Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([OH:22])(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16].[C:23](O)([CH3:26])([CH3:25])[CH3:24].C1CCN2C(=NCCC2)CC1.C([O-])(O)=O.[Na+]>CN(C=O)C>[OH:16][C:15]1[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=1[C:13]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: O=C(O)c1ccccc1O
Reactant: CC(C)(C)O
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)c1ccccc1O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
CDI (2.40 g, 14.79 mmol) was added to a solution of salicylic acid (2.02 g, 14.62 mmol) in DMF (20 mL). The reaction mixture was stirred at 50° C. for 30 min and tert-butyl alcohol (2.80 mL, 29.84 mmol) and DBU (4.4 mL, 29.45 mmol) were dropwise added. The reaction mixture was stirred at 50° C. for 16 h and allowed to reach r.t. It was poured into NaHCO3 (100 mL, saturated aqueous solution) and extracted with EtOAc (70 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (5% EtOAc/hexanes) to furnish 2.089 g of tert-butyl 2-hydroxybenzoate (colourless oil, yield: 73%).
Reaction SMILES: [C:1]([C:5]1C=C(C2N=C(C)C3C(C=2)=C[C:17]([O:21]C)=[C:16](OC)C=3)[CH:8]=[CH:9][CH:10]=1)(C)(C)[CH3:2].[CH2:26]1[C:31](=[O:32])N(Br)C(=O)C1>C(Cl)(Cl)(Cl)Cl.CCCCCC.CC(N=NC(C#N)(C)C)(C#N)C>[CH3:16][CH2:17][O:21][C:31]([CH3:26])=[O:32].[CH3:2][CH2:1][CH2:5][CH2:10][CH2:9][CH3:8]
Reactant: COc1cc2cc(-c3cccc(C(C)(C)C)c3)nc(C)c2cc1OC
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(C)=O
Temperature: 25 °C
Yield: 168.4 %

Procedure:
3-(3-(tert-Butyl)phenyl)-6,7-dimethoxy-1-methylisoquinoline (400 mg), NBS (223 mg, 1.05 eq.), and AIBN (20 mg, 0.1 eq.) in 7 mL CCl4 were heated at 85° C. for 2 hours. Reaction mixture was then cooled to room temperature and diluted with hexane. Solid precipitate was filtered off and filtrate was concentrated. Chromatography achieved using ISCO max gradient 15% EtOAc/hexane yielding product as a white solid (350 mg, 71% yield). 1H NMR (400 MHz) (CDCl3) δ 8.15-8.14 (m, 1H), 7.94-7.91 (m, 2H), 7.48-7.45 (m, 3H), 7.18 9s, 1H), 5.10 (s, 2H), 4.11 (s, 3H), 4.07 (s, 3H), 1.45 (s, 9H). 13C NMR (100 MHz) (CDCl3) δ 153.03, 152.89, 151.50, 150.11, 149.96, 139.19, 134.59, 128.46, 125.45, 124.18, 123.86, 121.45, 116.56, 105.75, 103.56, 56.16, 56.10, 34.90, 32.97, 31.47.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[C:12]([S:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=12.[P:20](Cl)([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].C(=O)([O-])[O-]>CN(C=O)C.C(OCC)(=O)C>[P:20]([O:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[C:12]([S:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=12)([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21]
Reactant: Oc1cc2c(c3ccccc13)Nc1ccccc1S2
Reactant: CCOP(=O)(Cl)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)Oc1cc2c(c3ccccc13)Nc1ccccc1S2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-hydroxy-12H-benzo[a]phenothiazine (1.5 g) and diethyl chlorophosphate (2 ml) in DMF (20 ml) there was added a powdered mixture of potassium carbonate (2 g) and potassium iodide (2 g). The reaction mixture was stirred at room temperature. After 30 minutes, a further addition of potassium carbonate and potassium iodide (2 g each) was made and stirring was continued. Two hours later more carbonate (2 g) and diethyl chlorophosphate (2 ml) were added, and then three hours later a final addition of carbonate (2 g) was made. The mixture was stirred for 3 days then diluted with ethyl acetate (60 ml) and the insolubles filtered. The filtrate was washed with water, dried and evaporated down. This residue was crystallized from acetone, then chromatographed on a column of silica gel, eluting first with 1:1, then 3:1 mixtures of ethyl acetate and hexane to afford pure title compound (337 mg), m.p. 162°-163° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH:12][CH2:13][CH2:14][CH3:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[CH:2].C(O)(=O)C1C=CC=CC=1.[CH2:25]([O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32](I)=[CH:31][CH:30]=1)[CH3:26]>C(N(CC)CC)C.[Cu]I.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>[CH2:13]([NH:12][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:32]3[CH:33]=[CH:34][C:29]([C:28]([O:27][CH2:25][CH3:26])=[O:36])=[CH:30][CH:31]=3)=[CH:4][CH:5]=2)[CH2:10][CH2:11]1)[CH2:14][CH3:15]
Reactant: C#Cc1ccc(C2(NCCC)CC2)cc1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Product: CCCNC1(c2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
Using General Procedure F; [1-(4-ethynylphenyl)-cyclopropyl]-propylamine (Intermediate 120, 38.0 mg, 0.19 mmol) and ethyl-4-iodo benzoate (Reagent A, 58.0 mg, 0.21 mmol) in triethyl amine (6 mL) was treated with copper(I)iodide (8.0 mg, 0.04 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (27 mg, 0.04 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (5-15% EtOAc-hexanes) afforded 40.0 mg (61%) of the title compound as an orange oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.C(=O)(O)[O-].[Na+]>C(O)CCC>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:11][CH2:12][N:13]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:15]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(C2CCNCC2)cc1
Reactant: Clc1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: O=[N+]([O-])c1ccc(C2CCN(c3ccncc3)CC2)cc1
Yield: 4.4 %

