Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[C:14]([F:15])=[CH:13][C:12]([C:16]2[O:17][C:18]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][C:19]=3[CH:20]=2)=[CH:11][N:10]=1)C)(C)(C)C.B(Br)(Br)Br>C(Cl)Cl>[F:15][C:14]1[CH:13]=[C:12]([C:16]2[O:17][C:18]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:19]=3[CH:20]=2)[CH:11]=[N:10][C:9]=1[NH:7][CH3:6]
Reactant: COc1ccc2oc(-c3cnc(N(C)C(=O)OC(C)(C)C)c(F)c3)cc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CNc1ncc(-c2cc3cc(O)ccc3o2)cc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 40.9 %

Procedure:
To a solution of [3-fluoro-5-(5-methoxy-benzofuran-2-yl)-pyridin-2-yl]-methyl-carbamic acid tert-butyl ester (130 mg, 0.35 mmol) in dry CH2Cl2 (400 mL), BBr3 (2.1 mL, 2.10 mmol) was added at −78° C. The reaction mixture was allowed to warm to room temperature and the stirring was continued for 14 hours. The reaction was then quenched by addition of saturated aqueous NaHCO3 and the product was extracted with EtOAc (3×30 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The crude residue was purified by preparative TLC using 30% EtOAc in CH2Cl2 to afford 2-(5-fluoro-6-methylamino-pyridin-3-yl)-benzofuran-5-ol (37 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[C:24]2[O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:23]=2[CH:22]=[CH:21][C:20]=1[O:32][CH3:33]>>[CH3:33][O:32][C:20]1[CH:21]=[CH:22][C:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[O:25][C:24]=2[C:19]=1[NH:18][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: COc1ccc2c(oc3ccccc32)c1N
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: COc1ccc2c(oc3ccccc32)c1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol) and 4-amino-3-methoxydibenzofuran (61 mg, 0.288 mmol) similar to Example 185 and was isolated as a solid (6 mg, 7%). 1H NMR (CDCl3): 9.73 (brs, 1H), 8.88 (d, J=7.8 Hz, 1H), 8.77 (brs, 1H), 7.89 (m, 1H), 7.19–7.59 (m, 6H), 7.02 (s, 1H), 4.05 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>O.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([O:7][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:24])=[O:6]
Reactant: CCCCCCCCCCCCCCBr
Reactant: COc1ccc(C(=O)O)cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCOC(=O)c1ccc(OC)c(N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
16.7 g (0.1 mol) of 3-amino-4-methoxybenzoic acid was added to 50 ml of N,N-dimethylformamide. Then 13.8 g (0.1 mol) of potassium carbonate was added to the solution obtained above, and the resulting mixture was stirred in the temperature range of from 20 to 30° C. for 30 min. 30.5 g (0.11 mol) of tetradecyl bromide was poured into the solution thus obtained, and the resulting solution was heated to 80° C., and allowed to react at the temperature for 1 hour. After completing the reaction, 50 ml of ethyl acetate, and 50 ml of water were added to the reaction mixture, and the organic layer obtained was separated, concentrated, diluted with 100 ml of methanol, and then cooled to precipitate crystals. The crystals were separated by filtration, and then dried to obtain 33.1 g (yield 91%) of the desired product. Purity 98% or higher. Melting point 54.0-56.0° C. A result of the elemental analysis of this sample was as follows:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25])=[C:11]1[C:6]([CH2:7][CH2:8][CH2:9][C:10]1=[O:28])=[N:5]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:25])([F:27])[F:26])=[C:11]1[C:6]([CH2:7][CH2:8][CH2:9][CH:10]1[OH:28])=[N:5]2
Reactant: O=C1CCCc2nc3cc(F)ccc3c(NCc3ccccc3C(F)(F)F)c21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1CCCc2nc3cc(F)ccc3c(NCc3ccccc3C(F)(F)F)c21
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a cooled solution of 5.7 g of 3,4-dihydro-6-fluoro-9-(2-trifluoromethylbenzylamino)acridin-1(2H)-one in 80 ml of tetrahydrofuran was added 7.5 ml of 1 molar solution of lithium aluminium hydride in THF. This was stirred for 0.5 hour and then quenched with 6 ml of saturated ammonium chloride solution. The inorganics were filtered, rinsed with ethyl acetate and the combined organics were dried over anhydrous magnesium sulfate. This was concentrated to a solid which was triturated with ether to give 5.1 g of a powder. This was twice recrystallized from ethyl acetate/hexane to give 3.1 g of analytically pure crystals, mp 149°-153° C.
