Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH:20][C:21](=[O:35])[CH:22]([C:26]2[C:31]([F:32])=[CH:30][CH:29]=[C:28]([OH:33])[C:27]=2[F:34])[O:23][CH2:24][CH3:25])=[CH:15][CH:14]=1)=[NH:12])C1C=CC=CC=1.[ClH:37]>CCO.[Pd]>[ClH:37].[C:11]([C:13]1[CH:14]=[CH:15][C:16]([CH2:19][NH:20][C:21](=[O:35])[CH:22]([C:26]2[C:31]([F:32])=[CH:30][CH:29]=[C:28]([OH:33])[C:27]=2[F:34])[O:23][CH2:24][CH3:25])=[CH:17][CH:18]=1)(=[NH:10])[NH2:12]
Reactant: CCOC(C(=O)NCc1ccc(C(=N)NC(=O)OCc2ccccc2)cc1)c1c(F)ccc(O)c1F
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(C(=O)NCc1ccc(C(=N)N)cc1)c1c(F)ccc(O)c1F
Reaction time: 2 h
Yield: 87 %

Procedure:
(RS)-[(4-{[2-(2,6-Difluoro-3-hydroxy-phenyl)-2-ethoxy-acetylamino]-methyl}-phenyl)-imino-methyl]-carbamic acid benzyl ester (250 mg) was dissolved in EtOH (20 ml) and 0.9 N HCl in EtOH (5 ml) was added. After 10 min stirring 10% Pd/C (11 mg) was added and the mixture was hydrogenated 2 h at rt under 1 atm H2. Filtration, evaporation of the solvent and trituration with MeCN (4 ml) afforded the solid product that was washed with two portions of Et2O (5 ml). After drying on the vacuum at 50° C. 175 mg (87%) of (RS)-N-(4-carbamimidoyl-benzyl)-2-(2,6-difluoro-3-hydroxy-phenyl)-2-ethoxy-acetamide hydrochloride were obtained. White solid. MS 364.0 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]([C:11]([OH:13])=O)=[CH:8][C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:6][C:5]=2[N:4]([CH:20]([CH3:22])[CH3:21])[N:3]=1.Cl.[NH2:24][CH2:25][C:26]1[C:27](=[O:34])[NH:28][C:29]([CH3:33])=[CH:30][C:31]=1[CH3:32].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.CN1CCOCC1.[Al].C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O.O>[Br:1][C:2]1[C:10]2[C:9]([C:11]([NH:24][CH2:25][C:26]3[C:27](=[O:34])[NH:28][C:29]([CH3:33])=[CH:30][C:31]=3[CH3:32])=[O:13])=[CH:8][C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:6][C:5]=2[N:4]([CH:20]([CH3:21])[CH3:22])[N:3]=1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CC(C)n1nc(Br)c2c(C(=O)O)cc(-c3ccccc3)nc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccccc3)nc3c2c(Br)nn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-Bromo-1-(1-methylethyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (93 mg, 0.258 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone hydrochloride (64 mg, 0.336 mmol), HOBT (60 mg, 0.387 mmol) and EDC (74 mg, 0.387 mmol) were suspended in DMSO (14 mL) and stirred at room temperature for 10 minutes, after which time DIEA (0.9 ml, 5.16 mmol) was added. After stirring for 2 h, 4-methylmorpholine (1 ml, 9.04 mmol) was added. The reaction mixture was stirred first at room temperature for 21 h, and then at 80° C. (aluminum heating block) for 31 h. The reaction mixture was cooled to room temperature and then added dropwise to a cold, slightly basic solution (pH˜8-10) of water (100 mL) and 1N Na2CO3 (8 mL). After stirring for 20 min., the contents were extracted with EtOAc (2×100 mL). The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated to a residue. The crude residue was dissolved in 10% MeOH/DCM and purified by silica gel chromatography (eluent: 10-95% gradient EtOAc/Hexanes and then 10% (5% NH4OH/MeOH)/DCM and EtOAc, 10-90% gradient). The product was collected as an off-white solid. (35 mg, 27%). LCMS E-S (M+H)=494.1/496.0. 1H NMR (400 MHz, CHLOROFORM-d) δ 11.58 (br. s., 1H), 8.11 (dd, J=1.89, 7.71 Hz, 2H), 7.68 (br. s., 1H), 7.60 (br. s., 1H), 7.44-7.53 (m, 3H), 5.92 (s, 1H), 5.42 (quin, J=6.69 Hz, 1H), 4.63 (br. s., 1H), 2.41 (br. s., 3H), 2.11 (br. s., 3H), 1.62 (d, J=6.57 Hz, 6H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[N:7][CH:8]=1.N1C=CC=CC=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>C1COCC1.C(Cl)Cl>[C:22]1([O:21][C:19](=[O:20])[NH:9][C:5]2[CH:6]=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1cncc(C(F)(F)F)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cncc(C(F)(F)F)c1)Oc1ccccc1
Reaction time: 2 h

