Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[N:20]4[N:21]=[C:22]([NH2:24])[N:23]=[C:19]4[C:18]4[C:17](F)=[CH:16][C:15]([F:26])=[CH:14][C:13]=4[N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.O1C2C=CC(CC3N4N=C(N)N=C4C4C=CC(F)=CC=4N=3)=CC=2OC1.[OH:52][CH2:53][CH2:54][NH2:55]>>[NH2:24][C:22]1[N:23]=[C:19]2[N:20]([C:11]([CH2:10][C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)=[N:12][C:13]3[CH:14]=[C:15]([F:26])[CH:16]=[C:17]([NH:55][CH2:54][CH2:53][OH:52])[C:18]=32)[N:21]=1
Reactant: Nc1nc2c3c(F)cc(F)cc3nc(Cc3ccc4c(c3)OCO4)n2n1
Reactant: NCCO
Agent: Nc1nc2c3ccc(F)cc3nc(Cc3ccc4c(c3)OCO4)n2n1
Product: Nc1nc2c3c(NCCO)cc(F)cc3nc(Cc3ccc4c(c3)OCO4)n2n1
Yield: 17 %

Procedure:
Operating as in Example 54, but employing 5-benzo[1,3]dioxol-5-ylmethyl-8,10-difluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-ylamine prepared as described in Example 30 instead of 5-benzo[1,3]dioxol-5-ylmethyl-8-fluoro-[1,2,4]triazolo[1,5-c]quinazolin-2-ylamine and 2-hydroxy-ethylamine instead of morpholine, the title compound was obtained in 17% yield.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1.Br[C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C@H:26]2[CH2:31][CH2:30][CH2:29][C@@H:28]([N:32]3[CH:36]=[N:35][N:34]=[CH:33]3)[CH2:27]2)(=[O:24])=[O:23])=[C:18]([CH2:37][CH3:38])[CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:37]([C:18]1[CH:17]=[C:16]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=2)[CH:21]=[CH:20][C:19]=1[S:22]([NH:25][C@H:26]1[CH2:31][CH2:30][CH2:29][C@@H:28]([N:32]2[CH:36]=[N:35][N:34]=[CH:33]2)[CH2:27]1)(=[O:24])=[O:23])[CH3:38]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CCc1cc(Br)ccc1S(=O)(=O)N[C@H]1CCC[C@@H](n2cnnc2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCc1cc(-c2ccc(OC(F)(F)F)cc2)ccc1S(=O)(=O)N[C@H]1CCC[C@@H](n2cnnc2)C1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (336 mg, 0.411 mmol) was added to a stirred solution of 4-(trifluoromethoxy)phenylboronic acid (1.27 g, 6.17 mmol), 2a (1.70 g, 4.11 mmol) and sodium carbonate (5.14 mL of a 2.0 M aqueous solution) in ethanol (32.0 mL) and toluene (8.0 mL). The resulting mixture was degassed and heated to 90° C. After 3 h, the reaction mixture was cooled to rt and filtered through a short column of Celite, eluting copiously with EtOH. The combined organics were concentrated in vacuo, and the crude residue was purified by column chromatography on silica gel (gradient elution, 1-9% MeOH/DCM as eluent), yielding a brown solid that was subsequently purified by reversed phase HPLC on YMC Pack Pro C18 phase (gradient elution; 10%-70% acetonitrile/water as eluent, 0.05% TFA modifier) to afford the title compound 2b. m/z (ES) 495 (MH)+. 1HNMR (500 MHz, CD3OD) δ 9.45 (s, 1H), 8.03 (d, 1H, J=1.7 Hz), 7.78 (d, 2H, J=3.3 Hz), 7.70 (d, 1H, J=0.3 Hz), 7.66 (dd, 1H, J=1.5, 3.5 Hz), 7.39 (d, 2H, J=1.7 Hz), 4.15 (m, 1H), 3.13 (m, 2H), 2.55 (d, 1H, J=2.3 Hz), 2.15 (d, 1H, 2.4 Hz), 1.60-1.90 (m, 6H), 1.23 (m, 6H). IC50=3.6 nM
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([CH3:8])[NH:6][CH:7]=1.C.[Cl:18][CH2:19][C:20](Cl)=[O:21].[OH-].[Na+]>O>[C:9]([C:4]1[C:3]([NH:2][C:20](=[O:21])[CH2:19][Cl:18])=[CH:7][NH:6][C:5]=1[CH3:8])(=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1[nH]cc(N)c1C(=O)c1ccccc1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1[nH]cc(NC(=O)CCl)c1C(=O)c1ccccc1
