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][CH:18]4[CH2:23][CH2:22][CH2:21][CH:20]([OH:24])[CH2:19]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][N:8]([S:26]([C:29]3[CH:34]=[CH:33][C:32](C)=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1.ClC1C=C2C(C3N=C(NC4CCC[C@H](O)C4)C(F)=CN=3)=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[CH2:19]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][N:8]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CCCC(O)C4)n3)c3cc(Cl)cnc32)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CCC[C@H](O)C4)n3)c3cc(Cl)cnc32)cc1
Solvent: ClCCl
Product: O=C1CCCC(Nc2nc(-c3cn(S(=O)(=O)c4ccccc4)c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanol, 27a, (0.54 g. 1.05 mmol) in 20 ml CH2Cl2 was added Dess-Martin periodinane (0.62 g, 1.47 mmol). The suspension was stirred at room temperature for 6 h. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (45% ethyl acetate/hexanes gradient) to afford 430 mg of the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)=[N:6][C:7]=1Br.[NH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:31])[CH3:30].O>C(Cl)(Cl)Cl.CC(C)=O>[NH2:1][C:2]1[C:7]([NH:25][CH2:26][CH2:27][NH:28][C:29](=[O:31])[CH3:30])=[N:6][C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: CC(C)n1nc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Reactant: CC(=O)NCCN
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)NCCNc1nc(-c2ccc(=O)n(C(C)C)n2)c(-c2ccccc2)nc1N
Temperature: 122.5 °C

Procedure:
A mixture of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (150 mg) and N-(2-aminoethyl)acetamide (0.112 ml) in 1,2-dimethyl-2-imidazolidinone (0.3 ml) was heated at 120-125° C. for 50 hours. After addition of water (3 ml), an aqueous layer was removed by decantation to give a residue. The residue was dissolved in CHCl3, dried over MgSO4, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a mixture of MeOH and EtOAc (3:97 v/v) to give a solid. The solid was suspended in acetone to give N-(2-{[3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-phenyl-2-pyrazinyl]amino}ethyl)acetamide (28 mg).
Reaction SMILES: [C:1]([C:4]1[C:21]([OH:22])=[CH:20][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=[O:16])=[C:6]([CH2:23][CH3:24])[CH:5]=1)(=O)[CH3:2].Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+]>CO>[OH:27][N:26]=[CH:2][CH2:1][C:4]1[C:21]([OH:22])=[CH:20][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=[O:16])=[C:6]([CH2:23][CH3:24])[CH:5]=1
Reactant: NO
Reactant: CCc1cc(C(C)=O)c(O)cc1OCCCCCC(C)(C)C(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCc1cc(CC=NO)c(O)cc1OCCCCCC(C)(C)C(=O)O
Temperature: 25 °C
Yield: 42.5 %

Procedure:
A mixture of 7.1 g of 7-(4-acetyl-2-ethyl-5-hydroxyphenoxy)-2,2-dimethylheptanoic acid, 0.149 g of hydroxylamine hydrochloride, 0.176 g of sodium acetate, and 50 ml of methanol were heated at reflux for 48 hours. The reaction mixture was allowed to cool to room temperature and the resulting solid collected by filtration. The solid was crystallized from methylene chloride/hexane to provide 0.32 g of the desired titled product.
Reaction SMILES: [OH-].[Na+].C1COCC1.[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20]C)=[O:19])[CH:16]=2)[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:10]1.Cl>CO>[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=2)[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:10]1
Reactant: COC(=O)c1ccc2c(-c3ccccc3)nn(C)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nc(-c2ccccc2)c2ccc(C(=O)O)cc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
In a 50-mL egg plant-type flask, aqueous 5 N sodium hydroxide solution (1.3 mL, 6.5 mmol) was added to a THF (5 mL)-methanol (5 mL) mixed solution of methyl 1-methyl-3-phenyl-1H-indazole-6-carboxylate (604 mg, 22 mmol), and stirred overnight at 60° C. With cooling with ice, aqueous 5 N hydrochloric acid solution (1.3 mL, 6.5 mmol) was added to the reaction solution, and concentrated to obtain a mixture of the title compound with salt, as a colorless solid.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:6][CH2:5][CH:4]([C:7]([O-:9])=O)[CH2:3][CH2:2]1.[NH2:17][CH:18]([CH3:28])[C:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=O>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[O:9][C:7]([CH:4]3[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)=[N:17][C:18]=2[CH3:28])=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)[O-])CC1
Reactant: CC(N)C(=O)c1ccc(Cl)cc1
Product: Cc1nc(C2CCNCC2)oc1-c1ccc(Cl)cc1

