Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([S:6][CH2:7][NH:8][CH3:9])([CH3:5])([CH3:4])[CH3:3].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14]([N:18]=[C:19]=[O:20])[CH:15]=[CH:16][CH:17]=1.C(N(CC)CC)C>C(#N)C>[CH3:9][N:8]([CH2:7][S:6][C:2]([CH3:5])([CH3:4])[CH3:3])[C:19]([NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([F:10])([F:21])[F:22])[CH:13]=1)=[O:20]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CNCSC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(CSC(C)(C)C)C(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 0 °C

Procedure:
Two grams of the product of Example I (0.0118 mole), 2.2 g. (0.0118 mole) of 3-trifluoromethylphenylisocyanate, and 100 ml. of acetonitrile are combined in a 250 ml. Erlenmeyer flask. The mixture is magnetically stirred, and 1.9 g. (0.0118 mole) of triethylamine are then added. The resulting mixture is stirred at room temperature for one hour and then poured into 300 ml. of ice water. The crystalline product is collected by filtration and dried to yield 2.0 g. (53% of theory) of the title compound, mp = 96°-99° C. Structure is confirmed by IR and NMR.
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].O>CS(C)=O>[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3]
Reactant: OCCCCCCBr
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cn1cnc2c1c(=O)n(CCCCCCO)c(=O)n2C
Reaction time: 0.83 h
Yield: 90.9 %

Procedure:
This example is a method of synthesis for inventive compound no. 3506 (see above for chemical name and structure). A mixture of theobromine (1.0 g, 5.5 mmol, available from Sigma) and 50% sodium hydride in oil (264 mg, 5.5 mmol) in dimethylsulfoxide (20 ml) was stirred for 50 minutes and then 6-bromo-1-hexanol (1.0 g, 5.5 mmol, available from Aldrich) was added. After stirring for 18 hours, the solution was treated with water (50 ml) and then extracted with two 25 ml aliquots of hexanes. The aqueous phase was extracted with three 35 ml aliquots of 25% ethanol-dichloromethane. The combined ethanol-dichloromethane extracts were dried over magnesium sulfate. The solvents were then evaporated under vacuum and remaining dimethylsulfoxide was removed by distillation under full pump vacuum, leaving 1.4 g of a white powder, 1-(6-hydroxyhexyl)-3,7-dimethylxanthine (5.0 mmol, 91% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C@@H:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH2:14]Cl)[CH:3]=1.[I-:22].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C@@H:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH2:14][I:22])[CH:3]=1
Reactant: [I-]
Reactant: N#Cc1ccc(Cl)cc1O[C@H](CCCCl)c1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: N#Cc1ccc(Cl)cc1O[C@H](CCCI)c1ccccc1
Yield: 89.5 %

Procedure:
A solution of the product from step (b) (2.80 g) and sodium iodide (20 g) in acetone (100 ml) was heated under reflux for 20 h. The mixture was filtered, evaporated, dissolved in water (50 ml) and extracted with ethyl acetate (three times). The organic extracts were washed with water, dried (magnesium sulphate) and evaporated to give the title compound (3.22 g).
Reaction SMILES: Cl.O1CCOCC1.CC([N:12]([CH2:16][CH2:17][NH:18][C:19]1[N:24]=[C:23]([C:25]2[S:29][C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])=[N:27][C:26]=2[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][S:41]([C:44]3[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=3[F:51])(=[O:43])=[O:42])[C:35]=2[F:52])[CH:22]=[CH:21][N:20]=1)C(=O)[O-])(C)C.CO>C(Cl)Cl>[NH2:12][CH2:16][CH2:17][NH:18][C:19]1[N:24]=[C:23]([C:25]2[S:29][C:28]([C:30]([CH3:33])([CH3:31])[CH3:32])=[N:27][C:26]=2[C:34]2[C:35]([F:52])=[C:36]([NH:40][S:41]([C:44]3[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=3[F:51])(=[O:42])=[O:43])[CH:37]=[CH:38][CH:39]=2)[CH:22]=[CH:21][N:20]=1
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(NCCN(C(=O)[O-])C(C)(C)C)n2)s1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(NCCN)n2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 117.2 %