Procedure:
A mixture of 4-(4-nitrophenyl)piperidine [J. Chem. Soc. (B), 128, 1970] (4.12 g), 4-chloropyridine hydrochloride (3.00 g), sodium bicarbonate (5.04 g) and n-butanol (60 ml) was heated under reflux for 48 hours and then evaporated. The residue was partitioned between water and ethyl acetate. The organic phase was washed with water, dried (Na2SO4) and evaporated to give a solid which was chromatographed on silica gel. The column was eluted initially with ethyl acetate and then the eluent polarity was gradually increased to ethyl acetate/methanol (10:1). Earlier fractions contained impurity and the product was eluted in the later fractions. The product-containing fractions were combined and evaporated, and the residue was crystallised from ethyl acetate to give the title compound, (0.25 g), m.p. 173°-174°.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14](=O)[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)(=O)C.[Pd]>[C:4]1([NH2:1])[CH:5]=[CH:6][CH:7]=[C:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]=12
Reactant: O=C1CCCCc2c1cccc2[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1cccc2c1CCCCC2
Reaction time: 16 h

Procedure:
A solution of 1-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-one (CAS #251554-42-4, 2.5 g, 12 mmol), palladium (413 mg, 10% on carbon, 0.4 mmol) in acetic acid (25 ml) under the hydrogen atmosphere (60 PSI) was heated at 60° C. and stirred at for 16 hours. The mixture was filtered through a layer of diatomaceous earth, washed with methanol and concentrated under reduced pressure to provide the title compound. 1H NMR (CDCl3) δ 1.50-1.69 (m, 4H), 1.75-1.86 (m, 2H), 2.71-2.86 (m, 4H), 5.46 (s, 2H), 7.03-7.12 (m, 3H). MS (M+H)+ m/z 162.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([CH2:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=1)=[O:5])[CH3:2].C(N(CC)C(C)C)(C)C.[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([CH2:11][N:12]([C:28](=[O:30])[CH3:29])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1cc(CNc2ccccc2)c[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc(CN(C(C)=O)c2ccccc2)c[nH]1
Temperature: 0 °C

