Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].I[C:8]1[CH:9]=[N:10][N:11]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1.[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1(C)C=CC=CC=1.O.O.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>[C:32]1([C:8]2[CH:9]=[N:10][N:11]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:12]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: OB(O)c1ccccc1
Reactant: Ic1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Yield: 45 %

Procedure:
Na2CO3 (146 mg, 1.37 mmol) was added to a stirred solution of 4-iodo-1-trityl-1H-pyrazole (300 mg, 0.69 mmol) in toluene: H2O (5:1, 11.5 mL). Pd (PPh3)4 (80 mg, 0.07 mmol) and phenylboronic acid (126 mg, 1.03 mmol) were then added and the reaction mixture was heated to reflux for 2 hrs. The reaction mixture was then diluted with water and the product was extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulphate and concentrated to get the residue. The residue obtained was purified by column chromatography (using silica gel of 60-120 mesh and 5% EtOAc in Hexane as eluent) afford 120 mg (48.38% yield) of 4-phenyl-1-trityl-1H-pyrazole. 1H NMR (CDCl3): δ 7.96-7.94 (s, 1H), 7.64-7.6 (s, 1H), 7.46-7.4 (d, 2H), 7.36-7.0 (m, 1H), 7.24-7.16 (m, 7H).
Reaction SMILES: [OH:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24](OC)=[CH:23][CH:22]=1>CS(C)=O>[CH2:20]([O:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: COc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1OCc1ccccc1
Reaction time: 0.5 h
Yield: 58 %

Procedure:
To a solution of 2-hydroxyisoindoline-1,3-dione (1.0 g, 6.13 mmol) in DMSO (10 mL) was added Cs2CO3 (1.997 g, 6.13 mmol). The resulting mixture was stirred at it for 30 min. 1-bromomethyl 4-methoxy-benzene (0.88 mL, 6.13 mmol) was then added dropwise. After stirring at 50° C. overnight, the reaction mixture was quenched with NH4Cl (aq), extracted with EtOAc, washed with NH4Cl (aq), dried over Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel column with gradient hexanes:EtOAc to give 2-(benzyloxy)isoindoline-1,3-dione as a white solid (0.9 g, 49%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.85 (s, 4H), 7.42 (d, 2H), 6.94 (d, 2H), 5.08 (s, 2H), 3.75 (s, 3H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.I[C:15]1[N:16]=[C:17]([CH3:32])[N:18]([C:20]2[CH:21]=[C:22]3[C:27](=[C:28]([CH3:30])[CH:29]=2)[NH:26][C:25](=[O:31])[CH:24]=[CH:23]3)[CH:19]=1>CCCCCC.O1CCCC1.[Cl-].[Zn+2].[Cl-].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>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:15]2[N:16]=[C:17]([CH3:32])[N:18]([C:20]3[CH:21]=[C:22]4[C:27](=[C:28]([CH3:30])[CH:29]=3)[NH:26][C:25](=[O:31])[CH:24]=[CH:23]4)[CH:19]=2)=[CH:8][CH:9]=1
Reactant: Cc1cc(-n2cc(I)nc2C)cc2ccc(=O)[nH]c12
Reactant: Fc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(-n2cc(-c3ccc(F)cc3)nc2C)cc2ccc(=O)[nH]c12
Temperature: 25 °C

Procedure:
n-Butyllithium (3.5 cm3 of a 1.43M solution in n-hexane) was added dropwise to a stirred solution of 4-bromo-fluorobenzene (0.88 g) in tetrahydrofuran (THF) (20 cm3) at -70° under nitrogen. After 0.5 hours a solution of anhydrous zinc chloride (0.68 g) in THF (10 cm3) was added dropwise, and the mixture was warmed to room temperature over 1 hour. 6-(4-Iodo-2-methylimidazol-1-yl)-8-methyl-2-(1H)-quinolone (0.37 g) and tetrakis(triphenylphosphine)palladium (O) (0.01 g) were added and the mixture heated under reflux for 1.5 hours. The cooled solution was quenched with water (10 cm3) and poured into a saturated solution of ethylenediaminetetraacetic acid disodium salt in water (30 cm3), which had been adjusted to pH 9 by addition of sodium carbonate solution. This mixture was extracted with dichloromethane (3×100 cm3) and the combined and dried (MgSO4) extracts were evaporated in vacuo to give a residue which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with methanol:dichloromethane, 1:19 by volume. Collection and evaporation of appropriate fractions afforded a solid which was recrystallised from ethyl acetate to give the title compound, m.p. 289°-291° (0.14 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][N:13]1[CH2:17][CH:16]2[CH2:18][CH:19](O)[CH2:20][CH:15]2[CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH:19]3[CH2:20][CH:15]4[CH2:14][N:13]([CH3:12])[CH2:17][CH:16]4[CH2:18]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]cc(I)c12
Reactant: CN1CC2CC(O)CC2C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CC2CC(n3cc(I)c4c(Cl)ncnc43)CC2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.7 %

