Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.B(Br)(Br)Br.[OH-].[Na+]>ClCCl.O>[OH:2][C:3]1[CH:4]=[C:5]2[CH:11]=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1
Reactant: COc1cnc2[nH]ccc2c1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Oc1cnc2[nH]ccc2c1
Yield: 56.7 %

Procedure:
A suspension of 5-methoxy-1H-pyrrolo[2,3-b]pyridine (210 mg, 1.42 mmol), (Heterocycles 50, (2), 1065–1080, (1999)), in dichloromethane (10 ml) was stirred in an inert atmosphere, a 1.0M solution of boron tribromide in dichloromethane (4.3 ml, 4.3 mmol) added dropwise and the mixture stirred at ambient temperature overnight. The reaction mixture was taken to pH6 by the dropwise addition of 5N aqueous sodium hydroxide and further diluted with water. The aqueous solution was extracted several times with ethyl acetate, the extracts combined, washed with water followed by brine and dried over magnesium sulphate. The ethyl acetate solvent was removed ‘in vacuo’ and the residue purified by column chromatography, eluting with dichloromethane/methanol (95/5), to give a white solid. The solid was triturated with ether, filtered and dried to give 5-hydroxy-1H-pyrrolo[2,3-b]pyridine (108 mg, 57%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([O:22][C:23]2[C:35]([F:36])=[CH:34][C:26]([C:27]([O:29]C(C)(C)C)=[O:28])=[C:25]([F:37])[CH:24]=2)[CH:12]=[N:13][C:14]=1[O:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(Cl)Cl.O>[Cl:8][C:9]1[CH:10]=[C:11]([O:22][C:23]2[C:35]([F:36])=[CH:34][C:26]([C:27]([OH:29])=[O:28])=[C:25]([F:37])[CH:24]=2)[CH:12]=[N:13][C:14]=1[O:15][CH:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)c1cc(F)c(Oc2cnc(OC3CCOCC3)c(Cl)c2)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)c1cc(F)c(Oc2cnc(OC3CCOCC3)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.2 %

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of tert-butyl 4-{[5-chloro-6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]oxy}-2,5-difluorobenzoate (Preparation 23, 0.28 g, 0.64 mmol) in DCM (10 mL) and stirred at room temperature for 16 hours. The reaction mixture was diluted with water (50 mL), and extracted with DCM (3×50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to yield a yellow oil, which was purified by silica gel chromatography eluting with EtOAc to afford an off white solid. The solid was triturated with 4:1, heptane: EtOAc to afford the title compound as a white solid (0.24 g):
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH3:18])[C:11]3[N:12]([C:14](I)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH3:18])[C:11]3[N:12]([C:14]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)cn2c(I)cnc12
Reactant: C#C[Si](C)(C)C
Product: Cc1cc(-c2ccc(Cl)cc2)cn2c(C#C[Si](C)(C)C)cnc12
Yield: 79.7 %

Procedure:
Prepared from 6-(4-chloro-phenyl)-3-iodo-8-methyl-imidazo[1,2-a]pyridine (example C.21 step 2) (3.686 g, 10 mmol ) and trimethylsilylacetylene (2.8 mL, 20 mmol) as described in example C.20 step 4. Obtained the title compound as a yellow foam (2.70 g, 80%). MS (ISP) 339.1 [(M+H)+], 341 [(M+2+H)+].
Reaction SMILES: [H-].[Na+].[CH:3]1([CH:6]([C:8]2[C:13]3[N:14]4[CH2:20][CH2:19][CH2:18][N:17]([C:21]5[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=5[Cl:28])[C:15]4=[N:16][C:12]=3[CH:11]=[CH:10][CH:9]=2)[OH:7])[CH2:5][CH2:4]1.[CH3:29]I>CN(C)C=O.O>[CH:3]1([CH:6]([O:7][CH3:29])[C:8]2[C:13]3[N:14]4[CH2:20][CH2:19][CH2:18][N:17]([C:21]5[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=5[Cl:28])[C:15]4=[N:16][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4]1
Reactant: OC(c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Reaction time: 0.08 h
Yield: 64 %

