Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4C[CH2:22][CH2:21][C:20](C)(O)[CH2:19]4)[C:14]([F:26])=[CH:13][N:12]=3)=[CH:9][N:8]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:5]2=[N:6][CH:7]=1.[CH3:37][O-:38].[Na+].[CH2:40]1COCC1>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C:37]4([CH3:40])[OH:38])[C:14]([F:26])=[CH:13][N:12]=3)=[CH:9][N:8]([S:27]([C:30]3[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=3)(=[O:29])=[O:28])[C:5]2=[N:6][CH:7]=1
Reactant: C1CCOC1
Reactant: C[O-]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCC(C)(O)C4)n3)c3cc(Cl)cnc32)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CCCCC4(C)O)n3)c3cc(Cl)cnc32)cc1

Procedure:
To a solution of (3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-1-methyl-cyclohexanol, 29f, (2.85 g, 5.38 mmol) in THF (200 mL) was added 1.5 ml 25% W/W sodium methoxide solution at room temperature. The reaction mixture was immediately injected into LC/MS. LC/MS indicated the reaction was complete. The reaction mixture was diluted with 200 ml EtOAc and the organic phase was washed twice with aqueous saturated NaHCO3 and then twice with brine. The organic phase was dried with MgSO4, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (80 g silica, 5% MeOH/CH2Cl2) to afford 1.7 g of the desired product. The resulting product was dissolved in 70 ml THF, to it was added 1.8 ml 5M HCl/IPA. The resulting suspension was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure to afford 1.7 g of the desired product, 655 as an HCl salt.
Reaction SMILES: C([O:5][C:6]([C:8]1[S:9][C:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:11][C:12]=1[C:13](=[O:26])[N:14]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])[CH:15]([CH3:17])[CH3:16])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[N:14]([CH:15]([CH3:17])[CH3:16])[C:13]([C:12]1[CH:11]=[C:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:9][C:8]=1[C:6]([OH:7])=[O:5])=[O:26]
Reactant: CC(C)N(C(=O)c1cc(-c2ccccc2)sc1C(=O)OC(C)(C)C)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(C(=O)c1cc(-c2ccccc2)sc1C(=O)O)c1ccc(Cl)cc1Cl
Yield: 77.7 %

Procedure:
A solution of 3-[(2,4-Dichloro-phenyl)-isopropyl-carbamoyl]-5-phenyl-thiophene-2-carboxylic acid tert-butyl ester (37 mg, 0.08 mmol) in CH2Cl2 (0.2 ml) at room temperature, under nitrogen was treated with trifluoroacetic acid (0.8 ml). After 1 h the reaction was concentrated the residue was taken into EtOAc and washed sequentially with 2N HCl (2×15 ml), water, brine dried and evaporated to a foam (33 mg). The foam was redissolved in EtOAc and above acidic wash was repeated to yield 27 mg (84%) of 3-[(2,4-Dichloro-phenyl)-isopropyl-carbamoyl]-5-phenyl-thiophene-2-carboxylic acid compound as pale brown foam. NMR 1H: (CD3OD; 400 MHz) 7.57-7.55 (m, 2H); 7.49-7.36 (m, 6H), 7.30-7.27 (m, 1H); 4.89 (quint, J=6.73 Hz, 1H); 1.42 (d, J=6.73 Hz, 3H); 1.12 (d, J=6.73 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:11]=3[C:12]=2[C:13](O)=[O:14])=[CH:4][CH:3]=1.CN.C1COCC1.C1C=CC2N(O)N=[N:34][C:32]=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:11]=3[C:12]=2[C:13]([NH:34][CH3:32])=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(O)c1c(-c2ccc(F)cc2)oc2ccc(O)cc12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(O)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 2-(4-flourophenyl)-5-hydroxybenzofuran-3-carboxylic acid (1 g, 3.7 mmol, 1 eq), methylamine in THF (2 M solution) (0.689 g, 21.5 mmol, 1 eq), HOBT (0.83 g, 6.2 mmol, 1.7 eq), EDC.HCl (1.24 g, 6.6 mmol, 1.8 eq) in DMF at ambient temperature under nitrogen was added Diisopropyl ethylamine (2.32 g, 18.5 mmol, 3.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The LCMS indicated the desired product. The mixture was concentrated cooled in an ice-water bath, further diluted with water. The white solid was filtered and washed with water and dried in vacuum. Yield: 0.85 g (90%). 1H NMR (400 MHz, DMSO-d6): δ 2.81-2.82 (d, 3H, J=4.5 Hz), 6.80-6.83 (m, 1H), 6.94-6.95 (d, 1H, J=2.3 Hz), 7.34-7.38 (t, 2H, J=8.7 Hz), 7.44-7.47 (d, 1H, J=8.8 Hz), 7.90-7.93 (m, 2H), 8.39-8.40 (d, 1H, J=4.4 Hz), 9.3 (s, 1H). LCMS: (ES+) m/z=286.1 (M+H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].B([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)(O)O.C(N(CC)CC)C>CN(C=O)C>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[C:3]([CH3:12])[CH:4]=1)=[O:7]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2ccc(C(=O)O)cc2)c(C)c1
Temperature: 100 °C
Yield: 38.7 %