Procedure:
A mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (0.38 g, 1.36 mmol), 2-methylperhydrocyclopenta[c]pyrrol-5-ol (0.23 g, 1.63 mmol) and triphenylphosphine (0.71 g, 2.72 mmol) in tetrahydrofuran (20 mL) was treated with diethylazodicarboxylate (0.474 g, 2.72 mmol) and stirred for 2 hours at ambient temperature. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane (30 ml) and water (10 ml). The organic layer was washed with saturated aqueous sodium chloride (10 ml) then dried over magnesium sulfate then filtered and the filtrate evaporated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica using dichloromethane/methanol (8:2) as mobile phase to yield 4-chloro-5-iodo-7-(2-methylperhydrocyclopenta[c]pyrrol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine (0.25 g): 1H NMR (DMSO-d6, 400 MHz) δ 8.62 (s, 1H), 7.44 (s, 1H), 7.26 (s, 2H), 5.36 (m, 1H), 2.88 (m, 2H), 2.68 (m, 2H), 2.43 (m, 2H), 2.36 (s, 3H), 2.06-2.02 (m, 4H); TLC (dichloromethane/methanol 8:2) Rf =0.29; RP-HPLC (Hypersil HS C18, 5 μm, 100 A, 250×4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 10 min, 1 ml/min) tr=6.50 min; MS: MH+403.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.FC(F)(F)C(O)=O.[NH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[C@H:27]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:26][CH2:25]2>CC#N.O1CCOCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[C@H:27]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:26][CH2:25]3)=[N:3][CH:4]=1)#[N:7]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCN)ccc21
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CC#N
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3ccc(C#N)cn3)ccc21
Temperature: 25 °C
Yield: 54.2 %

Procedure:
A mixture of 6-chloronicotinonitrile (0.78 9, 5.54 mmol) and ethyl [(1S)-5-(3-aminopropoxy)-2,3-dihydro-1H-inden-1-yl]acetate trifluoroacetate (Example 263, 2.17 g, 5.54 mmol) in CH3CN (14 mL) and 1,4-dioxane (14 mL) was heated to reflux for 8 h, cooled to rt, and then concentrated under reduced pressure. The product (1.14 g, 54%) was isolated after column chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD2Cl2) δ 8.20 (s, 1H), 7.45 (dd, 1H), 6.94 (d, 1H), 6.67 (s, 1H), 6.58 (dd, 1H), 6.32 (d, 1H), 5.42 (b, 1H), 4.02 (q, 2H), 3.95 (t, 2H), 3.50-3.35 (m, 3H), 2.85-2.68 (m, 2H), 2.59 (dd, 1H), 2.32-2.20 (m, 2H), 2.00 (qt, 2H), 1.70-1.60 (m, 1H), 1.17 (t, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH2:13][CH2:14][CH2:15][CH3:16])[C:9]([O:11]C)=O.[CH3:17][P:18](=[O:23])([O:21][CH3:22])[O:19][CH3:20]>>[CH3:20][O:19][P:18]([CH2:17][C:9](=[O:11])[CH:8]([O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH2:13][CH2:14][CH2:15][CH3:16])(=[O:23])[O:21][CH3:22]
Reactant: CCCCC(OC1CCCCO1)C(=O)OC
Reactant: COP(C)(=O)OC
Product: CCCCC(OC1CCCCO1)C(=O)CP(=O)(OC)OC

Procedure:
Prepared from methyl 2-(2-tetrahydropyranyl)oxycaproate and dimethyl methylphosphonate according to the known method. (Yield 48%).
Reaction SMILES: C([NH:8][C:9]1[C:19]([N+:20]([O-])=O)=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([O:23][CH2:24][CH3:25])[CH:10]=1)C1C=CC=CC=1.C(O)C>[Pd].C1COCC1>[NH2:8][C:9]1[C:19]([NH2:20])=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([O:23][CH2:24][CH3:25])[CH:10]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(NCc2ccccc2)cc1OCC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1cc(N)c(N)cc1OCC