Procedure:
A 4N solution of HCl in 1,4-dioxane (1.7 ml, 7.1 mmol) was added to a stirring solution of 1,1-dimethylethyl[2-({4-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinyl}amino)ethyl]carbamate (0.31 g, 0.47 mmol) (composite batches prepared as described in the previous step) in DCM (10 ml) at rt. MeOH (1 ml) was added to aid in solubility. The reaction was allowed to stir at rt for 3 h. The volatiles were removed and the residue was dried in vacuo to afford the title compound of Step B (0.31 g, quantitative yield) as a hydrochloride salt that was used without further purification; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.77 (s, 1H), 7.93-8.18 (m, 4H), 7.20-7.69 (m, 7H), 3.37-3.53 (m, 2H), 2.96 (d, J=5.1 Hz, 2H), 1.41 (s, 9H). MS (ES+): 563 [M+H]+.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]1([C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:19][CH:18]2[C:20]#N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S(=O)(=O)(O)[OH:29]>CCCCCC.C1(C)C=CC=CC=1>[C:11]1([C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:19][CH:18]2[CH:20]=[O:29])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S(=O)(O)O
Reactant: N#CC1CC1(c1ccccc1)c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=CC1CC1(c1ccccc1)c1ccccc1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
A solution of diisobutylaluminum hydride in hexane (25%; 212 mL) was added over 30 minutes to a solution of 2,2-diphenylcyclopropanecarbonitrile (45.4 g) in dry toluene (400 mL) maintained at -40° C. during the addition. After the reaction had been stirred at room temperature for 1 hour, it was rechilled to 0°-5° C. and 2N sulfuric acid (400 mL) was added dropwise. The two phase system was stirred at ambient temperature for 1 hour then the layers were separated and the aqueous phase was extracted with ethyl acetate (2×300 mL). The organic layers were washed with Rochelle salt solution (5%; 2×200 mL), then were dried (Na2SO4) and evaporated to give 2,2-diphenylcyclopropanecarboxaldehyde as a solid, mp 71°-73° C. A sample was crystallized from benzene-hexane to provide the purified aldehyde, mp 75°-76° C.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:21]=[CH:20][C:19]([NH:22]C(=O)OCC5C=CC=CC=5)=[C:18]([F:33])[CH:17]=4)=[CH:11][N:10]3[CH:34]=2)=[O:5])[CH2:3][CH2:2]1.[OH-].[Ba+2].[OH-].Cl>COCCOC>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:12]2[CH:13]=[CH:14][C:9]3[N:10]([CH:34]=[C:7]([NH:6][C:4]([CH:1]4[CH2:3][CH2:2]4)=[O:5])[N:8]=3)[CH:11]=2)=[CH:17][C:18]=1[F:33]
Reactant: O=C(Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1F)OCc1ccccc1
Agent: Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Product: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1F
Temperature: 90 °C
Reaction time: 16 h
Yield: 62.5 %

Procedure:
To a suspension of benzyl [4-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-a]pyridin-6-yl}oxy)-2-fluorophenyl]carbamate (9.7 g, 21.1 mmol) in 1,2-dimethoxyethane (291 mL) was added 0.15 mol/L aqueous barium hydroxide solution (194 mL), and the mixture was stirred at 90° C. for 16 hr. After cooling to room temperature, the reaction mixture was adjusted to about pH 8 with 2N hydrochloric acid, and extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate and collected by filtration to give the title compound (4.3 g, 63%).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=O.[Cl:9][C:10]1[CH:11]=[C:12]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][C:33]=3[O:35][CH2:36][CH2:37][NH:38][CH3:39])[N:28]=[CH:27][N:26]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[Cl:9][C:10]1[CH:11]=[C:12]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][C:33]=3[O:35][CH2:36][CH2:37][N:38]([CH3:39])[C:4](=[O:6])[C:3]([CH3:8])([CH3:7])[CH2:2][OH:1])[N:28]=[CH:27][N:26]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CC(C)(CO)C(=O)O
Product: CN(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(=O)C(C)(C)CO
Yield: 25 %