Reaction SMILES: [OH-].[Na+].C([O:11][C:12]1[CH:27]=[CH:26][C:15]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[C:14]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:13]=1)(=O)C1C=CC=CC=1.Cl>CO>[CH2:29]([O:28][C:14]1[CH:13]=[C:12]([OH:11])[CH:27]=[CH:26][C:15]=1[C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(Oc1ccc(C(=O)OCc2ccccc2)c(OCc2ccccc2)c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(OCc1ccccc1)c1ccc(O)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.2 %

Procedure:
A 2 mol/L aqueous solution of sodium hydroxide (6.39 mL) was added to a mixture of benzyl 4-benzoyloxy-2-benzyloxybenzoate (2.80 g) in methanol/tetrahydorofuran (1/1, 20 mL), and the mixture was stirred at room temperature for 5 hrs. To the reaction mixture was added 2 mol/L hydrochloric acid (6.39 mL). The solvent was evaporated under reduced pressure, and water was added to the residue. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium-pressure silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1) to afford benzyl 2-benzyloxy-4-hydroxybenzoate (0.859 g)
Reaction SMILES: Cl.CC(C)([O:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][CH2:11][CH2:12][O:13][N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)=[CH:8][CH:7]=1)C>C(O)C.O>[OH:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][O:13][N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)Oc1ccc(OCCOn2cccn2)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Oc1ccc(OCCOn2cccn2)cc1
Temperature: 25 °C
Yield: 96.7 %

Procedure:
9 ml of concentrated hydrochloric acid were added to a solution of 38.4 g (139 mmol) of N-2-[4-(1,1-dimethylethoxy)phenoxy]ethoxypyrazole in 400 ml of ethanol/water (10/1) and the mixture was then refluxed for 8 h. After cooling to RT, the solvent was removed under reduced pressure, the residue was taken up in ethyl acetate, and the solution was washed several times with water. Drying and concentration of the organic phase resulted in 29.6 g (97%) of the required compound as a viscous oil which was employed without further purification in the next stage.
Reaction SMILES: [CH:1]1[C:14]2[CH:13](O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.O=S(Cl)Cl.[C:20]([Cu])#[N:21].C1C2CC3C(=CC=CC=3)SC=2C=CC=1.C1C2C(=O)C3C(=CC=CC=3)SC=2C=CC=1>CCOCC.C1C=CC=CC=1>[CH:1]1[C:14]2[CH:13]([C:20]#[N:21])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OC1c2ccccc2Sc2ccccc21
Reactant: N#C[Cu]
Agent: O=c1c2ccccc2sc2ccccc12
Agent: c1ccc2c(c1)Cc1ccccc1S2
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Solvent: c1ccccc1
Product: N#CC1c2ccccc2Sc2ccccc21
Temperature: 2.5 °C
Yield: 58.3 %

Procedure:
A suspension of 9H-Thioxanthen-9-ol [32] (2.14 g, 9.98 mmol) in anhydrous Et2O (20 mL) under N2 and SOCl2 (0.8 mL, 11.48 mmol) was added with caution via syringe with stirring at 0-5° C. The alcohol dissolved before a white solid began to separate. After stirring (1 hr.) at room temperature, the solvent was removed under reduced pressure and C6H6 (10 mL) was added and solvent removed to dryness again. All manipulations were performed with rigorous exclusion of air. Anhydrous C6H6 (20 mL) and CuCN powder (1.79 g, 19.97 mmol) were added and the suspension was stirred at reflux (4 hr.).The reaction mixture was filtered while hot and the residue was washed with hot C6H6 (50 mL). The filterate was evaporated to give a crystalline residue containing thioxanthene and thioxanthen-9-one as well as the desired nitrile. One recrystallizations from hexane removed thioxanthene and one recrystallizations from 2-propanol removed most of the thioxanthen-9one to provide 1.3 g (59%) of the pure nitrile, mp. 97-98° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C@H:5]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:9]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:8]=2[NH:7][C:6]1=[O:24].[CH2:26](Br)[CH:27]([CH3:29])[CH3:28]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C@H:5]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:9]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:8]=2[N:7]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:6]1=[O:24]