Procedure:
A stirred solution of methyl 4-bromo-3-methylbenzoate (EP 0533268 A1) (1.0 g, 0.0044 mole) in dry DMF (10 ml) under argon was treated with 4-boronobenzoic acid (0.73 g, 0.0044 mole) and tetrakis (triphenylphosphine)palladium(0) (80 mg), followed by triethylamine (1.8 ml, 0.016 mole). The mixture was heated at 100° C. for 18 hours, then concentrated in vacuo. The residue was treated with ethyl acetate and extracted with 10% NaHCO3 solution. The basic extract was acidified with dil. HCl and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated in vacuo to afford the title compound as a white solid (0.46 g, 39%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH:9]=[O:10].C1(=[O:18])CCCCC1>N(C(C)(C)C#N)=NC(C)(C)C#N>[C:3]1([CH3:8])[CH:4]=[C:5]([CH3:7])[CH:6]=[C:1]([CH3:11])[C:2]=1[C:9]([OH:18])=[O:10]
Reactant: Cc1cc(C)c(C=O)c(C)c1
Reactant: O=C1CCCCC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: Cc1cc(C)c(C(=O)O)c(C)c1
Yield: 87.9 %

Procedure:
To a flask equipped with a stirrer, oxygen inlet and condenser were added mesitaldehyde (10.0 g, 67.6 mmol), 25 mL (0.242 mol) of cyclohexanone and 100 mg of azobisisobutyronitrile. Oxygen was bubbled in while the solution was stirred and maintained at 60°. After 45 hr the solution was mixed with 250 mL of water and 250 mL of methylene chloride; 20% aqueous potassium hydroxide was added dropwise until a pH of 8-9 was reached. The aqueous layer was separated and acidified with concentrated hydrochloric acid, after which the white solid product was collected by filtration, washed with water and air dried: 9.76 g (88% yield) of mesitoic acid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH2:7].[C:8]([O:14]CC)(=O)[CH2:9][C:10]([CH3:12])=O.[C:17](O)(=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[C:17]([O:1][CH2:2][CH2:3][N:4]1[C:8](=[O:14])[CH2:9][C:10]([CH3:12])=[N:7][CH2:6][CH2:5]1)(=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCCCCCCCCCCC(=O)O
Reactant: NCCNCCO
Product: CCCCCCCCCCCC(=O)OCCN1CCN=C(C)CC1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 104.2 g (1 mole) of N-hydroxyethylethylenediamine and 130.1 g (1 mole) of ethyl acetoacetate. At 150° to 160° C., 18 g of water and 46 g of ethanol were distilled off. Then, after addition of 200.3 g (1 mole) of lauric acid, the esterification was effected at 200° to 210° C. to distil off 18 g of water and to obtain 4-lauroyloxyethyl-7-methyl-3,6-dihydro-2H-1,4-diazepin-5-one.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.C([O-])=O.[NH4+]>[Pd].CCO>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc([N+](=O)[O-])cn3)cc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)CC1CCC(c2ccc(-c3ccc(N)cn3)cc2)CC1
Temperature: 25 °C