Procedure:
Example 7-A, 5-trifluoromethyl-pyridin-3-ylamine, (385 mg, 2.37 mmol) is taken up in THF (25 mL) and pyridine (0.38 mL, 4.75 mmol) at 0° C. before phenyl chloroformate (558 mg, 3.56 mmol) is added. After 2 h, the reaction is diluted with DCM (50 mL) and washed with water (50 mL). The organic layer is separated, dried over anhydrous Na2SO4, filtered and concentrated. The residue is then separated via FCC (EtOAc/heptanes 1:9 to EtOAc/heptanes 1:1) to give the title compound.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])=[O:4].C=CC.Cl.[CH3:15][CH2:16][CH2:17][CH2:18]C>[Cl-].[Cl-].[Cl-].[Al+3]>[F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])([OH:4])[CH2:15][CH:16]=[CH:17][CH3:18]
Reactant: CCCCC
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C=CC
Product: CC=CCC(O)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Yield: 70 %

Procedure:
Referring to scheme (1) above, pentane (300 mL) can be placed in a 500 mL three neck flask and chilled below −30° C. To the pentane can be added hexafluoroacetone (59 grams, 0.36 mole), propylene (16.2 grams, 0.38 mole), and anhydrous aluminum trichloride (0.77 g, 0.006 mole) to form a mixture. This mixture can be stirred and the temperature can be allowed to warm to room temperature over a 3 hour period. A 15% (wt/wt) aqueous HCl solution (20 mL) can be added to the mixture, and the mixture can be washed 3 times with H2O. The aqueous layer, after the wash, can be decanted off, and the organic layer (pentane and propylene) can be dried with MgSO4. Remaining pentane and propylene can be flash vaporized off at 60° C. to give 54.4 grams (70% area percent by gas chromatography) of isomeric 1,1-bis(trifluoromethyl)-3-penten-1-ol.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([CH2:10][O:11]COC)=[CH:5][N:4]=1)[CH3:2].O.[OH-].[Na+].C(=O)([O-])O.[Na+]>O1CCOCC1.Cl.C(OCC)(=O)C>[CH2:1]([C:3]1[N:4]=[CH:5][C:6]([CH2:10][OH:11])=[CH:7][C:8]=1[F:9])[CH3:2]
Reactant: CCc1ncc(COCOC)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1ncc(CO)cc1F
Temperature: 35 °C
Reaction time: 1 h
Yield: 101.5 %