Reactant: CC(C)CBr
Reactant: COC(=O)C[C@H]1N=C(c2ccccc2Cl)c2cc(Cl)ccc2NC1=O
Product: COC(=O)C[C@H]1N=C(c2ccccc2Cl)c2cc(Cl)ccc2N(CC(C)C)C1=O
Yield: 52.2 %

Procedure:
(3R)-7-Chloro-5-(2-chlorophenyl)-2,3-dihydro-2-oxo-1H,1,4-benzodiazepine-3-acetic acid methyl ester (0.5 g) obtained in Example 11 and isobutyl bromide (0.23 g) were allowed to proceed in substantially the same manner as in Example 4 to give 0.3 g of a colorless oily compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[C:11]([CH2:25][OH:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[C:11]([CH:25]=[O:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1
Reactant: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=CC1(C=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 50 mg (0.14 mmol) of 1-9 in 1 mL of CH2Cl2 was added 71 mg (0.17 mmol) of Dess-Martin Periodinane (Lancaster Synthesis) and the mixture was left to stir for 15 min at room temperature. The reaction was diluted with 10 mL of CH2Cl2, quenched with 5 mL of 5% aqueous NaHSO3 and 10 mL of saturated aqueous NaHCO3 and the biphasic mixture was stirred for 30 min. The layers were separated, the organic was washed with NaHCO3 and water, dried over Na2SO4, and concentrated to provide 3-1 as a white solid. Data for 3-1: 1HNMR (500 MHz, CDCl3) δ 9.6 (s, 1H), 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.2 (s, 1H), 4.9 (d, 1H), 4.8 (d, 1H), 3.0 (s, 6H) ppm.
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10]O)=[CH:5][CH:4]=1>>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][Cl:1])=[CH:5][CH:4]=1
Reactant: OCCc1ccc(O)cc1
Reactant: Cl
Product: Oc1ccc(CCCl)cc1

Procedure:
In a similar process using 12N HCl, 2-(4-hydroxyphenyl) ethanol gave 70% isolated yield of the (2-[4-hydroxyphenyl]ethyl) chloride. 1H NMR (CDCl3) δ 2.96 (2H, t, J=7.8 Hz), 3.67 (2H, t, J=7.2 Hz), 6.79 (2H, d, J=8.4 Hz), 6.94 (2H, d, J=8.1 Hz)
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[CH3:47][O:48][C:49]1[CH:57]=[CH:56][C:52]([C:53](Cl)=[O:54])=[CH:51][CH:50]=1.O>N1C=CC=CC=1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:53]([C:52]3[CH:56]=[CH:57][C:49]([O:48][CH3:47])=[CH:50][CH:51]=3)=[O:54])[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C(=O)Nc2cccc(-c3n[nH]c4ccc(-c5nc[nH]n5)cc34)c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.4 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.200 g, 0.33 mmol) in pyridine (2 mL) was added 4-methoxybenzoyl chloride (0.068 g, 0.40 mmol). The reaction was stirred at room temperature for 15 h. Water (10 mL) was added and the solid collected by suction filtration. The solid was dried in a vacuum oven for 3 h. The residue was dissolved in 4 N hydrochloric acid in 1,4-dioxane (10 mL) and the mixture was stirred at room temperature for 2 h. After neutralization with aqueous sodium bicarbonate, the reaction mixture was extracted with ethyl acetate. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and evaporated. Addition of dichloromethane (10 mL) to the residue gave the title compound (0.090 g, 66% yield) which was isolated by filtration: 1H NMR (DMSO-d6) δ 10.33 (s, 1H), 8.73 (s, 1H), 8.44 (s, 1H), 8.30 (s, 1H), 8.11 (d, 1H), 8.03 (d, 2H), 7.93 (d, 1H), 7.10 (m, 2H), 7.53 (t, 1H), 7.09 (d, 2H), 3.85 (s, 3H); ES-MS (m/z) 411 [M+1]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=2)=[CH:7][N:6]=1)=[O:4].[Li+].[OH-]>C1COCC1.CO.O>[F:23][C:20]([F:21])([F:22])[O:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][CH2:11][C:8]1[N:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1cnc(COc2cccc(OC(F)(F)F)c2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cnc(COc2cccc(OC(F)(F)F)c2)cn1