Procedure:
To a solution of {4-[4-(5-Nitropyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (1.4 g, 4.0 mmol) in 20 Ml EtOH was added Pd/C (0.4 g) followed by ammonium formate (2 g). The reaction mixture was heated to reflux for 4 h, then cooled to room temperature and filtered through Celite. Removal of solvent in vacuo afforded the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.20 (m, 2H) 1.43-1.54 (m, 1H) 1.48 (dd, J=12.57, 2.46 Hz, 2H) 1.81 (d, J=11.75 Hz, 6H) 2.26 (d, J=6.69 Hz, 2H) 3.61 (s, 3H) 6.98 (dd, J=8.59, 2.78 Hz, 1′H) 7.24 (d, J=8.34 Hz, 2H) 7.57 (d, J=8.59 Hz, 1H) 7.81 (d, J=8.34 Hz, 2H) 8.00 (d, J=2.65 Hz, 1H); (M+H)+325.2.
Reaction SMILES: C([O:3][C:4](=[O:22])/[C:5](/[CH3:21])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:8]=1)C.O[Li].O.OP(O)(O)=O>O1CCOCC1.O.CCOCC>[CH:16]1([O:15][C:9]2[CH:8]=[C:7](/[CH:6]=[C:5](\[CH3:21])/[C:4]([OH:22])=[O:3])[CH:12]=[CH:11][C:10]=2[O:13][CH3:14])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCOC(=O)/C(C)=C/c1ccc(OC)c(OC2CCCC2)c1
Agent: O=P(O)(O)O
Agent: [Li]O
Solvent: CCOCC
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(/C=C(\C)C(=O)O)cc1OC1CCCC1
Temperature: 45 °C
Yield: 79.2 %

Procedure:
To a solution of (E)-ethyl-3-(3-cyclopentoxy-4-methoxyphenyl)-2-methyl-prop-2-en-oate (970 mg, 3.2 mmol) in 3 mL of 1,4-dioxane was added a solution of LiOH·H2O (156 mg, 3.8 mmol) in 3 mL of H2O. The resulting mixture was heated at 80° C. for 2 hr and 45° C. for 16 hr. The resulting solution was diluted with ether and poured into 1M H3PO4. The aqueous layer was extracted with ethyl acetate (2×), washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. Silica gel chromatography (95:5, CH2Cl:methanol) provided (E)-3-(3-cyclopentoxy-4-methoxyphenyl)-2-methyl-prop-2-enoic acid as a colorless solid (700 mg, 79%). Anal. Calcd for C16H20O4 : C, 69.55; H, 7.29. Found: C, 69.39; H, 7.29.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH:6]1([C:9](=[O:27])[C:10](=[CH:23]OCC)[C:11]([C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])=[O:12])[CH2:8][CH2:7]1.Cl.[NH2:29]O>C(O)C>[CH:6]1([C:9]2[O:27][N:29]=[CH:23][C:10]=2[C:11](=[O:12])[C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[CH2:8][CH2:7]1
Reactant: NO
Reactant: CCOC=C(C(=O)c1ccc(SC)cc1OC)C(=O)C1CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1cc(SC)ccc1C(=O)c1cnoc1C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium acetate (7.87 g) was added to a stirred mixture of 3-cyclopropyl-2-ethoxymethylene-1-[2-methoxy-4-(methylsulphenyl)phenyl]propan-1,3-dione (30.6 g) and hydroxylamine hydrochloride (8.0 g) in ethanol. The mixture was stirred at room temperature overnight, then evaporated to dryness. The residue was dissolved in ethyl acetate, washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was triturated with ether and filtered to give 5-cyclopropyl-4-[2-methoxy-4-(methylsulphenyl)benzoyl]isoxazole as a white solid, m.p. 107.5°-108.5° C.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=[O:3])[CH3:2].C1C=CC=CC=1.C1(C)C=CC=CC=1.C[OH:30]>S(=O)(=O)(O)O>[C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=[O:3])[CH3:2].[CH2:8]([C:7]([OH:6])=[O:14])[C:9]([CH2:4][C:5]([OH:15])=[O:30])=[O:10].[C:5]([O:6][C:7](=[O:14])[CH3:8])(=[O:15])[CH3:4]
Reactant: CO
Agent: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: CC(=O)OC(C)=O
Product: O=C(O)CC(=O)CC(=O)O

