@H:14]([O:17][CH2:18][C:19]([CH3:21])([CH3:22])[CH3:20])[C@H:13]([CH3:23])[NH:12]1)[OH:24]
Reactant: [H][H]
Reactant: C[C@@H]1N[C@@H]([C@@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)CO[C@H]1OCC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H]1N[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)CO[C@H]1OCC(C)(C)C
Yield: 98.4 %

Procedure:
Add 20% palladium hydroxide on carbon (679 mg) to a solution of dibenzyl-{(1S,2R)-2-benzyloxy-1-(3,5-difluorobenzyl)-2-[(3R,5S,6R)-6-(2,2-dimethylpropoxy)-5-methylmorpholin-3-yl]-ethyl}-amine (284 mg, 0.442 mmol) in absolute ethanol (5 mL) and stir under 1 atmosphere of hydrogen gas at room temperature for 18 hours. Filter through a pad of Celite®, wash thoroughly with ethanol and concentrate to give the desired compound as a glass (162 mg, 98%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[S:6][C:5]=1[C:15]([NH2:17])=[O:16])[CH3:2].[CH3:18][CH2:19][C:20](=O)[CH2:21][CH3:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:1]([N:3]1[C:4]2[CH:8]=[C:7]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)[S:6][C:5]=2[C:15](=[O:16])[NH:17][C:20]1([CH2:21][CH3:22])[CH2:19][CH3:18])[CH3:2]
Reactant: CCC(=O)CC
Reactant: CCNc1cc(-c2ccncc2)sc1C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCN1c2cc(-c3ccncc3)sc2C(=O)NC1(CC)CC
Temperature: 120 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
A mixture of 3-(ethylamino)-5-(pyridin-4-yl)thiophene-2-carboxamide (0.100 g, 0.400 mmol), 3-pentanone (3.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (3.0 mL) was stirred for 1 h at 120° C. in a sealed tube. Then, this mixture was stirred for 2 h at 150° C. and stirring was continued for 2 days at 110° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (150 mL). Extraction with ethyl acetate (100 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. This oil was purified by column chromatography (Combiflash, 40 g silica gel, dichloromethane to ethyl acetate), then recrystallized from ethyl acetate, and the precipitate was collected by filtration to afford the title compound (0.0194 g, 12%) as a yellow solid:
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][CH2:9][C:10]([CH3:32])([CH3:31])[CH:11]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[N:19]=[CH:18]2)[CH2:12][CH:13]=[CH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].B1C2CCCC1CCC2.[OH-:42].[Na+].OO>C1COCC1.O>[C:1]([NH:5][C:6]([NH:8][CH2:9][C:10]([CH3:32])([CH3:31])[CH:11]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[N:19]=[CH:18]2)[CH2:12][CH2:13][CH2:14][OH:42])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(C)(C)CNC(=O)NC(C)(C)C
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)NCC(C)(C)C(CCCO)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of 1-tert-butyl-3-(3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethylhex-5-enyl)urea (5.0 mg, 0.01 mmol) in anhydrous THF (2 mL) at 0 C was added 9-BBN (50 μL, 0.02 mmol) under nitrogen. Allowed reaction mixture to warm to RT and stirred overnight then added 10% NaOH solution (0.2 mL) and 30% H2O2 (1 mL). and stirred for 10 min. The reaction mixture was poured into a water (4 mL), extracted with ethyl acetate (2×10 mL), dried (Na2SO4) and purified by chromatography to give 3.2 mg (50% yield) of 1-tert-butyl-3-(3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-6-hydroxy-2,2-dimethylhexyl)urea. MS found: (M+H)+=455.
Reaction SMILES: C([N:8]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH:15]=[CH:16][CH2:17][CH2:18][CH3:19])(OC(C)(C)C)=O>FC(F)(F)C(O)=O.ClCCl>[CH:15]([C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:13]([CH3:14])[NH:8]1)=[CH:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCC=C[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC=C[C@H]1CCC[C@H](C)N1