Procedure:
The procedure described in Example 1 was repeated using 3-hydroxy-2,2-dimethylpropanoic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(methylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 1, preparation of starting materials) to give the title compound in 25% yield; NMR spectrum (DMSO-d6) 1.07 (s, 6H), 3.15 (s, 3H), 3.35 (d, 2H), 3.91 (t, 2H), 4.41-4.48 (m, 3H), 5.30 (s, 2H), 7.18 (d, 1H), 7.24 (d, 1H), 7.34 (d, 1H), 7.35-7.39 (m, 1H), 7.56-7.61 (m, 2H), 7.71-7.76 (m, 1H), 7.86-7.91 (m, 1H), 7.98 (d, 1H), 8.45 (s, 1H), 8.60 (d, 1H), 9.81 (s, 1H); Mass spectrum MH+ 536.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19](=[O:22])[CH2:20]Br)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:23]([C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)#[N:24].C(=O)([O-])[O-].[K+].[K+].Cl>CC(CC)=O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19](=[O:22])[CH2:20][N:27]4[C:28]5[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:25]([C:23]#[N:24])=[CH:26]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1csc(-c2cc3cc(C(=O)CBr)ccc3o2)n1
Reactant: N#Cc1c[nH]c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)c1csc(-c2cc3cc(C(=O)Cn4cc(C#N)c5ccccc54)ccc3o2)n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
A mixture of 4-tert-butyl-2-[5-(bromoacetyl)benzofuran-2-yl]thiazole (0.20 g), 3-cyanoindole (75 mg) and potassium carbonate (146 mg) in methylethylketone (3 ml) was stirred at 40° C. for 2 hours. After being cooled to room temperature, the mixture was poured into ice-water and the mixture was acidified with diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was collected by trituration with diisopropyl ether to give -1-{2-[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]-2-oxoethyl}indole-3-carbonitrile (0.20 g).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([S:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:9]([O:17]CC2C=CC(OC)=CC=2)=[CH:8][N:7]=1)(=[O:3])[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([S:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:9]([OH:17])=[CH:8][N:7]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(COc2cnc(COC(C)=O)cc2SC(C)(C)C)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OCc1cc(SC(C)(C)C)c(O)cn1
Reaction time: 0.17 h
Yield: 83.2 %