Yield: 81.4 %

Procedure:
A solution of 5-(3-trifluoromethoxy-phenoxymethyl)-pyrazine-2-carboxylic acid methyl ester (0.234 g, 0.712 mmol) in THF:MeOH (4:1, 5 mL) was treated with LiOH (0.150 g, 3.564 mmol) in 1.5 mL of water by the general procedure C to give 0.182 g of 5-(3-trifluoromethoxy-phenoxymethyl)-pyrazine-2-carboxylic acid. LCMS: 316 (M+2)+
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH3:7])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:3]=1.[CH2:16](Br)[CH:17]=[CH2:18].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[CH2:18]([O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:4]2[CH:3]=[C:2]([Br:1])[S:6][C:5]=2[CH3:7])=[CH:10][CH:11]=1)[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: Cc1sc(Br)cc1Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(Cc2cc(Br)sc2C)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
To a solution of phenol 12 (860 mg, 3.04 mmol) in acetone (20 mL) were added allyl bromide (0.5 mL, 4.56 mmol) and Cs2CO3 (2.0 g, 6.08 mmol) at room temperature. The mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature and filtered off through celite. The filtrate was concentrated in vacuo. The residue was purified by silica column chromatography (Biotage) to provide the title compound 13 (906 mg, 92%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].[CH:12]([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][S:22]([CH2:25][CH2:26][NH:27][C:28]([C:30]2[S:31][C:32]([Cl:35])=[CH:33][CH:34]=2)=[O:29])(=[O:24])=[O:23])[CH2:17][CH2:16]1)([CH3:14])[CH3:13]>>[C:8]([Si:5]([CH3:7])([CH3:6])[O:4][CH2:3][CH2:2][N:21]([CH:18]1[CH2:19][CH2:20][N:15]([CH:12]([CH3:14])[CH3:13])[CH2:16][CH2:17]1)[S:22]([CH2:25][CH2:26][NH:27][C:28]([C:30]1[S:31][C:32]([Cl:35])=[CH:33][CH:34]=1)=[O:29])(=[O:23])=[O:24])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)N1CCC(NS(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Product: CC(C)N1CCC(N(CCO[Si](C)(C)C(C)(C)C)S(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1

Procedure:
5-Chloro-thiophene-2-carboxylic acid {2-[[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-(1-isopropyl-piperidin-4-yl)-sulfamoyl]-ethyl}-amide was prepared by an analogous procedure as described in example 15 starting from 2.3 ml (3.5 equiv.) (2-bromo-ethoxy)-tert-butyl-dimethyl-silane and 1.2 g (3.05 mmol) 5-chloro-thiophene-2-carboxylic acid [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-amide. 5-Chloro-thiophene-2-carboxylic acid {2-[[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-(1-isopropyl-piperidin-4-yl)-sulfamoyl]-ethyl}-amide was obtained as crude material which was pure enough for further transformations.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]2[N:15]=[C:16]([CH2:25][O:26][CH2:27][CH3:28])[C:17]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:4]2[N:3]=1.CCN(C(C)C)C(C)C.[NH:38]1[CH2:42][CH2:41][CH2:40][C@H:39]1[CH2:43][OH:44]>C(#N)C>[CH2:27]([O:26][CH2:25][C:16]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[C:4]2[N:3]=[C:2]([N:38]3[CH2:42][CH2:41][CH2:40][C@H:39]3[CH2:43][OH:44])[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[N:5]2[N:15]=1)[CH3:28]
Reactant: OC[C@@H]1CCCN1
Reactant: CCOCc1nn2c(-c3ccc(F)cc3)cc(Cl)nc2c1-c1ccc(C)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOCc1nn2c(-c3ccc(F)cc3)cc(N3CCC[C@H]3CO)nc2c1-c1ccc(C)cc1

Procedure:
5-Chloro-2-(ethoxymethyl)-7-(4-fluorophenyl)-3-(4-methylphenyl)pyrazolo[1,5-a]pyrimidine (22 mg), DIPEA (0.1 mL) and (S)-2-pyrrolidinemethanol (0.1 mL) are stirred for 2 hours in an acetonitrile (7 mL) solvent at 84° C. The reaction solvent is removed by distillation under reduced pressure. The remainder is purified by column chromatography to yield the target compound (24 mg).