Procedure:
Sodium hydride (60% in oil, 45.3 mg, 1.13 mmol) was added to a stirred solution of cyclopropyl[1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]methanol (400 mg, 1.03 mmol) in N,N-dimethylformamide (3.0 mL) at 0° C. After stirring 5 min, methyl iodide (219 mg, 1.55 mmol) was added to the mixture, and the mixture was stirred at room temperature for 5 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-30% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (265 mg, 0.659 mmol, 64%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:30])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2SC)=[CH:17][C:16]=1[F:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:32]1C=C(C=CC=1)C(OO)=O.[O-:42][S:43]([O-:46])(=S)=O.[Na+].[Na+]>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:30])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=2[S:43]([CH3:32])(=[O:46])=[O:42])=[CH:17][C:16]=1[F:29])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Reactant: CSc1ccccc1-c1ccc(NC(=O)C2CCCN2C(=O)OC(C)(C)C)c(F)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(-c2ccccc2S(C)(=O)=O)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(3-Fluoro-2′-methylsulfanyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.2 g, 2.8 mmol) was dissolved in 30 mL EtOAc, added m-chloroperoxybenzoic acid (3.2 g, 11 mmol) in one portion and stirred at ambient temperature for 3 hours. A 10% aqueous solution (50 mL) of Na2S2O3 was added to the vigorously stirring reaction in order to quench peroxide. After 30 minutes the solution was diluted with 100 mL EtOAc, separated layers, washed organics with sat. NaHCO3 (3×100 mL), brine, dried with MgSO4, filtered and concentrated. Purified on a silica gel column eluted with 50% EtOAc in hexanes. Combined and concentrated pure fractions to yield title compound as a yellow foam. (1.01 g, 78%) APCI (AP−): 461.1 (M−H)−.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([Sn](CCCC)(CCCC)CCCC)=[N:6][C:7]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.Br[C:42]1[C:43]2[N:44]([CH:48]=[N:49][CH:50]=2)[CH:45]=[CH:46][CH:47]=1>O1CCOCC1.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.S1C=CC=C1C([O-])=O.[Cu+]>[CH:50]1[N:49]=[CH:48][N:44]2[CH:45]=[CH:46][CH:47]=[C:42]([C:5]3[N:4]=[C:3]4[C:8]([N:9]=[C:10]([CH2:11][N:12]5[CH2:13][CH2:14][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:16][CH2:17]5)[N:2]4[CH3:1])=[C:7]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[N:6]=3)[C:43]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Reactant: Brc1cccn2cncc12
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-c3cccn4cncc34)nc21
Temperature: 150 °C
Yield: 59.1 %

Procedure:
A mixture of 2-[1-(9-methyl-6-morpholin-4-yl-2-(tributylstannanyl)-9H-purin-8-ylmethyl)piperidin-4-yl]propan-2-ol (135 mg, 0.20 mmol), 8-bromoimidazo[1,5-a]pyridine (44 mg, 0.22 mmol), Pd(PPh3)4 (24 mg, 10 mol %) and copper(I)-thiophene-2-carboxylate (8 mg, 20 mol %) in dioxane (2 mL) was purged with argon gas then heated at 150° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si—PCC, 0-10% MeOH in DCM) to give 222 as a yellow solid (58 mg, 58%). LCMS (Method G): RT=4.86 min, [M+H]+ 491.4. 1H NMR (400 MHz, CHCl3-d): δ 8.42 (s, 1 H), 8.19 (s, 1 H), 8.02 (d, J=6.9 Hz, 1H), 7.95 (dd, J=6.9, 0.9 Hz, 1 H), 6.74-6.67 (m, 1 H), 4.38 (m, 4 H), 3.96 (s, 3 H), 3.91-3.87 (m, 4 H), 3.80-3.66 (m, 2 H), 2.97 (d, J=11.0 Hz, 2 H), 2.22-1.99 (m, 2 H), 1.75 (d, J=11.0 Hz, 2 H), 1.44-1.26 (m, 4 H), 1.20-1.17 (s, 6 H)
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.C(Cl)(=O)CC>ClCCl>[CH2:11]([O:10][C:6]1[C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:26])=[O:2])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1cccc(OCc2ccccc2)c1OCc1ccccc1
Agent: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)c1cccc(OCc2ccccc2)c1OCc1ccccc1
Yield: 65.8 %