Procedure:
A solution of [4-[(1,1-dimethylethyl)thio]-5-({[4-(methoxy)phenyl]methyl}oxy)-2-pyridinyl]methyl acetate (9 g, 24 mmol) in dichloromethane (100 mL) was treated with triethylsilane (3.86 mL, 24 mmol). The reaction mixture was stirred for 10 minutes before adding trifluoroacetic acid (10 mL). The reaction mixture was stirred at room temperature for 3 hours under argon atmosphere. The solvents were evaporated under vacuum. The residue was taken up in dichloromethane and chromatographed on silica gel eluting with 10%-30% ethyl acetate in hexane to afford the product as an oil (5.1 g, 83%); MS (+ve ion electrospray) m/z 256 (MH+).
Reaction SMILES: [NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:2][C:3]([NH:5][C@H:6]([C:8]([OH:10])=O)[CH3:7])=[O:4].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl.[NH2:41][C@@H:42]([C:44]([NH:46][CH2:47][C:48]([NH:50][CH2:51][C:52]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:53])=[O:49])=[O:45])[CH3:43].Cl>CN(C=O)C>[NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:2][C:3]([NH:5][C@H:6]([C:8]([NH:41][C@@H:42]([C:44]([NH:46][CH2:47][C:48]([NH:50][CH2:51][C:52]([O:54][CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)=[O:53])=[O:49])=[O:45])[CH3:43])=[O:10])[CH3:7])=[O:4]
Reactant: C[C@@H](N)C(=O)NCC(=O)NCC(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)NCC(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
To a solution of Boc-Gly-Ala prepared as in Example 33B (10.2 g, 41.5 mmol) in anhydrous DMF (300 ml), was added HOBT.H2O (6.21 g, 46.0 mmol), EDC.HCl (8.81 g, 46.0 mmol) and DAla-Gly-Gly-OBzl.HCl (13.7 g, 41.5 mmol). The pH of the resulting solution was adjusted to ~8 (measured by spotting the reaction mixture on moistened Hydrion paper) and the reaction mixture was allowed to stir at room temperature for 12 h thereafter. The solution was concentrated in vacuo and the residue was dissolved in water (40 ml). The resulting solution was extracted with ethyl acetate (3×150 ml). The combined ethyl acetate layers were washed with iN sodium bisulfate (100 ml), saturated sodium bicarbonate (100 ml) and brine (100 ml). The ethyl acetate solution was dried (magnesium sulfate), filtered and concentrated to half volume. The product crystallized out upon standing at RT for 30 min. Collection of the crystals by filtration and drying at high vacuum afforded 17.4 g (80% yield) of the pure product: 1H NMR (DMSO-d6) δ 1.21 (d, J=7.4 Hz, 3 H), 1.23 (d, J=7.3 Hz, 3 H), 1.38 (s, 9 H), 3.56 (d, J=6.3 Hz, 2 H), 3.75 (d, J=5.7 Hz, 2 H), 3.93 (d, J=6.0 Hz, 2 H), 4.24-4.34 (m, 2 H), 5.14 (s, 2 H), 6.98 (t, J=5.7 Hz, 1 H), 7.34-7.40 (m, 5 H), 7.93 (d, J=7.2 Hz, 1 H), 8.17-8.24 (m, 3 H).
Reaction SMILES: [C:1]([C:3]1([C:20]2[C:28]3[C:27]4[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=4[O:25][C:24]=3[C:23]([O:33][CH3:34])=[CH:22][CH:21]=2)[CH2:12][CH2:11][C:10]2[N:9]=[CH:8][N:7]([CH2:13][C:14]([O:16]CC)=[O:15])[C:6](=[O:19])[C:5]=2[CH2:4]1)#[N:2].[OH-].[Na+]>C(O)C.O>[C:1]([C:3]1([C:20]2[C:28]3[C:27]4[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=4[O:25][C:24]=3[C:23]([O:33][CH3:34])=[CH:22][CH:21]=2)[CH2:12][CH2:11][C:10]2[N:9]=[CH:8][N:7]([CH2:13][C:14]([OH:16])=[O:15])[C:6](=[O:19])[C:5]=2[CH2:4]1)#[N:2]
Reactant: CCOC(=O)Cn1cnc2c(c1=O)CC(C#N)(c1ccc(OC)c3oc4ccccc4c13)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C2(C#N)CCc3ncn(CC(=O)O)c(=O)c3C2)c2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of the compound obtained in example 19 (100 mg, 0.2188 mmol) in 4 ml of ethanol was added 1N NaOH solution (3 ml) and the reaction mass was allowed to stir at room temperature for 4 hrs. The reaction mass was diluted with 20 ml water and washed 3 timed with 25 ml diethyl ether. The aqueous layer was acidified with 1N aq. HCl to pH 2-3 and extracted with chloroform. The organic layer was washed with water followed by brine, and concentrated under vacuum. The residue was triturated with ether to give 45 mg (Yields-48%) of product.
Reaction SMILES: O=[C:2]([CH2:7][C:8](=[O:10])[CH3:9])[C:3]([O:5][CH3:6])=[O:4].C[O-].[Na+].Br[C:15](=[N:20][NH:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:24][CH2:23]1)[C:16]([F:19])([F:18])[F:17].C([O-])(O)=O.[Na+]>CO.CCOC(C)=O>[C:8]([C:7]1[C:15]([C:16]([F:19])([F:18])[F:17])=[N:20][N:21]([CH:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[O:29])[CH2:26][CH2:27]2)[C:2]=1[C:3]([O:5][CH3:6])=[O:4])(=[O:10])[CH3:9]
Reactant: COC(=O)C(=O)CC(C)=O
Reactant: O=C(OCc1ccccc1)N1CCC(NN=C(Br)C(F)(F)F)CC1
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C(C)=O)c(C(F)(F)F)nn1C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38.6 %