Procedure:
The starting materials of formula II above used herein are generally prepared by reaction of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one with the appropriate amine (RNH2). The reactants are usually heated at reflux in an inert organic solvent such as benzene, toluene or methanol for from two to twelve hours. 3,5-Diacetyl-4,6-dihydroxy-2H-pyran-2-one is obtained by reaction of acetonedicarboxylic acid and acetic anhydride in sulfuric acid at elevated temperature.
Reaction SMILES: O.[NH2:2][NH2:3].[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[CH:11][CH:12]=O)[CH:5]=1>CC(O)(C)C>[N:2]1[NH:3][CH:10]([C:6]2[CH:5]=[N:4][CH:9]=[CH:8][CH:7]=2)[CH2:11][CH:12]=1
Reactant: NN
Reactant: O=CC=Cc1cccnc1
Solvent: CC(C)(C)O
Solvent: O
Product: C1=NNC(c2cccnc2)C1

Procedure:
Under N2 atmosphere, hydrazine hydrate (3.65 mL, 2 equiv.) was added to a solution of 3-(3-pyridyl)acrolein (5.0 g) in t-BuOH (25 mL). The mixture was refluxed for 3 days, followed by evaporation under reduced pressure. The residue was taken up in DCM and washed with 5% aqueous NaHCO3. The organic phase was dried over Na2SO4 and evaporated under reduced pressure. This gave 5.0 g of a red oil, containing 74% of the anticipated product and 26% of the hydrazone intermediate that failed to undergo ring-closure. This material was used in subsequent steps without further purification. Characteristic pyrazoline signals in 1H NMR (400 MHz, CDCl3): δ 2.63-2.75 (m, 1H), 3.13-3.25 (m, 1H) 4.72-4.82 (m, 1H), 6.85 (br s, 1H).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([OH:32])[CH:10]2[NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C@:20]2([CH3:31])[C:25]([CH3:27])([CH3:26])[C:24](=[O:28])[N:23]([CH3:29])[C:22]([NH2:30])=[N:21]2)[CH:14]=1)=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O>[NH2:30][C:22]1[N:23]([CH3:29])[C:24](=[O:28])[C:25]([CH3:26])([CH3:27])[C@:20]([C:15]2[CH:14]=[C:13]([NH:12][CH:10]3[C@H:9]([OH:32])[CH2:8][C@@H:7]4[C@H:11]3[C@H:6]4[C:4]([OH:5])=[O:3])[CH:18]=[CH:17][C:16]=2[F:19])([CH3:31])[N:21]=1
Reactant: CCOC(=O)[C@H]1[C@@H]2C[C@@H](O)C(Nc3ccc(F)c([C@@]4(C)N=C(N)N(C)C(=O)C4(C)C)c3)[C@@H]21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC3[C@H]4[C@@H](C[C@H]3O)[C@@H]4C(=O)O)ccc2F)N=C1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (1S,3R,5R,6S)-2-[3-((S)-2-Amino-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-4-yl)-4-fluoro-phenylamino]-3-hydroxy-bicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester (example 100, 0.05 mmol) in THF (1 ml), MeOH (0.3 ml) and H2O (0.3 ml) was added LiOH (1N, 0.1 mmol) and the reaction mixture was stirred at room temperature for 4 h. The mixture was concentrated in vacuo, the residue diluted with aqueous HCl (0.5 N) until pH=5 and evaporated again. The solid residue was triturated with dichloromethane/MeOH (10:1), filtered and the filtrate was concentrated in vacuo to yield a mixture of isomers of the title compound as a white solid. MS (ESI): m/z=419.3 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3]CC(C(=O)C)C(=O)C.[C:12]([CH:15]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][Br:27])[C:16]([O:18]CC)=O)(=[O:14])[CH3:13].Br[CH2:29]COCCC(C=O)C(=O)CC>>[Br:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH:15]([C:12](=[O:14])[CH2:13][CH3:29])[C:16](=[O:18])[CH2:2][CH3:3]
Reactant: CCOC(=O)C(CCCCCCBr)C(C)=O
Reactant: CC(=O)C(CCCBr)C(C)=O
Reactant: CCC(=O)C(C=O)CCOCCBr
Product: CCC(=O)C(CCCCCCBr)C(=O)CC