Procedure:
To a solution of 0.11 g of 2-ethyl-3-fluoro-5-((methoxymethoxy)methyl)pyridine in 2 mL of 1,4-dioxane, 1 mL of 6 mol/L hydrochloric acid was added, and the mixture was stirred at 30 to 40° C. for 1 hour. After cooling to room temperature, the reaction mixture was charged with water and ethyl acetate and adjusted to pH 7.9 with a 20% aqueous sodium hydroxide solution and a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 87 mg of (6-ethyl-5-fluoropyridin-3-yl)methanol as a light yellow oily substance.
Reaction SMILES: C(OC([N:8]([CH2:19][CH2:20][C:21]1[CH:42]=[CH:41][C:24]([CH2:25][C:26]2[CH:40]=[CH:39][C:29]([O:30][CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])=[CH:28][CH:27]=2)=[CH:23][CH:22]=1)[CH2:9][C@@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[OH:11])=O)(C)(C)C.Cl.O1CCCC1>O1CCOCC1>[ClH:18].[Cl:18][C:14]1[CH:13]=[C:12]([C@@H:10]([OH:11])[CH2:9][NH:8][CH2:19][CH2:20][C:21]2[CH:42]=[CH:41][C:24]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:39][CH:40]=3)=[CH:23][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cc2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(Cc2ccc(CCNC[C@H](O)c3cccc(Cl)c3)cc2)cc1
Reaction time: 0.08 h
Yield: 75.1 %

Procedure:
A solution of tert-butyl [4-[4-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-amino]ethyl]benzyl]phenoxy]acetate (240 mg) and 4N hydrochloride in 1,4-dioxane (3.0 ml) was stirred at room temperature for 24 hours. The mixture was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (methanol/acetic acid/chloroform=10/1/100) to give a product. To a tetrahydrofuran (2.0 ml) solution of the product, 4N hydrogen chloride in 1,4-dioxane (1.0 ml) was added. The mixture was stirred for 5 minutes and evaporated under reduced pressure to give [4-[4-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]benzyl]phenoxy]acetic acid hydrochloride (72 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:8]=2)[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:30][C:31]1[N:32]=[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]2[CH:39]=1>CS(C)=O>[N:32]1[C:31]([CH2:30][N:6]2[C:2]([CH3:1])=[N:3][C:4]([C:7]3[O:11][N:10]=[C:9]([C:12]4[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=4)[N:8]=3)=[N:5]2)=[CH:39][N:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=12
Reactant: ClCc1cn2ccccc2n1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cn2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.1 %

Procedure:
To a solution of 5-(5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (31 mg, 0.1 mmol) in DMSO (0.5 mL), Cs2CO3 (65 mg, 0.2 mmol) and 2-(chloromethyl)imidazo[1,2-a]pyridine (18 mg, 0.11 mmol) were added at RT. The mixture was stirred at RT overnight. The resulting crude product was purified by pre-HPLC (Mobile phase: A=0.01% TFA/H2O, B=0.01% TFA/MeCN; Gradient: B=10%-50% in 20 min; Column: C18) and then a silica gel column with (EtOAc/Hexane 16% to 100% EtOAc) to give 5-(1-(imidazo[1,2-a]pyridin-2-ylmethyl)-5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole as a white solid (4 mg, 10%). MS (ES+) C20H14F3N7O2 requires: 441. found: 442 [M+H]+; 1H NMR (600 MHz, DMSO-d6) δ 8.53 (d, J=6.8 Hz, 1H), 8.21 (d, J=8.8 Hz, 2H), 8.01 (s, 1H), 7.61 (d, J=8.5 Hz, 2H), 7.51 (d, J=9.1 Hz, 1H), 7.26 (dd, J=7.5, 8.2 Hz, 1H), 6.91 (t, J=6.8 Hz, 1H), 5.66 (s, 2H), 2.69 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[O:17]=[C:18]1[C:27]([C:28]#[N:29])=[C:26]([N:30]2[CH2:35][CH2:34][N:33]([C:36]([C:38]3[S:39][CH:40]=[CH:41][CH:42]=3)=[O:37])[CH2:32][CH2:31]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19]1>ClCCl>[O:17]=[C:18]1[C:27]([C:28]#[N:29])=[C:26]([N:30]2[CH2:35][CH2:34][N:33]([C:36]([C:38]3[S:39][CH:40]=[CH:41][CH:42]=3)=[O:37])[CH2:32][CH2:31]2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:19]1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2ccccc2[nH]c1=O
Reactant: OB(O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2ccccc2n(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 31 %