Temperature: 25 °C

Procedure:
4-Amino-3-benzoyl-2-methylpyrrole hydrochloride (0.019 mole) was dissolved in water (40 ml) and the solution was treated with charcoal (0.1 g) and filtered. Toluene was added and chloroacetylchloride (0.067 mole) and aqueous NaOH (58.1 ml, 20% w/v) were added separately but simultaneously during 1 hour to the stirred two-phase solution. The reaction mixture was maintained under an inert atmosphere and at room temperature for 1.5 hour. The compound of the title which spontaneously crystallized out of the reaction mixture, was collected by filtration.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:9]=[C:8]2[CH:10]=[CH:11][N:12]([CH3:13])[C:7]2=[CH:6][C:5]=1[N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)[CH3:3].[Cl:19][C:20]1[C:21]([NH2:28])=[N:22][C:23]([NH2:27])=[N:24][C:25]=1Cl.CCN(CC)CC>C(#N)C.O>[NH2:27][C:23]1[N:24]=[C:25]([NH:1][CH:2]([C:4]2[N:9]=[C:8]3[CH:10]=[CH:11][N:12]([CH3:13])[C:7]3=[CH:6][C:5]=2[N:14]2[CH2:17][CH:16]([OH:18])[CH2:15]2)[CH3:3])[C:20]([Cl:19])=[C:21]([NH2:28])[N:22]=1
Reactant: CC(N)c1nc2ccn(C)c2cc1N1CC(O)C1
Reactant: Nc1nc(N)c(Cl)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CC(Nc1nc(N)nc(N)c1Cl)c1nc2ccn(C)c2cc1N1CC(O)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 8.5 %

Procedure:
To a 10 mL vial were added 1-(5-(1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)azetidin-3-ol (75 mg, 0.304 mmol), 5,6-dichloropyrimidine-2,4-diamine (65.4 mg, 0.365 mmol) and Et3N (0.085 mL, 0.61 mmol) in acetonitrile (2 mL) and water (0.5 mL). The resulting brown solution was heated to 90° C. and stirred overnight. The crude product was purified by preparative HPLC eluting with 20-40% ACN in water (with 0.05% ammonium bicarbonate). The fractions containing the desired product were combined and lyophilized to give the title compound as an off-white solid (10 mg, 8.5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.14 (m, 3 H), 1.28-1.37 (m, 3 H), 3.48-3.56 (m, 1 H), 3.65-3.74 (m, 1 H), 3.74-3.83 (m, 3 H), 4.02-4.15 (m, 1 H), 4.23-4.33 (m, 1 H), 4.51-4.61 (m, 1 H), 5.33-5.48 (m, 1 H), 5.56-5.63 (m, 1 H), 5.64-5.73 (m, 2 H), 5.86-6.00 (m, 2H), 6.40-6.52 (m, 2 H), 7.07-7.16 (m, 1 H), 7.35-7.46 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C17H21ClN8O, 389; found 389.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=2)=[N:9][S:10][CH:11]=1)(=O)=O.O[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[C:23]([CH3:34])[C:22]=1[CH3:35]>>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:8]2[C:7]([CH2:6][O:5][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[C:23]([CH3:34])[C:22]=3[CH3:35])=[CH:11][S:10][N:9]=2)=[CH:13][CH:14]=1)#[CH:19]
Reactant: C#Cc1ccc(-c2nscc2COS(C)(=O)=O)cc1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Product: C#Cc1ccc(-c2nscc2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 91 following Step 5 and 6 by coupling (3-(4-ethynylphenyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.31 (m, 4H), 6.86 (t, J=7.0 Hz, 1H), 6.62 (t, J=7.0 Hz, 1H), 5.21 (s, 2H), 2.95 (t, J=6.1 Hz, 2H), 2.68 (m, 4H), 1.26 (t, J=7.5 Hz, 3H).