Procedure:
Starting from mono-tert-butyl piperidine-1,4-dicarboxylate and 2-amino-1-(4-chlorophenyl)-propane-1-one (see J. Med. Chem. 1974, 416) (V-27) may be prepared analogously to (V-26) (see 73.1 and 73.2). Analytical HPLC-MS (method B): RT=1.30 min.
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[N:14]=[C:15]([NH:18][CH:19]([CH3:21])[CH3:20])[S:16][CH:17]=2)=O)=[C:8]([Cl:22])[C:7]([O:23][CH2:24][CH:25]([O:28][CH3:29])[O:26][CH3:27])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[H-].[Na+].CC(O)=O>C1(C)C=CC=CC=1.O>[Cl:22][C:8]1[C:7]([O:23][CH2:24][CH:25]([O:28][CH3:29])[O:26][CH3:27])=[CH:6][CH:5]=[C:4]2[C:9]=1[N:10]=[C:11]([C:13]1[N:14]=[C:15]([NH:18][CH:19]([CH3:21])[CH3:20])[S:16][CH:17]=1)[CH:2]=[C:1]2[OH:3]
Reactant: COC(COc1ccc(C(C)=O)c(NC(=O)c2csc(NC(C)C)n2)c1Cl)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(COc1ccc2c(O)cc(-c3csc(NC(C)C)n3)nc2c1Cl)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
2-Isopropylamino-thiazole-4-carboxylic acid [6-acetyl-2-chloro-3-(2,2-dimethoxy-ethoxy)-phenyl]-amide (18 g, 40.7 mmol) was suspended in toluene (400 ml). NaH (2.4 g, 61 mmol) was added to the vigorously stirred mixture while monitoring H2 evolution. The mixture became a clear solution during heating to reflux. After refluxing for 3 h, the mixture was cooled to room temperature. A solution of AcOH (69.2 mmol) in H2O (3 vol) was added to the mixture. After vigorous agitation for 1 h at 0° C., the solids were collected by filtration and rinsed with H2O. The wet cake was dried under high vacuum to a constant weight to provide 8-chloro-7-(2,2-dimethoxy-ethoxy)-2-(2-isopropylaminothiazol-4-yl)-quinolin-4-ol (15 g, 86% yield).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)=[CH:18][CH:17]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (1 g, 5 mmol), 4-fluoroaniline (0.56 g, 5 mmol) and acetic acid (0.26 ml, 5 mmol) in 1,2-DCE (30 ml) was stirred at room temperature for 24 h. Sodium tri(acetoxy)borohydride (1.48 g, 7 mmol) was then added and stirring continued for 24 h. The reaction mixture was washed with water, dried (MgSO4) and then concentrated in vacuo to give the title compound as a crude solid (1.6 g). δH (CDCl3, 250 MHz) 6.88 (2H, t), 6.54 (2H, dd), 4.04 (2H, m), 3.35 (1H, m), 2.91 (2H, m), 2.02 (2H, m), 1.46 (9H, s), 1.30 (2H, m).
Reaction SMILES: [F:1][S:2]([OH:5])(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:18]=[CH:17][C:16](=[N:19][NH2:20])[CH:15]=[CH:14]2)=[CH:9][CH:8]=1.O.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>C(O)C>[F:1][S:2]([OH:5])(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH:14]=[CH:15][C:16](=[N:19][N:20]=[CH:27][C:26]3[CH:29]=[CH:30][C:23]([Cl:22])=[CH:24][CH:25]=3)[CH:17]=[CH:18]2)=[CH:11][CH:12]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NN=c1ccn(-c2ccc(Cl)cc2)cc1
Agent: O=S(=O)(O)F
Solvent: CCO
Solvent: O
Product: Clc1ccc(C=NN=c2ccn(-c3ccc(Cl)cc3)cc2)cc1