Reaction SMILES: Cl[C:2]1[N:27]=[CH:26][C:5]2[N:6]=[C:7]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][OH:25])[CH2:19][CH2:18]3)[C:8](=[O:16])[N:9]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH3:15])[C:4]=2[CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][N:31]=1>O1CCOCC1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:25][CH2:24][CH2:23][N:20]1[CH2:21][CH2:22][N:17]([C:7]2[C:8](=[O:16])[N:9]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH3:15])[C:4]3[CH:3]=[C:2]([C:33]4[CH:32]=[N:31][C:30]([O:29][CH3:28])=[CH:35][CH:34]=4)[N:27]=[CH:26][C:5]=3[N:6]=2)[CH2:18][CH2:19]1
Reactant: CCCOCCn1c(=O)c(N2CCN(CCO)CC2)nc2cnc(Cl)cc21
Reactant: COc1ccc(B(O)O)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: CCCOCCn1c(=O)c(N2CCN(CCO)CC2)nc2cnc(-c3ccc(OC)nc3)cc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 7-chloro-3-[4-(2-hydroxyethyl)piperazin-1-yl]-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one (218 mg, 0.55 mmol) in 1,4-dioxane (3.0 mL) was treated with tetrakis(triphenylphosphine) palladium(0) (19 mg, 0.016 mmol, Strem) and stirred at room temperature for five minutes. A warm solution of 2-methoxy-5-pyridineboronic acid (41 mg, 0.27 mmol, Frontier) in ethanol (0.5 mL) and 2.0 M aqueous sodium carbonate 1.5 mL) were added. The mixture was refluxed for 2.0 hours, filtered hot through celite and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, concentrated under reduced pressure, and passed through a column of silica gel with 2.5% methanol/dichloromethane. Fractions were concentrated at reduced pressure and triturated with diethyl ether. The 7-(6-methoxypyridin-3-yl)-3-(piperazin-1-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one was obtained as a pink powder. 1H NMR (CDCl3) δ 8.77-8.76 (2H), 8.24 (1H), 7.64 (1H), 6.86 (1H), 4.43 (2H), 4.06-4.03 (4H), 4.00 (3H), 3.79 (2H), 3.71-3.67 (2H), 3.37 (2H), 2.78 (1H), 2.72-2.69 (4H), 2.66-2.62 (2H), 1.53-1.46 (2H), 0.78 (3H); HRMS m/z 469.2572 (calcd for M+H, 469.2558).