Procedure:
2-methoxy-5-nitroaniline (1) (10.1 g, 60.0 mmol) in 250 mL dichloromethane at 0°-5° C. was treated with triethylamine (10.0 g, 100.0 mmol) and propionyl chloride (6.7 g, 6.3 mL, 72.0 mmol) for 1 hour and 0.5 h at room temperature (RT). Normal aqueous workup and removal of solvent gave a light yellow solid which was washed with hexane/EtOAc (9:1) to yield solid N-(2-Methoxy-5-nitro-phenyl)-propionamide (2) (13.2 g, 98%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[CH:7]/[CH:8]=[CH:9]/[CH2:10]O)=[CH:2]1.P(Br)(Br)Br.C([O:19][CH2:20][CH3:21])(=O)C>>[S:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[CH:7]/[CH:8]=[CH:9]/[CH2:10][C:4]2[CH:5]=[C:21]([CH:7]=[CH:6][CH:3]=2)[CH:20]=[O:19])=[CH:2]1
Reactant: CCOC(C)=O
Reactant: OC/C=C/C=C/c1ccsc1
Agent: BrP(Br)Br
Product: O=Cc1cccc(C/C=C/C=C/c2ccsc2)c1
Reaction time: 1 h

Procedure:
20 mg of the resulting alcohol compound was dissolved in 1.5 ml of ethyl acetate, and under ice cooling, an ethyl acetate solution (0.5 ml) of 16.2 mg of phosphorus tribromide was added dropwise. The mixture was stirred for 1 hour, and then the solvent was evaporated. The residue was dissolved in 3 ml of toluene, and under a nitrogen atmosphere, 59 mg of 3-(tributylstannyl)benzaldehyde and 3 mg of tetrakis(triphenylphosphine)palladium were added. After the mixture was refluxed for 3 hours, 1 ml of a saturated aqueous solution of potassium fluoride was added, and the mixture was stirred at room temperature for 30 minutes. Water and ethyl acetate were added, and the organic layer separated was worked up in a customary manner. The product was purified by medium-pressure liquid chromatography [hexane/ethyl acetate=8/1] to give 7 mg of (E,E)-3-[5-(3-thienyl)-2,4-penta-dienyl]benzaldehyde as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](=O)[CH:8]=[C:9](O)[C:10]([F:13])([F:12])[F:11])[C:4]([CH3:16])=[N:3]1.[Br:17][C:18]1[CH:22]=[C:21]([NH2:23])[NH:20][N:19]=1.[C:24](O)(=O)C>>[Br:17][C:18]1[CH:22]=[C:21]2[N:23]=[C:7]([C:5]3[C:4]([CH3:16])=[N:3][N:2]([CH2:1][CH3:24])[CH:6]=3)[CH:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[N:20]2[N:19]=1
Reactant: Nc1cc(Br)n[nH]1
Reactant: CC(=O)O
Reactant: Cc1nn(C)cc1C(=O)C=C(O)C(F)(F)F
Product: CCn1cc(-c2cc(C(F)(F)F)n3nc(Br)cc3n2)c(C)n1
Temperature: 25 °C
Yield: 73.1 %