Procedure:
To a solution of 2.4 g. (7.5 mmole) of 1-(4-chlorophenyl)-4(1H)-pyridinone hydrazone fluorosulfonate, prepared by the process set forth in Example 2, in 35 ml. ethanol and 30 ml. water was added a solution of 1.27 g. (9 mmole) of p-chlorobenzaldehyde in 5 ml. ethanol. After heating the reaction mixture on the steam bath for 3 minutes, the mixture was concentrated to remove most of the ethanol, cooled and the product collected by filtration. Yield 3.1 g. (94%), recrystallized from EtOH-H2O, m.p. 252°-253° C. The elemental analyses for C, H, N and Cl were within ±0.4% of the theoretical values.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]4[CH:25]=[CH:24]C([N+]([O-])=O)=C[CH:21]=4)=[O:18])[CH2:13][CH2:12]3)=[N:7][C:6]=12.[O:29]1CC[C@@H](O)C1.[H-].[Na+]>C1COCC1.CCOC(C)=O>[O:29]1[CH2:24][CH2:25][C@@H:20]([O:19][C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:8]3[CH:9]=[CH:10][N:5]4[N:4]=[CH:3][C:2]([Br:1])=[C:6]4[N:7]=3)[CH2:12][CH2:13]2)=[O:18])[CH2:21]1
Reactant: O[C@@H]1CCOC1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O[C@@H]1CCOC1)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
To 112 mg (0.25 mmol) of 4-nitrophenyl 4-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate dissolved in 10 mL of THF, was added (R)-tetrahydrofuran-3-ol (44 mg, 0.5 mmol), followed by 60% NaH (40 mg, 1.0 mmol) and stirred at RT for 2 hr. After 2 hr it was diluted with 20 mL of EtOAc and slowly quench with brine. The organic layer was dried over MgSO4 and concentrated, it was purified over 12 gram silica gel column eluting with 0-10% MeOH/DCM to obtain 71 mg (72% yield) of the desired product.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[OH-].[Na+].[CH2:10]([C@H:12]1[CH2:17][C@H:16]2[C@H:18]3[C@H:27]([CH2:28][CH2:29][C@:14]2([CH3:15])[C@H:13]1[O:31][C:32](=[O:35])[CH2:33]Br)[C@@H:26]1[C:21](=[CH:22][C:23](=[O:30])[CH2:24][CH2:25]1)[CH2:20][CH2:19]3)[CH3:11].C(OCC)(=O)C>CN(C=O)C>[CH2:10]([C@H:12]1[CH2:17][C@H:16]2[C@H:18]3[C@H:27]([CH2:28][CH2:29][C@:14]2([CH3:15])[C@H:13]1[O:31][C:32](=[O:35])[CH2:33][O:4][C:3](=[O:5])[CH:2]([OH:1])[CH2:6][CH3:7])[C@@H:26]1[C:21](=[CH:22][C:23](=[O:30])[CH2:24][CH2:25]1)[CH2:20][CH2:19]3)[CH3:11]
Reactant: CCC(O)C(=O)O
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(O)C(=O)OCC(=O)O[C@H]1[C@@H](CC)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.5 %

Procedure:
In 40 ml of DMF is dissolved 0.6 g of α-hydroxybutyric acid, and 6.0 ml of 1N-NaOH and 1.4 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one are added. The mixture is stirred at room temperature (15°-25° C.) for 16 hours. To the reaction mixture is added 150 ml of ethyl acetate and the mixture is washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography. Following passage of 50 ml of dichloromethane and 100 ml of diisopropyl ether in that order, elution is carried out with 150 ml of diisopropyl ether and 250 ml of diisopropyl ether-ethyl acetate (1:10). The eluates are combined and evaporated under reduced pressure to remove the solvent, giving 0.82 g of the above-identified compound as a colorless viscous oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:18]O>>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:18])=[O:5]
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc([N+](=O)[O-])c1C
Temperature: 0 °C

