Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].OCC[N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.N1C=CC=CC=1>O>[C:5]([O:4][CH2:1][CH2:2][N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: OCCn1cccc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCCn1cccc1
Temperature: 25 °C
Yield: 55 %

Procedure:
The resulting product is reacted with acetic anhydride in accordance with the method of F. F. Blicke and E. S. Blake, J. Am. Chem. Soc., 53, 1015(1931). A mixture of 1-(2-hydroxyethyl)pyrrole (147 g, 1.32 mole), pyridine (415 ml) and acetic anhydride (139 ml) is heated on a steam bath for 0.5 hours. The reaction mixture is cooled to room temperature, poured into water (one l) and the product is extracted into ethyl acetate (3×1 l ). The extract is washed successively with dilute hydrochloric acid, saturated sodium chloride solution, dilute sodium bicarbonate solution, and again with saturated sodium chloride solution. The extract is dried over sodium sulfate, evaporated in vacuo and the residue (150 g) is subjected to column chromatography on Florisil® activated magnesium silicate. The desired product is eluted with hexane-dichloromethane (1:1) to give 128 g (55%) 1-(2-acetoxyethyl)pyrrole, an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:12][CH2:13]Br>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:9]#[N:10])[CH2:13][CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCc1cccc(Br)c1
Reactant: BrCCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: N#CC1(c2cccc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
3-Bromophenylacetonitrile (5.0 g, 26 mmol) and 1,2-dibromoethane (6.6 mL, 77 mmol) were added to a solution of benzyltriethylammonium chloride (0.30 g, 1.3 mmol) in 50% sodium hydroxide aqueous solution (20 mL), and the mixture was stirred at room temperature overnight. Ice-water (70 mL) was added to the reaction mixture, and the whole was extracted with ethyl acetate (50 mL). The organic layer was washed with brine (30 mL), and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography to give the title reference compound (5.4 q) as brown oil (yield 95%).
Reaction SMILES: [CH:1]12[N:8]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:5]12[N:8]([C:9]3[CH:16]=[CH:15][C:12]([CH2:13][NH2:14])=[C:11]([Cl:17])[CH:10]=3)[CH:1]([CH2:7][CH2:6]1)[CH2:2][CH2:3][CH2:4]2
Reactant: N#Cc1ccc(N2C3CCCC2CC3)cc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(N2C3CCCC2CC3)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-(8-Azabicyclo[3.2.1]oct-8-yl)-2-chlorobenzonitrile in THF (50 mL) was treated with solid LAH (0.47 g, 12 mmol) at 0° C. portionwise. The mixture was heated at reflux for 1 hour, allowed to cool to 0° C., and quenched by addition of (Na2SO4 10H2O). The mixture was stirred for 30 minutes, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 5% to 10% MeOH/CH2Cl2 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 7.27 (d, 1H, J=8.6 Hz), 6.74 (d, 1H, J=2.4 Hz), 6.70 (dd, 1H, J=8.6, 2.4 Hz), 4.16 (bs, 2H), 3.65 (s, 2H), 2.05 (bs, 2H), 1.97 (m, 2H), 1.88-1.65 (m, 5H), 1.40 (m, 1H), 1.23 (m, 2H); MS (ESI) 234 (M−NH2)+.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH:38]=O)=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[N:26][CH:27]=2)[CH:21]=1.[Br:40][C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=1.CC(O)=O>C(Cl)Cl.ClCCCl>[Br:40][C:41]1[CH:47]=[CH:46][C:44]([NH:45][CH2:38][C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][C:20]=2[C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[N:26][CH:27]=2)=[CH:43][CH:42]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C=O)cn1