Reaction SMILES: Cl.Cl.Cl.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]2[S:20][C:21]3[CH2:22][NH:23][CH2:24][CH2:25][C:26]=3[N:27]=2)[CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>>[CH3:28][S:29]([N:23]1[CH2:24][CH2:25][C:26]2[N:27]=[C:19]([NH:18][C:8]3[CH:9]=[CH:10][C:11]([N:12]4[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]4)=[C:6]([O:5][CH3:4])[CH:7]=3)[S:20][C:21]=2[CH2:22]1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(Nc2nc3c(s2)CNCC3)ccc1-n1cnc(C)c1
Agent: Cl
Product: COc1cc(Nc2nc3c(s2)CN(S(C)(=O)=O)CC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 45 from 90 mg (0.2 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-amine trihydrochloride and 23 mg (0.2 mmol) methanesulfonyl chloride yielding 39 mg (46%) (5-methanesulfonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a yellow solid. MS ISP (m/e): 420.1 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.38 (s, 1H), 7.65 (s, 1H), 7.48 (s, 1H), 7.30 (d, 1H), 7.25 (d, 1H), 7.02 (s, 1H), 4.34 (br s, 2H), 3.79 (s, 3H), 3.52 (t, 2H), 2.96 (s, 3H), 2.76 (br t, 2H), 2.14 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[C:5](=[CH:10][C:11]([NH:14][CH2:15][C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>C(O)C>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[CH2:15][NH:14][C:11]1[CH:10]=[C:5]([C:6]([OH:8])=[O:7])[C:4](=[CH:13][CH:12]=1)[C:3]([OH:21])=[O:2]
Reactant: COC(=O)c1ccc(NCc2ccco2)cc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(NCc2ccco2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.9 %

Procedure:
A mixture of 4-[(furan-2-ylmethyl)-amino]-phthalic acid dimethyl ester (1.11 g, 3.84 mmol) and 3N sodium hydroxide (50 mL) in ethanol (100 mL) was refluxed for one hour. The reaction mixture was cooled to room temperature, and the solvent was removed under vacuum. The residue was dissolved in water (100 mL), washed with CH2Cl2 (2×100 mL) and acidified (HCl). The resulting mixture was extracted with ethyl acetate (2×100 mL), and the organic phase was washed with water (2×100 mL), and dried (MgSO4) and evaporated. The resulting solid was stirred in ether for 2 hours. The solid was filtered to give the 0.44 g of 4-[(furan-2-ylmethyl)-amino]-phthalic acid, in 44% yield; 1H NMR (DMSO-d6) δ 4.33 (d, J=5.1 Hz, 2H), 6.31 (d, J=3.0 Hz, 1H), 6.39 (dd, J=3.0 Hz, 1.8 Hz, 1H), 6.65-6.71 (m, 2H), 7.00 (t, J=5.7 Hz, 1H), 7.57-7.60 (m, 2H), 12.51 (br, 2H).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([C:17]([OH:19])=O)[C:14]3[C:9](=[C:10]([C:20]([F:23])([F:22])[F:21])[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]1([C:30]2N=C(C(N3CCCCCC3)=O)C3[C:32](=[CH:33]C=CC=3)[N:31]=2)C=CC=CC=1>>[CH2:30]([N:31]([CH2:32][CH3:33])[C:17]([C:15]1[C:14]2[C:9](=[C:10]([C:20]([F:21])([F:23])[F:22])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:16]=1)=[O:19])[CH3:24]
Reactant: O=C(c1nc(-c2ccccc2)nc2ccccc12)N1CCCCCC1
Reactant: O=C(O)c1cc(-c2ccccc2)nc2c(C(F)(F)F)cccc12
Product: CCN(CC)C(=O)c1cc(-c2ccccc2)nc2c(C(F)(F)F)cccc12

Procedure:
The 2-phenyl-8-trifluoromethylquinoline-4-carboxylic acid can be prepared by the process described by D. W. BOYKIN et al., J. Med. Chem., 11 (2), 273-277 (1968).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1>[Pd].CO>[CH3:1][O:2][C:3](=[O:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[CH:7]=1