Procedure:
Cupric acetate (497 mg, 2.74 mmol), triethylamine (380 μL, 2.74 mmol), and phenyl boronic acid (335 mg, 2.74 mmol) were added successively to a solution of Compound 116 (500 mg, 1.37 mmol) in dichloromethane. The solution was stirred at room temperature for 48 h. The solution was filtered through celite and washed successively by saturated NaHCO3 solution, water, and brine. The organic phase was dried over Na2SO4 and evaporated to yield a residue which was purified by flash chromatography eluting with 0-1% MeOH in dichloromethane gradient to get 187 mg (31%) of white solids. M.P. 289° C. 1H NMR (DMSO-d6): δ 3.78 (m, 4H), 4.02 (m, 4H), 6.60 (d, J=7.6 Hz, 1H), 7.22 (m, 1H), 7.38 (m, 3H), 7.57-7.71 (m, 5H), 7.88 (dd, J=0.8, 4.8 Hz, 1H), 8.02 (d, J=7.2 Hz, 1H). EIMS m/z 441 (M+1). Anal. (C25H20N4O2S) C, H, N.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:11]=2)(=O)=O.[C:31]([C:33]1([OH:41])[CH:38]2[CH2:39][CH2:40][N:35]([CH2:36][CH2:37]2)[CH2:34]1)#[CH:32].C(N(CC)CC)C.N>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.CN(C)C=O>[CH2:22]([C:8]1[C:7]([C:32]#[C:31][C:33]2([OH:41])[CH:38]3[CH2:39][CH2:40][N:35]([CH2:36][CH2:37]3)[CH2:34]2)=[CH:16][C:15]2[C:10](=[CH:11][C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:14]=2)[N:9]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1ccc2cc(OS(=O)(=O)C(F)(F)F)c(Cc3ccccc3)nc2c1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2cc(C#CC3(O)CN4CCC3CC4)c(Cc3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.7 %

Procedure:
A mixture of 220 mg of 2-benzyl-7-ethoxycarbonyl-3-quinolyl Trifluoromethane sulfonate, 83 mg of 3-ethynyl-3-quinuclidinol, 116 mg of tetrakis(triphenylphosphine)palladium(0), 19 mg of cuprous iodide, 209 μl of triethylamine and 5.0 ml of N,N-dimethylformamide was stirred at room temperature for 45 minutes in a nitrogen atmosphere. The reaction solution was poured into aqueous dilute ammonia, followed by extracting with ethyl acetate. Then, the organic phase was washed with brine and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) chromatography and eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (15:1), to give 220 mg of the target compound.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([C:18]([OH:20])=[O:19])=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH2:23])=[N-]>CCOC(C)=O.CCOCC>[C:1]1([C:7]2[S:8][C:9]([C:18]([O:20][CH3:23])=[O:19])=[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1sc(-c2ccccc2)nc1-c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)c1sc(-c2ccccc2)nc1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 106.9 %

Procedure:
To a pre-cooled (0° C.) solution of 2,4-Diphenyl-1,3-thiazole-5-carboxylic acid 72 (400 mg, 1.422 mmol) in EtOAc (7.109 ml) was added a 0.5 M solution of diazomethane (5.69 ml, 2.84 mmol) in Et2O (freshly prepared) (c.a. 5 mL) and the resulting white suspension was stirred at 0° C. for 1 h. TLC showed completion. Then, the small amount of white solid left was filtered off and the filtrate was concentrated in vacuo to afford methyl 2,4-diphenylthiazole-5-carboxylate 73 (0.449 g, 107% yield).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[F:29][C:30]1([F:36])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[F:29][C:30]1([F:36])[CH2:35][CH2:34][N:33]([CH2:2][C:3]2[N:4]([CH3:28])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH3:27])[N:6]=3)[CH2:32][CH2:31]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: FC1(F)CCNCC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(F)(F)CC3)n(C)c2n1