Procedure:
Palladium on charcoal (3.50 g 10%) was added to the product obtained at (655c) (16.7 g, 46.1 mmol) in 200 mL THF with 200 mL ethanol and the mixture was hydrogenated using a Parr apparatur at 60 psi H2 pressure and 50° C. for 3 h. The mixture was filtered, washed with ethanol and the filtrate concentrated i. vac. The residue was triturated with dichloromethane and evaporated to dryness. The product was reacted without further purification.
Reaction SMILES: [CH2:1]([C:3](=[CH2:6])[CH:4]=[O:5])[CH3:2].[SH:7][C:8]1[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].C(N(CC)CC)C>C1COCC1.CCOCC>[C:10]([C:9]1[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=1[S:7][CH2:6][CH:3]([CH2:1][CH3:2])[CH:4]=[O:5])(=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(c1ccccc1)c1ccccc1S
Reactant: C=C(C=O)CC
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(C=O)CSc1ccccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 63.6 %

Procedure:
To an ice bath cooled solution of 9.76 g (0.116 mole) of 2-ethylacrolein in 40 mL of dry THF was added 24.6 g (0.116 mole) of 2-mercaptobenzophenone in 40 mL of THF followed by 13 g (0.128 mole) of triethylamine. The reaction mixture was stirred at room temperature for 3 days, diluted with ether, and was washed successively with dilute HCl, brine, and 1 M potassium carbonate. The ether layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by HPLC (10% EtOAc-hexane) to give 22 g (64%) of 11 in the second fraction. An attempt to further purifiy this material by kugelrohr distillation at 0.5 torr (160-190° C.) gave a fraction (12.2 g) which contained starting material indicating a reversed reaction during distillation. This material was dissolved in ether (100 mL) and was washed with 50 mL of 1 M potassium carbonate three times to give 6.0 g of a syrup which was purified by HPLC (10% EtOAc-hexane) to give 5.6 g of pure 11.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[NH:10][C:9](=[O:11])[CH2:8][N:7]([C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:6]1)=[O:4].[C:18](=[N:31][C:32]1[CH:39]=[C:38]([CH2:40]Br)[CH:37]=[CH:36][C:33]=1[C:34]#[N:35])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([CH:5]1[N:10]([CH2:40][C:38]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[C:32]([N:31]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:39]=2)[C:9](=[O:11])[CH2:8][N:7]([C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:6]1)=[O:4]
Reactant: N#Cc1ccc(CBr)cc1N=C(c1ccccc1)c1ccccc1
Reactant: C=CCOC(=O)N1CC(=O)N[C@H](C(=O)OC)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1CC(=O)N(Cc2ccc(C#N)c(N=C(c3ccccc3)c3ccccc3)c2)C(C(=O)OC)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To a solution containing (S)-5-oxo-piperazine-1,3-dicarboxylic acid 1-allyl ester 3-methyl ester (0.43 g, 1.77 mmol), EXAMPLE 56, and 2-(benzhydrylidene-amino)-4-bromomethyl-benzonitrile (0.66 g, 1.77 mmol), EXAMPLE 13, in anhydrous DMF (5 mL) at 0° C. is added 60% NaH (78 mg, 1.95 mmol). After 30 min, the reaction mixture is warmed to ambient temperature and maintained for 6 hours. The reaction mixture is carefully quenched with water and then diluted with water and diethyl ether. The layers are separated and the organic phase is washed twice with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue is chromatographed on silica gel (2:1 hexane/ethyl acetate to 1:1 hexane/ethyl acetate) to provide 0.37 g (39%) of the title compound as a glassy solid.
Reaction SMILES: [C:1]([C:9]1[CH:13]=[CH:12][NH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:14]OS(O)(=O)=O>[OH-].[K+]>[NH2:14][N:11]1[CH:12]=[CH:13][C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10]1
Reactant: NOS(=O)(=O)O
Reactant: O=C(c1ccccc1)c1cc[nH]c1
Agent: [K+]
Agent: [OH-]
Product: Nn1ccc(C(=O)c2ccccc2)c1