Reactant: Nc1ccc(Br)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(Br)cc2)cn1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (709 mg, 3.3 mmol) was added to a DCE solution (8 mL) of ethyl 3-(5-(5-chloro-2-formylphenyl)picolinamido)propanoate (603 mg, 1.7 mmol), 4-bromoaniline (287.6 mg, 1.67 mmol) and HOAc (0.10 mL, 1.7 mmol) the resulting mixture was stirred at room temperature. After 16 h the resulting mixture diluted with DCM and washed with saturated aqueous NaHCO3 and water. The organic layer was dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([NH2:12])=[O:11])[CH:5]=[N:4][C:3]=1[C:15]#[N:16].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)[CH:18]=1.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:15]([C:3]1[N:4]=[CH:5][C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([NH2:12])=[O:11])=[N:7][C:2]=1[NH:27][C:26]1[CH:25]=[CH:24][C:23]([C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)=[CH:29][CH:28]=1)#[N:16]
Reactant: Nc1ccc(-c2cccnc2)cc1
Reactant: CC[C@@H](Nc1cnc(C#N)c(Cl)n1)C(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC[C@@H](Nc1cnc(C#N)c(Nc2ccc(-c3cccnc3)cc2)n1)C(N)=O
Reaction time: 20 h
Yield: 57.8 %

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)butanamide (100 mg, 0.417 mmol), 4-(pyridin-3-yl)aniline (77 mg, 0.452 mmol), K2CO3 (100 mg, 0.724 mmol), BINAP (30 mg, 0.048 mmol) and Pd(OAc)2 (15 mg, 0.066 mmol) in dioxane (3 mL) was degassed with Ar, then was stirred at 110 C for 20 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give (R)-2-(5-cyano-6-(4-(pyridin-3-yl)phenylamino)pyrazin-2-ylamino)butanamide (90 mg).
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[F:13][C:14]([F:29])([F:28])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[NH2:27])=[CH:17][CH:16]=1.N1C=CC=CC=1.C(OC)(C)(C)C>C1(C)C=CC=CC=1>[F:13][C:14]([F:28])([F:29])[C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[NH:27][C:8]([C:7]2[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=2)=[O:9])=[CH:19][CH:20]=1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: Nc1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: COC(C)(C)C
Product: Cn1cc(C(=O)Nc2ccccc2-c2ccc(C(F)(F)F)cc2)c(C(F)F)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At room temperature, 0.29 g of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride was added dropwise to a solution of 0.36 g of 4′-trifluoromethyl-2-aminobiphenyl and 0.18 g of pyridine in 10 ml of toluene, after which the mixture was stirred at room temperature for 16 hours. 30 ml of methyl tert-butyl ether were added, and the organic phase was washed successively with 2% strength hydrochloric acid, 2% strength aqueous sodium hydroxide solution and then with dilute sodium chloride solution. The organic phase was dried and concentrated under reduced pressure. The crude product was stirred with 5 ml of diisopropyl ether. The solid that remained was separated off and dried. This gave 0.45 g of the desired product as a white powder; m.p. 164-165° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@H:4]([CH2:13][NH:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:5]C(OC(C)(C)C)=O>ClCCl.FC(F)(F)C(O)=O>[CH3:1][O:2][C:3](=[O:23])[C@H:4]([CH2:13][NH:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH2:5]
Reactant: COC(=O)[C@H](CNC(=O)c1ccccc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](N)CNC(=O)c1ccccc1
Yield: 1.7 %

Procedure:
Bromine (10 mL, 194.1 mmol) was added to a solution of sodium hydroxide (40.00 g, 1000 mmol) in water (330 mL) cooled in a bath at −10° C. The clear yellow solution was stirred for 15 min, and then 2-[(1,1-dimethylethoxy)carbonyl]-L-asparagine (Boc-Asn; 39.50 g, 170.1 mmol) was added as a solid. The resulting solution was heated at ˜70° C. for 1 h. After cooling, a solution of benzoyl chloride (25.30 g, 180.0 mmol) in ether (50 mL) was added and the reaction mixture was allowed to stir at room temperature overnight. The pH of the solution was adjusted to ˜10 with 1 M NaOH solution and the solution was extracted with ethyl acetate (200 mL). The organic layer was discarded and the aqueous layer was made acidic to pH ˜2 with 1 M HCl solution. The resulting solution was extracted with ethyl acetate (2×200 mL), washed with brine (200 mL), dried (MgSO4), filtered, and evaporated to give a white solid (31.5 g). This was dissolved in dichloromethane (200 mL) and ethereal diazomethane was added until the yellow color persisted. Acetic acid (ca 2 mL) was added to quench the excess diazomethane and the solution was washed with water and brine (200 mL each), dried (MgSO4), filtered, evaporated, and chromatographed (30-50% ethyl acetate/hexanes) to give methyl benzoate (13.86 g, Rf 0.75 in 30% ethyl acetate/hexanes) and of 3-(benzoylamino)-N-[(1,1-dimethylethoxy)carbonyl]-L-alanine methyl ester (Rf 0.12 in 30% ethyl acetate/hexanes) as a colorless oil (6.39 g, 11.5%) that solidified on standing along with 3.54 g of less pure fractions (6.5%). A solution of pure 3-(benzoylamino)-N-[(1,1-dimethylethoxy)carbonyl]-L-alanine methyl ester (200 mg, 0.62 mmol) in dichloromethane/trifluoroacetic acid (1:1; 2.5 mL) was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure. Ethyl acetate (10 mL) was added and the solution was washed with saturated aqueous NaHCO3 solution (10 mL), dried (Na2SO4), filtered, concentrated and then dried under high vacuum to give 3-(benzoylamino)-L-alanine methyl ester (77 mg, 56%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=O)[CH:5]=[CH:6][CH:7]=1.[Si](OCC)(OCC)(OCC)OCC.[CH:30]([C:33]1[CH:39]=[CH:38][CH:37]=[C:36]([CH:40]([CH3:42])[CH3:41])[C:34]=1[NH2:35])([CH3:32])[CH3:31].OS(O)(=O)=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[N:35][C:34]2[C:36]([CH:40]([CH3:41])[CH3:42])=[CH:37][CH:38]=[CH:39][C:33]=2[CH:30]([CH3:32])[CH3:31])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)c2cccc(Br)c2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: CCO[Si](OCC)(OCC)OCC
Agent: O=S(=O)(O)O
Product: Cc1ccc(C(=Nc2c(C(C)C)cccc2C(C)C)c2cccc(Br)c2)cc1
Temperature: 170 °C
Reaction time: 55 h
Yield: 83.5 %

Procedure:
In 50 mL Claisens flask in an argon atmosphere, a mixture of 9.63 g (35.0 mmol) of 40, 8.75 g (42.0 mmol) of Si(OEt)4, and 6.83 g (38.5 mmol) of 2,6-diisopropylaniline was heated to 170° C., and then 0.23 mL of 96% H2SO4 was added. This mixture was stirred at this temperature for 55 hr, and the formed ethanol was slowly distilled off. Further on, 300 mL of cold water was added, and the product was extracted with 2×100 mL of diethyl ether. The combined extract was dried over K2CO3 and then evaporated to dryness. The product was isolated by flash-chromatography on silica gel 60 (40-63 um, eluent: from hexanes to hexanes-diethyl ether, 100:1, vol.) to give 12.7 g (84%) of the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]2[C:10](Cl)=[CH:9][C:8]([CH2:12][CH3:13])=[N:7][C:6]=12.[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][NH:29][CH3:30])=[CH:24][CH:23]=1)#[N:15]>C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([N:29]([CH2:28][C:25]3[CH:26]=[CH:27][C:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:14]#[N:15])=[CH:23][CH:24]=3)[CH3:30])=[CH:9][C:8]([CH2:12][CH3:13])=[N:7][C:6]=12
Reactant: CCc1cc(Cl)n2ncc(Cl)c2n1
Reactant: CNCc1ccc(-c2ccccc2C#N)cc1
Solvent: CCO
Product: CCc1cc(N(C)Cc2ccc(-c3ccccc3C#N)cc2)n2ncc(Cl)c2n1

Procedure:
3.1 g (14.4 mmol) of the chloro compound (Example 3, Step A) and 3.2 g (14.4 mmol) of the amine (Example 1, Step C) were heated in 75 ml ethanol according to Example 4, Step C. The title compound was obtained as an oil after chromatography (silica gel; dichloromethane with ascending polarity by addition of up to 3% ethanol).