Procedure:
4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 4,4-difluoropiperidine via General Procedure E to give 19.3 mg of 278 following reverse phase purification. MS (Q1) 483.2 (M)+
Reaction SMILES: CN(C)S([N:6]1[CH:10]=[C:9]([CH:11]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:20][CH3:21])O)[N:8]=[C:7]1[Si](C(C)(C)C)(C)C)(=O)=O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH2:20]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH2:11][C:9]1[N:8]=[CH:7][NH:6][CH:10]=1)[CH3:21]
Reactant: CCc1cccc(F)c1C(O)c1cn(S(=O)(=O)N(C)C)c([Si](C)(C)C(C)(C)C)n1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cccc(F)c1Cc1c[nH]cn1

Procedure:
Prepared in analogy to Example 57(e) from rac-2-(tert-butyl-dimethyl-silanyl)-4-[(2-ethyl-6-fluoro-phenyl)-hydroxy-methyl]-imidazole-1-sulfonic acid dimethylamide, triethylsilane and trifluoroacetic acid in dichloromethane in a pressure tube at 100° C. for 16 h. White crystalline solid. MS (ISP): 205.3 ([M+H]+).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)C[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:50][C:45]2[CH:46]=[CH:47][CH:48]=[N:49][C:44]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N1CCC[C@@H](N)C1)(OC(C)(C)C)=O>>[CH:1]1([N:7]2[CH2:13][C:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([NH:50][C@@H:45]5[CH2:46][CH2:47][CH2:48][NH:49][CH2:44]5)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: C=CC1(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Agent: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Agent: F[P-](F)(F)(F)(F)F
Product: C=CC1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)N[C@@H]4CCCNC4)cc3OC)ncc2N(C)C1=O

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and (R)-1-Boc-3-aminopiperidine. Further, after washing with water (10 ml), t-butoxycarbonyl (Boc) protection group was removed using 40% TFA in dichloromethane (6 ml) and purified the product using preparative HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41-2.00 (m, 12 H) 2.39 (t, J=6.5 Hz, 2 H) 2.81 (d, J=12.38 Hz, 1 H) 2.96 (d, J=12.38 Hz, 1 H) 3.28 (s, 3 H) 3.70-3.88 (m, 3 H) 3.94 (s, 2 H) 4.88 (m, 1 H) 5.37 (d, 2 H) 6.00 (m, 1 H) 7.47 (d, J=8.0 Hz, 1 H), 7.48 (br. s., 1 H) 7.82 (s, 1 H) 7.98 (d, J=8.0 Hz, 1 H) 8.12 (s, 1 H) 8.30 (d, J=8.0 Hz, 1 H). Melting point: 169-172° C. [M+H] calculated for C28H36FN7O3, 538; found 538.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH3:22])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2)=[O:2].C[Si](C)(C)[C:25]([F:28])([F:27])[F:26]>C1COCC1.[F-].C[N+](C)(C)C>[CH3:22][C:5]1[CH:6]=[C:7]2[C:12](=[C:3]([CH:1]([OH:2])[C:25]([F:28])([F:27])[F:26])[CH:4]=1)[O:11][CH:10]([C:13]([F:16])([F:14])[F:15])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2
Reactant: CCOC(=O)C1=Cc2cc(C)cc(C=O)c2OC1C(F)(F)F
Reactant: C[Si](C)(C)C(F)(F)F
Agent: C[N+](C)(C)C
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)C1=Cc2cc(C)cc(C(O)C(F)(F)F)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 116 %

Procedure:
The aldehyde from Example 605a, Step 1 (2.0 g, 6.37 mmol) in THF (20 mL) was cooled to 0° C. and treated with 98% trimethyl(trifluoromethyl)silane (1.18 g, 8.28 mmol) and 15 mg tetramethylammonium fluoride. The reaction was allowed to warm to room temperature and stirred for overnight. The HF (48%, 0.24 mL) was added to the reaction and the reaction was stirred for 6 hours. After LCMS indicated that there was no starting material in the reaction, the reaction was quenched with water, extracted with ethyl acetate, washed with water, brine, dried over MgSO4, and concentrated in vacuo to give a yellow semisolid (2.84 g), which had suitable purity to use without further purification.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][CH2:6]1)=[O:4].O.[OH-].[Na+].Cl>C1COCC1>[C:14]([O:13][C:11]([N:9]1[CH:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:10]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)C1CCC(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1CCC(C(=O)O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.3 %