Reactant: COC(=O)COc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)COc1cccc(N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Add 1.3 g of palladium on activated carbon (10%) to 13 g (61.6 mmol) of 3-nitrophenoxyacetic acid methyl ester in 150 ml of methanol under argon. Stir the mixture at RT under a hydrogen atmosphere (standard pressure) for 18 h. Filter the catalyst off through kieselguhr and concentrate the filtrate under reduced pressure. After drying under high vacuum, 10.7 g (95.9% of theory) of the target compound are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[N:11]=[C:4]2[CH:3]=1.[CH3:18][C:19]1[N:24]=[C:23]([CH2:25][OH:26])[CH:22]=[CH:21][CH:20]=1>CN1CCCC1=O>[CH3:18][C:19]1[N:24]=[C:23]([CH2:25][O:26][C:2]2[CH:7]=[C:6]([NH2:8])[N:5]3[N:9]=[C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=4)[N:11]=[C:4]3[CH:3]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cccc(CO)n1
Reactant: Nc1cc(Br)cc2nc(-c3ccccn3)nn12
Solvent: CN1CCCC1=O
Product: Cc1cccc(COc2cc(N)n3nc(-c4ccccn4)nc3c2)n1

Procedure:
A mixture of 1 eq. 7-bromo-2-pyridin-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine, 5 eq. (6-methyl-pyridin-2-yl)-methanol and a catalytic amount of CS2CO3 in 200 μl N-methyl-pyrrolidon was heated for 2 h to 160°. The mixture was, after filtration, purified with reversed phase column chromatography eluting with an acetonitrile/water gradient yielding the title compound, MS m/e (%): 332 M+H+ (100%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][O:26]2)[C:12](=O)[CH2:13][CH2:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([O-])(=O)C.[NH4+:34].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:12]2[NH:34][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:14][CH:13]=2)[CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][O:26]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: [NH4+]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCO2)C(=O)CCC(=O)c2ccccn2)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(C(CC2CCCO2)c2ccc(-c3ccccn3)[nH]2)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
To a solution of 5-[4-(methylsulfonyl)phenyl]-1-(pyridin-2-yl)-6-(tetrahydrofuran-2-yl)hexane-1,4-dione (302 mg) in acetic acid (7.3 mL) was added ammonium acetate (897 mg), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (177 mg, yield 61%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio). MS: 397 (MH+).
Reaction SMILES: [F:1][C:2]1[C:10]2[C:9]([CH3:12])([CH3:11])[O:8][B:7]([OH:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:14](Cl)=[N:15][OH:16].[Cl:18][C:19]1[CH:24]=[C:23]([C:25]([C:27]([F:30])([F:29])[F:28])=[CH2:26])[CH:22]=[C:21]([Cl:31])[C:20]=1[Cl:32]>CN(C=O)C>[F:1][C:2]1[C:10]2[C:9]([CH3:12])([CH3:11])[O:8][B:7]([OH:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:14]1[CH2:26][C:25]([C:23]2[CH:22]=[C:21]([Cl:31])[C:20]([Cl:32])=[C:19]([Cl:18])[CH:24]=2)([C:27]([F:30])([F:29])[F:28])[O:16][N:15]=1
Reactant: CC1(C)OB(O)c2ccc(C(Cl)=NO)c(F)c21
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)c(F)c21
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a solution of the crude compound 4-fluoro-N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (257 mg, 1 mmol) and 1,2,3-trichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (327 mg, 1.2 mmol) in DMF (5 mL) at rt was added TEA (167 μL, 1.2 mmol). The reaction mixture was stirred for 12 h, poured into ice-water and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC eluted with PE-EA (3:2) and then purified by combiflash to give the title compound 4-fluoro-3,3-dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol (80 mg; yield 16.1% over 3 steps from the aldehyde) as a white solid. 1H NMR (500 MHz, DMSO-d6): δ 9.461 (s, 1H), 7.891 (s, 2H), 7.754 (t, J=7.0 Hz, 1H), 7.586 (d, J=7.5 Hz, 1H), 4.377 (d, J=18.5 Hz, 1H), 4.291 (d, J=18.5 Hz, 1H), 1.55 (s, 6H) ppm; HPLC purity: 100% at 220 nm and 100% at 254 nm; MS: m/z=496.0 (M+1, ESI+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:11])[NH:6]2.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:14]([N:6]1[C:7]2[C:3](=[C:2]([O:1][CH2:4][C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=3)[CH:10]=[CH:9][CH:8]=2)[CH:4]=[C:5]1[CH3:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc2c(O)cccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc2c(OCc3ccccc3)cccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 155 %