Procedure:
To 2-methyl-3-nitrobenzoic acid (10.0 g) is added methanol (100 ml) and thereto thionyl chloride (8 ml) is added dropwise at room temperature. After reflux for 2 hours, the reaction mixture is poured into ice-water and extracted with dichloromethane. The solvent is concentrated to give methyl 2-methyl-3-nitrobenzoate (10.8 g).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]1(Cl)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
In the drybox, 14.4 mg (0.087 mmol) of (Me3C)2PH(O) from Experiment 2, 20.0 mg (0.0218 mmol) of Pd2(dba)3 and 4.0 mL of 1,4-dioxane were loaded into a reactor (20 mL) equipped with a magnetic stir bar. The resulting mixture was stirred at room temperature overnight. Next, 651 mg (2.0 mmol) of CSCO3 and 146.3 mg (1.2 mm) of PhB(OH)2 were added into the mixture above, followed by syringing 122 μl (1.2 mmol) of PhCl into the reactor. The resulting mixture was refluxed for 24 h. The reaction mixture was then cooled to room temperature, chromatographed on silicon gel using ethyl acetate/hexane (5% volume ratio) as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to yield 163 mg (88% yield) of biphenyl. It was >95% pure by 1H NMR and GC/MS. 1H NMR (500 MHz, CDCl3): δ7.77 (d, J=7.75 Hz, 4H), 7.60 (t, J=7.65 Hz, 4H), 7.50 (t, J=7.38 Hz, 2H).ppm. 13C NMR (125 MHz, CDCl3): δ141.2, 128.7, 127.2, 127.1 ppm.
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:15][O:16][C@H:17]([CH3:30])[CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].[Br:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[N:39]1[C:43]2=[N:44][CH:45]=[N:46][C:47](Cl)=[C:42]2[CH:41]=[N:40]1>C1COCC1.CCOC(C)=O>[Br:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[N:39]1[C:43]2[N:44]=[CH:45][N:46]=[C:47]([O:3][C@@H:4]([CH2:15][O:16][C@H:17]([CH3:30])[CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:21]([CH3:23])[CH3:22])[CH:24]([CH3:26])[CH3:25])[C:5]([NH:7][C:8]3[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=3)=[O:6])[C:42]=2[CH:41]=[N:40]1
Reactant: Cc1cnc(NC(=O)[C@@H](O)CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)cn1
Reactant: Clc1cccc(Br)c1-n1ncc2c(Cl)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cnc(NC(=O)[C@H](CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)Oc2ncnc3c2cnn3-c2c(Cl)cccc2Br)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93.5 %

Procedure:
Sodium hydride (0.875 g, 21.87 mmol) was added to (S)-2-hydroxy-N-(5-methylpyrazin-2-yl)-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamide (Intermediate AZ2) (3.0 g, 7.29 mmol) in anhydrous THF (35 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then a solution of 1-(2-bromo-6-chlorophenyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (Intermediate BO2) (2.507 g, 7.29 mmol) in anhydrous THF (20 mL) was added dropwise over 1 minute. The mixture was stirred at 0° C. for 10 minutes and then allowed to warm to ambient temperature for 6 hours. It was then cooled to ˜0° C., the mixture poured into ice cold 1M citric acid and diluted with EtOAc (50 mL). It was stirred vigorously for 10 minutes. The organic phase was separated, washed with water and brine, dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane to afford the product (4.90 g, 93%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:11]([C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]2[CH:22]=[CH:21][N:20]3[N:23]=[CH:24][C:25]([C:26]([O:28]CC)=[O:27])=[C:19]3[N:18]=2)=[CH:10][C:9]([F:31])=[CH:8][N:7]=1.[OH-].[Li+]>C1COCC1.CO>[NH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:11]([C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]2[CH:22]=[CH:21][N:20]3[N:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[C:19]3[N:18]=2)=[CH:10][C:9]([F:31])=[CH:8][N:7]=1
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3CCCN)nc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: NCCCc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Temperature: 70 °C
Yield: 11.7 %

Procedure:
To (R)-ethyl 5-(2-(2-(3-aminopropyl)-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate hydrochloride (160 mg, 0.356 mmol) in THF/MeOH (2 mL/1 mL) was added lithium hydroxide (1.1 mL, 2.20 mmol). The reaction mixture was heated to 70° C. for 5 hours, then concentrated under reduced pressure. Water (10 mL) was added and the mixture washed with Et2O (2×5 mL), then neutralized with HCl (1M) to pH=4. The aqueous solution was extracted with DCM (2×10 mL). The organic extract was dried with Na2SO4, filtered and concentrated under reduced pressure to give the crude desired product (16.0 mg, 11.7% yield). MS (apci) m/z=385.0 (M+H).
Reaction SMILES: [CH3:1][Mg]Cl.[CH2:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](N(OC)C)=[O:16])=[CH:12][CH:13]=2)[N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[N:7]=1)[CH3:5]>O1CCCC1>[CH2:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:16])[CH3:1])=[CH:12][CH:13]=2)[N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[N:7]=1)[CH3:5]
Reactant: CCc1nn(COCC[Si](C)(C)C)c2cc(C(=O)N(C)OC)ccc12
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CCc1nn(COCC[Si](C)(C)C)c2cc(C(C)=O)ccc12
Temperature: 25 °C