Procedure:
Piperidine-1,2,5-tricarboxylic acid 1,2-di-tert-butyl ester 5-methyl ester (36.7 mmol, 12.6 g) was dissolved in 180 mL of 2:1 THF:H2O. To this solution was added 2N sodium hydroxide solution (52 mL) and the reaction mixture was stirred for 16 h at room temperature. The reaction mixture is acidified to pH=3 with 1N HCl(aq) and extracted with dichloromethane (3×100 mL). The combined organics are then dried over Na2SO4 and the solvent removed in vacuo to yield the title compound (12.0 g, 100% yield).
Reaction SMILES: ClC(Cl)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[CH:8][C:7]=1[C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2([C:29]([F:32])([F:31])[F:30])[N:28]=[N:27]2)=[CH:22][CH:21]=1)=[O:19])=O.[C-]#[N:35].[K+]>CCO.O>[NH2:35][C:3]1[C:18]([C:20]2[CH:21]=[CH:22][C:23]([C:26]3([C:29]([F:32])([F:31])[F:30])[N:28]=[N:27]3)=[CH:24][CH:25]=2)([OH:19])[C:7]2[C:6](=[CH:11][CH:10]=[C:9]([C:12]#[C:13][Si:14]([CH3:15])([CH3:16])[CH3:17])[CH:8]=2)[N:5]=1
Reactant: C[Si](C)(C)C#Cc1ccc(NC(=O)C(Cl)Cl)c(C(=O)c2ccc(C3(C(F)(F)F)N=N3)cc2)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)C#Cc1ccc2c(c1)C(O)(c1ccc(C3(C(F)(F)F)N=N3)cc1)C(N)=N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.2 %

Procedure:
2,2-dichloro-N-[2-({4-[3-(trifluoromethyl)diazirin-3-yl]phenyl}carbonyl)-4-[2-(trimethylsilyl)ethynyl]phenyl]acetamide (57 mg, 0.11 mmol, 1 eq.) was dissolved in EtOH (3 mL). Potassium cyanide (9.4 mg, 0.14 mmol, 1.3 eq.) in water (1 mL) was added to the reaction, and the reaction was stirred at room temperature for 16 hours. The EtOH was evaporated, and additional water (8 mL) was added. The reaction was then extracted three times with 5% isopropanol in DCM (20 mL each), and the organic layer was dried over sodium sulfate. The solvent was evaporated, and the residue was purified on silica column (DCM/MeOH, 39:1→19:1→9:1→4:1) to result in 39.2 mg (82%) of the title compound as a yellow solid. 1H NMR (500 MHz, CD3OD) δ 7.44 (d, J=8.5, 2H, Ar—H), 7.29 (dd, J=1.8, 8.8, 1H, Ar—H), 7.22 (d, J=8.3, 2H, Ar—H), 7.02-6.94 (m, 2H, Ar—H), 0.18 (s, 9H, SiC3H9). 13C NMR (126 MHz, CD3OD) δ 180.56 (C—NH2), 156.85 (C—Ar), 144.59 (C—Ar), 140.89 (C—Ar), 135.13 (C—Ar), 129.58 (C—Ar), 127.89 (d, J=0.88, C—Ar), 127.66 (C—Ar), 126.99 (C—Ar), 123.70 (q, J=273.80, CF3), 117.82 (C—Ar), 116.69 (C—Ar), 107.08 (CSi(CH3)3), 92.94 (CCSi(CH3)3), 84.20 (Ar—COH), 29.55 (q, J=40.25, CN2), 0.23 (Si(CH3)3). Exact Mass, 428.13.