Procedure:
1-(1,3-dimethyl-1H-pyrazol-4-yl)-4,4,4-trifluoro-3-hydroxybut-2-en-1-one (Preparation 5, 1.7 g) and 3-bromo-1H-pyrazol-5-amine (Preparation 6, 1.18 g) in Acetic acid (52.61 mL) was heated at 120° C. in a sealed tube overnight. The reaction solution was cooled to room temperature, and poured into ice water (500 mL) resulting in a white precipitate. The precipitate was filtered and washed with copious amounts of water. The precipitate was then collected and dried in vacuo to afford the title compound as a white powder (1.9 g, 73.1%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C=O.[CH3:13][NH:14][CH3:15].[C:16](O)(=O)C>O1CCOCC1>[CH3:13][N:14]([CH2:16][C:5]1[C:4]2[CH:3]=[C:2]([Br:1])[CH:10]=[CH:9][C:8]=2[NH:7][CH:6]=1)[CH3:15]
Reactant: CC(=O)O
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CNC
Agent: C=O
Solvent: C1COCCO1
Product: CN(C)Cc1c[nH]c2ccc(Br)cc12

Procedure:
This material was prepared by the method of Procedure 67B from 49.5 g. of 5-bromoindole, 20 ml. of 37% aqueous formaldehyde, 55 ml. of 25% aqueous dimethylamine, 250 ml. of acetic acid and 250 ml. of dioxane; yield 60.6 g., m.p. 154°-156° C. The structure was confirmed by examination of the NMR spectrum.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[CH:3]=1.[NH2:15]C1C(C)=CC(C(OC)=O)=NC=1.N([O-])=O.[Na+].O>C1COCC1.[Pd].CC(O)=O>[NH:8]1[C:7]2=[CH:6][N:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[CH:3]=[C:2]2[CH:1]=[N:15]1
Reactant: COC(=O)c1cc(C)c(N)cn1
Reactant: COC(=O)c1cc(C)c([N+](=O)[O-])cn1
Agent: [Pd]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc2cn[nH]c2cn1
Reaction time: 8 h
Yield: 80.5 %

Procedure:
To a stirring solution of methyl 4-methyl-5-nitro-pyridine-2-carboxylate (3.00 g) in THF (40 mL) was added Pd/C catalyst (300 mg). The flask was evacuated and back-filled with hydrogen from a balloon three times and then stirred under hydrogen overnight. The mixture was filtered through Celite, and the filter cake was extracted several times with ethyl acetate. The combined organic extracts were concentrated and the resulting white powder (2.58 g, 100%) consisting of methyl 5-amino-4-methyl-pyridine-2-carboxylate was used in the next step without further purification and characterization. To a stirring solution of methyl 5-amino-4-methyl-pyridine-2-carboxylate (2.58 g, 15.53 mmol) in AcOH (60 mL), was added 2.0 M sodium nitrite in water (9.3 mL, 18.63 mmol) and the mixture was stirred for 4 h at room temperature. The acetic acid and other volatiles were removed at high vacuum, the resulting solid was suspended in water and filtered to give the title compound as a yellowish solid (2.18 g, 79% yield). 1HNMR (DMSO-d6): δ ppm 13.98 (bs, 1H), 9.10 (s, 1H), 8.57 (s, 1H), 8.39 (s, 1H), 3.88 (s, 3H). LCMS (API-ES M+Na+) 200.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[NH2:11][CH2:12][CH2:13][N:14]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])=[CH:18][C:17](=[O:30])[NH:16][C:15]1=[S:31].Cl.[N:33]1([C:38](N)=[NH:39])C=CC=N1>CN(C=O)C.CCO>[CH3:29][O:28][C:21]1[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:20]=1[C:19]1[N:14]([CH2:13][CH2:12][N:11]=[C:38]([NH2:39])[NH2:33])[C:15](=[S:31])[NH:16][C:17](=[O:30])[CH:18]=1
Reactant: N=C(N)n1cccn1
Reactant: COc1ccc(-c2cc(=O)[nH]c(=S)n2CCN)c(OC)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(=O)[nH]c(=S)n2CCN=C(N)N)c(OC)c1
Temperature: 55 °C
Reaction time: 3 h