Procedure:
4-hydroxy-2-methyl indole 1 (50 g, 0.339 mole) was dissolved in anhydrous DMF (1 L). To the mixture sodium hydride 60% in mineral oil (27.9 g, 0.697 mole) was added. The mixture was left to stir at rt. for 1 h. To the mixture benzyl bromide (82.7 mL, 0.697 mole) was added drop-wise. The mixture was left to stir at room temperature for 18 h. The reaction was diluted with ethyl acetate (4 L) and washed with water (5×500 mL) then brine (1 L). The organic layer was separated and dried with magnesium sulphate and concentrated. The orange oily residue was purified by column chromatography (6:1 Hexane:EtOAc) to afford 86 g (72%) of 2 as an yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O.C(O)C.COCCOC>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:13][CH:12]=1
Reactant: Brc1ccc(I)cc1
Reactant: OB(O)c1cccnc1
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: O
Solvent: COCCOC
Solvent: CCO
Product: Brc1ccc(-c2cccnc2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
In a 100 mL three-necked flask were placed 2.4 g (20 mmol) of 3-pyridineboronic acid, 5.6 g (19 mmol) of para-bromoiodobenzene, and 4.5 g (42 mmol) of sodium carbonate. The atmosphere in the flask was replaced with nitrogen, and to the flask were added 15 mL of water, 25 mL of DME, and 10 mL of ethanol. The mixture was degassed by being stirred under reduced pressure, to which 0.22 g (0.19 mmol) of tetrakis(triphenylphosphine)palladium(0) was added. The mixture was stirred under nitrogen stream at 80° C. for 12 hours. After a predetermined time, water was added to the mixture, and an organic substance was extracted with chloroform from the aqueous layer. The obtained extract was washed with a saturated aqueous sodium chloride solution together with the organic layer and then dried over magnesium sulfate. The mixture was subjected to suction filtration through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), and the filtrate was condensed to obtain an oily substance. The obtained substance was purified by silica gel column chromatography (hexane:ethyl acetate=3:1); thus, 1.8 g of the target yellow oily substance was obtained with a yield of 38%.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:11]([CH3:12])=[CH:10][C:9]([NH2:13])=[C:8]([CH3:14])[CH:7]=1.ClCCl.C(N(C(C)C)CC)(C)C.[C:27](Cl)(=[O:30])[CH:28]=[CH2:29]>O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:11]([CH3:12])=[CH:10][C:9]([NH:13][C:27](=[O:30])[CH:28]=[CH2:29])=[C:8]([CH3:14])[CH:7]=1
Reactant: C=CC(=O)Cl
Reactant: Cc1cc(C2OCCO2)c(C)cc1N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(C)c(C2OCCO2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.2 %

Procedure:
To a 500 mL round-bottom flask was added crude 4-[1,3]dioxolan-2-yl-2,5-dimethylphenylamine (5.6 g, 29 mmol), dichloromethane (100 mL) and diisopropylethylamine (7.6 mL, 43.5 mmol). The resulting mixture was stirred at room temperature until the ingredients dissolved and then the mixture was cooled to 0° C. Acryloyl chloride (2.35 mL, 29 mmol) was then added dropwise over a 5 minute period. The reaction mixture was stirred at 0° C. to 5° C. for 1 hour and then water (50 mL) was added and stirring was continued for about 30 minutes at which time fine solids had formed. The mixture was filtered to collect the solids. The layers of the filtrate were then separated and the organic layer was concentrated under reduced pressure to dryness. Dichloromethane (50 mL) was added to the residue and this mixture was stirred until a free-flowing slurry developed. The slurry was filtered (using the same funnel used to collect the fine solids above) and the filter cake was washed with dichloromethane (10 mL) and dried to provide N-(4-[1,3]dioxolan-2-yl-2,5-dimethylphenyl)acrylamide (3.1 g, 97% purity) as a white to off-white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[CH:9]=[C:8]([O:18][CH3:19])[C:7]=12)#[CH:2].I[C:21]1[CH:22]=[N:23][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:25]=1[CH3:26].