Procedure:
A 3-benzoylpyrrole of the formula ##STR25## in potassium hydroxide or other suitable base is reacted with hydroxylamine-O-sulfonic acid to yield a 1-amino-3-benzoylpyrrole of the formula ##STR26## This reaction typically takes place in the presence of a suitable solvent such as dimethylformamide at a temperature of about 0° to 25° C. (or at room temperature) for 0.5 to 4 hours.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([F:16])=[C:14]([F:17])[CH:13]=[C:12]([O:18][Si](C(C)(C)C)(C)C)[C:11]=2[O:26][CH3:27])=[O:9])=[CH:6][N:5]=[C:4]([NH:28][CH:29]2[CH2:34][CH2:33][N:32]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:31][CH2:30]2)[N:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:11]([O:26][CH3:27])=[C:12]([OH:18])[CH:13]=[C:14]([F:17])[C:15]=2[F:16])=[O:9])=[CH:6][N:5]=[C:4]([NH:28][CH:29]2[CH2:30][CH2:31][N:32]([S:35]([CH3:38])(=[O:36])=[O:37])[CH2:33][CH2:34]2)[N:3]=1
Reactant: COc1c(O[Si](C)(C)C(C)(C)C)cc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1c(O)cc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
To a solution of [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-[3-(tert-butyl-dimethyl-silanyloxy)-5,6-difluoro-2-methoxy-phenyl]-methanone (675 mg, 1.181 mmol, Example 270) in tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride (1.240 mL, 1.24 mmol, 1 M solution in tetrahydrofuran, Aldrich). The mixture was stirred at room temperature for 15 minutes and then concentrated to dryness. The residue was taken up in methylene chloride and washed with saturated solution of sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate. The solids were filtered off and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, 60 A silica gel, eluting with 65-80% ethyl acetate in hexanes then 5% methanol in ethyl acetate) yielded [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2,3-difluoro-5-hydroxy-6-methoxy-phenyl)-methanone as white solids (315 mg, 58%). HR-MS (ES, m/z) calculated for C18H22N5O5SF2 [(M+H)+]458.1308, observed 458.1304.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[N:7]([CH3:41])[CH:8]([CH3:40])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]3=[N:20][C:19]=2[CH3:27])=[C:14]([C:28]#[C:29][Si](C(C)C)(C(C)C)C(C)C)[N:13]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:42])[N:7]([CH:8]([CH3:40])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]3=[N:20][C:19]=2[CH3:27])=[C:14]([C:28]#[CH:29])[N:13]=1)=[O:10])[CH3:41])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc2ccccn2c1-c1ccc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)nc1C#C[Si](C(C)C)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C#Cc1nc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)ccc1-c1c(C)nc2ccccn12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of tert-butyl-N-methyl-N-[1-[[5-(2-methylimidazo[1,2-a]pyridin-3-yl)-6-[2-tri-(propan-2-yl)silylethynyl]pyridin-2-yl]-amino]-1-oxopropan-2-yl]carbamate E1k (16.7 g, 28.3 mmol), THF (200 ml) and tetrabutylammonium fluoride (1 mol/l solution in THF, 34 ml, 34 mmol) is stirred at RT for 15 minutes. The mixture is diluted with DCM and extracted with a saturated aqueous solution of NaHCO3. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The mixture is concentrated in vacuo and the product purified by NP chromatography. Yield: 10.6 g (86%). HPLC-MS: M+H=434; tR=1.20 min (*Method—1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[CH3:23][C:24]1[C:28]([CH2:29][CH2:30][C:31]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[O:32])=[C:27]([CH3:40])[NH:26][C:25]=1[CH:41]=O.N1CCCCC1>C(O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:41]\[C:25]1[NH:26][C:27]([CH3:40])=[C:28]([CH2:29][CH2:30][C:31]([N:33]2[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]2)=[O:32])[C:24]=1[CH3:23])(=[O:12])=[O:11]
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)N1CCN(C)CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 5-(2,6-Dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (122 mg, 0.34 mmol), 3,5-dimethyl-4-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-1H-pyrrole-2-carbaldehyde (1.4 eq.) and piperidine (0.5 eq.) in ethanol (2 mL) was stirred at rt for 72 hours. The reaction was concentrated and purified on a silica gel column to give the titled compound as a dark orange brown solid. 1HNMR (400 MHz, DMSO-d6) δ 13.44 (s, 1H, NH), 11.25 (s, 1H, NH), 8.18 (d, 1H), 7.75 (s, 11H), 7.48 (s, 1H), 7.46 (s, 1H), 7.38 (m, 2H), 6.99 (d, J=8 Hz, 1H), 4.85 (s, 2H), 3.3-3.42 (m, 2H), 2.62 (m, 2H), 2.44 (m, 2H), 2.30 (s, 3H, CH3), 2.28 (s, 3H, CH3), 2.1-2.2 (m, 4H), 2.11 (s, 3H, CH3). MS m/z 613 [M−1].
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1.[C:11](Cl)(=[O:15])[CH:12]([CH3:14])[CH3:13]>N1C=CC=CC=1>[C:7]([C:5]1[O:4][N:3]=[C:2]([NH:1][C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])[CH:6]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1cc(C(C)(C)C)on1
Temperature: 25 °C
Yield: 91.7 %