Procedure:
Diisopropylethylamine (0.22 mL, 1.3 mmol) was added to a suspension of 1-(2-aminoethyl)-6-(2,4-dimethoxyphenyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one hydrochloride (181.6 mg, 0.528 mmol) (the product of Example 6) and 1H-pyrazole-1-carboxamidine hydrochloride (90.6 mg, 0.618 mmol) in DMF (0.55 mL). After heating for 1 h at 55° C., the reaction mixture was cooled to ambient temperature, diluted with EtOH (1.6 mL), and the solid product collected by vacuum filtration, rinsing with additional EtOH. The isolated solid was re-suspended in EtOH (2.1 mL) for 3 h at r.t. before being collected again by vacuum filtration and rinsing with additional EtOH. The desired product was obtained, after drying, as a colorless solid. Solubility data for this product is consistent with it being in its zwitterionic form.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C([Li])CCC.CCCCCC.[Br:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][CH:29]=1>O1CCCC1>[Br:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]([OH:33])[C:2]2[CH:15]=[CH:14][CH:13]=[C:4]([O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[CH:3]=2)=[CH:30][CH:29]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(O)c2ccc(Br)cc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
3-Bromophenoxy-tert-butyldimethylsilane (146 g, 0.51 mol, Example 1, infra) was dissolved in dry tetrahydrofuran under nitrogen and cooled to −78° C. A solution of 1.6 M n-butyllithium in hexane (318 mL, 0.51 mol) was added dropwise at a rate to maintain temperature below −70° C. The reaction was stirred for 30 minutes after the addition was complete, and the cold solution was transferred to another vessel containing a cold (−78° C.) solution of 4-bromobenzaldehyde (94.3 g, 0.51 mol) in 1000 mL of dry tetrahydrofuran under nitrogen. The transfer rate was monitored to maintain reaction temperature below −70° C. The reaction mixture was stirred for another 45 minutes at −78° C. and then quenched with 100 mL of saturated aqueous ammonium chloride. After warming to room temperature, the mixture was diluted with 2000 mL of diethyl ether and washed with 2000 mL of water followed by 500 mL of saturated sodium chloride. The ethereal solution was dried over sodium sulfate and the solvent removed to give 197.2 g of crude α-(4-bromophenyl)-3-(tert-butyldimethylsilyloxy)benzyl alcohol as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:15][CH3:16])[C:8](=[O:14])[CH:9]([CH3:13])[CH2:10][CH:11]=C)=[CH:5][N:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1.[O:23]=[O+][O-].O=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.CO>[Cl:1][C:2]1[C:6]([N:7]([CH2:15][CH3:16])[C:8](=[O:14])[CH:9]([CH3:13])[CH2:10][CH:11]=[O:23])=[CH:5][N:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1
Reactant: O=[O+][O-]
Reactant: C=CCC(C)C(=O)N(CC)c1cn(-c2cccnc2)nc1Cl
Agent: O=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: CCN(C(=O)C(C)CC=O)c1cn(-c2cccnc2)nc1Cl
Temperature: -78 °C

Procedure:
To N-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-2-methylpent-4-enamide (0.450 g, 1.41 mmol) in a flask with a stir bar dissolved in CH2Cl2 (13 mL) and MeOH (1.3 mL) was added Sudan III indicator solution (0.01 M, 0.060 mL). The flask was attached to an ozone generator and a flow of oxygen was initiated, with stirring. The reaction was cooled to −78° C., and the ozone production was bubbled through the solution for approxmately 6 minutes before the pink color was absent and the yellow solution started to turn green/blue. The ozone generation was arrested, and pure oxygen was bubbled through the reaction for approximately 5 minutes as the dark colors faded and the yellow color became prominent. While still at −78° C., triphenylphosphine (0.555 g, 2.12 mmol) was added as a solid, and the cooling bath was removed. A nitrogen gas inlet was attached to the flask, and the reaction was allowed to warm slowly to room temperature. The product was then concentrated and loaded onto CELITE®. Purification by flash column chromatography using 0-40% acetone/hexanes provided the title compound as a clear yellow oil that crystallized upon standing (0.390 g, 73%).
Reaction SMILES: [N+:1]([CH:4]1[CH2:9][N:8]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)[C:12]([C:13]#[N:14])=[C:7]2[NH:6][CH2:5]1)([O-])=O>CO.C(Cl)Cl.[Pd]>[NH2:1][CH:4]1[CH2:9][N:8]2[N:10]=[C:11]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:19][CH:20]=3)[C:12]([C:13]#[N:14])=[C:7]2[NH:6][CH2:5]1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC([N+](=O)[O-])C2
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC(N)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.1 %