Procedure:
To a stirred solution of Methyl 2,4-dioxopentanoate (892 mg, 6.19 mmol) in MeOH (11.5 mL) at room temperature was added Sodium methoxide (25% in MeOH, 0.891 mL, 4.13 mmol). Then a solution of 111 (842 mg, 2.063 mmol) in MeOH (2.3 mL) was added drop-wise and the suspension was stirred for 10 min at room temperature, then for 2 h at 65° C. After cooling, the mixture was taken to dryness and AcOEt and saturated NaHCO3 were added, the organic layer was separated, dried over MgSO4, filtrated and evaporated and the residue was purified via Biotage (10% to 40% EtOAc/Hexane; 25S column) to afford 112 (361 mg, 38.6% yield) as red oil. LRMS (ESI): calc. 453.4; found 454.2 (MH)+.
Reaction SMILES: [N:1]1([S:5]([NH:8][C:9](=[O:32])[C:10]2[CH:15]=[C:14](Cl)[C:13]([O:17][CH2:18][C:19]34[CH2:28][CH:23]5[CH2:24][CH:25]([CH2:27][C:21]([CH2:29][OH:30])([CH2:22]5)[CH2:20]3)[CH2:26]4)=[CH:12][C:11]=2[F:31])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH:33]1(B(O)O)[CH2:35][CH2:34]1.F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCCC1>[N:1]1([S:5]([NH:8][C:9](=[O:32])[C:10]2[CH:15]=[C:14]([CH:33]3[CH2:35][CH2:34]3)[C:13]([O:17][CH2:18][C:19]34[CH2:28][CH:23]5[CH2:24][CH:25]([CH2:27][C:21]([CH2:29][OH:30])([CH2:22]5)[CH2:20]3)[CH2:26]4)=[CH:12][C:11]=2[F:31])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)C1CC1
Reactant: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(OCC23CC4CC(CC(CO)(C4)C2)C3)cc1F
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC23CC4CC(CC(CO)(C4)C2)C3)cc1F
Temperature: 25 °C
Yield: 52.7 %

Procedure:
A degassed mixture of N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((3-(hydroxymethyl)adamantan-1-yl)methoxy)benzamide (0.51 g, 1.04 mmol), cyclopropylboronic acid (0.89 g, 10.4 mmol), tricyclohexylphosphine tetrafluoroborate (0.23 g, 0.62 mmol), potassium phosphate (tribasic, 1.10 g, 5.20 mmol), water (3.0 mL), and tetrahydrofuran (3.0 mL) in toluene (15 mL) was added palladium (II) acetate (0.070 g, 0.31 mmol). The resulting mixture was refluxed under nitrogen for 18 hours. The reaction mixture was cooled to ambient temperature and added additional cyclopropylboronic acid (0.89 g, 10.40 mmol), tricyclohexylphosphine tetrafluoroborate (0.23 g, 0.62 mmol), and potassium phosphate (tribasic, 1.10 g, 5.20 mmol), and then refluxed under nitrogen for 10 hours. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (80 mL) and water (50 mL), acidified with 1 M aqueous hydrochloric acid solution. The organic layer was washed with 1 M aqueous hydrochloric acid solution (20 mL) and brine (2×50 mL); dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (1:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) to provide the title compound (0.27 g, 53%): 1H NMR (300 MHz, DMSO-d6) δ 11.56 (br s, 1H), 7.11 (d, J=8.5 Hz, 1H), 6.90 (d, J=13.0 Hz, 1H), 4.38-4.31 (m, 1H), 4.01 (t, J=7.5 Hz, 4H), 3.64 (s, 2H), 3.02-2.96 (m, 2H), 2.19-2.06 (m, 2H), 2.06-1.94 M, 3H), 1.64-1.47 (m, 6H), 1.45-1.32 (m, 6H), 0.92-0.83 (m, 2H), 0.96-0.61 (m, 2H); MS (ES+) m/z 493.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:10]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[N:11][N:12]([CH3:17])[C:13]=1[CH:14]=[N:15][OH:16].O.[NH2:26]O.CCOC(C)=O>C(OC(=O)C)(=O)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:10]([C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)=[N:11][N:12]([CH3:17])[C:13]=1/[C:14](=[N:15]/[OH:16])/[NH2:26]
Reactant: Cn1nc(-c2ccc(O)cc2)c(-c2c(F)cccc2F)c1C=NO
Reactant: NO
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cn1nc(-c2ccc(O)cc2)c(-c2c(F)cccc2F)c1/C(N)=N/O
Temperature: 25 °C
Reaction time: 3 h
Yield: 17.8 %