Procedure:
To a solution of 3-amino-5-t-butylisoxazole (2.80 g) in pyridine (10 ml) is dropwise added isobutyryl chloride (2.34 g) keeping the mixture below 10° C. The reaction mixture is stirred with cooling for 30 minutes and at room temperature for 1 hour and evaporated to remove the pyridine. The residue is mixed with 5% hydrochloric acid solution (40 ml) and shaken with methylene chloride. The methylene chloride layer is separated, washed with saturated aqueous sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate and evaporated to remove the methylene chloride. The residue is chromatographed on a column of silica gel and recrystallized from n-hexane to give N-(5-t-butyl-3-isoxazolyl)isobutyramide (3.85 g) as colorless needles melting at 123.0° to 124.0° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:35][C:36](=O)[O:37]C2C=CC=CC=2)[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:36]([NH:35][C:27]2[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=[C:25]([O:24][CH3:23])[CH:26]=2)=[O:37])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc(NC(=O)Oc2ccccc2)cc(C(F)(F)F)c1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Product: COc1cc(NC(=O)Nc2cccc(Oc3ncnc4cc(OC)c(OC)cc34)c2)cc(C(F)(F)F)c1
Yield: 46.7 %

Procedure:
3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 g, 0.3 mmol) and phenyl 3-methoxy-5-(trifluoromethyl)phenylcarbamate from Example 115A (140 mg, 0.45 mmol) were reacted using the procedure in Example 115C to give 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-methoxy-5-(trifluoromethyl)phenyl)urea (71 mg, 0.14 mmol, 46%). 1H NMR (300 MHz, DMSO-d6) δ 9.19 (s, 1H), 9.08 (s, 1H), 8.56 (s, 1H), 7.62-7.55 (m, 2H), 7.48 (s, 1H), 7.45-7.37 (m, 2H), 7.31-7.24 (m, 2H), 6.95 (d, 1H), 6.84 (s, 1H), 4.00 (s, 3H), 3.99 (s, 3H), 3.80 (s, 3H); LC-MS (ESI) m/z 515 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][C@H:8]([NH:23][C:24](=[O:39])[C@@H:25]([N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35](=[O:37])[CH3:36])[C:29]1=[O:38])[CH2:26][CH3:27])[C:9](=[O:22])[CH2:10][O:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[CH:15]=[C:14]([F:20])[C:13]=1[F:21])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:35]([NH:34][C:30]1[C:29](=[O:38])[N:28]([C@@H:25]([CH2:26][CH3:27])[C:24]([NH:23][C@H:8]([C:9](=[O:22])[CH2:10][O:11][C:12]2[C:17]([F:18])=[C:16]([F:19])[CH:15]=[C:14]([F:20])[C:13]=2[F:21])[CH2:7][C:6]([OH:40])=[O:5])=[O:39])[CH:33]=[CH:32][CH:31]=1)(=[O:37])[CH3:36]
Reactant: CC[C@@H](C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)COc1c(F)c(F)cc(F)c1F)n1cccc(NC(C)=O)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)COc1c(F)c(F)cc(F)c1F)n1cccc(NC(C)=O)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
A solution of (S,S)-3-[2-(3-Acetylamino-2-oxo-2H-pyridin-1-yl)-butyrylamino]-4-oxo-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid tert-butyl ester (187 mg, 0.327 mmol) in dichloromethane (5 mL) was cooled to 0° C. Trifluoroacetic acid (5 ml) was added and the resulting mixture allowed to warm to room temperature and stir for 2 hours. The mixture was then concentrated under reduced pressure and the residue redissolved in dichloromethane. This process was repeated several times in order to remove excess trifluoroacetic acid. The resulting solid was slurried in diethyl ether, filtered and washed with more diethyl ether. The solid was then dried to constant weight under vacuum. This gave the title product as a white solid (138 mg, 82%); 1H NMR (400 MHz, d6-DMSO) δ 0.78 (3H, t), 1.87-2.13 (5H, m), 2.56-2.78 (2H, m), 4.62 (1H, m), 5.18-5.29 (2H, m), 5.40 (1H, m), 6.28 (1H, t), 7.37 (1H, d), 7.53-7.66 (1H, m), 8.17-8.21 (1H, m), 8.92 (1H, d), 9.21 (1H, s), 12.51 (1H, br s); 19F NMR (376 MHz, d6-DMSO, proton-decoupled) δ−156.9, −141.1; M+H 516.2, M−H 514.2.