Reaction SMILES: I[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[Cl:28][C:29]1[C:38](B(O)O)=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[Cl:28][C:29]1[C:38]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[N:3]=2)=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(I)n2)cc1
Reactant: OB(O)c1cc2ccccc2nc1Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc4ccccc4nc3Cl)n2)cc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A 10 mL reaction vial was charged with 4-iodo-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.36 g, 0.75 mmol, Example 115), 2-chloroquinolin-3-ylboronic acid (0.31 g, 1.50 mmol, Aldrich, St. Louis, Mo.), sodium carbonate (0.16 g, 1.50 mmol), tetrakis(triphenylphosphine)palladium (0) (43 mg, 0.04 mmol, Strem, Newburyport, Mass.), DME (4 mL), and water (1 mL). The vial was sealed and purged with argon for several minutes. The reaction mixture was stirred at 90° C. for 5 h and then allowed to cool to room. The organic phase was taken and the solvents removed under vacuum. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g) eluting with a gradient of 0% to 1% 2 M NH3.MeOH in CH2Cl2. The title compound was obtained as a yellow solid (90% pure) and used without further purification. m/z (ESI, +ve ion) 511.8 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][CH2:8][C:9](=[O:20])[NH:10][C:11]([CH3:19])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]4([C:36]([OH:38])=[O:37])[CH2:35][CH2:34]4)=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[O:4][N:3]=1.I[CH3:40]>>[CH3:1][C:2]1[C:6]([CH2:7][CH2:8][C:9](=[O:20])[N:10]([CH3:40])[C:11]([CH3:19])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])=[C:5]([C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]4([C:36]([OH:38])=[O:37])[CH2:34][CH2:35]4)=[CH:29][CH:28]=3)=[CH:25][CH:26]=2)[O:4][N:3]=1
Reactant: CI
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CCC(=O)NC(C)(C)c1ccccc1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CCC(=O)N(C)C(C)(C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 34, Step 4, using 1-(4′-{3-methyl-4-[2-(1-methyl-1-phenyl-ethylcarbamoyl)-ethyl]-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid and iodomethane.
Reaction SMILES: [OH:1][C@:2]([CH3:33])([CH2:17][CH2:18][CH2:19][C@H:20]([CH3:32])[CH2:21][CH2:22][CH2:23][C@H:24]([CH3:31])[CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:3][CH2:4][C:5]1[C:6]([CH2:14][CH2:15][CH3:16])=[C:7]([OH:13])[CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11].C(#N)C.C(Cl)Cl.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>O>[OH:1][C@:2]([CH3:33])([CH2:17][CH2:18][CH2:19][C@H:20]([CH3:32])[CH2:21][CH2:22][CH2:23][C@H:24]([CH3:31])[CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:3][CH2:4][C:5]1[C:10](=[O:11])[C:9]([CH3:12])=[CH:8][C:7](=[O:13])[C:6]=1[CH2:14][CH2:15][CH3:16]
Reactant: CCCc1c(O)cc(C)c(O)c1CC[C@](C)(O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CCCC1=C(CC[C@](C)(O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)C(=O)C(C)=CC1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 45.2 %

Procedure:
A 50 mL RBF flask was charged with (R,R,R)-3-(3-hydroxy-3,7,11,15-tetramethyl-hexadecyl)-5-methyl-2-propyl-benzene-1,4-diol (Ex-1E-5) (110 mg, 0.24 mmol), ACN (15 mL) and DCM (2 mL), then cooled to 0° C. A solution of CAN (269 mg, 0.49 mmol) in water (1 mL) was added dropwise over 1 min to the reaction resulting in a bright orange solution. The reaction was stirred for 15 min then was diluted with water (5 mL). The aqueous layer was washed with DCM (3×30 mL). The combined DCM layers were dried over Na2SO4, filtered and concentrated by rotary evaporation to yield an orange oil. The oil was purified by column chromatography (gradient—hept to 20:1 hept.:EtOAc) to yield (R,R,R)-3-(3-hydroxy-3,7,11,15-tetramethyl-hexadecyl)-5-methyl-2-propyl-[1,4]benzoquinone (Ex-1E-6) as an orange oil (50 mg, 44%). 1H NMR (400 MHz, CDCl3) δ (ppm): 6.56 (s, 1H), 2.58-2.54 (m, 2H), 2.45 (t, J=7.9 Hz, 2H), 2.04 (s, 3H), 1.55-1.04 (m, 26H), 1.00 (t, J=7.4 Hz, 3H), 0.89-0.85 (m, 15H).