Procedure:
To a solution of 6-nitro-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (600 mg, 1.67 mmol) in 30 mL of methanol and 10 mL of DCM was added 10% w/w Pd/C (100 mg). The mixture was stirred at RT under H2 for 2 hr and filtered. The filtrate was concentrated and purified by chromatography column on silica gel eluting with PE/EA to afford 200 mg (36%) of 6-amino-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile as a white solid. MS (ESI) m/e [M+1]+ 332.1.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:12]2[C:7](=[CH:8][C:9]([OH:13])=[CH:10][CH:11]=2)[O:6][C:5](=[O:14])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH:25]=[CH2:26]>CN(C=O)C.C(OCC)(=O)C.CO.[Pd]>[F:16][C:2]([F:1])([F:15])[C:3]1[C:12]2[C:7](=[C:8]([CH2:24][CH2:25][CH3:26])[C:9]([OH:13])=[CH:10][CH:11]=2)[O:6][C:5](=[O:14])[CH:4]=1
Reactant: C=CCBr
Reactant: O=c1cc(C(F)(F)F)c2ccc(O)cc2o1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(O)ccc2c(C(F)(F)F)cc(=O)oc12
Reaction time: 18 h

Procedure:
To a solution of 4-trifluoromethyl-7-hydroxycoumarin (5.0 grams, 22.0 mmol) and potassium carbonate(3.6 grams, 26.0 mmol) in DMF (20.0 mL) at 40° C., was added 3-bromoprop-1-ene (2.0 mL, 23.0 mmol). This mixture was stirred 18 hours and then diluted with ethyl acetate. The organic phase was washed with 1M hydrochloric acid solution and brine. The organic was then dried over sodium sulfate and the solvent removed to give a tan solid. This was filtered through a pad of silica gel using 20% ethylacetate in hexane. This material was then dissolved in 1,2-dichlorobenzene (150 mL) and refluxed for 18 hours. The solvent was removed in vacuo to give a tan solid. This material was dissolved in methanol (150 mL) with 10% palladium on carbon (300.0 mg) under a hydrogen atmosphere (1 Atm) for 2 hours. The mixture was then filtered through a celite pad and the solvent removed in vacuo to give tan solid. This was chromatographed on silica gel using 20% ethyl acetate in hexane to give the titled compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.CS([C:19]1[N:20]=[CH:21][C:22]2[C:28](=[O:29])[C:27]([C:30]#[N:31])=[CH:26][N:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:23]=2[N:24]=1)(=O)=O>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:19]3[N:20]=[CH:21][C:22]4[C:28](=[O:29])[C:27]([C:30]#[N:31])=[CH:26][N:25]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:23]=4[N:24]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CS(=O)(=O)c1ncc2c(=O)c(C#N)cn(-c3ccccc3)c2n1
Product: CN1CCN(c2ccc(Nc3ncc4c(=O)c(C#N)cn(-c5ccccc5)c4n3)cc2)CC1

Procedure:
Using the procedure outlined in Example 1(G) the title compound was prepared from 4-(4-methyl-piperazin-1-yl)-phenylamine (32 mg, 0.16 mmol) and 2-methanesulfonyl-5-oxo-8-phenyl-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (Example 13 (D) above, 50 mg, 0.15 mmol). The product was obtained as a yellow solid (17.1 mg). 1H NMR (300 MHz, CDCl3) δ (ppm): 9.34 (s, 1H), 8.55 (br, 1H), 7.61 (m, 3H), 7.41 (d, 2H), 7.24 (m, 2H), 6.55 (d, 2H), 3.00 (m, 4H), 2.55 (m, 4H), 2.35 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C25H23N7O: 438.20 (M+H), Found: 438.5.