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:19][O:18][C:8]1[C:7]2[N:6]([N:5]=[CH:4][C:3]=2[C:1]#[C:2][C:21]2[CH:22]=[N:23][N:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:25]=2[CH3:26])[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)[CH:9]=1
Reactant: C#Cc1cnn2cc(-c3cnn(C)c3)cc(OC)c12
Reactant: Cc1c(I)cnn1-c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc(-c2cnn(C)c2)cn2ncc(C#Cc3cnn(-c4ccccc4)c3C)c12
Temperature: 80 °C

Procedure:
3-ethynyl-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (30.0 mg, 0.119 mmol), 4-iodo-5-methyl-1-phenyl-1H-pyrazole (67.6 mg, 0.238 mmol), and bis(triphenylphosphine)palladium(II) chloride (8.4 mg, 0.012 mmol) were combined into one vial fitted with a Teflon septum. The vial was flushed with nitrogen and tetra-n-butylammonium fluoride (0.36 mL, 0.36 mmol, 1M in THF) and tetrahydrofuran (0.2 mL) were added. After sparging with nitrogen for 5 minutes, the reaction was heated to 80° C. for one hour. The reaction was cooled to ambient temperature, then diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate. The organic layer was separated, and the aqueous layer was back extracted with ethyl acetate two times. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA. The fractions containing product were combined and diluted in ethyl acetate, then washed with aqueous sodium bicarbonate and dried over sodium sulfate. The solution was filtered and concentrated under reduced pressure to give 4-methoxy-3-[(5-methyl-1-phenyl-1H-pyrazol-4-yl)ethynyl]-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:18][NH:19][CH3:20]>C1COCC1>[CH3:18][N:19]([CH3:20])[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: CNC
Reactant: O=C(CCl)N1CCCc2ccc([N+](=O)[O-])cc21
Solvent: C1CCOC1
Product: CN(C)CC(=O)N1CCCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-chloro-1-(7-nitro-3,4-dihydroquinolin-1(2H)-yl)ethanone (1 g, 3.9 mmol) was dissolved in 10 ml of dry THF and 7.8 ml of a 1M solution of dimethylamine in THF (7.8 mmol) were added. This reaction mixture was stirred at ambient temperature for 24 h. The solvent was removed under reduced pressure and the residue was crystallized from diethyl ether to give the expected compound 2-(dimethylamino)-1-(7-nitro-3,4-dihydroquinolin-1(2H)-yl)ethanone in the form of a brown solid (m.p. 130-132° C.).
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:4](=[N:13][N:14]([CH3:16])[CH:15]=2)[N:5]=[CH:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].Br[CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:16][N:14]1[CH:15]=[C:3]2[C:4]([N:5]([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]2=[O:1])=[N:13]1
Reactant: CC(C)CCBr
Reactant: CCOC(=O)c1cnc2nn(C)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCC(C)C)c2nn(C)cc2c1=O

Procedure:
22.1 g. of 4-hydroxy-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester (0.1 mol.), 17 g. of 1-bromo-3-methylbutane and 21 g. of potassium carbonate are heated together with stirring in 100 ml. of dimethylformamide at 100° for 12 hours. The mixture is filtered hot, evaporated to dryness and the residue recrystallized from ethyl acetate to obtain 4,7-dihydro-2-methyl-7-(3-methylbutyl)-4-oxo-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester, yield (63%); m.p. 105°-106°.