Procedure:
By selecting the appropriate alkane dibromide and dione or keto-ester, there can be prepared 3-(3-bromopropyl)-2,4-pentanedione, 4-(6-bromohexyl)-2,2,6,6-tetramethyl-3,5-pentanedione, ethyl 2-acetyl-8-bromooctanoate, 4-[2-(2-bromoethoxy)ethyl]-3,5-pentanedione, and the like.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]=[C:17]3[CH:19]=[CH:20][N:21]([CH3:22])[C:16]3=[CH:15][C:14]=2[C:23]2[C:24]([CH3:28])=[N:25][NH:26][CH:27]=2)[CH3:12])[N:5]=[C:4](SC)[N:3]=1.O[O:32][S:33]([O-:35])=O.[K+].[C:37](#N)C>O.CCOC(C)=O>[CH3:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]=[C:17]3[CH:19]=[CH:20][N:21]([CH3:22])[C:16]3=[CH:15][C:14]=2[C:23]2[C:24]([CH3:28])=[N:25][NH:26][CH:27]=2)[CH3:12])[N:5]=[C:4]([S:33]([CH3:37])(=[O:35])=[O:32])[N:3]=1
Reactant: CSc1nc(C)c(C#N)c(N[C@@H](C)c2nc3ccn(C)c3cc2-c2c[nH]nc2C)n1
Reactant: O=S([O-])OO
Reactant: CC#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1n[nH]cc1-c1cc2c(ccn2C)nc1[C@H](C)Nc1nc(S(C)(=O)=O)nc(C)c1C#N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a round-bottomed flask was added a mixture of (S)-4-methyl-6-((1-(1-methyl-6-(3-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)-2-(methylthio)pyrimidine-5-carbonitrile (100 mg, 0.239 mmol) in acetonitrile (7 mL) and water (7 mL). The reaction mixture was cooled to 0° C. Oxone (367 mg, 0.597 mmol) was added and the reaction mixture was stirred at 0° C. for 30 minutes and then allowed to warm to RT. After 1.5 hours the reaction mixture was diluted with EtOAc and washed with H2O (3×). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the title compound as a yellow solid, which was used without further purification. ESI-MS m/z [M+H]+ calc'd for C21H22N8O2S, 451; found 451.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4](=[O:14])[C:3]=1[C:15]([O:17]C)=[O:16].O.[OH-].[Na+]>O1CCOCC1>[I:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4](=[O:14])[C:3]=1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1c(I)ccn(-c2ccccc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1c(I)ccn(-c2ccccc2)c1=O
Temperature: 50 °C
Yield: 79.7 %

Procedure:
To a stirred solution of methyl 4-iodo-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate (2.34 g, 6.59 mmol) in dioxane (39 mL) was added water (12 mL) followed by sodium hydroxide 6M solution (4.39 ml, 26.4 mmol). The reaction mixture was heated at 50° C. for 4 h. LCMS analysis of an aliquot showed the reaction was complete. The reaction mixture was cooled to room temperature and concentrated in vacuo. Water was added, and the pH was adjusted to ˜3 with 6M aqueous hydrochloric acid solution. The solid formed was isolated by filtration and was dried under high vacuum overnight to give 4-iodo-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (1.79 g, 5.25 mmol, 80% yield), which was used without further purification. MS (ESI pos. ion) m/z: 364 (M+Na). Calc'd exact mass for C12H81NO3: 341.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]2[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=2)[CH:5]=[C:6]([F:15])[C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:23]1(=O)[CH2:26][CH2:25][CH2:24]1.C([BH3-])#N.[Na+].C(O)(=O)C>CN(C=O)C.CO>[CH:23]1([N:12]2[CH2:13][CH2:14][CH:9]([O:8][C:7]3[C:2]([F:1])=[CH:3][C:4]([C:16]4[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=4)=[CH:5][C:6]=3[F:15])[CH2:10][CH2:11]2)[CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CCC1
Reactant: O=C1CCC(c2cc(F)c(OC3CCNCC3)c(F)c2)=NN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CC(=O)O
Product: O=C1CCC(c2cc(F)c(OC3CCN(C4CCC4)CC3)c(F)c2)=NN1
Yield: 27.5 %