Procedure:
4-Phenylaminomethyl-1H-pyrrole-2-carboxylic acid ethyl ester (183) (0.1523 g, 0.623 mmol) was weighed out into a 10 mL flask. A stir bar and septum were added, and the flask was purged with nitrogen. The amine was dissolved in methylene chloride (1.6 mL, 0.4 M) and then the flask was cooled to 0° C. N,N-diisopropyl ethyl amine (0.1194 mL, 0.686 mmol) was added, then acetyl chloride (0.0488 mL, 0.686 mmol) was added slowly by syringe to the stirring 0° C. solution. The reaction was then allowed to warm to room temperature. When the reaction was judged complete by HPLC (35 min) the reaction was diluted with methylene chloride and quenched with water. The organic phase was removed, washed with brine, dried with Na2SO4, filtered and concentrated en vacuo. The crude product was sufficiently pure by HPLC and NMR analysis that it was used in the next step without further purification (0.1625 g, 91%, white crystalline solid). 1H (CD3OD, 400 MHz): δ 11.22 (1H, broad s), 7.43-7.31 (3H, m), 7.08 (2H, dd, J=7.0, 1.5 Hz), 6.75 (1H, d, J=1.5 Hz), 6.68 (1H, d, J=1.5 Hz), 4.70 (2H, s), 4.24 (2H, q, J=7.0 Hz), 1.81 (3H, s), 1.31 (3H, t, J=7.0 Hz) ppm. 13C (CD3OD, 100 MHz): δ 172.47, 162.64, 143.86, 130.68, 129.34, 129.27, 124.50, 124.33, 122.19, 116.72, 61.16, 46.60, 22.64, 14.75 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 22.64, 14.75; CH2 carbons: 61.16, 46.60; CH carbons: 130.68, 129.34, 129.27, 124.33, 116.72 ppm. HPLC: 8.738 min.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5](=[O:10])[O:6][C:7]=1[CH2:8][Br:9].[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][C:17]([OH:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:9][CH2:8][C:7]1[O:6][C:5](=[O:10])[O:4][C:3]=1[CH2:2][O:19][C:17](=[O:18])[CH2:16][O:15][CH2:14][CH2:13][O:12][CH3:11]
Reactant: COCCOCC(=O)O
Reactant: O=c1oc(CBr)c(CBr)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCOCC(=O)OCc1oc(=O)oc1CBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
4,5-Dibromomethyl-2-oxo-1,3-dioxolene (136 mg, 0.50 mmol) was dissolved in acetonitrile (5.0 mL). Thereto were added 2-methoxyethoxyacetic acid (0.057 mL, 0.50 mmol) and potassium carbonate (69 mg, 0.50 mmol) This mixture was stirred at 25° C. for 30 minutes. After the ordinary post-treatment, the reaction product was purified by thin-layer chromatography (developed with chloroform) to obtain Compound S-32 (45 mg, yield 28%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([O:11][CH2:12][CH:13]=C)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[O:16]=[O+][O-].CSC>ClCCl>[CH3:1][O:2][C:3](=[O:15])[CH:4]([O:11][CH2:12][CH:13]=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=CCOC(C(=O)OC)c1ccccc1
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CSC
Product: COC(=O)C(OCC=O)c1ccccc1
Temperature: -75 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
Allyloxy-phenyl-acetic acid methyl ester (described in EJOC 2000, 3145-3163; 3 g, 14.5 mmol) was dissolved in dichloromethane (300 mL) and cooled to −75° C. O3 was blubbled through the solution for 6 hours until the solution turned blue. Argon was blubbled through the solution for 1 hour, then dimethyl sulfide (9.04 g, 10.8 mL, 145 mmol) was added to the reaction mixture and kept at room temperature for 12 hours. The reaction mixture was evaporated and the residue purified by flash chromatography over 50 g SiO2-flash pack using gradient 10-100% EtOAc in heptane over 60 minutes to give the title compound as light yellow oil (2.72 g, 90%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH:11]1[CH2:14][CH2:13][CH2:12]1.[H-].[Na+].Cl[CH2:18][C:19]#[N:20]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:18][C:19]#[N:20])[N:6]=[C:5]2[CH:11]1[CH2:14][CH2:13][CH2:12]1
Reactant: N#CCCl
Reactant: Brc1ccc2[nH]nc(C3CCC3)c2c1
Agent: [H-]
Agent: [Na+]
Product: N#CCn1nc(C2CCC2)c2cc(Br)ccc21
Yield: 61.4 %