Reaction SMILES: [CH:1]1([NH:7][CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=3)[CH2:17][N:18]([CH3:27])[C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:43](OC(=O)C)(=[O:45])[CH3:44]>ClCCl>[CH:1]1([N:7]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=3)[CH2:17][N:18]([CH3:27])[C:19](=[O:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:10][CH2:9]2)[C:43](=[O:45])[CH3:44])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(CC(CCN1CCC(NC2CCCCC2)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(C1CCCCC1)C1CCN(CCC(CN(C)C(=O)c2ccccc2)c2ccc(Cl)c(Cl)c2)CC1
Reaction time: 2 h

Procedure:
N-[4-(4-cyclohexylaminopiperidino)-2-(3,4-dichlorophenyl)-butyl]-N-methylbenzamide was dissolved in dichloromethane (4.0 mL), and triethylamine (1.0 mL) and acetic anhydride (0.65 mL) were added. After being stirred for 2 hours, the mixture was washed with aqueous sodium bicarbonate, dried, and evaporated. The resulting material was chromatographed, with dichloromethane:methanol (95:5) as the eluent, to give the title compound (0.60 g) as a white solid; MS: m/z=558(M+1). Analysis for C31H41Cl2N3O2 ·0.6 CH2Cl2 : Calculated: C, 62.26; H, 6.98; N, 6.89. Found: C, 62.15; H, 6.99; N, 7.30
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([N:21]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:22]3)=[O:20])=[CH:15][CH:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:35]1C=CC(C(N2CCC(C3C=NC=CC=3)C2)=O)=[CH:37][C:36]=1[O:54]C(C)C>>[CH:36]([O:54][C:14]1[CH:15]=[C:16]([C:19]([N:21]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH2:22]2)=[O:20])[CH:17]=[CH:18][C:13]=1[C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=1)([CH3:37])[CH3:35]
Reactant: O=C(c1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1)N1CCC(c2cccnc2)C1
Reactant: CC(C)Oc1cc(C(=O)N2CCC(c3cccnc3)C2)ccc1Br
Product: CC(C)Oc1cc(C(=O)N2CCC(c3cccnc3)C2)ccc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Compound 5b was prepared following procedures similar to those described for the preparation of compound 1a, substituting 5a for i-21a. m/z (ES) 523 (MH)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12](=[O:13])[CH:11]2[CH:6]([CH:7]3[O:14][CH:10]2[CH:9]=[CH:8]3)[C:5]1=[O:15].CCN(CC)CC.[Br:23][C:24]([CH3:29])([CH3:28])[C:25](Br)=[O:26]>C1COCC1>[O:13]=[C:12]1[N:4]([CH2:3][CH2:2][O:1][C:25](=[O:26])[C:24]([Br:23])([CH3:29])[CH3:28])[C:5](=[O:15])[CH:6]2[CH:11]1[CH:10]1[O:14][CH:7]2[CH:8]=[CH:9]1
Reactant: CC(C)(Br)C(=O)Br
Reactant: O=C1C2C3C=CC(O3)C2C(=O)N1CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(Br)C(=O)OCCN1C(=O)C2C3C=CC(O3)C2C1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
In a 250 mL of round bottom flask were added 2 (2.0 g, 9.55 mmol) and Et3N (1.44 mL, 10.54 mmol) in 100 mL of THF. The mixture was cooled to 0° C., and a solution of 2-bromo isobutyryl bromide (2.34 g, 10.0 mmol) in 25 mL of THF was added dropwise (30 min) to the reaction mixture. The white suspension was stirred for 3 h at 0° C. and subsequently at ambient temperature for overnight. The ammonium salt was filtered off and the solvent was removed under reduced pressure to give a pale-yellow residue that was further purified by column chromatography over silica gel eluting with EtOAc/hexane (1:4) to give compound as a white solid. Yield: 2.5 g (91%). EIMS m/z 338.0 for [M+Na]+C14H16NO5BrNa calculated 380.02. 1H NMR (500 MHz, CDCl3, δ) 6.52 (s, 2H, CH═CH, bridge protons), 5.27 (s, 2H, —CHO, bridge-head protons), 4.33 (t, J=10.5 Hz, 2H, NCH2CH2OC═O), 3.77 (t, J=10.5 Hz, 2H, NCH2CH2OC═O), 2.87 (s, 2H, CH—CH, bridge protons), 1.90 (s, 6H, C(CH3)2—Br). 13C NMR (500 MHz, CDCl3, δ): 175.8, 171.3, 136.5, 80.8, 62.1, 55.6, 47.4, 37.5, 30.5.