Procedure:
A solution of 6-[3,5-difluoro-4-(piperidin-4-yloxy)-phenyl]-4,5-dihydro-2H-pyridazin-3-one (350 mg, 1.1 mmol) in a mixture of DMF (2 mL) and MeOH (9 mL) was stirred under argon. Cyclobutanone (0.38 mL, 5 mmol), sodium cyanoborohydride (0.53 g, 8.45 mmol) and acetic acid (0.4 mL, 7 mmol) were added sequentially and stirred at 60° C. for 3 h. The reaction mixture was concentrated at reduced pressure and partitioned between aqueous 1M sodium carbonate solution and methylene chloride. The aqueous layer was extracted twice with methylene chloride and the combined organics was washed with brine, dried (Na2SO4), filtered and concentrated to provide a crude product. The crude product was purified by ISCO (40 g) chromatography using 2 to 5% methanol in methylene chloride to 10% methanol containing 0.2% ammonium hydroxide in methylene chloride. The recovered product was dissolved in methylene chloride and washed with saturated aqueous sodium bicarbonate solution, brine, dried (Na2SO4), filtered, and concentrated to furnish a pure product. The pure product was crystallized with a mixture of methylene chloride, ethanol, ether and hexane to obtain 6-[4-(1-cyclobutyl-piperidin-4-yloxy)-3,5-difluoro-phenyl]-4,5-dihydro-2H-pyridazin-3-one (110 mg, yield), mp 162-164° C.; MS m/z 364 (M+H)
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:8]=[CH:9][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:20]=[C:21]([O:23][C@H:24]4[CH2:28][CH2:27][O:26][CH2:25]4)[CH:22]=3)[C:17]([OH:19])=O)=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:53][C:54]1[S:55][CH:56]=[C:57]([CH3:59])[N:58]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:1]1([C:5]([C:7]2[N:8]=[CH:9][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:20]=[C:21]([O:23][C@H:24]4[CH2:28][CH2:27][O:26][CH2:25]4)[CH:22]=3)[C:17]([NH:53][C:54]3[S:55][CH:56]=[C:57]([CH3:59])[N:58]=3)=[O:19])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1csc(N)n1
Reactant: O=C(O)c1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(O[C@H]2CCOC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc(NC(=O)c2cc(Oc3cnc(C(=O)N4CCC4)cn3)cc(O[C@H]3CCOC3)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
3-{[5-(Azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoic acid (200 mg, 0.52 mmol), HATU (475 mg, 1.25 mmol) and 2-amino-4-methylthiazole (119 mg, 1.04 mmol) were suspended in DMF (2 mL). DIPEA (0.220 mL, 1.26 mmol) was then added and the reaction mixture stirred at RT for 16 hours. The DMF was removed in vacuo and water (15 mL) added. The mixture was extracted with ethyl acetate (3×20 mL) and the extracts combined, washed with water (15 mL), 1N hydrochloric acid (10 mL), water (10 mL), a saturated aqueous solution of sodium bicarbonate (10 mL), brine (10 mL), dried (MgSO4), filtered, and evaporated in vacuo. The residue was chromatographed on silica, eluting with a gradient of 60-100% ethyl acetate in isohexane, to give the desired compound (70 mg).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH:23]([CH3:25])[CH3:24])[CH:17]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]([F:32])([F:31])[CH:28]1[O:30][CH2:29]1>>[O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH:23]([CH3:25])[CH3:24])[CH:17]=2)[CH2:29][CH:28]([OH:30])[C:27]([F:32])([F:31])[F:26])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Oc1cccc(CNc2cccc(Oc3ccccc3)c2)c1
Reactant: FC(F)(F)C1CO1
Product: CC(C)Oc1cccc(CN(CC(O)C(F)(F)F)c2cccc(Oc3ccccc3)c2)c1
Yield: 27.8 %

Procedure:
The N-(3-phenoxyphenyl)-[[3-isopropoxyphenyl]methyl]amine (0.528 g, 1.59 mmol) product from EX-645B and 1,1,1-trifluoro-2,3-epoxypropane (0.506 g, 4.51 mmol) were heated to 90° C. in a sealed container for 2 d under an argon atmosphere. The resulting mixture was eluted from silica gel with an ethyl acetate in hexane gradient (0-10% ethyl acetate) and fractions were pooled after TLC analysis to give 197 mg (28%) of the desired 3-[(3-phenoxyphenyl)[[3-(isopro-poxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as clear, colorless oil. HRMS calcd. for C25H26F3NO3: 446.1943 [M+H]+, found: 446.1936. 1H NMR (C6D6) δ 6.9-7.1 (m, 6H), 6.84 (tt, 1H), 6.74 (s, 1H), 6.66 (dd, 1H), 6.61 (d, 1H), 6.56 (t, 1H), 6.41 (td, 2H), 4.33 (s, 2H), 4.17 (septet, 1H), 3.91 (br s, 1H), 3.56 (dd, 1H), 3.31 (m, 1H,), 2.8 (br s, 1H), 1.06 (s, 6H). 19F NMR (C6D6) δ −78.85 (d, 3F).