Procedure:
The title compound was prepared by the method outlined for Preparative Example 59 using 5-bromo-3-cyclobutyl-1H-indazole intermediate (225 mg, 0.898 mmol), NaH (41 mg, 1.02 mmol), and chloroacetonitrile (78 mg, 1.03 mmol) to afford titled compound as an off-white solid (160 mg, 62%). 1H NMR (DMSO-d6) 7.99 (s, 1H), 7.72 (d, J=8.8, 1H), 7.62 (d, J=8.8, 1H), 5.74 (s, 2H), 3.91 (pent, J=8.8, 1H), 2.38-2.32 (m, 4H), 2.08-2.06 (m, 1H), 1.95 (m, 1H). LC/MS (Method B) 3.99 min, [M+1]+ 290/292].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[CH:13]=2)=[CH:5][CH:4]=1.Cl.[CH2:19]([N:21]([CH2:35][CH3:36])[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)[CH3:20]>>[CH2:35]([N:21]([CH2:19][CH3:20])[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([C:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:31])=[CH:33][CH:34]=1)[CH3:36]
Reactant: COc1ccc(-c2cc3ccccc3o2)cc1
Reactant: CCN(CC)CCCOc1ccc(C(=O)Cl)cc1
Agent: Cl
Product: CCN(CC)CCCOc1ccc(C(=O)c2c(-c3ccc(OC)cc3)oc3ccccc23)cc1

Procedure:
Acylation of 2-(p-methoxyphenyl)benzofuran with 4-(3-diethylaminopropoxy)benzoyl chloride hydrochloride by the procedure described in Example 6 gives the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[CH2:4][CH:5]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](C)=[CH:15]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CCNC)C=[CH:24]1>>[CH3:1][NH:2][CH2:3][CH2:4][CH:5]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH3:24])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CNC(=O)CC(c1ccccc1)c1ccc2[nH]c(C)cc2c1
Reactant: CNCCC(c1ccccc1)c1cccc2cc[nH]c12
Product: CNCCC(c1ccccc1)c1ccc2[nH]cc(C)c2c1
Yield: 68 %

Procedure:
Methyl-[3-(3-methyl-1H-indol-5-yl)-3-phenyl-propyl]-amine LXXIV (221 mg, 68% yield) was prepared from N-methyl-3-(2-methyl-1H-indol-5-yl)-3-phenyl-propionamide using the procedure described above for [3-(1H-indol-7-yl)-3-phenyl-propyl]-methyl-amine XX (see Example 4). MS (M+H)=279.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28]>C1COCC1>[C:8]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=[C:6]([C:4]([C:23]2[CH:24]=[C:25]([O:29][CH3:30])[C:26]([O:27][CH3:28])=[C:21]([O:20][CH3:19])[CH:22]=2)=[O:5])[CH:7]=1
Reactant: CON(C)C(=O)c1cccc(-c2ccccc2)c1
Reactant: COc1cc([Mg]Br)cc(OC)c1OC
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2cccc(-c3ccccc3)c2)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
To a solution of 38a (FIG. 2) (0.174 g, 0.72 mmol.) in 5 mL THF was added a THF solution of 3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 1.08 mmol) at 0° C. The mixture was allowed to stir for 30 min and quenched with satd. NH4Cl, extracted with ethyl ether, dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 1a as a white solid (43.8%). 1H NMR (CDCl3) δ 8.02 (t, 1H), 7.84-7.74 (m, 2H), 7.64-7.38 (m, 6H), 7.11 (s, 2H), 3.95 (s, 3H), 3.88 (s, 6H); MS (ESI) m/z 371.1 (M+Na)+.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:16][O-:17].[Na+].Cl>CO.O>[CH3:16][O:17][C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Oc1ccc(Sc2cccc(F)n2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cccc(Sc2ccc(O)cc2)n1