Reaction SMILES: Br[C:2]1[C:3]([C:18]#[N:19])=[CH:4][C:5]([F:17])=[C:6]([NH:8][C@H:9]([CH2:13][CH:14]2[CH2:16][CH2:15]2)[C:10]([NH2:12])=[O:11])[CH:7]=1.[NH2:20][C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=1.O.O.O.[O-]C1C=CC=CC=1.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:18]([C:3]1[C:2]([NH:20][C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]=2)=[CH:7][C:6]([NH:8][C@H:9]([CH2:13][CH:14]2[CH2:16][CH2:15]2)[C:10]([NH2:12])=[O:11])=[C:5]([F:17])[CH:4]=1)#[N:19]
Reactant: Nc1cc(-c2ccccc2)no1
Reactant: N#Cc1cc(F)c(N[C@H](CC2CC2)C(N)=O)cc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cc(F)c(N[C@H](CC2CC2)C(N)=O)cc1Nc1cc(-c2ccccc2)no1
Reaction time: 18 h
Yield: 40.2 %

Procedure:
A mixture of (R)-2-(5-bromo-4-cyano-2-fluorophenylamino)-3-cyclopropylpropanamide (150 mg, 0.460 mmol), 5-amino-3-phenylisoxazole (100 mg, 0.625 mmol), sodium phenoxide trihydrate (100 mg, 0.588 mmol), xantphos (60 mg, 0.103 mmol) and Pd2 dba3 (40 mg, 0.043 mmol) in dioxane (3 mL) was degassed with Ar, then was stirred at 120 C for 18 h. HOAc (0.5 mL) was added. The mixture was concentrated in vacuo. The residue was purified by HPLC to give (R)-2-(4-cyano-2-fluoro-5-(3-phenylisoxazol-5-ylamino)phenylamino)-3-cyclopropylpropanamide (75 mg).
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7][C:8](C)([O-])C.[K+].[C:13]([C:21]1[N:26]=[C:25]2[S:27][C:28]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][N:37]4[CH2:40][CH:39]([C:41]([OH:43])=[O:42])[CH2:38]4)=[CH:32][C:31]=3[F:44])=[N:29][C:24]2=[CH:23][CH:22]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>CC(O)(C)C.P([O-])([O-])([O-])=O.O>[F:44][C:31]1[CH:32]=[C:33]([CH2:36][N:37]2[CH2:40][CH:39]([C:41]([OH:43])=[O:42])[CH2:38]2)[CH:34]=[CH:35][C:30]=1[C:28]1[S:27][C:25]2[C:24]([N:29]=1)=[CH:23][CH:22]=[C:21]([C:13]1([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:8][CH2:7][O:20]1)[N:26]=2
Reactant: O=C(c1ccccc1)c1ccc2nc(-c3ccc(CN4CC(C(=O)O)C4)cc3F)sc2n1
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)(C)=O
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)C1CN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CCO5)nc4s3)c(F)c2)C1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of trimethylsulfoxonium iodide (230 mg, 1047 μmol) and potassium t-butoxide (1.0M in t-BuOH) (1.047 ml, 1.047 mmol) in t-BuOH (1.0 mL) was stirred at 50° C. for 30 min. 1-((4-(5-Benzoylthiazolo[5,4-b]pyridine-2-yl)-3-fluorophenyl)methyl)azetidine-3-carboxylic acid (93.7 mg, 0.209 mmol) was added in one portion, and the resulting suspension was stirred at 50° C. for 20 h. The reaction mixture was then diluted with 0.05M pH 6 phosphate buffer (2.0 mL), acidified with 1.0N HCl (750 μL), diluted with water (15 mL), and partially concentrated in vacuo. The resulting precipitate was collected by vacuum filtration, washed with water (3.0 mL), and dried in vacuo. Reverse-phase HPLC of this solid (C18, CH3CN/H2O+0.1% ammonium formate) afforded 1-((3-fluoro-4-(5-(2-phenyloxetan-2-yl)-thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)azetidine-3-carboxylic