Procedure:
Methylmagnesium chloride (7.7 mL, 3M in tetrahydrofuran) was added dropwise at −78° C. under an atmosphere of argon to a solution of 3-Ethyl-N-methoxy-N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-6-carboxamide (4.0 g, 0.011 mol) in tetrahydrofuran (114 mL). The resulting mixture was allowed to warm slowly to room temperature. The reaction was then quenched by the addition of a saturated solution of ammonium chloride. Ethyl acetate (150 mL) and water (100 mL) were then added, and the organic layer was separated, washed with water and with brine, and then dried (sodium sulfate). After filtration, the solvent was concentrated, and the residue was purified by column chromatography on silica gel, eluting with a gradient of 50% ethyl acetate in hexanes to 100% ethyl acetate over 30 minutes, to give 3.5 g (quantitative yield) of 1-(3-Ethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-6-yl)ethanone. 1H NMR (CDCl3) δ 0.0 (m, 1H), 1.0 (t, 3H), 1.1-1.4 (m, 2H), 2.7 (s, 3H), 2.9-3.1 (m, 2H), 3.5 (1, 2H), 5.7 (s, 2H), 7.5 (m, 2H), 8.0 (s, 1H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([CH2:13][C:14]1[C:15]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[N:16][O:17][C:18]=1[C:19](OCC)=[O:20])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].CC(C)([O-])C.[K+].S(Cl)(Cl)=O>C1COCC1.C(Cl)Cl>[OH:20][C:19]1[C:18]2[O:17][N:16]=[C:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:14]=2[CH:13]=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1c(-c2ccc(OC)cc2)noc1C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ncc2c(-c3ccc(OC)cc3)noc2c1O
Temperature: -78 °C
Reaction time: 14 h
Yield: 41.8 %

Procedure:
Ethyl 4-(((2,4-dimethoxybenzyl)(2-ethoxy-2-oxoethyl)amino)methyl)-3-(4-methoxyphenyl)isoxazole-5-carboxylate (13.7 g, 26.7 mmol) was dissolved in 230 mL of THF and cooled to −78° C. Potassium tert-butoxide solution (53.5 mL, 53.5 mmol, 1M in THF) was added dropwise, and the mixture was stirred for 14 hours, the cold bath allowed to evaporate spontaneously. The reaction mixture was quenched with 50 mL of 1M HCl and 300 mL of saturated ammonium chloride solution. The product was extracted with EtOAc and the organic layer was dried over MgSO4 and concentrated to give 11.4 g of crude oil. The crude intermediate was dissolved in 150 mL of CH2Cl2. Thionyl chloride (2.7 mL, 36.7 mmol) was added and the reaction mixture was stirred for 16 h. The mixture was filtered through a medium porosity funnel. The solid was rinsed twice with cold CH2Cl2 and dried under vacuum to give 3.51 g of the title compound. MS: (+) m/z 315.40 (M+1).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([Cl:17])=[C:10]([C:13]([O:15]C)=[O:14])[CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2]>[OH-].[Na+].O1CCOCC1>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([Cl:17])=[C:10]([C:13]([OH:15])=[O:14])[CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc2c(C(C)=O)c[nH]c2cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(=O)c1c[nH]c2cc(Cl)c(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
A solution of methyl 3-acetyl-6-chloro-1H-indole-5-carboxylate (0.21 g, 0.84 mmol) in 1.5 N sodium hydroxide (0.7 mL) and dioxane (0.5 mL) was heated at 60 C for 6 h and stirred overnight at room temperature. The reaction was quenched by the addition of acetic acid and diluted with water. The resulting solid was filtered, washed with water and dried in vacuo to give the title compound (0.17 g, 96%) as pale yellow powder, m/z=238 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([CH3:15])([CH3:14])[CH:8]1[O:16][CH:7]21)(=[O:3])[CH3:2].[OH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCCC1>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([CH3:15])([CH3:14])[C@@H:8]([OH:16])[C@@H:7]2[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]1=[O:17])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)C1OC1C(C)(C)O2
Reactant: Oc1ccccn1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)[C@@H](n1ccccc1=O)[C@H](O)C(C)(C)O2
Yield: 49.8 %

Procedure:
A mixture containing 2.1 g of 6-acetyl-2,2-dimethyl-3,4-epoxychromane and 1.7 g of 2-hydroxypyridine in 40 ml of tetrahydrofuran is refluxed for 16 hours in the presence of 0.4 ml of benzyltrimethylammonium hydroxide. The mixture is cooled and the crystals formed are filtered off and washed with tetrahydrofuran. After drying under vacuum at 60° C., 1.5 g of the expected product are obtained.