Procedure:
A solution of 11.05 grams (0.05 mole) of 4-((6-fluoro-2-pyridyl)thio)phenol (prepared as above in Example VI) and 8.10 grams (0.15 mole) of sodium methoxide in 200 milliliters of methanol was heated at reflux overnight. The resulting solution was acidified with concentrated hydrochloric acid and thereafter diluted with water. The solid 4-((6-methoxy-2-pyridyl)thio)phenol product was recovered by filtration, water washed and dried. The product was recovered in a yield of 10 grams (86 percent of theoretical) and melted at 88.5°-94.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[CH2:7][CH2:6][C:5]2([CH3:15])[CH3:14].N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].O>CN(C)C=O>[C:24]([Si:21]([CH3:23])([CH3:22])[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[CH2:7][CH2:6][C:5]2([CH3:15])[CH3:14])([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1cc2c(cc1O)C(C)(C)CCC2=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1O[Si](C)(C)C(C)(C)C)C(C)(C)CCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
A solution of 6-hydroxy-4,4,7-trimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 171, 2.04 g, 10 mmol) in anhydrous N,N-dimethyl formamide (10 mL) under argon was treated with imidazole (1 g, 14.7 mmol) followed by tert-butyldimethylsilyl chloride (1.5 g, 10 mmol). After stirring the reaction mixture at ambient temperature overnight, it was poured into water and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to a residue that was purified by flash column chromatography on silica gel (230-400 mesh) using 8-14% ethyl acetate in hexane as the eluent to afford the title compound (2.5 g, 79%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[CH:11][CH2:10][CH:9]1B1OC(C)(C)C(C)(C)O1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:34][C:33]([NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=3)=[N:32][CH:31]=2)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[O:34][C:33]([NH:35][C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=4)=[N:32][CH:31]=3)=[CH:28][CH:29]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC=CCC1B1OC(C)(C)C(C)(C)O1
Reactant: Clc1cccc(Nc2ncc(-c3ccc(Br)cc3)o2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(-c3cnc(Nc4cccc(Cl)c4)o3)cc2)CC1
Temperature: 100 °C

Procedure:
Preparation of -(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester has been described [Tet. Lett. 41-(19), 3705-3708, 2000]. The boronate ester (1.1 g, 3.6 mmol, 1.5 equiv) and [5-(4-bromo-phenyl)-oxazol-2-yl]-(3-chloro-phenyl)-amine (0.84 g, 2.4 mmol, 1.0 equiv) were dissolved in 12 mL DME and then charged with 3 mL of a 2M Na2CO3 solution. Pd(Ph3)4 on polystyrene resin (0.72 g, 0.072 mmol) was added, and the suspension was sparged with nitrogen for 10 min, then heated to 100° C. overnight. The reaction was then filtered to remove catalyst, and following solvent removal the product was triturated with hexanes and ether to afford the title compound: (M+H)+452.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6](=O)[CH2:7]Cl)[CH3:2].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=1>C(O)C>[CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6]1[N:11]=[C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]2[CH:7]=1)[CH3:2]
Reactant: Nc1ccc(Br)cn1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCO
Product: CCOC(=O)Cc1cn2cc(Br)ccc2n1
Temperature: 25 °C