acid as a colorless solid. MS (ESI) m/z: Calculated: 475.1; Observed: 476.1 (M++1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[N:12][CH:11]=[C:10](Cl)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:28]1[CH:33]=[N:32][CH:31]=[CH:30][N:29]=1)CCC>>[C:1]([O:5][C:6](=[O:22])[N:7]([C:8]1[N:9]=[C:10]([C:28]2[CH:33]=[N:32][CH:31]=[CH:30][N:29]=2)[CH:11]=[N:12][CH:13]=1)[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(c1ccc(Cl)cc1)c1cncc(Cl)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Product: CC(C)(C)OC(=O)N(c1ccc(Cl)cc1)c1cncc(-c2cnccn2)n1

Procedure:
Was prepared according to Example 6 from (4-chloro-phenyl)-(6-chloro-pyrazin-2-yl)-carbamic acid tert-butyl ester and 2-tributylstannylpyrazine.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=2)=[CH:6][C:5]=1[C:21]1[CH:30]=[CH:29][C:28]2[C:27]([CH3:32])([CH3:31])[CH2:26][CH2:25][C:24]([CH3:34])([CH3:33])[C:23]=2[CH:22]=1.Br[CH2:36][CH2:37][CH2:38][CH2:39][N:40]([CH:47]([CH3:49])[CH3:48])[C:41](=[O:46])[C:42]([F:45])([F:44])[F:43].[Cl-].[NH4+]>CN(C=O)C>[CH:47]([N:40]([C:41](=[O:46])[C:42]([F:44])([F:45])[F:43])[CH2:39][CH2:38][CH2:37][CH2:36][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:15]=2)=[CH:6][C:5]=1[C:21]1[CH:30]=[CH:29][C:28]2[C:27]([CH3:32])([CH3:31])[CH2:26][CH2:25][C:24]([CH3:33])([CH3:34])[C:23]=2[CH:22]=1)([CH3:48])[CH3:49]
Reactant: CC(C)N(CCCCBr)C(=O)C(F)(F)F
Reactant: CCOC(=O)c1ccc(-c2ccc(O)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccc(OCCCCN(C(=O)C(F)(F)F)C(C)C)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
1.6 g (39 mmol) of 60% sodium hydride are suspended in 200 ml of anhydrous DMF under an inert atmosphere, and the mixture is cooled to 0° C. 13.9 g (32 mmol) of ethyl 4′-hydroxy-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate dissolved in 20 ml of DMF are added slowly. After 20 minutes, 11.3 g (39 mmol) of N-(4-bromobutyl)-2,2,2-trifluoro-N-isopropylacetamide are added. The reaction medium is then heated at 60° C. for 3 hours, and then cooled to room temperature and poured into 500 ml of saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed with water and dried, and the residue obtained is purified by chromatography on a column of silica (eluent: 9/1 heptane/ethyl acetate). A pasty white oil is obtained (m=21.2 g, yield=100%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[NH:4][N:3]=1.[C:13](/[CH:15]=[C:16](\[O-:18])/[CH3:17])#[N:14].[Na+]>>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](/[CH:11]=[C:15](/[C:16](=[O:18])[CH3:17])\[C:13]#[N:14])[CH:9]=2)[NH:4][N:3]=1
Reactant: O=Cc1ccc2[nH]nc(Br)c2c1
Reactant: C/C([O-])=C/C#N
Agent: [Na+]
Product: CC(=O)/C(C#N)=C/c1ccc2[nH]nc(Br)c2c1

Procedure:
The title compound was prepared from 2.85 g (70% purity, 8.87 mmol) 3-bromo-1H-indazole-5-carbaldehyde (Example 10A) and 1.03 g (9.75 mmol) sodium (1Z)-1-cyanoprop-1-en-2-olate in analogy to the procedure described in Example 9A yielding 1.12 g (43% of th.) of product which was used in subsequent steps without further purification.