Procedure:
To a stirred solution of trans-N-Boc-2-(1-pentenyl)-6-methylpiperidine (2.5 g, 9.35 mmol) in 15% trifloroacetic acid (35 mL) in dichloromethane was stirred for 2 h at room temperature, and the reaction mixture was quenched with 90 mL saturated NaHCO3 solution. The mixture was extracted with ether *5 and the combined extracts were dried over K2CO3 and then concentrated to give trans-2-(1-pentenyl)-6-methylpiperidine as an oil. The crude oil was immediately dissolved in a small amount of ether, and ether saturated with HCl (g) was added slowly via pipette. This solution was allowed to stand for 10 minutes, and the solvent was evaporated. More ether was added and the flask was swirled constantly until crystallization occurred. The solid was collected via filtration, and dried in vacuo to give the piperidinium hydrochloride as a white solid that was homogeneous by TLC analysis. mp 150.4-150.9° C.; 1H NMR (250 MHz) δ 9.5-9.3 (br. d, 2H), 5.74-5.62 (m, 2H), 4.19 (s, 1H), 3.55 (s, 1H), 2.1-1.3 (m, 13H), 0.87 (t, 3H); 13C NMR (62.7 MHz) δ 136.8 (s), 123.0 (s), 48.3 (s), 47.9 (s), 29.9 (s), 28.8 (s), 28.4 (s), 22.3 (s), 17.6 (s), 17.1 (s), 13.8 (s). FT-IR (neat): 3424, 3171, 2939, 1635, 1597, 1582, 1459, 1432, 1384, 1287, 1123, 1075, 895. Elemental Analysis for C11H22NCl: C, 64.83%; H, 10.9%; N, 6.87%. Found: C, 64.77%; H, 10.82%; N, 6.85%.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:30]([O:32][C:33]([CH:35]1[CH2:38][C:37](=O)[CH2:36]1)=[O:34])[CH3:31]>C(O)(=O)C.C1COCC1>[CH2:30]([O:32][C:33]([CH:35]1[CH2:38][CH:37]([N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:36]1)=[O:34])[CH3:31]
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CCOC(=O)C1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)C1CC(N(Cc2ccccc2)Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.5 %

Procedure:
Dibenzyl amine (0.150 g, 0.77 mmol) and sodium triacetoxyborohydride (0.300 g, 1.4 mmol) were added to a solution of 3-oxo-cyclobutanecarboxylic acid ethyl ester (0.100 g, 0.700 mmol) and acetic acid/THF (10%, 4.4 mL), stirred at room temperature for 72 hours and concentrated in vacuo. The resulting residue was dissolved in dichloromethane, washed with water, saturated NaHCO3 and brine, dried (Na2SO4) and concentrated in vacuo to give crude product. Purification by flash chromatography (silica, 1:9-3:7 EtOAc:hexanes) provided the title compound (0.180 g, 73% yield, 10:1 cis:trans ratio) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15]([CH2:17][CH2:18][NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]([CH3:12])([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].Cl[C:32]1[N:37]=[CH:36][C:35]([CH2:38][CH3:39])=[CH:34][N:33]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:16]=[C:15]([CH2:17][CH2:18][N:19]([C:32]2[N:37]=[CH:36][C:35]([CH2:38][CH3:39])=[CH:34][N:33]=2)[CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:25][CH:26]=2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]([CH3:11])([CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCc1cnc(Cl)nc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2)cc1Br
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ncc(CC)cn2)cc1Br
Yield: 23 %

Procedure:
Condensation of ethyl 2-[2-bromo-4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (500 mg; 1.02 mmol) with 2-chloro-5-ethyl-pyrimidine (1 eq) as per general procedure E (conditions: 1.1 eq DIEA, toluene, 200C, 14 hr) provided the intermediate ethyl 2-[2-bromo-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (134 mg; 23% yield).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[N:13]([CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:14]=[C:15]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1)=O)C>C1COCC1.CCOC(C)=O>[C:31]([O:30][C:28](=[O:29])[NH:27][CH2:26][CH2:25][N:13]1[C:12]([CH2:10][OH:9])=[CH:16][C:15]([CH2:17][O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:14]1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CCOC(=O)c1cc(COc2ccccc2)nn1CCNC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCn1nc(COc2ccccc2)cc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.1 %

Procedure:
A 1M solution of lithium aluminum hydride in THF (6.98 mL, 6.98 mmol) was added dropwise to a stirred solution of 2-(2-tert-butoxycarbonylamino-ethyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (2.72 g, 6.98 mmol) in THF (47 mL) under N2 at 0° C. The mixture was stirred at room temperature for 1 hour and diluted with AcOEt. Na2SO4.10H2O was added at 0° C. and the mixture was stirred for 15 minutes at this temperature, filtered through a pad of diatomaceous earth and then washed with additional AcOEt. The solvents were evaporated in vacuo to yield [2-(5-hydroxymethyl-3-phenoxymethyl-pyrazol-1-yl)-ethyl]-carbamic acid tert-butyl ester (2.5 g, 76% yield) as a white solid that was used in the next step without further purification.