Procedure:
4.90 ml of ethyl4-chloro-3-oxobutanoate was dissolved in 50 ml of ethanol, 5.19 g of 2-amino-5-bromopyridine was added, and the mixture was stirred all night by heating under reflux. After cooling down to room temperature, the solvents were distilled outunder reduced pressure, and then, ethyl acetate followed by saturated sodium bicarbonate aqueous solution were added. Organic layer was dried with anhydrous sodium sulfate, and the solvents were distilled outunder reduced pressure. The obtained residues were purified by preparative thin-layer chromatography (hexane:ethyl acetate=60:40) to obtain 9.49 mg of the above compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9]O)=[CH:4][CH:3]=1.CCN(S(F)(F)[F:19])CC>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][F:19])=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(CO)c1ccc(Br)cc1
Solvent: ClCCl
Product: CC(C)(CF)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(4-bromophenyl)-2-methylpropan-1-ol (500 mg, 2.182 mmol) was dissolved in Dichloromethane (7.2 mL) in a 20 mL vial. DAST (0.433 mL, 3.27 mmol) was then slowly added to the solution. Stirred at ambient temperature overnight. TLC showed presence of starting material. Another 0.5 eq. of DAST was added and stirred for 4 hours. TLC then showed consumption of starting material. The reaction was loaded directly on a silica column and the column was then dried out. Purified with a Teledyne Isco Combiflash Rf purification system using a gradient of 5% EtOAc/hexanes. Isolated 1-bromo-4-(1-fluoro-2-methylpropan-2-yl)benzene as a clear liquid. 1H NMR (500 MHz, CDCl3) δ 7.43-7.42 (d, 2H), 7.10-7.09 (d, 2H), 2.88 (s, 1H), 2.83 (s, 1H), 1.35 (s, 3H), 1.30 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Br:9].[N-:10]=[N+:11]=[N-:12].[Na+].O>CN(C)C=O>[N:10]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Br:9])=[N+:11]=[N-:12]
Reactant: BrCc1ccccc1Br
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCc1ccccc1Br
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.9 %

Procedure:
After a mixture of 30 g (120 mmol) of 1-bromomethyl-2-bromobenzene and 15.6 g (240 mmol) of sodium azide in 300 ml of dimethylformamide was stirred at 25° C. for 20 hours it was poured into 500 ml of water and extracted with ethyl acetate. The extracts were washed with water and brine, dried (Na2SO4) and concentrated to give 24.9 g (98%) of the product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([OH:26])=O)[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[O:41][C:40]([SH:42])=[N:39][N:38]=2)=[CH:33][CH:32]=1.O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([C:37]5[O:41][C:40]([SH:42])=[N:39][N:38]=5)=[CH:35][CH:36]=4)=[O:26])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(N3CCCC(C(=O)O)C3)nc3scnc23)cc1OC
Reactant: Nc1ccc(-c2nnc(S)o2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Nc2nc(N3CCCC(C(=O)Nc4ccc(-c5nnc(S)o5)cc4)C3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 11.3 %

Procedure:
To a solution of 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxylic acid (50 mg, 0.12 mmol) and 5-(4-aminophenyl)-1,3,4-oxadiazole-2-thiol (23 mg, 0.12 mmol) in pyridine (10 mL) was added POCl3 (0.3 mL, 3.29 mmol) at 0° C., the reaction mixture was stirred at room temperature for 6 hours, a sat. NaHCO3 solution was added slowly, the solvent was removed in vacuo, methanol (20 mL) were added and filtrated. The filtrate was collected, concentrated and purified by a silica column chromatography (silica gel 200-300 mesh, eluting with dichloromethane:methanol=40:1) to afford 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(4-(5-mercapto-1,3,4-oxadiazol-2-yl)phenyl)piperidine-3-carboxamide (8.0 mg, 11.3%) as a white solid. 1H NMR (300 MHz, DMSO): δ 10.42 (s, 1H), 9.67 (s, 1H), 8.86 (s, 1H), 7.86-7.78 (m, 4H), 7.66 (s, 1H), 7.35 (d, 1H, J=8.7 Hz), 6.81 (brs, 1H), 4.81 (d, 1H, J=11.7 Hz), 4.66 (d, 1H, J=13.2 Hz), 3.69 (s, 3H), 3.63 (s, 3H), 3.15-3.07 (m, 1H), 3.01-2.93 (m, 1H), 2.73-2.61 (m, 1H), 2.07-1.74 (m, 3H), 1.78-1.74 (m, 1H). LC-MS: 591 [M+H]+, tR=1.56 min. HPLC: 97.80% at 214 nm, 97.26% at 254 nm, tR=5.91 min