Procedure:
To 4-(2,6-difluorophenyl)-3-(4-hydroxyphenyl)-1-methyl-1H-pyrazole-5-carbaldehyde oxime (30.0 mg, 0.09 mmol) in acetic anhydride (1 mL) was irradiated in the microwave for 20 min 1.5 ml water was added and the mixture was stirred at rt for 3 h, extracted with DCM, filtered through a phase separator and concentrated. The raw product was dissolved in DMSO (1 mL) and neutral hydroxylamine solution (50 wt % in water, 0.12 mL, 1.96 mmol) was added. The mixture was stirred in the microwave at 130° C. for 10 min. EtOAc and water were added and the phases were separated. The mixture was purified on preparative HPLC to give (Z)-4-(2,6-difluorophenyl)-N′-hydroxy-3-(4-hydroxyphenyl)-1-methyl-1H-pyrazole-5-carboximidamide (5.2 mg, 0.016 mmol, 18%). Identification of the title compound by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. ES/MS m/z: 345.11 (M+H), 343.26 (M−H); 1H NMR (MeOD, 500 MHz): 7.37 (m, 1H), 7.15 (m, 2H), 6.96 (m, 2H), 6.65 (m, 2H) and 3.99 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].Cl.[C:19]1([C@H:25]2[C@@H:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[CH2:29][CH2:28][NH:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:6]([N:27]2[CH2:28][CH2:29][C@H:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=3)[C@H:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26]2)=[O:7])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1
Reactant: FC(F)(F)c1cccc([C@H]2CCNC[C@H]2c2ccccc2)c1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2cccc(C(F)(F)F)c2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=546.1 (M+H+), was prepared in accordance with the general method of example 1 from 3,5-bis(trifluoromethyl)benzoyl chloride and rac-cis-3-phenyl-4-(3-trifluoromethylphenyl)piperidine hydrochloride.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[C:8]([C:31]2[CH:32]=[N:33][N:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=23)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:26][CH2:25][C@@H:24]([N:27]([CH3:29])[CH3:28])[CH2:23]3)=[C:16]([NH2:30])[CH:15]=2)=[N:11][CH:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:6][C:7]1[C:8]([C:31]2[CH:32]=[N:33][N:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=23)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:26][CH2:25][C@@H:24]([N:27]([CH3:29])[CH3:28])[CH2:23]3)=[C:16]([NH:30][C:1](=[O:4])[CH:2]=[CH2:3])[CH:15]=2)=[N:11][CH:12]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3cnn4ccccc34)n2)c(OC)cc1N1CC[C@@H](N(C)C)C1
Reaction time: 2 h
Yield: 57.8 %

Procedure:
A solution of acryloyl chloride (0.042 mL, 0.51 mmol) in CH2Cl2 (1 mL) was added dropwise to a mixture of N-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-[(3R)-3-dimethylamino-pyrrolidin-1-yl]-6-methoxybenzene-1,3-diamine (Intermediate 18, 245 mg, 0.51 mmol) and DIPEA (0.097 mL, 0.56 mmol) in CH2Cl2 (10 mL), which was cooled in an ice/water bath. The mixture was stirred for 2 h and then washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 2% 7N methanolic ammonia in CH2Cl2 gave a foam after concentration in vacuo. This foam was triturated using CH2Cl2 and diethyl ether, and the resulting solid was collected by filtration and dried to give the title compound (157 mg, 58%) as a yellow solid; 1H NMR: 1.68-1.83 (1H, m), 2.05-2.16 (1H, m), 2.18 (6H, s), 2.64-2.76 (1H, m), 3.18-3.29 (3H, m), 3.36-3.47 (1H, m), 3.77 (3H, s), 5.67 (1H, dd), 6.16 (1H, dd), 6.48 (1H, dd), 6.54 (1H, s), 7.12 (1H, t), 7.37 (1H, t), 7.43 (1H, s), 8.28-8.46 (2H, m), 8.55 (1H, s), 8.83 (1H, d), 8.94 (1H, s), 9.37 (1H, s); m/z: ES+ MH+ 533.5.